Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF
Phase: NA
Conditions: Atrial Fibrillation
Sponsor: Medtronic Cardiac Ablation Solutions

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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title  Pulsed Field Ablation to Irreversibly 
Electroporate Tissue and Treat AF (PULSED AF) 
Clinical Investigation Plan Identifier MDT16027 
Study Product Name Pulsed Field Ablation (PFA) system 
Sponsor/Local Sponsor United States of America 
Medtronic, Inc. 
8200 Coral Sea Street NE 
Mounds View, MN U.S.A. 55112 
1-800-328-2518 
 
Australia 
Medtronic Australasia Pty Ltd. 
2 Alma Road  
Macquarie Park, NSW 2113, Australia 
+61-2-9857-9000 
 
Canada 
Medtronic Canada ULC 
99 Hereford Street 
Brampton, Ontario, L6Y 0R3, Canada  
+1-905-460-3800 
 
Europe 
Medtronic, Bakken Research Center B.V. 
Endepolsdomein 5 
6229 GW Maastricht, The Netherlands 
+31-43-3566566 
 
Japan 
Medtronic Japan Co. Ltd. 
1-2-70 Konan, Minato-ku,  
Tokyo, Japan 108-0075 
+81-3-6776-0056 
Document Version Version 3.0, 19-JAN-2020 

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Lead Principal/Coordinating Investigator 
 
 
 
 
 
 
 
 
Atul Verma, MD 
Staff Cardiac Electrophysiologist/Cardiologist 
Southlake Regional Health Centre 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of 
Medtronic. Any distribution, copying, or disclosure without the prior written authorization of 
Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that it 
is confidential and that it may not be further disclosed by them. 
 
 

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Table of Contents  
 
Table of Contents ...................................................................................................................... 3 
Listing of Tables ........................................................................................................................ 8 
Listing of Figures ....................................................................................................................... 9 
Listing of Appendices ................................................................................................................ 9 
Sponsor Contact Information.................................................................................................... 9 
Steering Committee ................................................................................................................ 11 
Contract Research Organizations............................................................................................ 12 
1. 
Glossary ............................................................................................................................ 13 
2. 
Synopsis ........................................................................................................................... 17 
3. 
Introduction ..................................................................................................................... 29 
3.1. Background ........................................................................................................................ 29 
3.2. Purpose .............................................................................................................................. 32 
4. 
Objectives and Endpoints ................................................................................................. 33 
4.1. Pilot Phase Objectives .......................................................................................................... 33 
4.1.1. 
Pilot Phase Safety Objective .................................................................................................. 33 
4.1.2. 
Pilot Phase Effectiveness Objective ...................................................................................... 33 
4.2. Pivotal Phase Objectives ...................................................................................................... 33 
4.2.1. 
Primary Objectives ................................................................................................................ 33 
4.2.1.1. 
Primary Safety Objective ................................................................................................... 33 
4.2.1.2. 
Primary Effectiveness Objective ........................................................................................ 33 
4.2.2. 
Secondary Objective.............................................................................................................. 33 
 
 
5. 
Study Design .................................................................................................................... 35 
5.1. Duration ............................................................................................................................. 37 
5.2. Rationale ............................................................................................................................ 37 
5.3. Minimization of Bias ............................................................................................................. 38 
6. 
Product Description.......................................................................................................... 39 
6.1. General .............................................................................................................................. 39 
6.1.1. 
System Description ................................................................................................................ 41 

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6.2. PFA Generator .................................................................................................................... 42 
6.3. Catheter Electrode Distribution System (CEDS) ...................................................................... 43 
6.4. Remote Control ................................................................................................................... 43 
6.5. Cable, Generator to Remote Control ..................................................................................... 43 
6.6. Cable, Generator to CEDS .................................................................................................... 44 
6.7. Cable, CEDS to EP Recording System (EGM) .......................................................................... 44 
6.8. Cable, Sterile, Catheter to CEDS ........................................................................................... 44 
 
6.10. 
Cardiac Trigger Monitor and Cables ................................................................................. 44 
6.11. 
Power Cord ................................................................................................................... 44 
6.12. 
Uninterruptible Power Supply (UPS) ................................................................................ 45 
6.13. 
Power Cord – C14M-C13F ............................................................................................... 45 
6.14. 
Packaging ..................................................................................................................... 45 
6.15. 
Product Training Requirements ....................................................................................... 46 
6.16. 
Product Receipt, Tracking and Return .............................................................................. 46 
6.17. 
Product Storage ............................................................................................................. 48 
7. 
Selection of Subjects ........................................................................................................ 49 
7.1. Study Population ................................................................................................................. 49 
7.2. Subject Enrollment .............................................................................................................. 49 
7.2.1. 
Roll-in Subjects ...................................................................................................................... 49 
7.3. Inclusion Criteria ................................................................................................................. 50 
7.4. Exclusion Criteria................................................................................................................. 50 
8. 
Study Procedures ............................................................................................................. 52 
8.1. Schedule of Events .............................................................................................................. 52 
8.2. Subject Consent .................................................................................................................. 53 
8.3. Enrollment, Baseline, and Pre-ablation .................................................................................. 55 
8.4. Procedure ........................................................................................................................... 57 
8.4.1. 
Esophageal Visualization and Temperature Monitoring ....................................................... 58 
8.4.2. 
Diaphragm Movement .......................................................................................................... 58 
8.4.3. 
Peri-procedural Anticoagulation ........................................................................................... 58 
8.4.4. 
Pulmonary Vein (PV) Ablation with the PFA system ............................................................. 58 

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8.4.5. 
Other Ablations during Index Procedure .............................................................................. 60 
8.4.6. 
Procedure Documentation .................................................................................................... 60 
8.4.7. 
Cardioversion ........................................................................................................................ 61 
8.4.8. 
Role of Medtronic Personnel at Study Procedure ................................................................ 61 
8.5. Hospital Discharge .............................................................................................................. 61 
8.6. Medications ........................................................................................................................ 62 
8.6.1. 
Paroxysmal AF Cohort ........................................................................................................... 62 
8.6.2. 
Persistent AF Cohort ............................................................................................................. 62 
8.7. Repeat Ablations with PFA ................................................................................................... 63 
8.8. Post-Procedural Cardioversions ............................................................................................. 64 
8.9. Scheduled Follow-up Visits ................................................................................................... 65 
8.9.1. 
Seven Day Phone or Office Visit ............................................................................................ 65 
8.9.2. 
Thirty Day Visit ...................................................................................................................... 66 
8.9.3. 
Three Month Visit ................................................................................................................. 66 
8.9.4. 
Six Month Visit ...................................................................................................................... 66 
8.9.5. 
Twelve Month Visit ............................................................................................................... 67 
8.10. 
Unscheduled Office Visits ............................................................................................... 67 
8.11. 
Holter and Patient Activated Ambulatory ECG Monitor Management ................................... 67 
8.12. 
12-lead Electrocardiograms ............................................................................................ 68 
8.13. 
Assessment of Safety ..................................................................................................... 68 
8.14. 
Assessment of Effectiveness ........................................................................................... 68 
 
 
 
 
8.17. 
Recording Data.............................................................................................................. 68 
8.18. 
Deviation Handling ........................................................................................................ 69 
8.19. 
Subject Withdrawal or Discontinuation (Subject Exit) ........................................................ 71 
9. 
Risks and Benefits ............................................................................................................ 72 
9.1. Potential Risks .................................................................................................................... 72 
9.2. Risk Minimization ................................................................................................................ 72 
9.3. Potential Adverse Events from Risk Assessment ..................................................................... 77 
9.4. Potential Benefits ................................................................................................................ 78 

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9.5. Risk-Benefit Rationale .......................................................................................................... 79 
10. 
Adverse Events and Device Deficiencies ....................................................................... 80 
10.1. 
Adverse Event Assessment ............................................................................................. 80 
10.2. 
Device Deficiencies Assessment ...................................................................................... 80 
10.3. 
Definitions/Classifications ............................................................................................... 80 
10.4. 
Reporting of Adverse Events, including Death .................................................................. 86 
10.4.1. 
Subject Death .................................................................................................................... 88 
10.4.2. 
Adverse Event Reporting Requirements ........................................................................... 89 
10.5. 
Reporting of Product Complaints ..................................................................................... 93 
11. 
Data Review Committees .............................................................................................. 95 
11.1. 
Data Monitoring Committee (DMC) .................................................................................. 95 
11.2. 
Clinical Events Committee (CEC) ..................................................................................... 96 
12. 
Statistical Design and Methods ..................................................................................... 97 
12.1. 
Pilot Phase ............................................................................................................................. 98 
12.1.1. 
Pilot Phase Safety Objective .............................................................................................. 98 
12.1.2. 
Pilot Phase Effectiveness Objective ................................................................................. 100 
12.2. 
Pivotal Phase ....................................................................................................................... 101 
12.2.1. 
Planned Analyses ............................................................................................................. 101 
12.2.2. 
Primary Safety Objective ................................................................................................. 102 
12.2.3. 
Primary Effectiveness Objective ...................................................................................... 107 
12.2.4. 
Overall Study Sample Size Rationale ............................................................................... 118 
12.3. 
Secondary Objective............................................................................................................ 119 
12.3.1. 
Secondary Objective: Quality of Life ............................................................................... 119 
12.3.1.1. 
Atrial Fibrillation Effect on Quality-of-Life (AFEQT) ..................................................... 120 
12.3.1.2. 
EQ-5D Questionnaire ................................................................................................... 122 
 
 
 
 
 
 
 
 
 
 

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13. 
Ethics ........................................................................................................................... 131 
13.1. 
Statement(s) of Compliance ......................................................................................... 131 
14. 
Study Administration ................................................................................................... 134 
14.1. 
Monitoring .................................................................................................................. 134 
14.2. 
Data Management ....................................................................................................... 134 
14.3. 
Confidentiality ............................................................................................................. 136 
14.4. 
Liability ....................................................................................................................... 136 
14.5. 
CIP Amendments ......................................................................................................... 136 
14.6. 
Record Retention and Reports ...................................................................................... 137 
14.6.1. 
Investigator Records ........................................................................................................ 137 
14.6.2. 
Investigator Reports ........................................................................................................ 138 
14.6.3. 
Sponsor Records .............................................................................................................. 143 
14.6.4. 
Sponsor Reports .............................................................................................................. 143 
14.7. 
Publication and Use of Information ................................................................................ 148 
14.8. 
Investigator / Site Selection .......................................................................................... 150 
14.9. 
Site Activation ............................................................................................................. 150 
14.10. 
Suspension or Early Termination ................................................................................... 151 
14.10.1. 
Early Termination or Suspension ..................................................................................... 151 
14.10.2. 
Study-wide Termination or Suspension .......................................................................... 151 
14.10.3. 
Investigator/Center Termination or Suspension ............................................................. 152 
14.10.4. 
Procedures for Termination or Suspension ..................................................................... 152 
14.10.4.1. 
Medtronic-Initiated and Regulatory Authority-Initiated ............................................. 152 
14.10.4.2. 
Investigator-Initiated ................................................................................................... 153 
14.10.4.3. 
Ethics Committee-Initiated .......................................................................................... 153 
15. 
References ................................................................................................................... 154 
16. 
Appendices .................................................................................................................. 158 
17. 
Version History ............................................................................................................ 172 
 

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Listing of Tables  
Table 1: Study Sponsor and Monitoring Contact Information ...................................................................... 9 
Table 2: Steering Committee Contact Information..................................................................................... 11 
Table 3: Contract Research Organization Information ............................................................................... 12 
Table 4: Complication Occurrence Rates for Catheter Ablation ................................................................. 31 
Table 5: PFA System Components .............................................................................................................. 39 
Table 6: PFA System Accessories ................................................................................................................ 40 
Table 7: Study Procedures and Data Collection per Subject Visit ............................................................... 52 
 
Table 9: Follow-up Schedule ....................................................................................................................... 65 
Table 10: Potential Risks and Mitigation Strategies ................................................................................... 72 
Table 11:  Adverse Event and Device Deficiency Definitions ...................................................................... 81 
Table 12: Adverse Event Classification Responsibilities ............................................................................. 87 
Table 13: Adverse Event and Device Deficiency Reporting Requirements ................................................. 90 
Table 14: Analysis of Serious Adverse Events for Pilot Phase Subjects ...................................................... 98 
Table 15: Summary of Published Literature on Safety Rates of Catheter Ablation for AF ....................... 105 
Table 16: Summary of Published Literature on Catheter Ablation for Paroxysmal AF ............................. 112 
Table 17: Summary of Published Literature on Catheter Ablation for Persistent AF ............................... 115 
Table 18: Investigator Reports Applicable for All Geographies per Medtronic Requirements ................ 139 
Table 19: Additional Investigator Reports Applicable to Australia ........................................................... 139 
Table 20: Additional Investigator Reports Applicable to Europe .............................................................. 140 
Table 21: Additional Investigator Reports Applicable to Japan ................................................................ 141 
Table 22: Additional Investigator Reports Applicable to the United States ............................................. 142 
Table 23: Sponsor Reports for Australia ................................................................................................... 144 
Table 24: Sponsor Reports for Canada ..................................................................................................... 144 
Table 25: Sponsor Reports for Europe ...................................................................................................... 145 
Table 26: Sponsor Reports for Japan ........................................................................................................ 146 
Table 27: Sponsor Reports for the United States ..................................................................................... 147 
 
Table C- 1: Foreseeable Adverse Events ................................................................................................... 165 
Table D- 1: Adverse Event Definitions ...................................................................................................... 168 
 
 
 

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Listing of Figures  
Figure 1: Subject-Level Study Design   ........................................................................................................ 35 
Figure 2: Phased Study Design .................................................................................................................... 36 
 
Figure 4: Current Safety Rates in Catheter Ablation Technologies for Paroxysmal AF and Persistent AF 104 
Figure 5: Current 12-Month Effectiveness Rates in Approved Catheter Ablation Technologies for 
Paroxysmal AF ........................................................................................................................................... 111 
Figure 6: Current 12-Month Effectiveness Rates in Catheter Ablation Technologies for Persistent AF .. 114 
 
 
Listing of Appendices  
Appendix A: Study-Specific Requirements by Country ............................................................................. 158 
 
Appendix C: Foreseeable Adverse Events ................................................................................................. 165 
Appendix D: Endpoint-Related Adverse Event Definitions ....................................................................... 168 
Appendix E: Instructions For Use .............................................................................................................. 170 
Appendix F: Data Collection Elements (Case Report Forms) .................................................................... 170 
Appendix G: Informed Consent Template ................................................................................................ 170 
Appendix H: Participating Investigators and Institutions ......................................................................... 170 
Appendix I: IRB/REB/EC List ...................................................................................................................... 170 
Appendix J: Pre-Clinical Testing ................................................................................................................ 170 
Appendix K: Centers for Medicare and Medicaid Services (CMS) IDE Study Criteria ............................... 171 
 
Sponsor Contact Information 
Medtronic contact information is provided in Table 1. This information is subject to change during 
the course of the clinical study. Periodic updates to study contact information will be sent to study 
sites as needed.  
Table 1: Study Sponsor and Monitoring Contact Information 
Study Contacts 
 
 
 
 
 
Worldwide Clinical Study Leader 
Jen Diouf, Principal Clinical Research Specialist 
 
 
 
 

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Study Contacts 
(continued) 
Australia 
John Porreca, Associate Clinical Research Specialist 
 
 
 
Canada 
Aarthi Kamath, Senior Clinical Research Specialist 
 
 
 
Europe 
Enneke Prinsen, Clinical Research Specialist 
 
 
 
Japan 
Yoshiko Ishiwatari, Clinical Research Manager 
  
 
 
 
US 
Josh Treadway, Clinical Research Specialist 
 
 
Monitoring 
Contacts 
US, Canada 
Shane Taylor, Senior Clinical Research Monitor 
 
 
 
Europe, Australia 
Anja Hesse, Monitoring Portfolio Specialist 
 
 
 
Japan 
Kenji Shinkai, Senior Clinical Research Monitor 
 
 
 
 
 
 

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Steering Committee 
Changes to Table 2 will be provided under a separate cover. 
Table 2: Steering Committee Contact Information 
Committee Member 
Contact Information 
Atul Verma, MD FRCPC 
Southlake Regional Health Centre 
 
 
Lucas Boersma, MD 
St. Antonius Hospital  
Cardiology Department 
 
 
Hugh Calkins, MD 
Johns Hopkins Hospital 
 
 
David Haines, MD 
Beaumont Hospital 
 
 
Gerhard Hindricks, MD 
Herzzentrum Leipzig GmbH 
 
 
Karl-Heinz Kuck, MD 
Asklepios Klinik St. Georg 
  
 
Francis Marchlinski, MD 
Hospital of the University of Pennsylvania 
Cardiovascular Division 
 
 
Andrea Natale, MD 
Texas Cardiac Arrhythmia Institute 
St. David’s Medical Center 
 
 
Douglas Packer, MD 
Mayo Clinic 
St. Mary’s Hospital 
 
 
Prashanthan Sanders, 
MBBS, PhD 
Royal Adelaide Hospital 
Department of Cardiology 
 
 
 

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Contract Research Organizations 
Changes to Table 3 will be provided under a separate cover.  
Table 3: Contract Research Organization Information 
Contact Information 
Duties Performed 
NAMSA 
400 Highway 169 South, Suite 500 
Minneapolis, MN 55426 
Phone: +1 866-666-9455 
Fax: +1 419-662-4386 
• 
Database development  
• 
Development of study electronic case report forms, 
edit checks, and study management reports. 
Cognizant Technology Solutions 
500 Frank W. Burr Blvd. 
Teaneck, NJ 07666, USA 
Phone: +1 201-801-0233 
Fax: +1 201-801-0243 
• 
Review of electronic case report forms and 
management of discrepancies 
 HeartCor Solutions 
2403 Harnish Dr., Suite 201 
Algonquin, IL 60102 
Phone: +1 800-987-4117 
Fax: +1 224-241-4117 
• 
Distribution of equipment for rhythm monitoring 
• 
Adjudication of atrial arrhythmias 
Syntactx 
150 Greenwich St, Floor 44 
New York, NY 10007 
Phone: +1 212-228-9000 
 
 
 
  
 
 
 
 
• 
Reviewing the Pilot Phase baseline and 3-month 
cardiac CT or MRI scans to characterize of any 
potential occurrences of PV stenosis 
HealthCarePoint.com Corporation 
10713 N FM 620 
Austin, TX 78726, USA 
Phone: +1 512-302-3113 
• 
Providing access to BlueCloud® Networking 
Management Systems for NIHSS translations, 
training, and certification tracking 
 
 

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1. Glossary 
Term 
Definition 
AAD 
Antiarrhythmic drug 
ACT 
Activated clotting time 
ADE 
Adverse device effect 
AE 
Adverse event 
AF 
Atrial fibrillation 
AFEQT 
Atrial Fibrillation Effect on QualiTy-of-life 
AFL 
Atrial flutter 
AHA 
America Heart Association 
AT 
Atrial tachycardia 
C 
Celsius 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CIP 
Clinical investigation plan 
CMAP 
Compound motor action potential 
CRF 
Case report form 
CTA 
Clinical trial agreement 
CTI 
Cavotricuspid isthmus 
CV 
Curriculum vitae 
DD 
Device deficiency 
EC 
Ethics committee 
ECG 
Electrocardiogram 
e.g. 
For example, 

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Term 
Definition 
EMG 
Electromyography 
EP 
Electrophysiology 
EQ-5D 
EuroQol 5 Dimensions Questionnaire 
Ethics Committee 
Term that will be used collectively in reference 
to an Institutional Review Board (IRB)/Medical 
Ethics Committee (MEC)/Human Research 
Ethics Committee (HREC)/Research Ethics 
Board (REB)/Head of Medical Institution 
(HOMI) unless otherwise stated 
FAL 
Foreseeable adverse event list 
FD 
Financial disclosure 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice   
HC 
Health Canada 
HOMI 
Head of Medical Institution 
HREC 
Human research and ethics committee 
IB 
Investigator brochure 
IC 
Informed consent 
ICMJE 
International Committee of Medical Journal 
Editors 
ID 
Identification 
IDE 
Investigational device exemption 
IFU 
Instructions For Use 
IRB 
Institutional review board 
IRE 
Irreversible electroporation 
ISO 
International Organization for Standardization 
LAD 
Left atrial diameter 

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Term 
Definition 
LVEF 
Left ventricular ejection fraction 
MDD 
Medical Device Directive 
MEC 
Medical ethics committee 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NIHSS 
National Institute of Health Stroke Scale 
NOAC 
Novel oral anticoagulant 
NYHA 
New York Heart Association 
OPC 
Objective performance criterion 
PAF 
Paroxysmal atrial fibrillation 
PFA 
Pulsed Field Ablation 
PMDA 
Pharmaceutical and Medical Devices Agency 
PV 
Pulmonary vein 
PVI 
Pulmonary vein isolation 
QoL 
Quality of life 
REB 
Research ethics board 
RF 
Radiofrequency 
RI 
Right inferior 
RS 
Right superior 
SAE 
Serious adverse event 
SADE 
Serious adverse device effect 
SAP 
Statistical analysis plan 
SCE 
Silent cerebral event 

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Term 
Definition 
SCL 
Silent cerebral lesion 
TEE 
Transesophageal echocardiogram 
TGA 
Therapeutic Goods Administration 
TIA 
Transient ischemic attack 
TTE 
Transthoracic echocardiogram 
TTM 
Transtelephonic monitoring 
UADE 
Unanticipated adverse device effect 
US 
United States 
USADE 
Unanticipated serious adverse device effect 
 
 

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2. Synopsis 
Title 
Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF 
(PULSED AF) 
Clinical Study 
Type 
Phased Study Design  
Product Name 
Pulsed Field Ablation (PFA) system 
Sponsor  
United States of America 
Medtronic, Inc. 
8200 Coral Sea Street NE 
Mounds View, MN U.S.A. 55112 
1-800-328-2518 
Local Sponsors 
Canada 
Medtronic Canada ULC 
99 Hereford Street 
Brampton, Ontario, L6Y 0R3, Canada  
+1-905-460-3800 
 
Europe 
Medtronic, Bakken Research Center B.V. 
Endepolsdomein 5 
6229 GW Maastricht, The Netherlands 
+31(0)43-3566566 
 
Australia 
Medtronic Australasia Pty Ltd. 
2 Alma Road  
Macquarie Park, NSW 2113, Australia 
+61-2-9857-9000 
Japan 
Medtronic Japan Co. Ltd. 
1-2-70 Konan, Minato-ku,  
Tokyo, Japan 108-0075 
+81-3-6776-0056 
Indication under 
investigation  
The planned indication for the PFA system evaluated in this Study is as 
follows: 
 
The PFA system, which includes a compatible Medtronic multi-electrode 
cardiac ablation catheter, is indicated for the treatment of atrial fibrillation. 
The Medtronic multi-electrode cardiac ablation catheter is also intended to 
be used for cardiac electrophysiological (EP) mapping and measuring of 
intracardiac electrograms, delivery of diagnostic pacing stimuli and verifying 
electrical isolation post-treatment. 

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Investigation 
Purpose 
The purpose of the study is to provide data demonstrating the safety and 
effectiveness of the PFA system for the treatment of atrial fibrillation. 
Product Status 
Product Name 
Model Number 
Geography Status at Study 
Start 
System Components 
PFA Generator  
M970163A001 
Investigational in all geographies 
Catheter Electrode 
Distribution System 
(CEDS) 
M970165A001 
Investigational in all geographies 
Remote Control 
M970127A001 
Investigational in all geographies 
Cable, Generator to 
Remote Control  
M970169A001 
Investigational in all geographies 
Cable, Generator to 
CEDS 
M970168A001 
Investigational in all geographies 
System Accessories 
Cable, CEDS to EP 
Recording System 
(EGM) 
990027 
CAN: Health Canada licensed  
EU: CE Marked 
AUS: TGA Approved 
US/JPN: Investigational 
Investigational when used with 
PFA system 
Cable, Sterile, 
Catheter to CEDS  
990004 
CAN: Health Canada licensed  
EU: CE Marked 
AUS: TGA Approved 
US/JPN:  Investigational 
Investigational when used with 
PFA system 
 
Catheter 
990078 
CAN: Health Canada licensed  
EU: CE Marked 
AUS: TGA Approved 
US/JPN:  Investigational 
Investigational when used with 
PFA system 
Cardiac Trigger 
Monitor and Cable 
7700 
CAN: Health Canada licensed  
EU: CE Marked 
AUS: TGA Approved  
US: FDA cleared 
JPN: Investigational 
Investigational when used with 
PFA system 

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Power Cord 
1038N - North 
America; Japan 
1038K - 
Australia 
1038E - EU 
 
CAN: not regulated  
EU: self-certified 
AUS: not regulated  
US: FDA approved 
JPN: PMDA approved 
Investigational when used with 
PFA system 
Uninterruptible 
Power Supply (UPS) 
SMART1200XL
HG (120V) 
SMX1200XLHG 
(230V) 
CAN: not regulated 
EU: not regulated 
AUS: not regulated 
US: not regulated 
JPN: not regulated 
Investigational when used with 
PFA system 
Power Cord – 
C14M-C13F 
P004-006-ABL 
CAN: not regulated 
EU: not regulated 
AUS: not regulated 
US: not regulated 
JPN: not regulated 
Investigational when used with 
PFA system 
Study Design 
The study is a prospective, multi-center, non-randomized, unblinded 
worldwide pre-market clinical study. The study is designed to have a 
continuously growing body of evidence across two phases, with data 
analyses planned at pre-specified timepoints. The data collected in this 
study will be used to support regulatory submissions around the world to 
obtain market approval for the PFA system, including, but not limited to, CE 
Mark, Health Canada, Therapeutic Goods Administration (TGA), 
Pharmaceutical and Medical Devices Agency (PMDA) and U.S. Food and Drug 
Administration (FDA) market applications.   
Description of 
Phased Study 
Design 
Pilot Phase 
 
The Pilot Phase of the PULSED AF study will include an early assessment of 
safety and confirmation of acute procedural success of pulmonary vein 
isolation (PVI) ablation with the PFA system. Specifically, this phase will 
include treatment of 20 subjects (paroxysmal AF or persistent AF) across up 
to 4 clinical sites. 
 
 
 
 
 
 
 

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The Pilot Phase subjects will not be included in the Pivotal Phase primary or 
secondary endpoint analyses but will be treated and followed in accordance 
with all other protocol requirements. In addition, the Pilot Phase subjects will 
complete a cardiac CT or MRI scan at baseline and 3 months to allow 
characterization of any potential occurrences of pulmonary vein (PV) 
stenosis. If PV stenosis (>70% diameter reduction) is identified in any of 
these 20 subjects, an additional report will be generated containing the 3-
month PV stenosis analysis once all 20 subjects have completed their 3-
month follow-up or exited. The report will be sent to regulatory authorities 
(as requested) while enrollment in the Pivotal Phase of the study continues.  
 
Pivotal Phase 
 
The purpose of the Pivotal Phase of the study is to provide data 
demonstrating the safety and effectiveness of the PFA system for the 
treatment of atrial fibrillation. Specifically, this phase will include treatment 
of 315 subjects (165 paroxysmal AF and 150 persistent AF) for analysis of 
primary objectives, across up to 40 total sites worldwide (including the 4 Pilot 
Phase sites). For the Pivotal Phase of the study, subjects will be separated 
into paroxysmal AF and persistent AF arms and analyzed separately.  It is 
expected that at least 50% of the treatments and supporting clinical data will 
come from the United States with no single site contributing more than 15% 
of the treatments to each arm of the Pivotal Phase. Each arm will have a 
primary safety objective and a primary effectiveness objective, in addition to 
secondary 
 objectives. 
 
To facilitate the investigators’ familiarity with the system, a cohort of roll-in 
subjects will also be included in the Pivotal Phase. There will be up to 80 roll-in 
subjects (up to 2 per site). Roll-in subjects will not be included in the Pivotal 
Phase primary or secondary endpoint analyses but will be treated and 
followed in accordance with all other protocol requirements.  
Sample Size 
The primary effectiveness objectives drive the sample size, as for both arms, 
the effectiveness sample sizes (165 for paroxysmal AF and 150 for persistent 
AF) are higher than the sample size needed to adequately power the safety 
objective (n=138 in each arm). 
 
Overall, up to 475 subjects will be enrolled to ensure there are 20 Pilot Phase 
subjects, up to 80 Pivotal Phase roll-in cohort subjects, and 315 Pivotal Phase 
primary analysis cohort subjects treated with the PFA system, and to account 
for subjects not treated prior to exit. 

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Pilot Phase 
Objectives 
Safety Objective:  Assess the incidence of PFA system-related and PFA 
procedure-related serious adverse events (SAEs) within 30 days post-
ablation: 
 
Serious Adverse Event 
Method of Analysis 
pulmonary vein stenosis (>70% diameter 
reduction); 
Review of symptoms 
post-procedure, at 7-
day visit and at 30-day 
visit 
phrenic nerve injury/diaphragmatic paralysis 
(ongoing at 30 days post-ablation); 
atrioesophageal fistula; 
cardiac tamponade/perforation;  
cerebrovascular accident; 
Review of symptoms 
post-procedure, at 7-
day visit and at 30-day 
visit; 
Confirmed by formal 
neurology assessment 
if required due to 
NIHSS assessments 
major bleeding requiring transfusion;  
Review of symptoms 
post-procedure, at 7-
day visit and at 30-day 
visit 
myocardial infarction;  
pericarditis requiring intervention; 
transient ischemic attack;  
vagal nerve injury resulting in esophageal 
dysmotility or gastroparesis; 
vascular access complications requiring 
intervention; 
death; 
any PFA system-related or PFA procedure-related 
cardiovascular and/or pulmonary adverse event 
that prolongs or requires hospitalization for more 
than 48 hours (excluding recurrent AF/AFL/AT) 
 
 
 
 
 
 

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Effectiveness Objective:  Assess the acute procedural success of PVI 
ablation with the PFA system.  
 
Acute procedural failure is defined as the occurrence of any of the following:  
 
• 
Inability to isolate all accessible targeted pulmonary veins (minimally 
assessed for entrance block and, where assessable, exit block) during 
the index procedure  
• 
Ablation using a non-study device to isolate any pulmonary vein 
 
Acute procedural success is the opposite of acute procedural failure. 
Pivotal Phase 
Primary 
Objectives  
Primary objectives, which will be reported separately by paroxysmal AF and 
persistent AF, are as follows:  
 
Safety Objective: Demonstrate an acceptable safety profile of PVI ablation 
with the PFA System.  
 
Effectiveness Objective:  Demonstrate an acceptable chronic effectiveness 
of PVI ablation with the PFA System, based on freedom from treatment 
failure.  
Pivotal Phase 
Secondary 
Objectives 
The following secondary objective will be reported separately by paroxysmal 
AF and persistent AF: 
 
1. Assess changes in quality of life from baseline through 12 months 
after the index ablation procedure. 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 

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Primary Safety 
Endpoint 
The primary safety endpoint definition, as follows, is identical for each arm 
(paroxysmal AF and persistent AF) of the Pivotal Phase. 
 
The following PFA system-related and PFA procedure-related serious 
adverse events (SAEs), as adjudicated by the Clinical Events Committee 
(CEC), will be considered a primary safety event: 
 
Within 6 months post-ablation: 
• 
Pulmonary vein stenosis (>70% diameter reduction) 
• 
Phrenic nerve injury/diaphragmatic paralysis (ongoing at 6 months) 
• 
Atrioesophageal fistula  
 
Within 30 days of ablation procedure: 
• 
Cardiac tamponade/perforation  
• 
Cerebrovascular accident  
• 
Major bleeding requiring transfusion 
• 
Myocardial infarction  
• 
Pericarditis requiring intervention 
• 
Transient ischemic attack 
• 
Vagal nerve injury resulting in esophageal dysmotility or gastroparesis  
• 
Vascular access complications requiring intervention  
• 
Death 
• 
Any PFA system-related or PFA procedure-related cardiovascular 
and/or pulmonary adverse event that prolongs or requires 
hospitalization for more than 48 hours (excluding recurrent 
AF/AFL/AT)  
Primary 
Effectiveness 
Endpoints 
The definition of treatment success and failure differs slightly between the 
paroxysmal and persistent arms of the Pivotal Phase. 
 
Primary Effectiveness Endpoint for Paroxysmal AF 
 
Treatment success is defined as freedom from treatment failure. The study 
requires 24-hour Holter monitoring at 6 and 12 months in addition to weekly 
and symptomatic patient activated ambulatory monitoring transmissions 
from 3 through 12 months, and 12-lead ECGs at all follow up visits. 
Treatment failure is defined as any of the following components:  
 

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• 
Acute procedural failure (see definition below) 
• 
Documented AF/AT/AFL on Holter/patient activated ambulatory 
monitoring/12-lead ECG after the 90-day post-ablation blanking 
period  
• 
Minimum of 30 seconds on Holter/patient activated ambulatory 
monitoring or 10 seconds on 12-lead ECG recording 
• 
Note: Documented occurrence and treatment of typical right-sided 
cavotricuspid isthmus dependent atrial flutter is not considered a 
failure. 
• 
Any subsequent AF surgery or ablation in the left atrium, except for 
repeat PVI ablations using PFA within the 90-day blanking period. 
• 
Direct current cardioversion for atrial tachyarrhythmia recurrences 
after the 90-day blanking period. 
• 
Class I or III antiarrhythmic drug (AAD) use after the 90-day blanking 
period.  
Blanking period is defined as the first 90 days after the index ablation 
procedure. Recurrences of atrial arrhythmias during the blanking period will 
not be counted in the determination of the first clinical failure for the primary 
endpoint. Within the blanking period, recurrent arrhythmias can be managed 
with antiarrhythmic drugs or cardioversions. Titration of Class I and III 
antiarrhythmic medications are allowed during the blanking period.  
 
Acute procedural failure is defined as the occurrence of any of the following:  
 
• 
Inability to isolate all accessible targeted pulmonary veins (minimally 
assessed for entrance block and, where assessable, exit block) during 
the index procedure  
• 
Ablation using a non-study device to isolate any pulmonary vein 
 
Primary Effectiveness Endpoint for Persistent AF 
 
Treatment success is defined as freedom from treatment failure. The study 
requires 24-hour Holter monitoring at 6 and 12 months in addition to weekly 
and symptomatic patient activated ambulatory monitoring transmissions 
from 3 through 12 months, and 12-lead ECGs at all follow up visits. 
Treatment failure is defined as any of the following components:  
 
• 
Acute procedural failure (see definition below) 
• 
Documented AF/AT/AFL on Holter/patient activated ambulatory 
monitoring/12-lead ECG after the 90-day post-ablation blanking 
period  
• 
Minimum of 30 seconds on Holter/patient activated ambulatory 
monitoring or 10 seconds on 12-lead ECG recording 

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• 
Note: Documented occurrence and treatment of typical right-sided 
cavotricuspid isthmus dependent atrial flutter is not considered a 
failure. 
• 
Any subsequent AF surgery or ablation in the left atrium, except for 
repeat PVI ablations using PFA within the 90-day blanking period. 
• 
Direct current cardioversion for atrial tachyarrhythmia recurrences 
after the 90-day blanking period. 
• 
Class I or III antiarrhythmic drug (AAD) dose increase from the 
historic maximum ineffective dose (prior to the ablation procedure) 
or initiation of a new Class I or III AAD after the 90-day blanking 
period. Note: remaining on the same pre-ablation dose or decreased 
dose of a previously failed or not tolerated Class I or III AAD after the 
90-day blanking is not considered a failure.  
 
Blanking period is defined as the first 90 days after the index ablation 
procedure. Recurrences of atrial arrhythmias during the blanking period will 
not be counted in the determination of the first clinical failure for the primary 
endpoint. Within the blanking period, recurrent arrhythmias can be managed 
with antiarrhythmic drugs or cardioversions. Titration of Class I and III 
antiarrhythmic medications are allowed during the blanking period.  
 
Acute procedural failure is defined as the occurrence of any of the following:  
 
• 
Inability to isolate all accessible targeted pulmonary veins (minimally 
assessed for entrance block and, where assessable, exit block) during 
the index procedure  
• 
Ablation using a non-study device to isolate any pulmonary vein 
Inclusion/ 
Exclusion 
Criteria 
Inclusion Criteria 
1. Failure of at least one AAD (class I or III) for AF as evidenced by 
recurrent symptomatic AF, or intolerable side effects due to AAD. 
2. A diagnosis of recurrent symptomatic paroxysmal or persistent AF 
with the following documentation:  
a. Paroxysmal: (1) physician’s note indicating symptoms 
consistent with recurrent self-terminating (within 7 days) AF or 
paroxysmal AF; and (2) any ECG documented AF episode(s) 
within 12 months prior to enrollment  
OR 
b. Persistent: (1) physician’s note indicating symptoms consistent 
with continuous AF episode lasting longer than 7 days but less 
than 1 year; and (2) any 24-hour continuous ECG recording 
documenting persistent AF within 6 months of enrollment; OR 
(2) two ECGs from any form of rhythm monitoring showing 
continuous AF taken at least 7 days apart  
3. Age 18 through 80 years old (or older than 18 if required by local law) 
 

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Exclusion Criteria 
1. Long-standing persistent AF (continuous AF that is sustained >12 
months)  
2. Left atrial diameter > 5.0 cm (anteroposterior)  
3. Prior left atrial ablation or surgical procedure (including left atrial 
appendage closures) 
4. Planned LAA closure procedure or implant of a permanent pacemaker, 
biventricular pacemaker, loop recorder/insertable cardiac monitor 
(ICM), or any type of implantable cardiac defibrillator (with or without 
biventricular pacing function) for any time during the follow-up period 
5. Patient who is not on oral anticoagulation therapy for at least 3 weeks 
prior to the ablation procedure 
6. Presence of a permanent pacemaker, biventricular pacemaker, loop 
recorder/insertable cardiac monitor (ICM), or any type of implantable 
cardiac defibrillator (with or without biventricular pacing function) 
7. Presence of any pulmonary vein stents 
8. Presence of any pre-existing pulmonary vein stenosis 
9. Pre-existing hemidiaphragmatic paralysis 
10. Presence of any cardiac valve prosthesis 
11. Moderate to severe mitral valve stenosis  
12. More than moderate mitral regurgitation (i.e., 3+ or 4+ MR) 
13. Any cardiac surgery, myocardial infarction, PCI / PTCA or coronary 
artery stenting which occurred during the 3-month interval preceding 
the consent date 
14. Unstable angina 
15. NYHA Class III or IV congestive heart failure or documented left 
ventricular ejection fraction (LVEF) less than or equal to 35% measure 
by acceptable cardiac testing (e.g. TTE) 
16. Primary pulmonary hypertension 
17. Rheumatic heart disease 
18. Thrombocytosis, thrombocytopenia 
19. Any condition contraindicating chronic anticoagulation 
20. Active systemic infection 
21. Hypertrophic cardiomyopathy 
22. Known reversible causes of AF, including but not limited to 
uncontrolled hyperthyroidism, severe untreated obstructive sleep 
apnea, and acute alcohol toxicity 
23. Any cerebral ischemic event (strokes or TIAs) which occurred during 
the 6-month interval preceding the consent date 
24. History of thromboembolic event within the past 6 months or evidence 
of intracardiac thrombus at the time of the procedure 
25. Any woman known to be pregnant or breastfeeding, or any woman of 
child bearing potential who is not on a reliable form of birth regulation 
method or abstinence 

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26. Patient with life expectancy that makes it unlikely 12 months of follow-
up will be completed  
27. Current or anticipated participation in any other clinical trial of a drug, 
device or biologic during the duration of the study not pre-approved by 
Medtronic 
28. Known allergies or hypersensitivities to adhesives 
29. Unwilling or unable to comply fully with study procedures and follow-up 
30. Unable to provide own informed consent 
Study 
Procedures and 
Assessments 
Adult subjects with history of drug refractory recurrent symptomatic atrial 
fibrillation (AF) will undergo ablation of pulmonary veins and confirmation of 
entrance block and, where assessable, exit block with the PFA system. 
Following the index ablation procedure and hospital discharge, all study 
subjects from all participating geographies will be followed at 7 days, 30 days, 
3 months, 6 months, and 12 months, and will be exited from the study at the 
conclusion of the 12-month follow-up visit and associated 24-hour Holter. 
Safety 
Assessments 
All adverse events will be collected starting at the time of signing the IC Form 
through the duration of the subject’s participation in the study. 
 
Clinical Events Committee (CEC): 
An independent committee comprised of electrophysiologists not 
participating in the study will review and adjudicate, at a minimum, all 
procedure- and system-related adverse events, as well as adverse events 
resulting in death. 
Additional 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
Planned Primary 
Analyses 
 
 
 
 
The paroxysmal and persistent arms will be analyzed separately.  
 
 
 
   
 

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 all subjects will be 
followed for 12 months, and a final report will be prepared for each arm. 
 
 
 

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3. Introduction  
3.1. Background  
Atrial fibrillation (AF) is a common and disabling cardiac arrhythmia with a heterogeneous clinical 
presentation. The fundamental pathophysiology consists of atrial wavelets propagating in 
different directions, causing disorganized atrial depolarizations without effective atrial contraction, 
with concomitant rapid and irregular ventricular contractions. As published in the 2017 
HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement on Catheter and Surgical 
Ablation of Atrial Fibrillation, there are several classifications for AF: paroxysmal AF (PAF) is defined 
as AF that terminates spontaneously or with intervention within 7 days of onset; persistent AF is 
defined as continuous AF that is sustained beyond 7 days; and long-standing persistent AF is 
defined as continuous AF of greater than 12-month duration.1 
 
AF is the most common of the sustained arrhythmias affecting millions of people worldwide. The 
estimated global prevalence of AF is 33 million patients, and the number of AF patients in the US is 
expected to double by 2035.2,3 Prolonged AF may lead to electrical, mechanical, and structural 
changes to the left atrium, which may then progress to tachycardia-induced cardiomyopathy, 
heart failure and persistent AF. Persistent AF represents approximately 25% of AF cases.4 The 
prognosis is related to the underlying cause of the disease, with idiopathic causes having the best 
prognosis and ischemic cardiomyopathy having a poor prognosis. The mortality rate in patients 
with AF is twice that of patients without AF, and the risk of AF-related stroke is 5-fold compared to 
the risk in patients without AF.5 In comparison to patients with paroxysmal AF, patients with 
persistent AF are at a significantly greater risk for cardiac mortality (hazard ratio [HR], 2.37; 95% 
confidence interval [CI], 1.19-4.73) and all-cause mortality (HR, 1.89; CI, 1.30-2.74).6 
 
Catheter ablation is established as an acceptable line of treatment for patients with recurrent 
symptomatic atrial fibrillation (both paroxysmal and persistent) who have failed anti-arrhythmic 
drug therapy. In 2017, the HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement on 
Catheter and Surgical Ablation of Atrial Fibrillation continued the Class I Level A recommendation 
(as previously published in the 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter 
                                                            
1 Calkins H, et al., 2017 HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement on Catheter and Surgical 
Ablation of Atrial Fibrillation, Heart Rhythm (2017), doi:10.10106/j.hrthm.2017.05.012. 
2 Chugh, S. S., et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 129, 
837-847, doi:10.1161/circulationaha.113.005119 (2014). 
3 Naccarelli, G. V., Varker, H., Lin, J. & Schulman, K. L. Increasing prevalence of atrial fibrillation and flutter in the United 
States. The American journal of cardiology 104, 1534-1539, doi:10.1016/j.amjcard.2009.07.022 (2009). 
4 Zoni-Berisso M, et al. Epidemiology of atrial fibrillation: European perspective. Clinical Epidemiology. 2014;6:213-220. 
doi:10.2147/CLEP.S47385. 
5 Wolf P, et al. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983-
988. 
6 Ghanbari H, et al. Mortality and cerebrovascular events after radiofrequency catheter ablation of atrial fibrillation. Heart 
Rhythm. 2014;11:1503-1511. 

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and Surgical Ablation of Atrial Fibrillation7) for catheter and surgical ablation of AF for symptomatic 
paroxysmal AF (refractory or intolerant to at least one Class I or III AAD). Although in the US there 
are no approved catheter ablation options for treating persistent AF, there is a growing body of 
evidence supporting catheter ablation as a reasonable option for this patient population. The 2017 
HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement continued the Class IIa Level B 
recommendation for catheter and surgical ablation of AF for symptomatic persistent AF 
(refractory or intolerant to at least one Class I or III AAD), stating “the benefits of an AF ablation 
procedure exceed the risks, and that it is reasonable to perform AF ablation”.1 In the previously 
published 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation, 
the level of evidence supporting the recommendation moved to Class IIa, Level A.8  
 
Catheter ablation treatment strategies for AF have evolved over time and currently include 
pulmonary vein isolation (PVI) as the cornerstone of ablation therapy in all types of AF (paroxysmal 
and persistent),9, 10 with several recent studies reporting benefit using a minimal PVI-only type 
strategy.11,12,13,14 AF arises primarily from the left side of the heart in the atrium, particularly where 
the pulmonary veins (PVs) join the atrium. The fundamental basis for the AF ablation procedure is 
the elimination of initiating triggers and the creation of myocardial lesions that block the 
propagation of AF wave fronts from the triggering source. The muscular sleeves both within and 
near the PVs have been established as a critical source of AF triggers.15  
Currently approved catheter ablation options for the treatment of drug refractory recurrent 
symptomatic paroxysmal AF include radiofrequency (RF) ablation, cryoablation, and visually guided 
                                                            
7 Calkins H, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial 
Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, 
Definitions, Endpoints, and Research Trial Design. Heart Rhythm 2012;9:632-696. 
8 January C, Wann L, Alpert J, Calkins H, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial 
fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines 
and the Heart Rhythm Society. J Am Coll Cardiol. 2014. 
9 Raviele, et al. Venice Chart International consensus Document on Atrial Fibrillation: 2011 Update. J Cardiovasc 
Electrophysiol, 2012;23:890-923. 
10 Jais P, et al. Stepwise Catheter Ablation of Chronic Atrial Fibrillation: Importance of Discrete Anatomic Sites for 
Termination. J Cardiovasc Electrophysiol. 2006;17: S28-S36, Suppl. 3. 
11 Dong JZ, Sang CH, Yu RH, et al. Prospective randomized comparison between a fixed “2C3L” approach vs. stepwise 
approach for catheter ablation of persistent atrial fibrillation. Europace. doi:10.1093/europace/euv067. 
12 Wynn GJ, Panikker S, Morgan M, et al. Effect of linear ablation in substrate-based AF: Results of the substrate 
modification with ablation and antiarrhythmic drugs in non-permanent atrial fibrillation trial. Heart Rhythm. 2015;12:1715. 
13 Verma A, Jiang CY, Betts TR, et al, STAR AF II Investigators. Approaches to Catheter Ablation for Persistent Atrial 
Fibrillation. N Engl J Med. 2015;372:1812-1822. 
14 Scott P, Silberbauer J, Murgatroyd F. The impact of adjunctive complex fractionated atrial electrograms ablation and 
linear lesions on outcomes in persistent atrial fibrillation: a meta-analysis. Europace 2016; 18, 359-367. 
15 Calkins H, et al. HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: 
Recommendations for personnel, Policy, Procedures and Follow-Up. Europace. 2007;9(6):335-379. 

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laser balloon ablation. The goal of ablation technology is to create a safe and effective lesion 
without causing damage to adjacent structures or surrounding tissue thus resulting in no need for a 
maintenance treatment regimen (medications or cardioversions). The two dominant energy 
sources being utilized for catheter ablation today are radiofrequency and cryoablation. RF 
generators deliver energy to ablate cardiac tissue using a resistive heating mechanism applied 
through endocardial catheter electrodes.16 RF catheters maintain temperature control to provide 
electrode cooling, minimize heat and prevent charring by employing irrigation or modifying the 
electrode surface area.17 Cryoablation delivers pressurized refrigerant (liquefied nitrous oxide) to 
the distal end of endocardial catheters to treat AF using a freeze-thaw mechanism.18,19 RF catheter 
ablation and cryoablation are established treatment options for paroxysmal and persistent atrial 
fibrillation but are subject to safety risks and AF recurrence for AF patients. The 2017 
HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement summarizes AF ablation 
complication occurrence rates, as listed in Table 4, and further indicates that “our efforts to 
eliminate complications associated with AF ablation are incomplete and there is more work to do.”1  
Table 4: Complication Occurrence Rates for Catheter Ablation1 
Complication  
Occurrence rate due to catheter ablation 
Air embolism 
<1% 
Asymptomatic cerebral emboli 
2-15% 
Atrial-esophageal fistula 
0.02 – 0.11% 
Cardiac tamponade 
0.2 – 5% 
Coronary artery stenosis occlusion 
<0.1% 
Death 
<0.1% to 0.4% 
Gastric hypomotility 
0-17% 
Mitral valve entrapment 
<0.1% 
Pericarditis 
0 to 50% 
Permanent phrenic nerve paralysis 
0-0.4% 
Pulmonary vein stenosis 
<1% 
Radiation injury 
<0.1% 
Stiff left atrial syndrome 
<1.5% 
Stroke and TIA 
0-2% 
Vascular complications 
0.2% to 1.5% 
                                                            
16 Avitall, B. et al. The safety and efficacy of multiple consecutive cryo lesions in canine pulmonary veins-left atrial junction. 
Heart rhythm 1, 203-209, doi:10.1016/j.hrthm.2004.03.058 (2004). 
17  Dinerman, J. L., Berger, R. D. & Calkins, H. Temperature monitoring during radiofrequency ablation. Journal of 
cardiovascular electrophysiology 7, 163-173 (1996) 
18 Harrison, L. et al. Cryosurgical ablation of the A-V node-His bundle: a new method for producing A-V block. Circulation 
55, 463-470 (1977). 
19 Georgiopoulos, G., Tsiachris, D. & Manolis, A. S. Cryoballoon ablation of atrial fibrillation: a practical and effective 
approach. Clinical cardiology 40, 333-342, doi:10.1002/clc.22653 (2017). 

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Reducing safety risks as compared to current catheter ablation technologies is warranted. The 
Medtronic Pulsed Field Ablation (PFA) system is a novel method of PVI ablation that has the 
potential to offer a safer and more effective treatment option for AF over existing, approved 
methods of AF ablation. Medtronic proposes there is a need to investigate PVI ablation with a novel 
technology (i.e., PFA system) that is capable of potentially reducing or eliminating collateral 
damage, improving lesion formation and durability, and reducing the AF ablation procedure time. 
The PFA system is expected to be a safe and effective alternative to the currently approved 
technologies used to achieve PVI ablation in a paroxysmal AF patient population. Indication in the 
US would fulfill an unmet clinical need for symptomatic persistent AF patients in which 
antiarrhythmic drugs fail or are not tolerated.       
3.2. Purpose 
The purpose of the study is to provide data demonstrating the safety and effectiveness of the PFA 
system for the treatment of atrial fibrillation. The study will also provide first in human insights into 
clinical safety and device function of the PFA system for pulmonary vein isolation as a treatment for 
AF. To this end, the clinical study has been designed into phases (Pilot and Pivotal), with each phase 
comprising a separate data set that will be analyzed and reported on per the below objectives. 
The proposed indication for the PFA system evaluated in this Study is as follows: 
The PFA system, which includes a compatible Medtronic multi-electrode cardiac ablation catheter, 
is indicated for the treatment of atrial fibrillation. The Medtronic multi-electrode cardiac ablation 
catheter is also intended to be used for cardiac electrophysiological (EP) mapping and measuring of 
intracardiac electrograms, delivery of diagnostic pacing stimuli and verifying electrical isolation 
post-treatment.  
 
 
 
 
 
 
 
 
 
 
 
 
 

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4. Objectives and Endpoints 
Endpoint definitions for all study objectives are described in Section 12. 
 
 
4.1. Pilot Phase Objectives 
4.1.1. 
Pilot Phase Safety Objective 
Assess the incidence of PFA system-related and PFA procedure-related serious adverse events 
(SAEs) within 30 days post-ablation. 
4.1.2. 
Pilot Phase Effectiveness Objective 
Assess the acute procedural success of PVI ablation with the PFA system. 
4.2. Pivotal Phase Objectives 
4.2.1. 
Primary Objectives 
Primary objectives, which will be reported separately by paroxysmal AF and persistent AF, are as 
follows: 
4.2.1.1. 
Primary Safety Objective 
Demonstrate an acceptable safety profile of PVI ablation with the PFA system. 
4.2.1.2. 
Primary Effectiveness Objective 
Demonstrate an acceptable chronic effectiveness of PVI ablation with the PFA system, based on 
freedom from treatment failure.   
4.2.2. 
Secondary Objective 
The following secondary objective will be reported separately by paroxysmal AF and persistent AF: 
1. Assess changes in quality of life from baseline through 12 months after the index ablation 
procedure. 

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5. Study Design  
The
 study
 is
 a
 prospective,
 multi-center,
 non-randomized,
 unblinded
 worldwide
 pre-market 
clinical
 
study.
 
 Adult
 subjects
 with
 a
 history
 of
 drug
 refractory
 recurrent
 symptomatic
 atrial
 fibrillation
 (AF)
 
will
 undergo
 ablation
 of
 pulmonary
 veins
 and
 confirmation
 of
 entrance
 block
 and,
 where
 assessable,
 
exit
 block 
with
 the
 PFA
 system.
 Following
 the
 index
 ablation
 procedure 
and
 hospital
 discharge,
 all
 
study
 subjects
 from
 all
 participating
 geographies
 will
 be
 followed
 at
 7
 days,
 30
 days,
 3
 months,
 6
 
months,
 and
 12
 months,
 and
 will
 be
 exited
 from
 the
 study
 at
 the
 conclusion
 of
 the
 12-month
 
follow-up
 visit 
and
 associated 
24-hour 
Holter.
 The
 subject-level
 study
 design
 diagram
 is
 shown
 in
 
Figure
 1.
 
Figure
 1:
 Subject-Level
 Study
 Design 
 
 
 
 
As
 depicted
 in
 Figure
 2 
below,
 the
 study
 is
 designed
 to
 have
 a
 continuously
 growing
 body
 of
 
evidence
 across
 two 
phases,
 with
 data
 analyses
 planned
 at
 pre-specified 
timepoints.
 The
 data
 
collected
 in
 this
 study
 will
 be
 used
 to
 support
 regulatory
 submissions
 around
 the
 world
 to
 obtain
 
market
 approval
 for
 the
 PFA
 system,
 including,
 but
 not
 limited
 to,
 CE
 Mark,
 Health
 Canada 
(HC),
 
Therapeutic
 Goods
 Administration
 (TGA),
 Pharmaceutical
 and
 Medical
 Devices
 Agency
 (PMDA)
 and
 
U.S.
 Food
 and
 Drug
 Administration
 (FDA)
 market
 applications.
  

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The study consists of a Pilot Phase and a Pivotal Phase. Overall, up to 475 subjects will be enrolled 
to ensure there are 20 Pilot Phase subjects, up to 80 Pivotal Phase roll-in cohort subjects, and 315 
Pivotal Phase primary analysis cohort subjects treated with the PFA system, and to account for 
subjects not treated prior to exit. 
Figure 2: Phased Study Design 
 
Pilot Phase 
The Pilot Phase of the PULSED AF study will include an early assessment of safety and confirmation 
of acute procedural success of PVI ablation with the PFA system. Specifically, this phase will include 
treatment of 20 subjects (paroxysmal AF or persistent AF) across up to 4 clinical sites. 
 
 
 
 
 
 
 
 
 
The Pilot Phase subjects will not be included in the Pivotal Phase primary or secondary endpoint 
analyses but will be treated and followed in accordance with all other protocol requirements. In 
addition, the Pilot Phase subjects will complete a cardiac CT or MRI scan at baseline and 3 months 
to allow characterization of any potential occurrences of PV stenosis. If PV stenosis (>70% 
diameter reduction) is identified in any of these 20 subjects, an additional report will be generated 
containing the 3-month PV stenosis analysis once all 20 subjects have completed their 3-month 
follow-up or exited. The report will be sent to regulatory authorities (as requested) while 
enrollment in the Pivotal Phase of the study continues.  

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Pivotal Phase 
The purpose of the Pivotal Phase of the study is to provide data demonstrating the safety and 
effectiveness of the PFA system for the treatment of atrial fibrillation. Specifically, this phase will 
include treatment of 315 subjects (165 paroxysmal AF and 150 persistent AF) for analysis of 
primary objectives, across up to 40 sites worldwide (including the 4 Pilot Phase sites). For the 
Pivotal Phase of the study, subjects will be separated into paroxysmal AF and persistent AF arms 
and analyzed separately.  It is expected that at least 50% of the treatments and supporting clinical 
data will come from the United States with no single site contributing more than 15% of the 
treatments to each arm of the Pivotal Phase. Each arm will have a primary safety objective and a 
primary effectiveness objective, in addition to secondary 
 objectives. For each study 
arm to be considered a success, both the primary safety and effectiveness objectives must be met. 
To facilitate the investigators’ familiarity with the system, a cohort of roll-in subjects will also be 
included in the Pivotal Phase. It is estimated that there will be up to 80 roll-in subjects (up to 2 per 
site). Roll-in subjects will not be included in the Pivotal Phase primary or secondary endpoint 
analyses but will be treated and followed in accordance with all other protocol requirements. Roll-in 
subjects are defined in Section 7.2.1. 
5.1. Duration 
Subjects will be followed for 12 months after the index ablation procedure and then be considered 
exited from the study upon completion of the 12-month visit. Accordingly, the expected total 
study duration is approximately 2 years and 4 months, representing 16 months of enrollment and 
12 months of subject follow-up.  Subjects will not be replaced with newly enrolled subjects upon 
early study exit.   
5.2. Rationale  
The study has primary objectives designed to evaluate the safety and effectiveness of the PFA 
system for treatment of AF. This evaluation will support the proposed indication of the PFA 
system. The study will be scientifically sound and successful if it meets both primary safety and 
effectiveness objectives for one or both arms (paroxysmal and/or persistent).  
The potential benefits related to the use of the PFA system have been determined to outweigh any 
potential risks, providing justification to proceed with clinical investigation. Clinical data are needed 
to demonstrate that the safety profile and proper lesion creation established in preclinical testing 

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is confirmed in a clinical setting. Also, as demonstrated in preclinical studies20,21, 22, the PFA system 
offers potential advantages over existing approved or cleared alternatives such as 
reducing/eliminating collateral damage, improving lesion formation and durability, and reducing 
the AF ablation procedure time. A phased clinical study design with continuous enrollment and 
prospective data collection to demonstrate safety and effectiveness of the PFA system potentially 
reduces the time to patient access for this breakthrough device, as opposed to running separate 
pilot and pivotal studies. A multi-site, multi-national design helps to ensure a representative 
sample of the global population as well as maintain a reasonable enrollment duration. 
5.3. Minimization of Bias 
Selection of subjects, treatment of subjects, and evaluation of study data are potential sources of 
bias. Methods incorporated in the study design to minimize potential bias include (but are not 
limited to): 
• 
Subjects will be screened to confirm eligibility for enrollment with defined 
inclusion/exclusion criteria prior to enrollment. 
• 
Subject demographics will be collected at baseline in order to later assess possible 
characteristics that may influence endpoints.  
• 
All investigational site personnel and Medtronic personnel will be trained on their respective 
aspects of the study using standardized training materials. 
• 
All investigational site personnel will be trained on and required to follow the CIP. 
• 
An independent Clinical Events Committee (CEC) will be utilized to regularly review and 
adjudicate reported adverse events and deaths in the study. 
• 
An independent core lab will be utilized to regularly review and adjudicate the arrhythmia 
component of the primary endpoints. 
• 
A statistical analysis plan (SAP) will be developed prior to analyzing data. The plan will 
document all pre-specified analyses and analysis methods. 
• 
Monitoring will be conducted to review adherence to the CIP and perform source data 
verification per the Monitoring Plan. 
• 
No single site may contribute more than 15% of the treatments to each arm of the Pivotal 
Phase (25 paroxysmal AF subjects and 23 persistent AF subjects, excluding Pilot Phase and 
roll-in subjects) to ensure a reasonable distribution of subjects across sites. 
• 
An independent core laboratory will be used 
 to evaluate baseline and 3-
                                                            
20 Stewart, Mark T., et al. "Intracardiac pulsed field ablation: proof of feasibility in a chronic porcine model." Heart rhythm. 
16.5 (2019): 754-764. 
21 Howard, Brian T., et al. "Pulsed Field Ablation Reduces Pulmonary Vein Stenosis Risk: An Advanced Model for Assessment 
of PV Stenosis." Circulation 138.Suppl_1 (2018): A16516-A16516. 
22  Verma, A., et al. "Pulsed field ablation-feasibility, safety and comparison to radiofrequency." EUROPEAN HEART 
JOURNAL. Vol. 39. GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND: OXFORD UNIV PRESS, 2018. 

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month cardiac CT or MRI scans to characterize of any potential occurrences of PV stenosis 
for Pilot Phase subjects. 
 
In summary, potential sources of bias that may be encountered in this clinical study have been 
considered and minimized by thorough, careful study design. 
6. Product Description 
6.1. General 
Device information is described below and provided in Table 5 and Table 6. Investigator’s Brochure 
(IB) and Instructions For Use (IFU) of the PFA system will be provided to investigational sites for use 
in the clinical study. 
Any changes made to these devices during the investigation will be subject to IDE Change or 
Modification Reporting Requirements per 21 CFR Part 812, as applicable (see Section 13.1). 
Table 5: PFA System Components 
Component 
Model Number 
Geography Status at 
Study Start 
 
PFA Generator 
M970163A001 
Investigational in all 
geographies 
  
 
 
Catheter Electrode 
Distribution System 
(CEDS) 
M970165A001 
Investigational in all 
geographies 
Remote Control 
M970127A001 
Investigational in all 
geographies 
Cable, Generator to 
Remote Control 
M970169A001 
Investigational in all 
geographies 
 
 
  
 
 
  
Cable, Generator to CEDS 
M970168A001 
Investigational in all 
geographies 

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Table 6: PFA System Accessories 
Accessory 
Model Number 
Geography Status at 
Study Start* 
 
Cable, CEDS to EP 
Recording System (EGM) 
990027 
Commercially available in 
Europe, Canada, and 
Australia. Investigational in 
other geographies. 
  
 
 
Cable, Sterile, Catheter to 
CEDS 
990004 
Commercially available in 
Europe, Canada, and 
Australia. Investigational in 
other geographies. 
  
990078 
Commercially available in 
Europe, Canada, and 
Australia. Investigational in 
other geographies. 
  
 
 
Cardiac Trigger Monitor 
and Cable 
7700 
Commercially available in 
Europe, Canada, Australia, 
and US. Investigational in 
Japan. 
 
 
 
Power Cord 
1038N – North 
America; Japan 
1038K – Australia 
1038E – EU 
Commercially available in 
all geographies 
  
 
 
Uninterruptable Power 
Supply (UPS) 
SMART1200XLHG 
(120V) 
SMX1200XLHG 
(230V) 
Commercially available in 
all geographies 
 
 
 
Power Cord – C14M-C13F 
P004-006-ABL 
Commercially available in 
all geographies 
*All PFA system accessories will be considered investigational when used with PFA system 
 

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It is anticipated that at least 415 
 catheters and 415 Sterile, Catheter to CEDS, Cables 
will be used to ensure the study sample size is met. It is anticipated that at least one each of the 
remaining PFA system components and accessories will be used per site in the study. 
6.1.1. 
System Description  
The Medtronic Pulsed Field Ablation (PFA) system applies bipolar, biphasic pulsed electric fields 
through a circular multi-electrode array catheter to perform cardiac tissue ablation through 
irreversible electroporation. The system is intended to be used for the treatment of atrial 
fibrillation in humans by isolation of the major cardiac veins. 
Each PFA therapeutic delivery consists of a series of electric pulses delivered as a pulse train 
containing individual brief biphasic pulses. During each pulse, current flows in a bipolar manner 
between individual electrodes on the multi-electrode catheter array which radiates an electric field 
that surrounds the array. Cardiac tissue within the electric field undergoes cellular hyper-
permeabilization, which irreversibly disrupts the integrity of the cellular membrane leading to cell 
death in the targeted tissue site. This mechanism of cell death is known as irreversible 
electroporation (IRE). The ablated myocardium then undergoes replacement fibrosis over a period 
of days to weeks creating a fibrotic lesion. 
 
 
 catheters are sterile, single-use only intravascular devices designed for short-term 
use (< 24 hours) within the human vasculature and heart. 
 makes contact with the 
central circulatory system (blood contact). 
 is also intended for cardiac EP mapping of 
pulmonary vein potentials, delivery of diagnostic pacing stimuli and verifying electrical isolation of 
the pulmonary veins post-treatment. The PFA system is utilizing this catheter as a platform to 
deliver pulsed electric fields to cardiac tissue.  
The PFA system is for use by physicians in a clinical setting (e.g. a fully equipped electrophysiology 
laboratory) and has been developed for use under a clinical protocol and not for general commercial 
use. 
  

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6.2. PFA Generator 
 
 
 
 
 
 
 
 

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6.3. Catheter Electrode Distribution System (CEDS) 
 
 
 
 
 
 
 
 
 
  
6.4. Remote Control 
 
 
 
 
 
 
 
 
 
  
6.5. Cable, Generator to Remote Control 
 
 

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6.6. Cable, Generator to CEDS 
 
 
 
 
6.7. Cable, CEDS to EP Recording System (EGM) 
 
 
  
6.8. Cable, Sterile, Catheter to CEDS 
 
 
  
 
 
 
  
 
 
 
 
 
 
6.10. Cardiac Trigger Monitor and Cables 
 
 
 
 
 
 
6.11. Power Cord 
 
 

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6.12. Uninterruptible Power Supply (UPS) 
 
 
 
 
 
 
   
6.13. Power Cord – C14M-C13F 
 
 
6.14. Packaging 
In all geographies, the following PFA system components will be provided to sites and will be 
labeled as investigational: 
• 
PFA Generator 
• 
CEDS 
• 
Remote Control 
• 
Cable, Generator to CEDS 
• 
Cable, Generator to Remote Control 
 
In the US, Australia, and Japan, the following PFA system accessories will be provided to sites and 
will be labeled as investigational: 
• 
 catheter 
• 
Sterile catheter to CEDS cable 
• 
CEDS to EP recording cable (EGM cable) 
 
In Canada and Europe, the following PFA system accessories are commercially available and will not 
be provided to sites, but will be considered investigational upon opening to be used with the PFA 
system per the CIP.  
• 
 catheter 
• 
Sterile catheter to CEDS cable 
• 
CEDS to EP recording cable (EGM cable) 
 
 

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In Australia, Canada, Europe, and US, the Cardiac Trigger Monitor is commercially available. At 
study start, the Cardiac Trigger Monitor is not commercially available in Japan. In all geographies, 
this accessory will be provided to sites and will be considered investigational upon opening to be 
used with the PFA system per the CIP.  
 
In all geographies, the power cords (models 1038N, 1038K, 1038E, P004-006-ABL) are 
commercially available, but will be provided to sites and will be considered investigational upon 
opening to be used with the PFA system per the CIP. Medtronic personnel trained on the study will 
affix a sticker denoting the accessory model number. The appropriate geography-specific model 
cord should be used by each study site. 
In all geographies, the UPS is commercially available, but will be provided to sites and will be 
considered investigational upon opening to be used with the PFA system per the CIP.  
Market released components used in this study will be labeled investigational according to local 
requirements. See Appendix A (Study-Specific Requirements by Country) for details of 
investigational labeling of market released components. 
6.15. Product Training Requirements 
Investigators responsible as operators for the PFA system ablation procedure will be required to 
undergo product training (to include hands on experience) prior to treating any subject with the 
PFA system. A separate training document will overview topics and include details on the format of 
delivery. 
6.16. Product Receipt, Tracking and Return 
The Medtronic Pulsed Field Ablation system components will be considered investigational in 
geographies in which the product is not available commercially and will be labeled for exclusive use 
in clinical investigations.  
 
Investigational product will be distributed to a site only when Medtronic has received all required 
documentation, has notified the site of site activation and the site has been authorized to enroll in 
the study. Distribution of the investigational product to study sites during the clinical study will be 
managed by Medtronic. Investigational product can only be ordered by Medtronic personnel.  
Investigational products will be used only in the study according to the CIP and PFA system IFU. In 
Japan, the device control manager, assigned by the Head of Medical Institution controls the 
investigational device once the product arrives at the study site. 
 
The principal investigator or an authorized designee shall keep records documenting the receipt, 
use, return and disposal of the investigational devices, which shall include: 
• 
The date of receipt 
• 
Identification of each investigational device (batch number/serial number or unique code) 
• 
The expiration date (if applicable) 

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• 
The date(s) of use 
• 
Subject identification 
• 
The date of return of unused, expired or malfunctioning investigational devices (if 
applicable) 
 
All potentially defective products should be returned to Medtronic for analysis whenever possible 
and when permissible by local laws and regulations. Local Medtronic field personnel or 
representative can be contacted to receive a Return Mailer Kit. 
 
PFA system components and accessories are to be returned to Medtronic by each study site as 
described below: 
 
If no device deficiency, devices can be destroyed/disposed of according to local laws and 
regulations. If unused, device should be returned as described in the note below: 
• 
 catheter 
• 
Sterile catheter to CEDS cable 
Note:  For PFA system accessories shipped to sites as investigational, unopened or expired 
accessories are required to be returned to Medtronic. For PFA system accessories only considered 
investigational upon opening to be used with the PFA system per the CIP, there is no requirement 
to return unopened product to Medtronic. 
Upon completion of the study, unless otherwise directed by the Medtronic study team: 
• 
PFA Generator 
• 
CEDS 
• 
Remote Control 
• 
Cable, Generator to CEDS 
• 
Cable, Generator to Remote Control 
• 
CEDS to EP recording cable (EGM cable) 
• 
Cardiac Trigger Monitor 
• 
Power cord (models 1038N, 1038K, 1038E, P004-006-ABL) 
• 
Uninterruptible Power Supply (UPS) 
Note:  In all geographies, these PFA system components and accessories (including unopened or 
expired product) are required to be returned to Medtronic except in cases where the device is only 
considered investigational upon opening to be used with the PFA system per the CIP, in which case 
there is no requirement to return this product to Medtronic if unopened. 
Any sheath or guidewire used in conjunction with the PFA system with a reportable device 
deficiency should be returned to Medtronic following the study ablation procedure. 
 
Device disposition logs will be provided to all sites and used for tracking of all investigational 
product throughout the duration of the study. The logs must be maintained and updated when 
product is disposed of or returned to Medtronic. If the products are not returned to Medtronic, a 
justification is required to be reported on the appropriate case report form(s) or disposition log(s). 

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6.17. Product Storage 
The PFA system is investigational and will be maintained in locked, secure storage with 
access limited only to approved study staff.  
 
 

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7. Selection of Subjects 
7.1. Study Population 
The population being studied has documented drug refractory recurrent symptomatic paroxysmal 
or persistent atrial fibrillation with generally otherwise good cardiovascular health. The AF 
classifications that will be used for this study are defined in the 2017 
HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement on Catheter and Surgical 
Ablation of Atrial Fibrillation.1  
 
Paroxysmal AF is defined as AF that terminates spontaneously or with intervention within 7 days of 
onset. 
 
Persistent AF is defined as continuous AF that is sustained beyond 7 days. 
 
Patients in long-standing persistent AF are excluded from the study. Long-standing persistent AF 
is defined as continuous AF of greater than 12 months’ duration. 
7.2. Subject Enrollment 
Patients will be screened to ensure they meet all of the inclusion and none of the exclusion criteria 
prior to study enrollment. IRB/MEC and Medtronic approval of the Clinical Investigation Plan and 
the Patient Informed Consent Form must be obtained prior to enrolling subjects in the study. 
Enrollment of the subject must occur prior to performing any study procedures. Subjects are 
enrolled at the time the Patient Informed Consent Form is signed and dated. Pilot and Pivotal Phase 
subjects must meet the same inclusion and exclusion criteria and will follow the same consent 
process.  
7.2.1. 
Roll-in Subjects 
To facilitate the investigators’ familiarity with the system, a cohort of roll-in subjects will be 
included in the Pivotal Phase enrollments. The roll-in subjects will not be included in the 315 
subjects included in the analysis for the Pivotal Phase primary and secondary objectives but will be 
consented, enrolled, treated, and followed in accordance with all other protocol requirements. 
Sites that do not have previous experience with the 
 catheter will utilize up to two roll-
in subjects; Medtronic approval is required to utilize fewer than two roll-in subjects. Sites having 
prior recent experience with the 
 catheter may be allowed to waive the roll-in 
requirement, with Medtronic approval, prior to enrolling subjects into the primary analysis cohort. 
Investigators that participate as PFA system operators in the Pilot Phase will not be required to 
utilize roll-in subjects. Since paroxysmal AF and persistent AF subjects will be treated with the 
same ablation procedure approach (PVI-only), subjects with either AF type can contribute to the 

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roll-in cohort. Subjects will be identified as roll-in subjects prior to the ablation procedure. There 
will be up to 80 total roll-in subjects.  
7.3. Inclusion Criteria 
1. Failure of at least one AAD (class I or III) for AF as evidenced by recurrent symptomatic AF, 
or intolerable side effects due to AAD.  
2. A diagnosis of recurrent symptomatic paroxysmal or persistent AF with the following 
documentation: 
a. Paroxysmal: (1) physician’s note indicating symptoms consistent with recurrent 
self-terminating or terminating with intervention (within 7 days) AF or paroxysmal 
AF; and (2) any ECG documented AF episode(s) within 12 months prior to 
enrollment  
OR 
b. Persistent: (1) physician’s note indicating symptoms consistent with continuous AF 
episode lasting longer than 7 days but less than 1 year; and (2) any 24-hour 
continuous ECG recording documenting persistent AF within 6 months of 
enrollment; OR (2) two ECGs from any form of rhythm monitoring showing 
continuous AF taken at least 7 days apart 
3. Age 18 through 80 years old (or older than 18 if required by local law) 
7.4. Exclusion Criteria 
1. Long-standing persistent AF (continuous AF that is sustained >12 months)  
2. Left atrial diameter > 5.0 cm (anteroposterior)  
3. Prior left atrial ablation or surgical procedure (including left atrial appendage closures) 
4. Planned LAA closure procedure or implant of a permanent pacemaker, biventricular 
pacemaker, loop recorder/insertable cardiac monitor (ICM), or any type of implantable 
cardiac defibrillator (with or without biventricular pacing function) for any time during the 
follow-up period  
5. Patient who is not on oral anticoagulation therapy for at least 3 weeks prior to the ablation 
procedure  
6. Presence of a permanent pacemaker, biventricular pacemaker, loop recorder/insertable 
cardiac monitor (ICM), or any type of implantable cardiac defibrillator (with or without 
biventricular pacing function)  
7. Presence of any pulmonary vein stents 
8. Presence of any pre-existing pulmonary vein stenosis 
9. Pre-existing hemidiaphragmatic paralysis 
10. Presence of any cardiac valve prosthesis 
11. Moderate to severe mitral valve stenosis  
12. More than moderate mitral regurgitation (i.e., 3+ or 4+ MR) 

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13. Any cardiac surgery, myocardial infarction, PCI / PTCA or coronary artery stenting which 
occurred during the 3-month interval preceding the consent date 
14. Unstable angina 
15. NYHA Class III or IV congestive heart failure or documented left ventricular ejection fraction 
(LVEF) less than or equal to 35% measure by acceptable cardiac testing (e.g. TTE) 
16. Primary pulmonary hypertension 
17. Rheumatic heart disease 
18. Thrombocytosis, thrombocytopenia 
19. Any condition contraindicating chronic anticoagulation 
20. Active systemic infection 
21. Hypertrophic cardiomyopathy 
22. Known reversible causes of AF, including but not limited to uncontrolled hyperthyroidism, 
severe untreated obstructive sleep apnea, and acute alcohol toxicity 
23. Any cerebral ischemic event (strokes or TIAs) which occurred during the 6-month interval 
preceding the consent date 
24. History of thromboembolic event within the past 6 months or evidence of intracardiac 
thrombus at the time of the procedure 
25. Any woman known to be pregnant or breastfeeding, or any woman of child bearing 
potential who is not on a reliable form of birth regulation method or abstinence 
26. Patient with life expectancy that makes it unlikely 12 months of follow-up will be completed  
27. Current or anticipated participation in any other clinical trial of a drug, device or biologic 
during the duration of the study not pre-approved by Medtronic 
28. Known allergies or hypersensitivities to adhesives 
29. Unwilling or unable to comply fully with study procedures and follow-up 
30. Unable to provide own informed consent 
 
 

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8. Study Procedures  
8.1. Schedule of Events 
Data collection requirements are summarized in Table 7, below. 
Table 7: Study Procedures and Data Collection per Subject Visit 
 
Baseline 
Procedure 
Discharge 
7 Day 1 
30 Day 
3 Month 1 
6 Month 1 
12 Month 
Unscheduled 
Repeat 
Ablation 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Physical Exam  
X 
 
X 
 
X 
 
 
 
 
 
Pregnancy Screen 2 
X 
 
 
 
 
 
 
 
 
 
AAD & Anticoagulation Medication 
Review 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Arrhythmia Symptom Review 
X 
 
 
 
X 
X 
X 
X 
X 
X 
12 Lead ECG 
X 
 
X 
 
X 
X 
X 
X 
X 
 
NIHSS Assessment 
X 
 
X 
 
X 
 
 
 
 
X 
Cardiac CT Scan or MRI 3 
X 
 
 
 
 
X 
X 
X 
 
 
AFEQT & EQ-5D-5L 
X 
 
 
 
 
 
X 
X 
 
 
Transthoracic Echocardiogram (TTE) 4 
X 
 
 
 
 
 
 
 
 
 
Transesophageal Echocardiogram 
(TEE) 5 
X 
 
 
 
 
 
 
 
 
 
INR Assessment 6 
X 
 
 
 
 
 
 
 
 
 
Ablation Procedure Data 
 
X 
 
 
 
 
 
 
 
X 
24h Continuous Monitoring with Holter 
 
 
 
 
 
 
X 
X 
 
 
Patient Activated Ambulatory ECG 
Monitor 8 
 
 
 
 
 
Weekly and 
symptomatic episodes 
 
 
Adverse Events 
As they occur 
Device Deficiencies 
As they occur 
Study Deviations 
As they occur 
 
Notes: 
1 Multiple modes of data collections may be employed to support the collection of required visit data at the 7-day and 3- and 6-
month visits such as: In office patient clinic visit, direct to patient contact (i.e. telephone, email, mail contact, etc.), and remote 
technology transmissions/uploads. 
2 Female subjects of child bearing potential only. 
3 Baseline and 3-month cardiac CT/MRI required for all subjects in the Pilot Phase. For the Pivotal Phase, cardiac CT/MRI is 
required only for subjects with suspected PV stenosis at 3-, 6- or 12-month visits and who did not undergo cardiac CT/MRI at a 
previous visit. 
4 Only required if data not available from within 6 months prior to consent date. 

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5 TEE must be performed in all subjects. The TEE should occur within one day (on the day of or within the day prior to) the planned 
ablation procedure. 
6 Subjects taking a vitamin K antagonist (VKA) are required to have a therapeutic INR (2-3.5) on the day of the planned ablation 
procedure. INR assessment is not required for subjects on other types of anticoagulants. 
 
8 Subjects shall submit ECG transmissions weekly and whenever symptoms occur after the post-ablation blanking period 
through 12-month follow-up.   
8.2. Subject Consent 
Patient informed consent (IC) is defined as a legally effective documented confirmation of a 
subject’s voluntary agreement to participate in a particular clinical study after information has been 
given to the subject on all aspects of the clinical study that are relevant to the subject’s decision to 
participate. This process includes obtaining an IC Form and an Authorization to Use and Disclose 
Personal Health Information (US only) that has been approved by the study site’s IRB/REB/MEC and 
signed and dated by the subject. A subject may only consent after information has been given to 
the subject on all aspects of the clinical investigation that are relevant to the subject’s decision to 
participate.  
 
Prior to enrolling subjects, the IC Form must have been approved by each site’s IRB/REB/MEC. 
Each site must also use an Authorization to Use and Disclose Personal Health 
Information/Research Authorization (US only) or other privacy language as required by law. The IC 
Form must be controlled (i.e. versioned and dated) to ensure it is clear which version(s) were 
approved by the IRB/REB/MEC. Any adaptation of the sample IC Form must be reviewed and 
approved by Medtronic and the IRB/REB/MEC reviewing the application prior to enrolling subjects.  
 
The Investigator must notify the subject of any significant new findings about the study that 
become available during the study which are pertinent to the safety and well-being of the subject. 
This could impact a subject’s willingness to participate in the study. If relevant, approval may be 
requested from subjects to confirm their continued participation. 
 
Prior to initiation of any study-specific procedures, documented informed consent must be 
obtained from the subject. Likewise, privacy or health information protection regulation may 
require subjects to sign additional forms to authorize sites to submit subject information to the 
study sponsor. The informed consent process must be conducted by the Principal Investigator or 
an authorized designee, and the IC Form and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language (US only) as required by law must be 
given to the subject in a language he/she is able to read and understand. The process of informed 
consent must be conducted without using coercion, undue or improper influence on, or 
inducement of the subject to participate by the Investigator or other site personnel. The informed 
consent process shall not waive or appear to waive the subject’s legal rights. The language used 
shall be as non-technical as possible and must be understandable to the subject and the impartial 
witness, where applicable. 
 

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The subject must have ample time and opportunity to read and understand the IC Form, to inquire 
about details of the study, and to decide whether to participate in the clinical study. All questions 
about the study should be answered to the satisfaction of the subject.  
 
When the subject decides to participate in the clinical study, the IC Form and the Authorization to 
Use and Disclose Personal Health Information/Research Authorization/other privacy language (US 
only) as required by law must be signed and personally dated by the subject and either the 
Investigator or the Investigator’s authorized designee, as required by local law. If applicable, 
independent witness must be present throughout the entire informed consent process, and the 
written informed consent form and any other information related to the study must be read aloud 
and explained to the prospective subject. If applicable, witness shall also sign and personally date 
the consent form to attest that the information in the IC Form was accurately explained and clearly 
understood by the subject, and that informed consent was freely given.  
 
A copy of the IC Form and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law (US only), signed 
and dated as required by law, must be provided to the subject.  
 
If consent is obtained the same day the subject begins participating in study-related procedures, it 
must be documented in the subject’s case history that consent was obtained prior to participation 
in any study related procedures. It is best practice for the informed consent process to be 
documented in the subject’s case history, regardless of circumstance. 
 
In the event the subject cannot read and/or write, a witnessed (impartial third party) IC Form will be 
allowed, provided detailed documentation of the process is recorded in the subject’s case history 
and the witness signs and dates the IC Form. 
 
The original of the signed IC Form and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language (US only) as required by law must be 
filed in the hospital/clinical chart and/or with the subject’s study documents and should also be 
available for monitoring and auditing. Any Medtronic Field personnel who support the study 
procedure must be able to review the subject’s signed and dated IC Form and verify its 
completeness prior to proceeding with the procedure. In the event the Medtronic Field personnel 
identify an IC Form as being incomplete, the study procedure will not be allowed to occur until the 
consent of the subject can be adequately and appropriately obtained. 
 
 

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8.3. Enrollment, Baseline, and Pre-ablation 
When a patient and the Principal Investigator or authorized designee, as required, have signed and 
dated the IC Form, the patient is considered a subject enrolled in the study.  The date the subject 
signed the IC Form and Authorization to Use and Disclose Personal Health Information/Research 
Authorization/other privacy language as required by law must be documented in the subject’s 
medical records. 
The baseline visit can be a standalone visit or can be performed on the same day but prior to the 
PFA system ablation procedure. The following evaluations will be performed after consent, unless 
previously performed as part of routine clinical evaluations within the specified windows: 
Within 6 months prior to consent date: 
• 
Trans-thoracic echocardiogram (TTE) for the collection of left atrial size, left ventricular 
ejection fraction, and mitral valve impairment.  A repeat TTE procedure for the purpose of 
the study after the consent date is not required if a TTE was performed within 6 months of 
the consent date and all data are available. 
• 
Pilot Phase subjects only: cardiac Magnetic Resonance Imaging (MRI) or Computerized 
Tomography Scanning (CT scan) of the four PVs or their anomalous equivalent. 
Within 30 days prior to consent date: 
• 
12-lead ECG  
• 
Physical examination 
• 
CHA2DS2-VASc Score 
• 
Demographics 
• 
Medical history   
 
After consent date but prior to procedure:  
Note: The time between the consent date and the procedure should not exceed 30 days. If 30 days 
are exceeded, the subject must be re-evaluated against inclusion and exclusion criteria to ensure 
they still qualify for the study. 
• 
Final assessment of all factors specified for evaluation under Inclusion Criteria and 
Exclusion Criteria (Section 7) 
o Note: After required study testing, if a subject no longer meets the inclusion criteria 
or now meets exclusion criteria, the subject will be exited from the study. 
• 
Pregnancy screen (female subjects of child bearing potential only)  
o Note: For this study, a woman of childbearing potential is defined as a 
premenopausal female capable of becoming pregnant 

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• 
Review of AF symptoms 
• 
Review of medications to treat atrial arrhythmias and anticoagulation medications  
o Amiodarone use must be discontinued at least 14 days prior to the ablation 
procedure and not restarted after the ablation procedure.  
• 
EQ-5D (5L version) and AFEQT Questionnaires 
• 
INR assessment 
o Subjects taking a vitamin K antagonist (VKA) are required to have a therapeutic INR 
(2-3.5) on the day of the planned ablation procedure.  
o INR assessment is not required for subjects on other types of anticoagulants. 
• 
Transesophageal Echocardiogram (TEE)  
o A TEE must be performed in all subjects. The TEE should occur within one day (on 
the day of or within the day prior to) the planned ablation procedure. 
o The subject will not proceed with the study ablation procedure and will be exited 
from the study if a left atrial thrombus is visualized. 
• 
National Institute of Health Stroke Scale (NIHSS) Assessment 
o The NIHSS will be administered to all subjects within 3 days prior to, including day 
of, planned ablation procedure. 
o The NIHSS will be administered by study site personnel who have been certified to 
perform the NIHSS assessment and are delegated by their respective site to 
perform such assessment 
 
 
 
 
 
 
 

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8.4. Procedure 
Note: The time between the consent date and the procedure should not exceed 30 days. If 30 days 
are exceeded, the subject must be re-evaluated against inclusion and exclusion criteria to ensure 
they still qualify for the study. 
 
Perform the pulmonary vein isolation procedure using the PFA system with the 
 
cardiac ablation catheter.  
 
 The Investigator is to perform the procedure 
according to the procedural steps in this CIP and the PFA system Instructions For Use. Appropriate 
sedation and venous access should be attained at the Investigator’s standard practice according to 
their institution’s pre-established procedures/guidelines at the time of the procedure. Investigator 
may choose compatible guidewires, sheaths and mapping catheters at their discretion. ACT 
analyzer calibration records must be made available for sponsor review prior to each PFA ablation 
procedure. 
 
The anticoagulation protocol for PULSED AF is as follows: 
• 
Pre-procedure 
o Subjects who are not on oral anticoagulation therapy for at least 3 weeks prior to 
the ablation procedure are excluded from the study.   
o If VKA is used, 1 therapeutic INR reading (2-3.5) is required day of procedure. 
o Prior to ablation, TEE is required of all patients regardless of CHA2DS2-VASc score 
or anticoagulation. 
• 
Procedure 
o Continuous, uninterrupted oral anticoagulation (e.g. no bridging with low molecular 
weight heparin) is required. 
o Administer heparin bolus prior to (or immediately after) the transseptal puncture 
and start continuous heparin infusion to maintain a target ACT ≥ 350 seconds.  
o The ACT level should be checked at approximately 15–30 minute intervals for the 
duration of the procedure. 
o In the event of persistent bleeding or cardiac tamponade, protamine may be 
administered to reverse heparin. If bleeding resolves, reversal of oral anticoagulant 
is not recommended. 
• 
Post-procedure 
o Oral anticoagulation must be continued for at least 2 months post-procedure (e.g. 
no bridging post-procedure) for all subjects unless contraindicated. 
o Discontinuation of systemic anticoagulation therapy after 2 months post ablation is 
not recommended in male subjects with a CHA2DS2-VASc score >1 or female 
subjects with a CHA2DS2-VASc score >2. 

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8.4.1. 
Esophageal Visualization and Temperature Monitoring 
a. An esophageal temperature monitor is not required to be used for PFA therapy profile 
applications. If an esophageal temperature monitor is used, it should have an insulated 
tip. 
8.4.2. 
Diaphragm Movement 
a. Prior to the first PFA application, the Investigator must confirm absence of pre-
existing hemidiaphragmatic paralysis. 
8.4.3. 
Peri-procedural Anticoagulation 
a. Heparin should be administered prior to (or immediately following) transseptal 
puncture during AF ablation procedures and adjusted to achieve and maintain a target 
ACT of at least 350  seconds. ACT should be checked approximately every 15-30 
minutes. 
b. Performance of AF ablation in a subject systemically anticoagulated with VKA or novel 
oral anticoagulants (NOACs) does not alter the need for intravenous heparin to 
maintain a therapeutic ACT during the procedure.  
c. Performance of the ablation procedure on continuous, uninterrupted oral 
anticoagulation (e.g. no bridging with low molecular weight heparin) is required.  
d. In the event of persistent bleeding or cardiac tamponade, protamine may be 
administered to reverse heparin. If bleeding resolves, reversal of oral anticoagulant is 
not recommended. 
8.4.4. 
Pulmonary Vein (PV) Ablation with the PFA system 
a. Deploy diagnostic catheters and perform transseptal puncture. Introduction of the 
 catheter should be performed according to the PFA system IFU.  
b. Every effort consistent with subject welfare should be made to treat all PVs or their 
anomalous equivalents. 
c. The 
 catheter will be advanced into the left atrium and tracked over the 
guidewire so that it is positioned at the entrance of the PV. 
d. Assess the catheter’s spiral array positioning at the PV by fluoroscopy or other 
imaging technique. Reposition as needed. 
e. Map for pulmonary vein potentials. 

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f. Perform ablations. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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g. Verify isolation of each pulmonary vein a minimum of 20 minutes after the last PFA 
application of the initial PVI in that PV. Each pulmonary vein should be minimally 
assessed for entrance block and, where assessable, exit block to demonstrate 
electrical isolation.   
h. Upon the Investigator’s assessment of procedure completion, Isoproterenol and/or 
adenosine may be used to assess pulmonary vein isolation. 
i. 
In the event of an inability to electrically isolate all accessible targeted pulmonary veins 
with the PFA system, any commercially released catheter deemed appropriate for the 
procedure may be used to complete the ablation procedure. Ablation using a non-
study device to isolate any pulmonary vein will be considered a primary endpoint 
failure. 
8.4.5. 
Other Ablations during Index Procedure 
a. Ablation of the cavotricuspid isthmus, with the goal of achieving bi-directional 
isthmus block, is recommended for subjects with a history of typical atrial flutter or 
inducible cavotricuspid isthmus dependent atrial flutter.  It is recommended to 
attempt an induction of cavotricuspid isthmus dependent atrial flutter if the subject 
does not have a history of this arrhythmia.  Any commercially released catheter 
deemed appropriate for the procedure may be used. 
b. Additional right atrial ablations may be performed if clinically necessary. Any 
commercially released catheter deemed appropriate for the procedure may be used. 
8.4.6. 
Procedure Documentation  
During the procedure, the following data will be collected:  
• 
Catheters used 
• 
Vein location for each PFA application (e.g. right superior PV) 
• 
Use of test pulse or other phrenic nerve monitoring technique for each PFA application 
• 
PFA therapy profile and electrode configuration used for each PFA application 
• 
Procedural sedation methods/type, including any modifications to procedural sedation as a 
result of subject reaction to PFA applications 
• 
Stimulation of diaphragm or skeletal muscle as a result of PFA applications 
• 
Demonstrated electrical block and the device used to demonstrate 
• 
Adjunctive catheters, mapping or visualization devices, procedure information, ACT, 
cardioversion use and fluoroscopy time will be collected; esophageal temperature may be 
collected 

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8.4.7. 
Cardioversion 
Direct Current (DCCV) or pharmacological cardioversion may be considered at any point during the 
procedure when restoration of SR will assist in assessing the effectiveness of PFA or deemed 
necessary for the benefit of the patient. Electrical or pharmacological cardioversion to sinus 
rhythm must be attempted at the conclusion of the procedure if sinus rhythm was not restored. 
8.4.8. 
Role of Medtronic Personnel at Study Procedure 
Medtronic personnel will provide technical support at the ablation procedures under the 
supervision of a study investigator, but no data entry into the electronic database shall be 
performed by Medtronic personnel at sites. Medtronic personnel may support completion of the 
study worksheets. Medtronic personnel will collect procedural data from the PFA generator post-
procedure via data download. It is the responsibility of the study site to ensure the subject is 
identified via subject ID number to prevent the distribution of personally identifiable information. 
8.5. Hospital Discharge 
At or shortly before hospital discharge, the following will be performed and collected: 
• 
Adverse event assessment 
• 
Review medications 
• 
12-lead ECG 
• 
Physical examination 
o The discharge physical examination will include, at a minimum, a 
cardiopulmonary examination. 
• 
NIHSS Assessment 
o The NIHSS will be administered by study site personnel who have been certified 
to perform the NIHSS assessment and are delegated by their respective site to 
perform the assessment. The discharge NIHSS assessment will be conducted 
no earlier than the day following the procedure and no later than the subject’s 
discharge. If the subject is discharged the same day as the ablation procedure, 
the NIHSS assessment will be conducted no earlier than 6 hours following the 
procedure. If the subject’s discharge NIHSS total score is higher (worse) than 
the baseline NIHSS total score, a formal neurology consult will be initiated by 
the study site team to confirm the presence or absence of stroke or TIA. If the 
site’s neurology team deems it necessary, imaging will be performed. 
• 
Review study requirements with the subject to help ensure compliance with follow-up 
procedures. 
 
 
 

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8.6. Medications 
Oral anticoagulation must be continued for at least two months post-ablation (e.g. no bridging 
post-ablation) for all subjects unless contraindicated. Decisions regarding the continuation of 
anticoagulation therapy more than two months following ablation should be based on the subject’s 
risk factors for stroke as estimated by the CHA2DS2-VASc score and not on the presence or type of 
AF. Discontinuation of systemic anticoagulation therapy after two months post-ablation is not 
recommended in male subjects with a CHA2DS2-VASc score >1 or female subjects with a 
CHA2DS2-VASc score >2. 
 
Information regarding medications prescribed for anticoagulation or to treat atrial arrhythmias will 
be collected from subject enrollment through study exit. The following information will be collected 
for medications to treat atrial arrhythmias: medication name, purpose for use, start and stop 
dates, dose, dosage changes (and reasons for changes), and route of administration. Data 
collection for anticoagulation medication will be limited to medication name and start and stop 
dates. 
 
Requirements for use of antiarrhythmic medications are described below for the Paroxysmal AF 
and Persistent AF cohorts. For both patient populations, the 2014 AHA/ACC/HRS Guideline for the 
Management of Patients with AF should be consulted for AAD prescriptions.8 Use of amiodarone is 
not permitted for any subject post-ablation. All other medications (those that are not specified 
below) are permitted in the study, with the exception of investigational drugs that may confound 
the study results. Beta-blockers may be prescribed per standard of care. 
8.6.1. 
Paroxysmal AF Cohort 
Per physician discretion, class I or III antiarrhythmic, including sotalol, medication use is permitted 
for up to 80 days following the ablation procedure. Prescriptions for these drugs should not allow a 
quantity that will last longer than 80 days post-procedure. It is recommended that site personnel 
contact subjects on day 80 post-ablation procedure to ensure they have stopped taking class I or III 
antiarrhythmic drugs. Class I or III antiarrhythmic drug use after the 90-day blanking period will be 
considered a primary endpoint failure. 
 
8.6.2. 
Persistent AF Cohort 
Up-titration of the Class I or III antiarrhythmic medication dose is allowed only in the 90-day post-
procedure blanking period. 

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Class I and III antiarrhythmic medication use after the 90-day post-procedure blanking period: 
• 
Subjects are allowed to remain on Class I or III antiarrhythmic medications at or lower than 
the historic maximum ineffective dose (prior to the ablation procedure) after the 90-day 
post-procedure blanking period. 
• 
Re-initiation, at any point during follow-up, of a Class I or III antiarrhythmic medication that 
was failed or was not tolerated prior to the ablation procedure at any dose will be 
considered a primary endpoint failure. 
• 
Initiation of a new Class I or III antiarrhythmic medication after the 90-day post-procedure 
blanking period will be considered a primary endpoint failure. 
• 
Remaining on a dose higher than the historic maximum ineffective dose (prior to the 
ablation procedure) after the 90-day post-procedure blanking period will be considered a 
primary endpoint failure. 
8.7. Repeat Ablations with PFA 
Repeat PVI ablations using PFA are permissible within the 90-day blanking period. Any repeat PVI 
using the PFA system throughout the study follow-up period should be performed according to the 
procedural steps in Section 8.4. Note, a repeat ablation after the 90-day blanking period will be 
considered a primary endpoint failure. Any repeat ablation in the left atrium using a non-study 
device at any time after the index PFA ablation procedure will be considered a primary endpoint 
failure. 
Subsequent ablations in the right atrium are allowed (e.g., typical atrial flutter ablation) at any time 
throughout the study follow-up period.   
If a repeat left atrial ablation is deemed necessary and performed by the Investigator, the following 
should be performed: 
 
 
 
 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
NIHSS Assessment 
o An NIHSS assessment will be administered to all subjects within 3 days prior to, 
including day of, repeat ablation procedure. 
o The NIHSS will be administered by study site personnel who have been certified to 
perform the NIHSS assessment and are delegated by their respective site to 
perform such assessment. 
• 
Discharge procedures will be completed in accordance with Section 8.5. 
 
 
 

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Repeat ablation procedures will be documented on an electronic case report form (eCRF) and as 
described in accordance with Section 8.4.6.  The subject’s procedures and follow-up windows will 
continue based on the index PFA ablation procedure date.   
8.8. Post-Procedural Cardioversions 
Electrically and pharmacologically cardioverting the subject to sinus rhythm is allowed in the 90-
day post-procedure blanking period at the discretion of the Investigator. Electrically or 
pharmacologically cardioverting the subject to sinus rhythm after the 90-day blanking period will 
be considered a primary endpoint failure. 
 
 

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8.9. Scheduled Follow-up Visits 
After receiving notice of a completed index ablation procedure, Medtronic will provide the target 
dates and windows for each visit to the site. Should a subject miss a visit or the visit fall outside the 
pre-specified window, a study deviation must be reported and the original follow-up schedule 
maintained for subsequent visits.  
Data analyses include follow-up visits, regardless of whether the visit occurs within the window.  
Therefore, a late visit is preferred over a missed visit but must be accompanied by a deviation.  
Follow-up visit windows are listed in Table 9 and are based on days after the index ablation 
procedure.   
Table 9: Follow-up Schedule 
Occurrence/ 
Visit 
Window  
(Calculated days after the 
ablation procedure) 
Window Start 
Window End 
Enrollment/Baseline1 
-30 days 
Day 0 
Index PFA System Ablation 
Procedure 
Day 0 
Day 0 
7 day (phone call or office) 
7 days 
14 days 
30 day 
30 days 
44 days 
3 month 
91 days 
105 days 
6 month 
183 days 
197 days 
12 month 
365 days 
395 days 
1Note: if the time between the consent date and the procedure exceeds 
30 days, the subject must be re-evaluated against inclusion and 
exclusion criteria to ensure they still qualify for the study. 
 
Multiple modes of data collections may be employed to support the collection of required visit data 
at the 7-day and 3- and 6-month visits such as: In office patient clinic visit, direct to patient contact 
(i.e. telephone, email, mail contact, etc.), and remote technology transmissions/uploads.  
 
The following information is required to be collected at the follow-up visits: 
8.9.1. 
Seven Day Phone or Office Visit 
• 
Review medications  
• 
Adverse event assessment 

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8.9.2. 
Thirty Day Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
12-lead ECG 
• 
Physical examination 
o The 30-day physical examination will include, at a minimum, a cardiopulmonary 
examination. 
• 
NIHSS Assessment 
o The 30-day visit NIHSS will be administered by study site personnel who have been 
certified to perform the NIHSS assessment and are delegated by their respective 
site to perform the assessment. If the subject’s 30-day visit NIHSS total score is 
higher (worse) than the baseline or discharge NIHSS total score, a formal neurology 
consult will be initiated by the study site team to confirm the presence or absence 
of stroke or TIA. If the site’s neurology team deems it necessary, imaging will be 
performed. 
8.9.3. 
Three Month Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
12-lead ECG 
• 
Provide the subject with patient activated ambulatory monitoring equipment and provide 
instructions for weekly and symptomatic transmissions  
• 
Cardiac MRI or CT scan: 
• 
Pilot Phase subjects are required to complete a cardiac MRI or CT scan (whichever 
technology was used at Baseline) of all PVs or their anomalous equivalents.  
• 
All subjects: only in the case of suspected PV stenosis, is cardiac MRI or CT scan required. It 
is not required at this visit if it was already completed at an earlier visit where PV stenosis 
was confirmed. 
 
 
 
 
8.9.4. 
Six Month Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
12-lead ECG 
• 
Remind subject of instructions on patient activated ambulatory monitoring equipment for 
weekly and symptomatic transmissions 

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• 
Only in the case of suspected PV stenosis, is cardiac MRI or CT scan required. It is not 
required at this visit if it was already completed at an earlier visit where PV stenosis was 
confirmed. 
• 
24h continuous monitoring with Holter 
• 
EQ-5D and AFEQT Questionnaires 
8.9.5. 
Twelve Month Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
12-lead ECG 
• 
Only in the case of suspected PV stenosis, is cardiac MRI or CT scan required. It is not 
required at this visit if it was already completed at an earlier visit where PV stenosis was 
confirmed. 
• 
24h continuous monitoring with Holter 
• 
EQ-5D and AFEQT Questionnaires 
• 
Collect or ensure return of ambulatory monitoring equipment  
8.10. Unscheduled Office Visits 
An unscheduled visit is defined as any unplanned cardiovascular-related office visit or early study 
exit at the study site that occurs between CIP required visits.  If the subject exits the study early, 
the site should attempt to complete an unscheduled office visit.  The following information is 
required to be collected at unscheduled follow-up visits: 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
12-lead ECG 
8.11. Holter and Patient Activated Ambulatory ECG Monitor 
Management 
Market-released Holters will be distributed by a core lab to sites after activation has occurred.  All 
subjects will wear a Holter in conjunction with their 6- and 12-month office visits.  Holters will be 
sent back to the core lab after they have been worn by the subject.  The core lab will be responsible 
for adjudication of atrial arrhythmias for the primary objective of the study.  The core lab will 
manage maintenance, calibration and tracking of the Holters.  
Market-released Patient Activated Ambulatory ECG Monitors will be distributed by a core lab to 
sites after activation has occurred.  All subjects will transmit weekly and symptomatic ECGs 
following their 3-month office visit.  The monitors will be returned to the core lab at the end of the 

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study.  The core lab will be responsible for adjudication of atrial arrhythmias for the primary 
effectiveness objectives of the study.  The core lab will manage maintenance, calibration and 
tracking of the monitors.  
8.12. 12-lead Electrocardiograms 
All 12-lead ECGs will be sent to the core lab. The core lab will be responsible for adjudication of 
atrial arrhythmias for the primary objectives of the study.  Copies of additional source documents 
may be requested.  
8.13. Assessment of Safety 
The Pilot Phase safety objective is based on the data collected as discussed in Sections 4.1 and 
12.1. 
 
The Pivotal Phase primary safety objective is based on the Adverse Event data collected. Further 
information on the collection of Adverse Events is discussed in Section 10. 
8.14. Assessment of Effectiveness 
The Pilot Phase effectiveness objective is based on the data collected as discussed in Sections 4.1 
and 12.1. 
The Pivotal Phase primary effectiveness objectives are based on the data collected as discussed in 
Sections 4.2 and 12.2. 
 
  
 
 
 
 
  
8.17. Recording Data 
The study will collect data using an electronic data management system for clinical studies. Sites 
will enter data onto case report forms (CRFs) within the electronic database. The Holter/Patient 
Ambulatory Monitoring/12-lead ECG core lab will also provide data in the electronic database. 
 

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Data reported on the CRFs shall be derived from source documents, which may include, but is not 
limited to, worksheets, quality of life questionnaires, patient medical records and ECG data. These 
source documents must be maintained by the site personnel. Further detail on data management 
is provided in Section 14.2. 
8.18. Deviation Handling 
A study deviation is defined as an event within a study that did not occur according to the CIP or the 
Clinical Trial Agreement. Prior approval by Medtronic is expected in situations where the 
Investigator anticipates, contemplates, or makes a conscious decision to deviate.  Prior approval 
for study deviations will be reported to local authorities and ethics boards per local requirements. 
Prior approval is not required when a deviation is necessary to protect the safety, rights or well-
being of a subject in an emergency or in unforeseen situations beyond the Investigator’s control 
(e.g. subject failure to attend scheduled follow-up visits, inadvertent loss of data due to computer 
malfunction, inability to perform required procedures due to subject illness).  If the deviation 
affects subject’s rights, safety and well-being, or the scientific integrity of the study, prior approval 
from IRB/REB/MEC may also be required, depending on local requirement.  Subjects’ failure to 
submit ambulatory monitoring transmissions per the CIP does not require a deviation to be 
reported. Ambulatory monitoring transmission compliance will be tracked by Medtronic personnel 
and the Core Lab. 
 
For medically justifiable conditions which preempt a subject’s ability to complete a study-required 
procedure, it may be permitted to report only one deviation which will apply to all visits going 
forward. This may also apply for other unforeseen situations (e.g. the subject permanently refuses 
to complete a study required procedure and the data will not contribute to the primary endpoint 
analysis). However, prior approval from Medtronic is required for such situations.   
All study deviations must be reported on the eCRF regardless of whether medically justifiable, pre-
approved by Medtronic, an inadvertent occurrence, or taken to protect the subject in an 
emergency.  The deviation description must be recorded with an explanation for the deviation. 
In the event the deviation involves a failure to obtain a subject’s consent or is made to protect the 
life or physical well-being of a subject in an emergency, the deviation must be reported to the 
IRB/REB/MEC as well as Medtronic within five (5) working days, or earlier according to local 
requirements.  In Japan, the deviation must be immediately reported to Head of Medical Institute 
(HOMI), to the Ethics Board via the HOMI, and to Medtronic.  Reporting of all other study deviations 
should comply with IRB/REB/MEC policies, local laws and/or regulatory agency requirements and 
must be reported to Medtronic as soon as possible upon the site becoming aware of the deviation.  
Refer to Investigator Reports, Section 14.6.2, for specific deviation reporting requirements and 
timeframes for reporting to Medtronic and/or regulatory bodies.  
 

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Medtronic is responsible for analyzing deviations, assessing their significance, and identifying any 
additional corrective and/or preventive actions (e.g. amend the CIP, conduct additional training, 
and terminate the investigation). Repetitive or serious Investigator compliance issues may result in 
initiation of a corrective action plan with the Investigator and site, and in some cases, 
necessitate suspending enrollment until the problem is resolved or ultimately terminating the 
Investigator's participation in the study. Medtronic will provide site-specific reports to 
Investigators summarizing information on deviations that occurred at the investigational site on 
a periodic basis. 
 
 

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8.19. Subject Withdrawal or Discontinuation (Subject Exit) 
A subject can exit from the study at any time and is not obliged to provide a reason. If the subject 
wishes to exit early from the study, the site is required to document the reason, if available, for exit 
on an eCRF and in the subject’s medical record. In addition, sites shall follow the regulations set 
forth by their IRB/REB/MEC. It is recommended that Investigators follow the subject until all device 
and/or procedure-related adverse events are recovered / resolved. For countries following ISO 
14155:2011, permission may be requested to follow-up with the subject outside of the study based 
on problems related to the study device safety or performance. Following completion of the 12-
month visit or early study exit, subjects will continue to receive standard medical care. All data 
available through the time of the subject’s exit will be available for analysis. 
 
Potential reasons for early study exit include: 
• 
Subject lost to follow-up 
• 
Subject did not meet inclusion/exclusion criteria after consent and did not undergo an 
ablation procedure 
• 
The PFA system was not used during the subject’s ablation procedure 
• 
Subject did not provide proper consent or data use protection authorization 
• 
Subject chooses to withdraw (e.g., consent withdrawal, relocation to another geographic 
location) 
• 
Investigator deems withdrawal necessary (e.g., medically justified, failure of subject to 
maintain adequate study compliance) 
• 
The sponsor decides the study will be closed or a particular site will be closed 
 
In the case that the subject is determined to be lost to follow-up, details of a minimum of two 
attempts and the method of attempt (e.g., one letter and one phone record or two letters) to 
contact the subject must be recorded. 
 
An unscheduled office visit should be attempted if the subject exits the study outside of a 
scheduled follow-up visit. Subjects treated with the PFA system who exit from the study should 
continue to be followed by an electrophysiologist for follow-up of any potential adverse events at 
the recommended interval of 12 months from the index PFA system ablation procedure. 
 
 

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9. Risks and Benefits 
9.1. Potential Risks 
Medtronic follows rigorous Quality Assurance and Control procedures throughout the life of a 
product, from the business analysis phase through development, market release, and post-market 
surveillance. The risk management process for the PFA system is being performed in accordance 
with ISO 14971 (Medical Device Risk Management) and will ensure that the level of risk has been 
reduced as low as possible prior to starting the clinical study. A summary of the risk analysis and 
risk assessment is provided in the Investigator Brochure.  
 
Risk analysis for the PFA system includes both Preliminary Hazard Analysis (PHA) and Failure Mode 
and Effect Analysis (FMEA) techniques.  Risk controls are implemented at both the design inputs 
stage and through evaluation via design verification and validation activities to demonstrate 
effectiveness of risk controls.    
 
If changes are made to components of the PFA system throughout the course of the study, 
Medtronic will ensure these changes do not impact the scientific soundness and safety of the 
study.  
 
Risk control strategies for the PULSED AF study risks were developed by a cross-functional team 
and in accordance with the Risk Management process. Potential risks associated with this study are 
further minimized by providing hands-on training to qualified investigators and training site 
personnel on the Clinical Investigation Plan. 
9.2. Risk Minimization 
 
The potential risks associated with the PFA system and other potential risks of study participation 
were identified and risk control measures were defined.  
Table 10: Potential Risks and Mitigation Strategies 
Risks 
Mitigation Strategies 
Thromboembolic complications 
resulting in: stroke / transient 
neurological ischemia, or 
asymptomatic cerebral embolism 
due to embolic particulates or gas 
bubble ingress into blood. 
 
 
 
Maintaining procedural ACT ≥350 and requiring 3-week 
anticoagulation prior to the ablation will reduce the 
likelihood of thromboembolic events associated with the 
procedure. Section 8.4 describes the full PULSED AF 
anticoagulation strategy. 
 
Rigorous sheath management during catheter 
introduction and exchanges has demonstrated a reduced 
likelihood of air egress during the ablation procedure. 
Sheath management will be covered in hands-on training 
of PFA system operators. 

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Risks 
Mitigation Strategies 
 
Patients who are predisposed to thromboembolic 
complications, for example patients with a large left atrial 
diameter >5.0 cm, or patients with a history of prior 
stroke/ TIA (within 6 months of consent to the procedure), 
or present with an intracardiac thrombus detected by TEE 
(required in all subjects prior to ablation) are excluded from 
this study. 
Arrhythmia induction (e.g. atrial 
flutter, bradycardia, heart block, 
tachycardia) 
The pre-programmed PFA therapy profiles were refined 
over the course of pre-clinical research to identify the 
range of PFA deliveries that do not impart charge of 
significance to the target tissue and reduce the risk of 
induced arrhythmias. PFA therapy profiles are not 
modifiable by the investigator. 
 
The patient’s ventricular R-wave is detected by a Cardiac 
Trigger Monitor, which allows synchronization of PFA 
therapy with the QRS complex. 
 
 
 
Neuromuscular stimulation upon 
delivery.   
Extensive pre-clinical testing has been performed to 
refine the PFA delivery waveform to minimize 
neuromuscular stimulation. Medtronic data on file. 
Collateral damage to cardiac 
structures (e.g. pulmonary vein 
stenosis). 
Extensive pre-clinical testing has been performed to 
refine the PFA delivery parameters to ablate myocardial 
tissue without incurring significant pulmonary vein 
stenosis. Medtronic data on file.  
 
 has been designed with safety features such 
as rounded edges and an ‘over the wire’ type design to 
minimize collateral damage during maneuvering when in 
the heart. 
Collateral damage to non-cardiac 
tissues  
 
Extensive pre-clinical testing has been performed to 
refine the PFA delivery parameters to ablate myocardial 
tissue without damage to extracardiac tissue. Medtronic 
data on file. 
Arcing or shorting of the catheter 
inside of the body. 
Failure modes that could affect patient safety were 
considered in the design of the PFA system. 
The PFA system has incorporated safety features to 
confirm system integrity, 
 
 
  
Catheter delivery outside of the 
body   
Instructions regarding the connection between the 
catheter and CEDS after the catheter has been placed 

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Risks 
Mitigation Strategies 
inside the body have been incorporated into the PFA 
system IFU. 
Bleeding, or severe blood loss from 
introduction of a catheter into the 
left atrium through femoral access. 
Instructions regarding catheter introduction into the body 
for the ablation procedure have been incorporated into 
the PFA system IFU. 
Damage to Heart Tissue / 
Vasculature through excessive 
catheter manipulation, catheter 
entrapment, placement of 
 
 in non-pulmonary vein 
areas, or lack of careful 
management of the guide wire. 
Procedural technique instructions intended to optimize 
safety are provided in the PFA system IFU. 
 
The protocol requires that the ablation procedure is to be 
performed by an investigator who has received hands-on 
training on all aspects of the procedure. Medtronic intends 
to use a proctorship strategy during the PULSED AF trial 
to ensure the knowledge and skills are transferred to new 
users. 
 
The PFA system is utilizing the 
 
 as a platform to deliver pulsed electric fields to 
cardiac tissue. 
 is designed to be used within 
the left atrium for mapping, pacing, and pulmonary vein 
isolation. The use of 
 with the PFA energy 
source will be within its intended use (mapping, pacing, 
and ablation of left atrial tissue). 
Unintended/excessive ablation, 
leading to thermal damage 
including: debris/ clot or coagulum 
formation 
The PFA system has specific therapy profiles pre-
programmed and cannot be altered by the clinician.  
Extensive pre-clinical testing has been performed to 
refine the PFA therapy profiles to ablate myocardial tissue 
without evidence of complications due to debris/ clot or 
coagulum formation. Medtronic data on file.  
 
Procedural technique instructions to adjust catheter 
positioning during the procedure are provided in the PFA 
system IFU.  
Device/System Fails to Function / 
Delay to Swap Out Capital 
Equipment 
  
System design verification has been performed to confirm 
catheter reliability performance 
 
 
 
 
 
Device/System Fails to function 
During Procedure 
 
This hazard is related to the 
functioning of the PFA equipment 
System design verification has been performed to confirm 
catheter reliability performance 
 
 
 

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Risks 
Mitigation Strategies 
following a groin poke, in which 
case a backup unit would be 
required. Hazards can be attributed 
to incompatible equipment or 
equipment failures.   The patient 
may or may not be under general 
anesthesia. 
 
 
Electrical shock to patient or 
clinician 
The PFA system is designed such that the patient and 
clinician is fully isolated to alleviate potential harmful 
electrical shock. 
 
 
 
Insufficient therapy resulting in an 
incomplete lesion and potential for 
re-entrant arrhythmogenic 
pathways to be formed 
 
Section 8.4 and PFA system IFU instruct ablation to be 
performed until acute electrical isolation has been 
achieved. i 
Physical Trauma to Clinician or 
Patient 
 
The PFA system IFU describes placement of the PFA 
system on a stable table during clinical use.   
X-ray Exposure 
 
 
The PFA system is intended for use in a cardiac 
electrophysiology lab.  Use of fluoroscopy is expected.  
Standard medical practices regarding limiting unnecessary 
radiation exposure is expected during electrophysiology 
procedures.  
Use of non-biocompatible 
materials on patient contacting 
products. 
 
 
 
 is constructed to contact blood and has 
undergone complete biocompatibility testing. 
Product sterilization is 
compromised. 
 is a sterile product designed for patient 
contact during an ablation procedure. The catheter has 
undergone complete sterility testing.  The catheter is 
supplied sterile. Catheter sterilization will be performed by 
a subcontract manufacturer using electron beam 
irradiation at a contract sterilization facility. 
 
The sterile catheter to CEDS cable will be supplied sterile 
and provides a connection between the sterilized catheter 
and non-sterilized PFA equipment. 
 
The PFA system IFU requires sterile packaging inspection 
prior to use during the procedure. 

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Risks 
Mitigation Strategies 
Procedural risks associated with 
endocardial catheter ablation, 
including:  
• 
Access site complications 
(e.g. bruising, ecchymosis, 
AV fistula, hematoma, 
pseudoaneurysm) 
• 
Allergic reaction to x-ray 
contrast media 
• 
Anesthesia reactions 
• 
Anemia 
• 
Back pain 
• 
Body temperature 
elevation 
• 
Cardiac tamponade 
• 
Chest discomfort 
• 
Cough 
• 
Cerebrovascular accident 
(CVA) 
• 
Collateral damage to the 
conduction system or 
coronary vasculature 
• 
Death 
• 
Hemoptysis 
• 
Hypotension/ hypertension 
• 
Infections 
• 
Obstruction, perforation, 
damage, or spasm of the 
vascular system including 
the coronary circulation 
system 
• 
Perforation of the heart or 
other organs during 
transseptal puncture or 
other procedures 
• 
Pericarditis or endocarditis 
• 
Pericardial effusion 
• 
Pleural effusion  
• 
Pneumonia 
• 
Pneumothorax 
• 
Pulmonary edema 
• 
Respiratory depression 
• 
Sore throat 
Procedural technique instructions intended to optimize 
safety are provided in the PFA system IFU. 
 
The protocol requires that the ablation procedure is to be 
performed by an investigator who has received hands-on 
training on all aspects of the procedure. Medtronic intends 
to use a proctorship strategy during the PULSED AF trial 
to ensure the knowledge and skills are transferred to new 
users.  
 
 

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Risks 
Mitigation Strategies 
• 
Vasovagal reaction 
i Per PULSED AF clinical study protocol in the interest of prioritizing patient care, in the event of an 
inability to electrically isolate all accessible targeted pulmonary veins with the PFA system, any 
commercially released catheter deemed appropriate for the procedure may be used to complete 
the ablation procedure. 
9.3. Potential Adverse Events from Risk Assessment  
 
The current PFA system IFU should be referenced as the list below may be updated during the 
course of the study. Possible additional risks for participating in the study include the following 
(although others are possible) and are further defined in Appendix C: 
 
• 
Access site complications (e.g. bruising, ecchymosis, AV fistula, hematoma, 
pseudoaneurysm) 
• 
Allergic reaction to x-ray contrast media 
• 
Anesthesia reactions 
• 
Anemia 
• 
Arrhythmias, proarrhythmia (e.g. atrial flutter, bradycardia, heart block, tachycardia) 
• 
Back pain 
• 
Bleeding, possibly requiring transfusion 
• 
Body temperature elevation 
• 
Cardiac perforation of the heart or other organs during transseptal puncture or other 
procedures 
• 
Cardiac tamponade 
• 
Chest discomfort 
• 
Cough 
• 
Embolism 
• 
Catheter entrapment in cardiac structures requiring intervention  
• 
Cerebrovascular accident (CVA) 
• 
Transient ischemic attack (TIA) 
• 
Collateral damage to the conduction system or coronary vasculature 
• 
Death 
• 
Esophageal damage (including atrial esophageal fistula) 
• 
Hemoptysis 
• 
Hypotension/ hypertension 
• 
Infections 
• 
Myocardial infarction or ischemia 
• 
Nerve injury or nerve damage (e.g. phrenic nerve injury) 
• 
Obstruction, perforation, damage, or spasm of the vascular system including the coronary 
circulation system 
• 
Pericarditis or endocarditis 
• 
Pleural effusion  

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• 
Pericardial effusion 
• 
Pneumonia 
• 
Pneumothorax 
• 
Pulmonary edema  
• 
Pulmonary vein stenosis 
• 
Radiation injury or damage and late malignancy 
• 
Respiratory depression 
• 
Sore throat 
• 
Unintended complete or incomplete atrioventricular node (AV-Node) or sinus node block or 
damage 
• 
Valvular insufficiency or damage 
• 
Vasovagal reaction 
 
There are additional potential risks to the patient that are outside of the ablation procedure. 
These are due to PULSED AF clinical study requirements and are not related to the PFA 
procedure or the PFA system. Potential additional risks identified for participation in this study 
include: 
• 
Claustrophobia (sense of anxiety in small areas) related to an MRI scan  
• 
Skin discomfort or irritation related to the Holter recorder 
• 
Exposure to radiation or allergic reaction to the contrast dye related to a CT scan  
9.4. Potential Benefits 
The PFA system utilizes a novel energy source that may increase efficacy through field-based 
ablation without the dependency on tissue contact, which is expected to lead to higher clinical 
success by effectively treating patients with AF. PFA has the potential to create contiguous lesions 
in highly trabeculated anatomical locations with varying tissue thickness or blood flow conditions 
that limit the effectiveness of thermal ablation technologies. PFA requires the catheter to be in 
close proximity to the target locations, but not in contact with tissue.  
PFA potentially increases the safety of catheter ablation for AF through applying a refined 
waveform with parameters (e.g. pulse width, number of pulses, voltage amplitude) that result in 
selective ablation of myocardial tissue. This could reduce collateral damage to extracardiac tissues 
such as the phrenic nerve, vagus nerve, and smooth muscle. 
The safety profile of the Medtronic PFA delivery may also be improved over other commercially 
available ablation energy sources due to the bipolar energy delivery method through the multi-
electrode array catheter that minimizes exposure of extracardiac tissue to the electric field 
compared to unipolar energy. 
PFA also potentially improves safety due to its non-thermal field-based ablation approach. 

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Operators using currently available technology must be careful to balance optimal contact force 
required for transmural lesion formation with potential adverse events associated with thermal 
mechanisms of catheter ablation. Overall, the potential improvement in the safety profile of PFA is 
due to the refined waveform, bipolar delivery, and non-thermal field-based approach which may 
reduce collateral damage. 
PFA delivery is performed within milliseconds and is predicted to achieve pulmonary vein isolation 
in approximately 1 minute. PFA may reduce both time to isolation and overall procedure time 
compared to standard of care ablation procedures that take up to 10 minutes and in some cases 
more than 10 minutes, to isolate each pulmonary vein23. The efficiency of PFA energy delivery is 
potentially increased in comparison to existing ablation technologies. 
Ablation with the PFA system may reduce or eliminate atrial fibrillation in subjects; however, some 
subjects may not receive this benefit. Clinical benefit has not been demonstrated as this study is 
the first in human use of the PFA system. The information gained from the study could result in 
improved management of atrial fibrillation. 
9.5. Risk-Benefit Rationale 
PFA therapy offers the opportunity to reduce the episodes of atrial fibrillation and therefore reduce 
the subject’s risk of stroke and symptoms. Results of the PULSED AF study are expected to be 
used to guide subsequent product development activities for the PFA system.  
 
The PFA system has been examined and tested via modeling, bench, and preclinical animal testing 
and the residual risks associated with the PFA system have been found to be acceptable. These 
residual risks have been mitigated to the fullest extent possible through design, manufacturing, 
labeling and training. The potential benefits related to the use of the PFA system have been 
determined to outweigh any potential risks and justify this investigation.  
 
 
 
 
                                                            
23  Attanasio, P. et al. Pain Reactions during Pulmonary Vein Isolation under Deep Sedation: Cryothermal versus 
Radiofrequency Ablation. Pacing and clinical electrophysiology: PACE 39, 452-457, doi:10.1111/pace.12840 (2016). 

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10. Adverse Events and Device Deficiencies 
Timely, accurate, and complete reporting and analysis of safety information for clinical studies are 
crucial for the protection of subjects.  Reporting and analysis of safety data are mandated by 
regulatory authorities worldwide. Medtronic has established procedures in conformity with 
worldwide regulatory requirements to ensure appropriate reporting of safety information.  The 
study is conducted in accordance with these procedures and regulations. 
Since the safety reporting requirements and classification systems vary for each regulatory 
agency, requirements from all geographies are taken into account for the collection and reporting 
of safety information.  
10.1. Adverse Event Assessment  
For the purposes of the study, all Adverse Events will be collected starting at the time of signing the 
IC Form through the duration of the subject’s participation in the study. 
10.2. Device Deficiencies Assessment 
Device deficiency (DD) information will be collected throughout the study and reported to 
Medtronic, as per Table 13. A Medtronic representative will review the device deficiency for 
completeness and accuracy and when necessary will request clarification and/or additional 
information from the Investigator. Note that device deficiencies that result in an adverse device 
effect (ADE) to the subject should be captured as an Adverse Event only. 
Device deficiencies that did not lead to an AE but could have led to a Serious Adverse Device Effect 
(SADE) (i.e., if suitable action had not been taken, if intervention had not been made, or if the 
circumstances had been less fortunate) require immediate reporting.  For device deficiencies that 
require immediate reporting, initial reporting may be done by contacting the study sponsor per the 
sponsor contact information.  
 
10.3. Definitions/Classifications 
Where the definition indicates “device”, it refers to any device used in the study. This might be any 
component of the system under investigation, or any market-released component or accessory of 
the system. Adverse events (AE) will be classified according to the definitions below. 

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Table 11:  Adverse Event and Device Deficiency Definitions 
General 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including abnormal 
laboratory findings) in subjects, users or other persons, 
whether or not related to the investigational medical device 
 
NOTE 1: This definition includes events related to the 
investigational medical device or the comparator. 
NOTE 2: This definition includes events related to the 
procedures involved. 
NOTE 3: For users or other persons, this definition is 
restricted to events related to investigational medical 
devices. 
(ISO 14155:2011, 3.2) 
Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational 
medical device 
 
NOTE 1: This definition includes adverse events resulting 
from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any 
malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from an 
error use or from intentional misuse of the investigational 
medical device. (ISO 14155:2011, 3.1) 
Device Deficiency (DD) 
Inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance.  
 
NOTE: Device deficiencies include malfunctions, use errors 
and inadequate labeling (ISO 14155:2011, 3.15) 
Relatedness 
Procedure related 
An Adverse Event directly related to any portion of the 
procedure.   
 
NOTE: Only those Adverse Events that are directly related 
to the PFA portion of the procedure will be considered as 
PFA procedure related. 
Sub-study 
 
related 
 
 

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System related 
An Adverse Event that results from the presence or 
performance (intended or otherwise) of the PFA system 
(including the PFA Generator, Catheter Electrode 
Distribution System (CEDS), Remote Control, Cable-
Generator to Remote Control, Cable-Generator to CEDS, 
Cable-CEDS to EP Recording System, Cable-Catheter to 
CEDS, 
 catheter, Cardiac Trigger Monitor and 
Cable, Uninterruptible Power Supply, Power Cord) or any 
other device used during the procedure. 
 
NOTE: Only those Adverse Events that result from the 
presence or performance (intended or otherwise) of the PFA 
system will be considered as PFA system related. 
Not related 
Relationship to the device or procedures can be excluded 
when: 
• 
The event is not a known side effect of the product 
category the device belongs to or of similar devices 
and procedures; 
• 
The event has no temporal relationship with the use 
of the device or the procedures; 
• 
The serious event does not follow a known response 
pattern to the medical device (if the response 
pattern is previously known) and is biologically 
implausible; 
• 
The discontinuation of medical device application or 
the reduction of the level of activation/exposure – 
when clinically feasible – and reintroduction of its use 
(or increase of the level of activation/exposure) do 
not impact the serious event; 
• 
The event involves a body-site or an organ not 
expected to be affected by the device or procedure; 
• 
The serious event can be attributed to another cause 
(e.g., an underlying or concurrent illness/clinical 
condition, an effect of another device, drug, 
treatment, or other risk factors); 
• 
The event does not depend on a false result given by 
the device used for diagnosis (when applicable); 
• 
Harms to the subject are not clearly due to use error; 
• 
In order to establish the non-relatedness, not all the 
criteria listed above might be met at the same time, 
depending on the type of device/procedures and the 
event. 

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Unlikely 
The relationship with the use of the device seems not 
relevant and/or the event can be reasonably explained by 
another cause, but additional information may be obtained. 
Possible 
The relationship with the use of the investigational device is 
weak but cannot be ruled out completely. Alternative causes 
are also possible (e.g. an underlying or concurrent 
illness/clinical condition or/and an effect of another device, 
drug or treatment). Cases were relatedness cannot be 
assessed or no information has been obtained should also be 
classified as possible. 
Probable 
The relationship with the use of the investigational device 
seems relevant and/or the event cannot reasonably be 
explained by another cause, but additional information may 
be obtained. 
Causal Relationship 
The event is associated with the device or study procedures 
beyond reasonable doubt when: 
• 
The event is a known side effect of the product 
category the device belongs to or of similar devices 
and procedures; 
• 
The event has a temporal relationship with device 
use/application or procedures; 
• 
The event involves a body-site or organ that the 
device or procedures are applied to or the device or 
procedures have an effect on; 
• 
The serious event follows a known response pattern 
to the medical device (if the response pattern is 
previously known); 
• 
The discontinuation of medical device application (or 
reduction of the level of activation/exposure) and 
reintroduction of its use (or increase of the level of 
activation/exposure) impact on the serious event 
(when clinically feasible); 
• 
Other possible causes (e.g., an underlying or 
concurrent illness/clinical condition or/and an effect 
of another device, drug, or treatment) have been 
adequately ruled out; 
• 
Harm to the subject is due to error in use; 
• 
The event depends on a false result given by the 
device used for diagnosis (when applicable); 
• 
In order to establish the relatedness, not all the 
criteria listed above might be met at the same time, 
depending on the type of device/procedures and the 
serious event. 

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Seriousness 
Serious Adverse Event (SAE) 
 
Adverse event that 
a) led to death, 
b) led to serious deterioration in the health of the subject, 
that either resulted in: 
     1) a life-threatening illness or injury, or 
     2) a permanent impairment of a body structure or a body  
          function, or 
     3) in-patient or prolonged hospitalization (>24 hours), or 
     4) medical or surgical intervention to prevent life-
threatening   
           illness or injury or permanent impairment to a body 
structure  
          or a body function, 
c) led to fetal distress, fetal death or a congenital 
abnormality or birth defect 
 
NOTE 1: Planned hospitalization for a pre-existing condition, 
or a procedure required by the CIP, without serious 
deterioration in health, is not considered a serious adverse 
event. 
(ISO 14155:2011, 3.37) 
Serious Adverse Event (SAE) – 
Germany Definition 
A serious adverse event is an event that occurs in a clinical 
investigation subject to approval or occurring in a 
performance evaluation which led, might have led or could 
lead directly or indirectly to death or serious deterioration of 
health of the subject, the user or a third party, without 
consideration if the event has been caused by the medical 
device itself; this applies accordingly to serious adverse 
events occurring in a clinical investigation or performance 
evaluation for which an exemption of the approval 
authorization as per MPG § 20 paragraph 1 sentence 2 has 
been granted. (MPSV § 2 Definitions Abs 5) 
Serious Adverse Device Effect 
(SADE) 
Adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
(ISO 14155:2011, 3.36) 

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Unanticipated Adverse Device Effect 
(UADE) 
Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, 
an (investigational) device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of 
incidence in the CIP or applicable (including a supplementary 
plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, 
safety, or welfare of subjects. (21 CFR 812.3(s)) 
Unanticipated Serious Adverse 
Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, 
severity or outcome has not been identified in the current 
version of the risk analysis report. 
NOTE: Anticipated serious adverse device effect (ASADE) is 
an effect which by its nature, incidence, severity or outcome 
has been identified in the risk analysis report. (ISO 
14155:2011 3.42) 
Significant Safety Issue (SSI) 
A safety issue that could adversely affect the safety of 
participants or materially impact on the continued ethical 
acceptability or conduct of the trial. (NHMRC Safety 
monitoring and reporting in clinical trials involving 
therapeutic goods November 2016) 
Urgent Safety Measure (USM) 
A measure required to be taken in order to eliminate an 
immediate hazard to a participant’s health or safety. 
 
NOTE: This type of significant safety issue can be instigated 
by either the investigator or sponsor and can be 
implemented before seeking approval from HRECs or 
institutions. (NHMRC Safety monitoring and reporting in 
clinical trials involving therapeutic goods November 2016) 
Other 
Unavoidable Adverse Event 
An Adverse Event inherent to a surgical procedure that is 
expected to occur in all subjects for a projected duration 
according to the Investigator’s opinion, including, but not 
limited to those provided below.  These are not reportable 
AEs unless they occur after or last longer than the timeframe 
specified.  If any other events below are classified as serious 
they must be reported as an adverse event.    

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Event Description 
Timeframe 
(hours) from 
the Surgical 
Procedure 
Anesthesia related nausea / vomiting  
24 
Low-grade fever (<100°F or 37.8°C) 
48 
Mild to moderate bruising / 
ecchymosis in groin area / groin pain 
168 
Sleep problems (insomnia) 
72 
Back pain related to laying on table 
72 
Hospitalization 
A therapeutic inpatient hospitalization (excludes 
observation unit, emergency room and outpatient visits) 
lasting greater than or equal to 24 hours. 
10.4. Reporting of Adverse Events, including Death 
Reporting of Adverse Events to Medtronic will occur on an Adverse Event (AE) eCRF, including a 
description of AE, date of onset of AE, date of awareness of study site, treatment, resolution, 
assessment of both the seriousness and the relatedness to the investigational system and/or 
procedure. Each AE must be recorded on a separate AE eCRF.  Exceptions include: 
• 
Documented pre-existing conditions are not considered AEs unless the nature or severity 
of the condition has worsened.  Additionally, arrhythmia episodes that are not new or 
worsening conditions and for which no action is taken are not reportable as AEs. 
• 
Unavoidable Adverse Events, listed in Table 11 need not be reported unless the adverse 
event worsens or is present outside the stated timeframe after the ablation procedure. 
• 
Cardioversions (DC or Drug) for recurrent symptomatic atrial fibrillation and other atrial 
arrhythmias are not considered serious adverse events 
 
For any changes in status of a previously reported adverse event (i.e. change in actions taken, 
change in outcome, change in relatedness), an update to the original AE must be provided. All 
adverse events must be followed until the adverse event has been recovered / resolved, the 
subject exits the study or until study closure, whichever occurs first.  
In the event that a subject is exited from the study prior to study closure, all efforts should be made 
to continue following the subject until all procedure or system related adverse events that are not 
resolved, as classified by the Investigator, are recovered / resolved.  
At the time of study exit, all adverse events with an outcome of “not recovered / not resolved”, 
“recovering / resolving” or “unknown” must be reviewed and updates provided as applicable.  

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All reported adverse events will be reviewed by a Medtronic representative. AEs will be classified 
according to the definitions provided.  
Upon receipt of adverse events at Medtronic, a Medtronic representative will review the adverse 
event for completeness and accuracy and when necessary will request clarification and/or 
additional information from the Investigator. Medtronic will utilize MedDRA, the Medical Dictionary 
for Regulatory Activities, to assign a MedDRA term for each adverse event based on the 
information provided by the Investigator.  
Regulatory reporting of AEs that could have led to a SADE will be completed according to local 
regulatory requirements. Refer to Section 10.4.2 for a list of required Investigator and Medtronic 
reporting requirements and timeframes. It is the responsibility of the Investigator to abide by any 
additional AE reporting requirements stipulated by the IRB/MEC responsible for oversight of the 
study. 
For a list of Foreseeable Adverse Event List (FAL), refer to Appendix C. This is a list of adverse 
events related to the PFA system or procedure that may be experienced by subjects. This list may 
help to assess if an adverse event is unexpected in nature. 
For emergency contact regarding a UADE/USADE, SAE, and/or SADE, contact a clinical study 
representative immediately (refer to the study sponsor per the sponsor contact information).  
Adverse Events and Deaths will be classified according to the standard definitions in Table 11 and 
the responsibilities in Table 12 below: 
Table 12: Adverse Event Classification Responsibilities 
What is classified?  Who classifies? Classification Parameters 
Relatedness 
Investigator 
Procedure related, System related, sub-study 
 
 related 
Sponsor 
Procedure related, System related, sub-study 
 
 related 
Seriousness 
Investigator 
SAE, Device Deficiency with SADE potential 
Sponsor 
SAE, UADE/USADE, Device Deficiency with SADE 
potential 
Diagnosis 
Investigator 
Based on presenting signs and symptoms and other 
supporting data 
Sponsor 
MedDRA term assigned based on the data provided 
by Investigator 
Death 
Classification 
Investigator 
Sudden Cardiac, Non-sudden Cardiac, Non-Cardiac, 
Unknown 

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10.4.1. 
Subject Death 
All subject deaths must be reported by the Investigator to Medtronic on an adverse event eCRF (AE 
with outcome of fatal) as soon as possible after the Investigator first learns of the death.  There 
should be one SAE with the outcome of fatal.  
A de-identified copy of the death certificate, if available and allowed by state/local law, should be 
sent to the Medtronic clinical study team. When a death occurs in a hospital, a copy of the death 
summary report and all relevant hospital records should be sent to Medtronic, if available. If an 
autopsy is conducted, the autopsy report should also be sent to Medtronic if available and allowed 
by state/local law. When the death occurs at a remote site, it is the investigative site’s 
responsibility to attempt retrieval of information about the death. In summary, the following data 
will be collected: 
• 
Date of death 
• 
Detailed description of death 
• 
Cause of death  
• 
Relatedness to system and/or procedure 
• 
Death summary/hospital records (if available and allowed by state/local law) 
• 
Autopsy report (if available and allowed by state/local law) 
• 
Death certificate (if available and/or allowed by state/local law) 
 
Sufficient information will be required in order to properly classify the subject’s death. The 
Investigator shall classify each subject death per the following definitions: 
• 
Cardiac Death: A death directly related to the electrical or mechanical dysfunction of the 
heart. 
• 
Sudden Cardiac Death (SCD): Natural death due to cardiac causes, indicated by abrupt loss 
of consciousness within one hour of the onset of acute symptoms; preexisting heart 
disease may have been known to be present, but the time and mode of death are 
unexpected. If time of onset cannot be determined, SCD will alternatively be defined as any 
unexpected cardiac death occurring out of the hospital or in the emergency room as dead 
on arrival. 
• 
Non-sudden Cardiac Death: All cardiac deaths that are not classified as sudden deaths, 
including all cardiac deaths of hospitalized subjects on inotropic support. 
• 
Non-cardiac Death: A death not classified as a cardiac death. 
• 
Unknown Classification: Unknown death classification is intended for use only when there is 
insufficient or inadequate information to classify the death.   
 
The CEC will review all deaths and provide an adjudication of the primary cause of death and death 
classification. Regulatory reporting of Subject Deaths will be completed according to local 
regulatory requirements. 

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10.4.2. 
Adverse Event Reporting Requirements 
Regulatory reporting of AEs will be completed according to local regulatory requirements. Refer to 
Table 13 for a list of required investigator reporting requirements and timeframes, and of required 
Medtronic reporting requirements and timeframes. 
The investigator is required to report all SAEs to Medtronic immediately, and to the Ethics 
Committee per local requirements. It is the responsibility of the investigator to abide by any 
additional AE reporting requirements stipulated by the Ethics Committee responsible for oversight 
of the study. Additionally, Medtronic is required to report these events to the local regulatory 
authority based on their requirements. In the case that the AE is related to a market-released 
device used during the study, post market surveillance is also applicable and the Investigator is 
responsible for immediate reporting of the product complaint via the regular channels for market-
released products. 
For AEs that require immediate reporting, initial reporting may be done by contacting the study 
sponsor per the sponsor contact information provided in this document. 
 
 

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Table 13: Adverse Event and Device Deficiency Reporting Requirements 
Serious Adverse Events (SAEs) 
Investigator submit to: 
Medtronic 
Australia: Without unjustified delay. (The National Health and Medical Research Council (NHMRC) 
Safety monitoring and reporting in clinical trials involving therapeutic goods November 2016 section 
C.2.b) 
Europe: To the sponsor in acceptable timely conditions, but not later than within 3 calendar days 
after investigational site study personnel’s awareness of the event, including new information in 
relation to an already reported event (ISO 14155:2011 and local law) 
Japan: Immediately (no later than 72 hours) (Japan GCP Article 68) 
All geographies: Submit per local reporting requirements 
Ethics Committee 
All geographies: Submit per local reporting requirements 
Regulatory authorities 
All geographies: Submit per local reporting requirements 
Head of Medical Institution 
(HOMI) 
Japan: Immediately (Japan GCP Article 68) 
Sponsor submit to: 
Investigators 
Japan: Annually (Japan GCP Article 28) 
All geographies: Submit per local reporting requirements 
Regulatory authorities 
Europe:  No later than 7 calendar days after awareness;  Report immediately, but no later than 2 
calendar days after awareness by sponsor for SAE and/or DD that may have led to a SADE which 
indicates an imminent risk of death, serious injury, or serious illness and that requires prompt 
remedial action for other patients/subjects, users or other persons or a new finding to it (occurred in 
the study under same CIP*)  
Japan: Annually (Enforcement Regulation of the PMDL Article 274- 2) 
All geographies: Submit per local reporting requirements 
Ethics Committee 
All geographies: Submit per local reporting requirements 
HOMI 
Japan: Annually (Japan GCP Article 28) 
Serious Adverse Device Effects (SADEs) 
Investigator submit to: 
Medtronic 
Australia: Without unjustified delay. (NHMRC Safety monitoring and reporting in clinical trials 
involving therapeutic goods November 2016 section C.2.b) 
Canada: SADEs on the patient, the user or any other person must be reported to the regulator and to 
the Sponsor within 72 hours after it comes to the attention of the qualified investigator. 
Japan: Immediately (no later than 72 hours) (Japan GCP Article 68) 
All geographies: Submit per local reporting requirements 
Ethics Committee 
All geographies: Submit per local reporting requirements 
Regulatory authorities 
Canada: SADEs on the patient, the user or any other person must be reported to the regulator and to 
the Sponsor within 72 hours after it comes to the attention of the qualified investigator. 
All geographies: Submit per local reporting requirements 
HOMI 
Japan: Immediately (Japan GCP Article 68) 
Sponsor submit to: 
Investigators 
Japan: Annually (Japan GCP Article 28) 
All geographies: Submit per local reporting requirements 
Regulatory authorities 
Canada: Report within 10 days after the sponsor becomes aware. 
Japan: [Life threatening or death] Individual reporting within 15 calendar days after awareness, and 
[All SADEs] Annually (Enforcement Regulation of the PMDL Article 274- 2) 
All geographies: Submit per local reporting requirements 

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Ethics Committee 
All geographies: Submit per local reporting requirements 
HOMI 
Japan: Annually (Japan GCP Article 28) 
Unanticipated Adverse Device Effects (UADEs) and Unanticipated Serious Adverse Device Effects (USADEs) 
Investigator submit to: 
Medtronic 
Canada: USADEs on the patient, the user or any other person must be reported to the regulator and 
to the Sponsor within 72 hours after it comes to the attention of the qualified investigator. 
US: An investigator shall submit to the sponsor and to the reviewing IRB a report of any UADE 
occurring during an investigation as soon as possible, but in no event later than 10 working days after 
the investigator first learns of the effect. (21 CFR 812.150(a)) 
Europe: Immediately after the investigator learns of the event or of new information in relation to an 
already reported event. (ISO 14155:2011 and local law) 
Japan: Immediately (no later than 72 hours) (Japan GCP Article 68) 
All geographies: Submit per local reporting requirements 
Regulatory Authority 
Canada: USADEs on the patient, the user or any other person must be reported to the regulator and 
to the Sponsor within 72 hours after it comes to the attention of the qualified investigator. 
All geographies: Submit per local reporting requirements 
Ethics Committee 
Australia: Report USADE to their institution without undue delay and no later than 72 hours of the 
Principal Investigator becoming aware of the event. (NHMRC Safety monitoring and reporting in 
clinical trials involving therapeutic goods November 2016 section C.2.g) 
US: An investigator shall submit to the sponsor and to the reviewing IRB a report of any UADE 
occurring during an investigation as soon as possible, but in no event later than 10 working days after 
the investigator first learns of the effect. (21 CFR 812.150(a)) 
All geographies: Submit per local reporting requirements 
Institution 
Australia: Report USADE to their institution without undue delay and no later than 72 hours of the 
Principal Investigator becoming aware of the event. (NHMRC Safety monitoring and reporting in 
clinical trials involving therapeutic goods November 2016 section C.2.g) 
HOMI 
Japan: Immediately (Japan GCP Article 68) 
Sponsor submit to: 
Investigator 
US: Notification as soon as possible, but not later than 10 working days after the sponsor first learns 
of the effect. (21 CFR 812.150(b)) 
Japan: Immediately (Japan GCP Article 28) 
All geographies: Submit per local reporting requirements  
Regulatory authorities 
Australia: Fatal or life-threatening Australian USADE – No later than 7 calendar days after being made 
aware of the case with any follow up information within a further 8 calendar days. Other Australian 
USADEs- No later than 15 calendar days after being made aware of the case.  (NHMRC Safety 
monitoring and reporting in clinical trials involving therapeutic goods November 2016 section C.1.f) 
Canada: Report within 10 days after the sponsor becomes aware. 
Japan: [Life-threatening or death) Individual reporting within 7 calendar days after awareness, [Non-
life threatening or death) Individual reporting within 15 calendar days after awareness, and [All 
USADE] Annually.  (Enforcement Regulation of PMDL Article 274-2) 
US: Notification as soon as possible to FDA, but not later than 10 working days after the sponsor first 
receives notice of the effect. (21 CFR 812.150(b)) 
All geographies: Submit per local reporting requirements 
Ethics Committee 
US: Notification as soon as possible, but not later than 10 working days after the sponsor first learns 
of the effect. (21 CFR 812.150(b))  
All geographies: Submit per local reporting requirements  
HOMI 
Japan: Immediately (Japan GCP Article 28) 

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Significant Safety Issue (SSI): Sponsor reporting in Australia 
Events to Report 
Reporting Requirement and Timeframe 
Significant Safety Issue 
• 
Urgent Safety Measure (USMs): within 24 hours (where possible) to TGA and without undue 
delay to investigators & HREC and in any case, no later than 72 hours of the measure being taken.  
- 
Reasons for the urgent safety measure, Measures taken, Further actions planned 
- 
Reasons for the termination, Measures taken, Further actions planned  
(NHMRC Safety monitoring and reporting in clinical trials involving therapeutic goods November 
2016 section C.1.k) 
Significant Safety Issue 
(continued)  
Submit to TGA 
• 
Notification of an amendment: Without undue delay and no later than 15 calendar days  
Note: TGA should receive notification that a SSI has occurred but the amendment revising trial 
documentation should be submitted to the HREC only 
• 
Action taken with respect to safety that has been taken by another country’s regulatory agency 
(relevant to an ongoing clinical trial in Australia): Without undue delay and no later than 72 hours 
of the trial sponsor becoming aware of the action (Australian clinical trial handbook version 2.2) 
Significant Safety Issue 
(continued) 
Submit to TGA, any Australian investigator and HREC 
• 
Other significant safety measures: Without undue delay and no later than 15 calendar days of 
the sponsor being aware of the issue. 
Details of significant safety issue, Further actions planned 
• 
Temporary halt of a trial for safety reasons: Without undue delay and no later than 15 calendar 
days of the sponsor’s decision to halt the trial. 
                     Reasons for the halt, the scope of the halt, Measures taken, Further actions planned  
• 
Early termination of a trial for safety reasons: Without undue delay and no later than 15 calendar 
days of the sponsor’s decision to termination the trial. 
Significant Safety Issue (SSI): Investigator Reporting in Australia 
Events to Report 
Reporting Requirements and Timeframe to submit to Sponsor, HREC and institution 
Significant Safety Issues 
 
 
• Urgent Safety Measure (USMs): Within 24 hours 
(NHMRC Safety monitoring and reporting in clinical trials involving therapeutic goods November 
2016 section C.2.c) 
• All other significant safety issues: without undue delay and no later than 72 hours of the principal 
investigator becoming aware of the event 
(NHMRC Safety monitoring and reporting in clinical trials involving therapeutic goods November 2016 
section C.2.g) 
Device Deficiencies with SADE potential 
Investigator submit to: 
Medtronic 
Australia: Without unjustified delay. (NHMRC Safety monitoring and reporting in clinical trials 
involving therapeutic goods November 2016 section C.2.b) 
Canada: DDs that have resulted in any of the consequences characteristic of an SAE on the patient, 
the user or any other person or could do so were it to reoccur must be reported to the regulator and 
the Sponsor within 72 hours after it comes to the attention of the qualified investigator. 
Europe: To the sponsor in acceptable timely conditions, but not later than within 3 calendar days 
after investigational site study personnel’s awareness of the event , including new information in 
relation to an already reported event (ISO 14155:2011 and local law) 
Japan: Immediately (no later than 72 hours) (Japan GCP Article 68) 
All geographies: Submit per local reporting requirements 

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Regulatory authorities 
Canada: DDs that have resulted in any of the consequences characteristic of an SAE on the patient, 
the user or any other person or could do so were it to reoccur must be reported to the regulator and 
the Sponsor within 72 hours after it comes to the attention of the qualified investigator. 
All geographies: Submit per local reporting requirements 
Ethics Committee  
All geographies: Submit per local reporting requirements 
HOMI 
Japan: Immediately (Japan GCP Article 68) 
Sponsor submit to: 
Investigator 
Japan: Immediately per the direction of PMDA and/or annually (Japan GCP Article 28) 
All geographies: Submit per local reporting requirements  
Regulatory authorities 
Canada: Submit to regulatory authorities within 30 calendar days of awareness by Sponsor. 
Japan: Within 30 calendar days after awareness and annually (Enforcement Regulation of PMDL 
Article 274-2) 
Europe:  No later than 7 calendar days after awareness;  Report immediately, but no later than 2 
calendar days after awareness by sponsor for SAE and/or DD that may have led to a SADE which 
indicates an imminent risk of death, serious injury, or serious illness and that requires prompt 
remedial action for other patients/subjects, users or other persons or a new finding to it (occurred in 
the study under same CIP*)  
All geographies: Submit per local reporting requirements 
Ethics Committee 
All geographies: Submit per local reporting requirements  
HOMI 
Japan: Immediately per the direction of PMDA and/or annually (Japan GCP Article 28) 
All other Adverse Events, Device Deficiencies, and new information that may  
adversely affect safety of the subjects or the conduct of the study 
Investigator submit to: 
Medtronic 
Europe: Submit in a timely manner after the investigator first learns of the event 
All geographies: Submit per local reporting requirements  
Regulatory Authorities 
All geographies: Submit per local reporting requirements  
Ethics Committee 
All geographies: Submit per local reporting requirements  
Sponsor submit to: 
Investigator 
All geographies: Submit per local reporting requirements  
Regulatory authorities 
All geographies: Submit per local reporting requirements  
Ethics Committee 
All geographies: Submit per local reporting requirements  
 
10.5. Reporting of Product Complaints 
In geographies where devices are market-released, product complaint reporting is applicable.  This 
includes when an AE is related to a market-released device during the study.  The reporting of 
product complaints is not part of the clinical study and should be done in addition to the Adverse 
Event and Device Deficiency reporting requirements.  Refer to local regulations for reporting 
requirements. 
Product Complaint: Any written, electronic or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness or performance of a medical 
device that has been placed on the market. 

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It is the responsibility of the Investigator to report all product complaint(s) associated with a 
medical device distributed by Medtronic, regardless whether they are related to intended use, 
misuse or abuse of the product. Reporting must be done immediately and via the regular channels 
for market-released products. 
Medtronic will notify the regulatory authorities (e.g. FDA) as applicable for the following incidents 
immediately upon learning of them: 
• 
Any malfunction or deterioration in the characteristics and/or performance of a device, as 
well as any inadequacy in the labeling or instructions for use which led or might have led to 
the death or serious deterioration in the state of health of a patient, user, or other person. 
• 
Any technical or medical reason resulting in withdrawal of a device from the market by the 
manufacturer. 
• 
A serious deterioration in the state of heath includes: 
o Life-threatening illness or injury 
o Permanent impairment of a body function or permanent damage to a body 
structure 
o A condition necessitating medical or surgical intervention to prevent permanent 
impairment of a body function or permanent damage to a body structure 
 
 

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11. Data Review Committees  
11.1. Data Monitoring Committee (DMC) 
Study Oversight  
Ongoing oversight for this study will be provided by an independent Data Monitoring Committee. 
Who will be involved 
The DMC will have one statistician with experience in the evaluation of clinical trials and at least two 
physicians that are not participating Investigators for the study. A chairperson from among those 
members will be identified.  
Responsibility of the DMC 
The DMC will be responsible for assessing the accumulating data on safety of the therapy during 
the study. The DMC will be responsible for safeguarding the interests of study subjects, assessing 
the safety of the PFA system during the study, and for monitoring the overall conduct of the clinical 
study. To enhance the integrity of the study, the DMC may also formulate recommendations 
related to the selection, recruitment, and retention of subjects, their management, improvement 
of adherence to protocol-specified regimens and procedures for data management and quality 
control. 
 
 
  
Recommendations  
The DMC will be advisory to the sponsor. The DMC may provide recommendations for early 
termination of the study. Review and consensus by the entire committee is required to 
recommend that the study should be stopped. The DMC may also make recommendations related 
to the selection, management and retention of subjects, improvement of adherence to protocol-
specified regimens, and procedures for data management and quality control. 
DMC Meetings 
All DMC meetings may be conducted either in person or by teleconference.  There will be an initial 
meeting prior to the start of the Pivotal Phase of the study.  Additionally, the DMC will meet 
approximately every 6 months to review study data.  The first meeting must be within 6 months of 
the first enrollment in the Pivotal Phase of the study.  Reports will consist of data on study conduct 
and aggregate adverse events review.  Once the study follow-up is completed, the DMC will be 
disbanded, with no need to review final results of the study. 

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11.2. Clinical Events Committee (CEC) 
An independent Clinical Events Committee (CEC) will review and adjudicate, at a minimum, all 
procedure- and system-related adverse events, as well as all adverse events resulting in death.    
The CEC will consist of a minimum of three (3) non-Medtronic employed physicians that are not 
participating Investigators for the study, including a CEC chairperson.  
Medtronic personnel may facilitate and participate in a CEC meeting but will be non-voting 
members. 
For adverse events and deaths reviewed by the CEC, Medtronic will provide the CEC with the 
Investigator’s description and classification. The CEC is responsible for reviewing the 
Investigator’s assessment and supportive documentation (when available), reviewing applicable 
definitions, and determining final classifications for all adjudication parameters. Additionally, the 
CEC will provide an adjudication of the death classification for all reported deaths including primary 
cause of death and death classification. 
If the CEC disagrees with the Investigator’s classification of the event, the difference will be 
provided to the Investigator. If the Investigator agrees with the CEC’s adjudication, the eCRF 
documenting the event will be updated accordingly. 
If the Investigator does not agree with the CEC’s adjudication classification, both determinations 
will be provided within the final report; however, the CEC’s adjudication will be used for data 
analysis. The disagreement will also be included in reporting to IRB/REB/MECs and regulatory 
authorities, if required. 
 
 

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12. Statistical Design and Methods 
This section includes a description of the statistical methods and analyses to be included in reports 
that include analysis of endpoints. Any change to the data analysis methods described in the CIP 
will require an amendment to the CIP only if it changes a principal feature of the CIP. Any other 
change to the data analysis methods described in the CIP, and the justification for making the 
change, will be described in the clinical study report. 
 
Standard baseline and relevant medical history will be collected on the CRFs for all enrolled 
subjects. Baseline variables to be summarized include, but are not limited to: age, sex, race (if 
allowed by local law), and physical exam findings. 
 
Additional exploratory analyses of the data may be conducted as deemed appropriate.  
 
Each arm (paroxysmal AF and persistent AF) of the Pivotal Phase of this study contains the 
following cohorts, with each enrolled subject belonging to one-and-only-one of the cohorts: 
• 
Non-treated Cohort – Subjects enrolled in the study who exit prior to having the PFA 
system multielectrode catheter inserted into vasculature. 
• 
Roll-in Cohort – roll-in subjects are defined in Section 7.2.1. 
• 
Primary Analysis Cohort – Treated (those who have the PFA system multielectrode 
catheter inserted into vasculature) subjects who are not part of the Roll-in Cohort.  
 
There is no intention to pool data from the Pilot Phase and the 3 Pivotal Phase cohorts.  All will be 
analyzed separately. 
 
 

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12.1. Pilot Phase  
12.1.1. 
Pilot Phase Safety Objective 
Assess the incidence of PFA system-related and PFA procedure-related serious adverse events 
(SAEs) within 30 days post-ablation. 
Endpoint Definition 
Table 14 displays the PFA system-related and PFA procedure-related serious adverse events 
(SAEs) that will be considered a Pilot Phase safety event against the Pilot Phase safety endpoint. 
Table 14: Analysis of Serious Adverse Events for Pilot Phase Subjects 
Serious Adverse Event 
Method of Analysis 
pulmonary vein stenosis (>70% diameter 
reduction); 
Review of symptoms post-procedure, at 7-
day visit and at 30-day visit 
phrenic nerve injury/diaphragmatic paralysis 
(ongoing at 30 days post-ablation); 
atrioesophageal fistula; 
cardiac tamponade/perforation;  
cerebrovascular accident; 
Review of symptoms post-procedure, at 7-day 
visit and at 30-day visit; Confirmed by formal 
neurology assessment if required due to NIHSS 
assessments 
major bleeding requiring transfusion;  
Review of symptoms post-procedure, at 7-
day visit and at 30-day visit 
myocardial infarction;  
pericarditis requiring intervention; 
transient ischemic attack;  
vagal nerve injury resulting in esophageal 
dysmotility or gastroparesis; 
vascular access complications requiring 
intervention; 
death; 
any PFA system-related or PFA procedure-
related cardiovascular and/or pulmonary 
adverse event that prolongs or requires 
hospitalization for more than 48 hours 
(excluding recurrent AF/AFL/AT)  
 

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Analysis Methods 
The percentage of procedures with a PFA system-related or PFA procedure-related SAE will be 
calculated as the number of procedures with at least one SAE meeting the endpoint definition 
divided by the number of PFA system ablation procedures. Each procedure will count, so subjects 
with repeat PFA system ablations will contribute more than once to the denominator. Exact 
methods will be used to construct a 95% confidence interval for the percentage of procedures with 
an SAE meeting the endpoint definition. 
 
Determination of Subjects/Data for Analysis 
All procedures in Pilot Phase subjects where the PFA system multielectrode catheter is inserted 
into vasculature will be included.  
 
 

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12.1.2. 
Pilot Phase Effectiveness Objective 
Assess the acute procedural success of PVI ablation with the PFA system. 
Endpoint Definition 
Acute procedural failure is defined as the occurrence of any of the following: 
 
a. Inability to isolate all accessible targeted pulmonary veins (assessed for entrance 
block and, where assessable, exit block) during the index ablation procedure.  
b. Ablation using a non-study device to isolate any pulmonary vein.  
 
Acute procedural success is the opposite of acute procedural failure. 
 
Analysis Methods 
The percentage of procedures with acute procedural success will be calculated as the number of 
procedures meeting the endpoint definition of acute procedural success divided by the number of 
PFA system ablation procedures. Each procedure will count, so subjects with repeat PFA system 
ablations will contribute more than once to the denominator. Exact methods will be used to 
construct a 95% confidence interval for the percentage of procedures with acute procedural 
success. 
 
Additionally, acute success at the pulmonary vein level will be calculated.  Each accessible targeted 
pulmonary vein will be classified as acute success or not. The percentage of total pulmonary veins 
attempted with the PFA system will be calculated.  Exact methods will be used to construct a 95% 
confidence interval. 
Determination of Subjects/Data for Analysis 
All procedures in Pilot Phase subjects where the PFA system multielectrode catheter is inserted 
into vasculature will be included. 
 
 
 
 

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12.2. Pivotal Phase 
12.2.1. 
Planned Analyses 
The paroxysmal and persistent arms will be analyzed separately.  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 all subjects 
will be followed for 12 months, and a final report will be prepared for each arm. 
Unless specified, the objectives are identical for the paroxysmal and persistent arms of the study. 
Primary objective results by age, sex, race, and site will be provided in the final report.  
 
 

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12.2.2. 
Primary Safety Objective 
Demonstrate an acceptable safety profile of PVI ablation with the PFA system. 
Hypothesis  
The following hypothesis will be tested in a one-sided test:  
Ho: PS ≥ 13%  
Ha: PS < 13%  
Where PS is the probability of a safety event through 6 months. 
 
Endpoint Definition  
The primary safety endpoint definition, as follows, is identical for each arm (paroxysmal AF and 
persistent AF) of the Pivotal Phase. 
 The following PFA system-related and ablation PFA procedure-related serious adverse events 
(SAEs), as adjudicated by the Clinical Events Committee (CEC), will be considered a primary safety 
event: 
Within 6 months post-ablation: 
• 
Pulmonary vein stenosis (>70% diameter reduction) 
• 
Phrenic nerve injury/diaphragmatic paralysis (ongoing at 6 months) 
• 
Atrioesophageal fistula  
 
Within 30 days of ablation procedure: 
• 
Cardiac tamponade/perforation  
• 
Cerebrovascular accident  
• 
Major bleeding requiring transfusion 
• 
Myocardial infarction  
• 
Pericarditis requiring intervention 
• 
Transient ischemic attack 
• 
Vagal nerve injury resulting in esophageal dysmotility or gastroparesis  
• 
Vascular access complications requiring intervention  
• 
Death  
• 
Any PFA system-related or PFA procedure-related cardiovascular and/or pulmonary 
adverse event that prolongs or requires hospitalization for more than 48 hours (excluding 
recurrent AF/AFL/AT)  
Analysis Methods  
The probability of a safety event at 6 months (183 days) will be estimated using survival analysis, 
the Kaplan-Meier method. The standard error will be approximated using Greenwood’s formula. A 
two-sided 95% log-log confidence interval for the probability will be constructed.  

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For every treated subject, day 0 is defined as the day of the index ablation procedure. For subjects 
with a safety event, the survival date will be set to the onset date of the safety event. For subjects 
without a safety event, those subjects will be censored at the last study contact date recorded on 
CRF which may include the last study visit, the exit date, or death date. If a subject without a safety 
event is lost to follow-up, the censoring date will be set to the last known study visit date.  
 
Safety events related to a repeat ablation procedure with the PFA system will not be counted as 
safety events against the primary safety objective.  However, all repeat PVI ablations using the PFA 
system and the safety events associated with them will be reported separately.  
 
Performance Requirements  
If the upper bound of the two-sided 95% confidence interval at 6 months is less than the 
performance goal of 13%, the objective will be considered met.  
 
Rationale for Performance Criteria  
Figure 4 and Table 15 display safety rates in recent studies in paroxysmal AF and persistent AF 
patients.24,25,26,27,28,29,30,31,32 Included are published literature where the search criteria include large 
multi-centered studies where the therapy was the use of catheter ablation (RF ablation, 
cryoablation, or visually guided laser balloon [VGLB] ablation) for a PVI-only approach for paroxysmal 
AF or persistent AF. The summary includes study results published as manuscripts in peer reviewed 
                                                            
24 P100010/R017 “STOP AF PAS Final Post-Approval Study Report”. 
25 Kuck, K. H., Brugada, J., Fürnkranz, A., et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. 
New England Journal of Medicine 374, 2235-2245 (2016). 
26 Squara, F., Zhao, A., Marijon, E., et al. Comparison between radiofrequency with contact force-sensing and second-
generation cryoballoon for paroxysmal atrial fibrillation catheter ablation: a multicentre European evaluation. Europace 17, 
718-724 (2015). 
27 Schmidt, M., Dorwarth, U., Straube, F., et al. Cryoballoon in AF ablation: impact of PV ovality on AF recurrence. Int J 
Cardiol 167, 114-120 (2013). 
28 Providencia, R., Defaye, P., Lambiase, P., et al. Results from a multicentre comparison of cryoballoon vs. radiofrequency 
ablation for paroxysmal atrial fibrillation: is cryoablation more reproducible? Europace 19, 48-57 (2017). 
29  Dukkipati, S., Cuoco, F., Kutinsky, I., et al. Pulmonary Vein Isolation Using the Visually Guided Laser Balloon: A 
Prospective, Multicenter, and Randomized Comparison to Standard Radiofrequency Ablation. Journal of the American 
College of Cardiology 66, 1350-1360 (2015). 
30 Boveda, S., Metzner, A., Nguyen, D., et al. Single-Procedure Outcomes and Quality-of-Life Improvement 12 Months 
Post-Cryoballoon Ablation in Persistent Atrial Fibrillation: Results From the Multicenter CRYO4PERSISTENT AF Trial. 
Journal of the American College of Cardiology, doi:10.1016/j.jacep.2018.07.007 (2018). 
31 Tondo, C., Iacopino, S., Pieragnoli, P., et al. Pulmonary Vein Isolation Cryoablation for Persistent and Long-Standing 
Persistent Atrial Fibrillation Patients. Clinical Outcomes from Real Word Multicentric Observational Project. Heart Rhythm 
15, 363-368, doi:10.1016/j.hrthm.2017.10.038 (2017). 
32 Aryana, A., Baker, J., Espinosa Ginic M., et al. Posterior wall isolation using the cryoballoon in conjunction with pulmonary 
vein ablation is superior to pulmonary vein isolation alone in patients with persistent atrial fibrillation: A multicenter 
experience. Heart Rhythm 15, 1121-1129 (2018). 

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medical journals. Note, these studies are the same studies utilized in rationales below for 
effectiveness performance criteria. 
 
Varying complication rates are observed, and varying definitions of complication were used in each 
study, but to test a novel catheter ablation technology, an objective performance criterion (OPC) of 
13% provides a reasonable margin to compare the PFA system against ablation technologies 
currently used to treat AF. 
 
Figure 4: Current Safety Rates in Catheter Ablation Technologies for Paroxysmal AF and Persistent AF 
 
 
PAF and perAF Complication Rates
Complication Rate (%)
STOP AF PASF&I CB
Squara
Schmidt
Providencia F&I RF
Squara
Providencia HeartLight
CRYO4
1STOP
Arayana
STAR AF II
0
10
20
30
40
50
n=354
n=374
n=178
n=124
n=393
n=376
n=198
n=467
n=167
n=101
n=434
n=168
n=67
Paroxsmal AF
Persistent AF
OPC 13%
NA

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Table 15: Summary of Published Literature on Safety Rates of Catheter Ablation for AF 
Reference 
AF Type 
Ablation 
Catheter Type 
Subjects 
Reported Safety 
Rate (95% CI) i 
STOP AF PAS 
P100010/R017 “STOP AF PAS Final Report”.24  
Paroxysmal 
Cryo 
354 
5.8%  
(3.6 – 8.8) 
FIRE AND ICE 
Kuck KH, et al. N Engl J Med. 2016; 374:2235-45.25  
Paroxysmal 
Cryo 
374 
10.2% 
(7.3 – 13.7) 
Squara F, et al.  
Europace. 2015;17:718-24.26  
Paroxysmal 
Cryo 
178 
7.3% 
(3.9 – 12.2) 
Schmidt M, et al.  
Int J Cardiol. 2013;167:114-120.27  
Paroxysmal 
Cryo 
124 
Not reported 
Providencia R, et al.  
Europace. 2017;19:48-57.28  
Paroxysmal 
Cryo 
393 
5.9% 
(3.8 – 8.7) 
FIRE AND ICE 
Kuck KH, et al. N Engl J Med. 2016; 374:2235-45.25  
Paroxysmal 
RF 
376 
12.8% 
(9.6 – 16.6) 
Squara F, et al.  
Europace. 2015;17:718-24.26  
Paroxysmal 
RF 
198 
7.1% 
(3.9 – 11.6) 
Providencia R, et al.  
Europace. 2017;19:48-57.28  
Paroxysmal 
RF 
467 
4.9% 
(3.1 – 7.3) 
HeartLight 
Dukkipati S, et al. J Am Coll Cardiol. 2015;66:1350-
60.29  
Paroxysmal 
VGLB 
167 
5.3% 
(2.4 – 9.9) 
CRYO4PERSISTENT AF  
Boveda S, et al. J Am Coll Cardiol. [Epub ahead of 
print].30  
Persistent 
Cryo 
101 
4.0% 
(1.1 – 9.9) 
1STOP 
Tondo C, et al. Heart Rhythm. 2017;15:363-368.31  
Persistent 
Cryo 
434 
4.3% 
(2.6 – 6.7) 
Aryana et al.  
Heart Rhythm 2018;15:1121–1129.32  
Persistent 
Cryo 
168 
(PVI only) 
2.4%  
(0.6 – 6.0) 
STAR AF II 
Verma A, et al. N Engl J Med. 2015;372:1812-22.13  
Persistent 
RF 
67 
(PVI only) 
6.0%  
(1.7 – 14.6) 
i 95% confidence interval calculated using binomial exact methods 
 
 

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Rationale for Timing of the Final Safety Analysis 
The PFA system is a novel catheter ablation technology, but analogous in procedural use to currently 
approved catheter ablation systems for the treatment of AF. The major complications related to 
traditional catheter ablation systems will describe the safety profile of the PFA system. The 2017 
HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial 
Fibrillation acknowledges that “AF ablation is an invasive procedure that entails risks, most of which 
are present during the acute procedural period. However, complications can also occur in the weeks 
or months following ablation.” Symptoms and complications associated with AF ablation are 
stratified by those that occur within 1 month post-ablation and those that occur more than 1 month 
post-ablation.3 To evaluate the safety profile of the PFA system, the primary safety events in this 
study align with the recognized AF ablation complications. Recognizing that most AF ablation 
complications present acutely, Medtronic proposes that the safety profile of the PFA system will be 
established with 6-month follow-up data. The study will continue to collect, analyze and report all 
adverse events for all subjects through 12 months follow-up.   
 
Sample Size Calculation  
A sample size of 138 treated subjects followed for 6 months affords 90% power based on the 
following assumptions:  
 
• 
6-month safety rate = 5% (desired rate for new catheter ablation technology) 
• 
OPC = 13% at 6 months  
• 
Overall alpha = 0.025, one-sided  
• 
One final analysis 
• 
Binomial exact methods  
 
The primary analysis will utilize Kaplan-Meier survival methods.  Binomial exact methods were 
utilized for sample size and power calculations, as with very low expected attrition, Kaplan-Meier 
and binomial methods yield very similar results. 
 
Determination of Subjects/Data for Analysis  
All Primary Analysis Cohort subjects (only their index PFA procedure) will be included. 
 
 

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12.2.3. 
Primary Effectiveness Objective 
Objective  
Demonstrate an acceptable chronic effectiveness of PVI ablation with the PFA System, based on 
freedom from treatment failure.   
 
Hypotheses  
For the paroxysmal AF arm: 
Ho: PS ≤ 55% 
Ha: PS > 55% 
For the persistent AF arm: 
Ho: PS ≤ 40% 
Ha: PS > 40% 
Where PS is the probability of treatment success at 12 months.   
Endpoint Definition  
The definition of treatment success and failure differs slightly between the paroxysmal and 
persistent arms of the Pivotal Phase.  
 
Primary Effectiveness Endpoint for Paroxysmal AF 
Treatment success is defined as freedom from treatment failure. The study requires 24-hour 
Holter monitoring at 6 and 12 months in addition to weekly and symptomatic patient activated 
ambulatory monitoring transmissions from 3 through 12 months, and 12-lead ECGs at all follow up 
visits. Treatment failure is defined as any of the following components:  
• 
Acute procedural failure (see definition below) 
• 
Documented AF/AT/AFL on Holter/patient activated ambulatory monitoring/12-lead ECG 
after the 90-day post-ablation blanking period  
• 
Minimum of 30 seconds on Holter/patient activated ambulatory monitoring or 10 seconds 
on 12-lead ECG recording 
• 
Note: Documented occurrence and treatment of typical right-sided cavotricuspid isthmus 
dependent atrial flutter is not considered a failure. 
• 
Any subsequent AF surgery or ablation in the left atrium, except for repeat PVI ablations 
using PFA within the 90-day blanking period. 
• 
Direct current cardioversion for atrial tachyarrhythmia recurrences after the 90-day 
blanking period. 
• 
Class I or III antiarrhythmic drug (AAD) use after the 90-day blanking period.  
 

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Blanking period is defined as the first 90 days after the index ablation procedure. Recurrences of 
atrial arrhythmias during the blanking period will not be counted in the determination of the first 
clinical failure for the primary endpoint. Within the blanking period, recurrent arrhythmias can be 
managed with antiarrhythmic drugs or cardioversions. Titration of Class I and III antiarrhythmic 
medications are allowed during the blanking period. 
Acute procedural failure is defined as the occurrence of any of the following:  
• 
Inability to isolate all accessible targeted pulmonary veins (minimally assessed for entrance 
block and, where assessable, exit block) during the index procedure  
• 
Ablation using a non-study device to isolate any pulmonary vein 
 
Primary Effectiveness Endpoint for Persistent AF 
Treatment success is defined as freedom from treatment failure. The study requires 24-hour 
Holter monitoring at 6 and 12 months in addition to weekly and symptomatic patient activated 
ambulatory monitoring transmissions from 3 through 12 months, and 12-lead ECGs at all follow up 
visits. Treatment failure is defined as any of the following components:  
• 
Acute procedural failure (see definition below) 
• 
Documented AF/AT/AFL on Holter/patient activated ambulatory/12-lead ECG after the 
90-day post-ablation blanking period  
• 
Minimum of 30 seconds on Holter/patient activated ambulatory or 10 seconds on 12-lead 
ECG recording 
• 
Note: Documented occurrence and treatment of typical right-sided cavotricuspid isthmus 
dependent atrial flutter is not considered a failure. 
• 
Any subsequent AF surgery or ablation in the left atrium, except for repeat PVI ablations 
using PFA within the 90-day blanking period. 
• 
Direct current cardioversion for atrial tachyarrhythmia recurrences after the 90-day 
blanking period. 
• 
Class I or III antiarrhythmic drug (AAD) dose increase from the historic maximum ineffective 
dose (prior to the ablation procedure) or initiation of a new Class I or III AAD after the 90-
day blanking period. Note: remaining on the same pre-ablation dose or decreased dose of a 
previously failed or not tolerated Class I or III AAD after the 90-day blanking is not 
considered a failure.  
 
Blanking period is defined as the first 90 days after the index ablation procedure. Recurrences of 
atrial arrhythmias during the blanking period will not be counted in the determination of the first 
clinical failure for the primary endpoint. Within the blanking period, recurrent arrhythmias can be 
managed with antiarrhythmic drugs or cardioversions. Titration of Class I and III antiarrhythmic 
medications are allowed during the blanking period. 

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Acute procedural failure is defined as the occurrence of any of the following:  
• 
Inability to isolate all accessible targeted pulmonary veins (minimally assessed for entrance 
block and, where assessable, exit block) during the index procedure  
• 
Ablation using a non-study device to isolate any pulmonary vein 
 
Analysis Methods  
The probability of a subject achieving effectiveness success at 12 months (365 days) will be 
estimated using survival analysis, the Kaplan-Meier method. The standard error will be 
approximated using Greenwood’s formula. A two-sided 95% log-log confidence interval for the 
probability will be constructed.  
 
For every treated subject, day 0 is defined as the day of the index ablation procedure. For subjects 
with treatment failure, the survival date will be set to the date of the treatment failure. For subjects 
without treatment failure through 12 months, those subjects will be censored at the last study 
contact date recorded on a CRF which may include the last study visit, the last weekly patient 
activated ambulatory, the exit date, or death date. If a subject without a treatment failure is lost to 
follow-up, the censoring date will be set to the last known study visit date.  
 
For the component of the endpoint, documented AF/AT/AFL, if this documentation resulted from 
rhythm monitoring occurring at the 12-month visit within the 12-month visit window, the date of 
recurrence will be set to 365 days from the study ablation procedure so that these events will be 
counted as treatment failures in the 12-month Kaplan-Meier analysis. 
 
Sensitivity Analyses  
A sensitivity analysis will be conducted to estimate the potential impact of subjects with less than 
12 months of follow-up at the final analysis. The mortality rate in this patient population is 
anticipated to be low. The total assumed attrition rate through one year is 5%. Because the 
primary endpoint will be tested using survival methods, all treated subjects are included in the 
primary analysis, and therefore no subjects will have complete missing data. For subjects that exit 
early, a tipping point analysis will be conducted to estimate the potential impact of subjects with 
less than 12 months of follow-up. These subjects will be defined as subjects with partial data. The 
tipping point analysis methods will be as follows. For each subject with less than 12 months of 
follow-up, each subject will be set to treatment failure (failure date set to date of study exit). The 
12-month Kaplan-Meier estimate will be re-calculated with the earliest (closest to index ablation) 
sequentially added to the Kaplan-Meier analysis, and the results presented in table format. The 
tipping point will be defined as the number of additional failures in which the performance goal 
(55% for paroxysmal and 40% for persistent) is crossed by the lower 95% confidence bound. 
 
Performance Requirements  
If the lower bound of the confidence interval (coverage level determined by the alpha spending 
function) is greater than the performance goal (55% for paroxysmal and 40% for persistent), the 
objective will be considered met. 
 
 

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Rationale for Performance Criteria (Paroxysmal) 
Traditionally, the choice of acceptable effectiveness performance criteria for paroxysmal AF with 
12-month follow-up data is selected based on the 2017 HRS/EHRA/ECAS Expert Consensus 
Statement on Catheter and Surgical Ablation of Atrial Fibrillation, which provides recommendations 
for success rates in clinical trials. The recommendation for evaluating the effectiveness of a 
treatment for paroxysmal AF is as follows: “If minimum chronic success rate is selected as an objective 
effectiveness endpoint for a clinical trial, we recommend that the minimum chronic acceptable success 
rate for paroxysmal AF at 12-month follow-up is 50%.”3 Medtronic proposes a single-arm, non-
randomized paroxysmal AF study is appropriate with performance criteria that is established based 
on effectiveness rates for currently approved ablation catheters (RF ablation, cryoablation, and 
VGLB ablation), in addition to the recommendation provided by the 2017 Expert Consensus 
Statement. 
 
Figure 5 and Table 16 display effectiveness rates observed in current clinical trials studying approved 
catheter ablation technologies in paroxysmal AF patients. Included are published literature where 
the search criteria include publications of large multi-centered studies where the therapy was the 
use of catheter ablation (RF ablation, cryoablation, or VGLB ablation) for a PVI-only approach for 
paroxysmal AF. The summary includes study results published as manuscripts in peer reviewed 
medical journals. Varying rates in 12-month effectiveness have been observed. Similarly, variations 
in definitions of primary effectiveness and variations in arrhythmia monitoring have been utilized.  
The proposed PULSED AF study design has an aggressive definition of primary paroxysmal AF 
effectiveness (requiring acute success; and disallowing AAD use and reablations after the 90-day 
blanking period) and a more rigorous study design (requiring weekly patient activated ambulatory 
monitoring through 12 months).   
 
To test a novel catheter ablation technology, under these study design requirements, an OPC of 
55% provides a reasonable margin to compare the PFA system against current approved ablation 
technologies. 

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Figure 5: Current 12-Month Effectiveness Rates in Approved Catheter Ablation Technologies for 
Paroxysmal AF 
 
 
PAF (12-month)
12 month efficacy
STOP AF PASF&I CB
Squara
Schmidt
Providencia F&I RF
Squara
Providencia HeartLight
0
10
20
30
40
50
60
70
80
90
100
n=354
n=374
n=178
n=124
n=393
n=376
n=198
n=467
n=167
OPC 55%

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Table 16: Summary of Published Literature on Catheter Ablation for Paroxysmal AF 
Reference 
Design 
Sites 
Subjects 
(Ablatio
n Type) 
Subject Monitoring  
(When/How) 
Effectiveness 
Endpoint 
Assessment  
Acute 
Procedural 
Success 
6M 
Effectiveness 
i, ii 
12M 
Effectiveness i 
STOP AF PAS 
P100010/R017 “STOP 
AF PAS Final 
Report”.24  
prospective, single 
arm 
39 
354 cryo 
ECG @ 3M, 6M, 12M; 
24hr Holter @ 6M; 48hr 
Holter @ 12M; 
Symptomatic event 
recorder for 30 days 
AF/AFL/AT > 30s; 
Intervention for 
AF 
 
98.0% 
 
89% 
(85-92) 
80% 
(75-84) 
 
FIRE AND ICE 
Kuck KH, et al. N Engl J 
Med. 2016; 374:2235-
45.25  
randomized (RF 
and cryo), 
noninferiority 
16 
374 cryo 
ECG and 24hr Holter @ 
3M, 6M, 12M; Weekly 
and symptomatic TTM 
AF/AFL/AT > 30s;  
AAD use; 
Reablation 
98.9% 
81% 
(77-85) 
65% 
(60-70) 
Squara F, et al. 
Europace. 
2015;17:718-24.26  
Consecutive, non-
randomized, 
ambidirectional 
(prospective and 
retrospective) 
4 
178 cryo 
ECG and 24hr Holter @ 
1M, 3M, 6M, 9M, 12M; 
Symptomatic 24hr Holter 
AF/AFL/AT >30s 
100% 
88% 
(82-92) 
82% 
(76-87) 
Schmidt M, et al. 
Int J Cardiol 
2013;167:114-120.27  
Consecutive 
patients 
3 
124 cryo 
ECG and 72hr Holter @ 
1M, 3M, 6M, 9M, 12M;  
Symptomatic event 
recorder 
AF or Flutter >30s 
100% 
86% 
(79-92) 
66% 
(57-74) 
Providencia R, et al. 
Europace. 2017;19:48-
57.28  
Consecutive, 
prospective, non-
randomized  
6 
393 cryo 
ECG and 24hr Holter @ 
1M, 3M, 6M, 9M, 12M; 
Symptomatic ECG and 
24hr Holter 
Any AF/AT >30s; 
AAD use 
99.0% 
89% 
(85-92) 
82% 
(78-86) 
FIRE AND ICE 
Kuck KH, et al. N Engl J 
Med. 2016; 374:2235-
45.25  
randomized (RF 
and cryo), 
noninferiority,  
16 
376 RF 
ECG and 24hr Holter @ 
3M, 6M, 12M; Weekly 
and symptomatic TTM 
AF/AFL/AT > 30s;  
AAD use; 
Reablation 
97.9% 
82% 
(78-86) 
64% 
(59-69) 
Squara F, et al. 
Europace. 
2015;17:718-24.26  
Consecutive, non-
randomized, 
ambidirectional 
(prospective and 
retrospective) 
4 
198 RF 
ECG and 24hr Holter @ 
1M, 3M, 6M, 9M, 12M; 
Symptomatic 24hr Holter 
AF/AFL/AT >30s 
100% 
89% 
(84-93) 
84% 
(78-89) 
Providencia R, et al.  
Europace. 2017;19:48-
57.28  
Consecutive, 
prospective, non-
randomized 
6 
467 RF 
ECG and 24hr Holter @ 
1M, 3M, 6M, 9M, 12M; 
Symptomatic ECG and 
24hr Holter 
Any AF/AT >30s; 
AAD use 
97.6% 
82% 
(78-85) 
73% 
(69-77) 
HeartLight 
Dukkipati S, et al. J Am 
Coll Cardiol. 
2015;66:1350-60.29  
Randomized (RF 
and VGLB), 
prospective 
19 
167 
VGLB 
ECG @ 1M, 3M, 6M, 9M, 
12M; 24hr Holter @ 6M, 
12M; Symptomatic and 
weekly TTM 
AF >1 min; 
Atypical/unknown 
AFL/AT; AAD use 
97.7% 
75% 
(68-81) 
61% 
(53-68) 
Weighted average (weights based on study sample sizes) 
84.5% 
73.2% 
i Confidence interval calculated with binomial Fisher’s exact method 
ii 6-month effectiveness rates are estimated from survival curves published in literature

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Rationale for Performance Criteria (Persistent) 
The choice of acceptable effectiveness performance criteria for persistent AF with 12-month 
follow-up data is selected based on the 2017 HRS/EHRA/ECAS Expert Consensus Statement on 
Catheter and Surgical Ablation of Atrial Fibrillation, which provides recommendations for success 
rates in clinical trials.  The recommendation for evaluating the effectiveness of a treatment for 
persistent AF is as follows: “If minimum chronic success rate is selected as an objective effectiveness 
endpoint for a clinical trial, we recommend that the minimum chronic acceptable success rate for 
persistent AF at 12-month follow-up is 40%.”3 
 
Additionally, there is mounting evidence in published literature on the use of catheter ablation in the 
treatment of persistent AF. Figure 6 and Table 17 display a summary of published literature where 
the search criteria were publications of large multi-centered studies where the therapy was the use 
of catheter ablation (RF ablation or cryoablation) for a PVI-only approach for persistent AF. The 
summary includes study results published as manuscripts in peer reviewed medical journals. Varying 
rates in 12-month effectiveness have been observed. Similarly, variations in definitions of primary 
effectiveness and variations in arrhythmia monitoring have been utilized.  The PULSED AF study 
design has an aggressive definition of primary persistent AF effectiveness (requiring acute success; 
and disallowing reablations after the 90-day blanking period, AAD dose increase from the historic 
maximum ineffective dose, or initiation of new AAD) and a more rigorous study design (requiring 
weekly patient activated ambulatory monitoring through 12 months).   
 
To test a novel catheter ablation technology under these study design requirements, the Expert 
Consensus Statement recommended OPC of 40% provides a reasonable margin to compare the 
PFA system against ablation technologies currently used to treat persistent AF. 

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Figure 6: Current 12-Month Effectiveness Rates in Catheter Ablation Technologies for Persistent AF 
 
 
perAF (12-month)
12 month efficacy
CRYO4
1STOP
Arayana
STAR AF
0
10
20
30
40
50
60
70
80
90
100
n=101
n=434
n=168
n=67
OPC 40%

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Table 17: Summary of Published Literature on Catheter Ablation for Persistent AF 
Reference 
Design 
Sites 
Subjects 
(Ablation 
Type) 
Subject 
Monitoring  
(When/How) 
Effectiveness 
Endpoint 
Assessment  
Acute 
Procedural 
Success 
6M 
Effectiveness  i, 
ii 
12M 
Effectiveness i 
CRYO4PERSISTENT 
AF 
Boveda S, et al. J Am 
Coll Cardiol. [Epub 
ahead of print].30  
prospective, 
single-arm, 
interventiona
l post-market 
clinical study 
11 
101 cryo 
ECG @ 3M, 6M, 
12M and 48hr 
Holter @ 6M, 
12M 
AF/AFL/AT > 
30s; 
Reablation 
98.0% 
 
81%  
(72-88) 
61%  
(51-71) 
 
1STOP 
Tondo C, et al. Heart 
Rhythm. 
2017;15:363-368.31  
Prospective, 
single-arm 
35 
434 cryo 
ECG and Holter 
@ 3M, 6M, 9M, 
12M 
AF > 30s; 
Reablation 
98.5% 
81% 
(77-84) 
64% 
(59-69) 
Aryana et al. 
Heart Rhythm. 
2018;15:1121–
1129.32  
Consecutive, 
double-arm 
non-
randomized  
≤7 
168 cryo 
(PVI only) 
ECG @ 3M, 6M, 
12M; 2-week 
TTM @ 6 weeks 
and 3–6 months 
AF/AFL/AT > 
30s 
99.3% 
67% 
(59-74) 
 
47% 
(39-55) 
STAR AF II 
Verma A, et al. 
N Engl J Med. 2015; 
372: 1812-1822.13  
Prospective, 
triple-arm 
randomized,  
48 
67 RF 
(PVI only) 
ECG and 24hr 
Holter @ 3M, 6M, 
9M, 12M; Weekly 
and symptomatic 
TTM 
AF > 30s; 
Reablation 
97.0% 
81% 
(70-90) 
60% 
(47-72) 
 
Weighted average (weights based on study sample size) 
77.9% 
59.5% 
i Confidence interval calculated with binomial Fisher’s exact method 
ii 6-month effectiveness rates are estimated from survival curves published in literature, with the exception of the 
CRYO4PERSISTENT manuscript, which reported the 6-month effectiveness rate 
 
 
Determination of Subjects/Data for Analysis  
All Primary Analysis Cohort subjects will be included. 
 
Sample Size Calculation  
Given the separation of primary effectiveness objectives for paroxysmal AF and persistent AF, the 
study sample size is powered independently for paroxysmal AF and persistent AF arms. 
For both arms, the sample size was computed using a simulation program.  Given the assumptions 
below, the program ran through 10,000 simulations of this study for each potential sample size.  The 
lowest sample size (going by units of 5 subjects) where at least 9000 studies were successful (i.e., 
power >90%) was chosen as the sample size for that arm. 
The simulation program took into account the 
, alpha boundaries, the enrollment 
rate, and other assumptions listed below.  Where percentages are assumed, it gave each simulated 
subject that chance of the event occurring (e.g., each simulated subject had a 2% chance of having 
an acute failure).  It performed the primary effectiveness objective’s analysis as stated above on 
each simulated study to determine whether that study would have been successful 
 
. 

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Assumptions (Paroxysmal Arm) 
• 
The overall alpha will be 0.025, 
 
 
• 
Power=90% 
• 
The number of Primary Analysis Cohort subjects enrolled per month will average 5 (1st 
month), 7 (2nd month), 11, 24, 35, 43, 51, 56, 60, 60, 60…   
• 
Daily enrollments follow a Poisson distribution with an average of x/30, where x is the 
average number of enrollments in that month.  This allows multiple ablation procedures in a 
day. 
• 
50% of enrollments are persistent AF subjects, and the other 50% are paroxysmal AF 
subjects 
• 
12-month effectiveness rate = 68% (A weighted average 12-month effectiveness was 
calculated at the bottom of the Table 16, resulting in an average effectiveness rate of 
73.2%. Only three of the studies utilized weekly TTMs (similar to the weekly patient 
activated ambulatory monitoring requirement), so due to the additional arrhythmia 
monitoring and a more stringent endpoint definition in PULSED AF, the 12-month 
paroxysmal AF effectiveness point estimate for this study has been set to 68%.) 
• 
6-month effectiveness rate = 79% (based on past studies (Table 16), the 6-month rate is 
approximately 11% higher than 12-month rate) 
• 
2% of patients will have an acute failure and these will occur on the first day post-ablation 
procedure 
• 
Chronic failures (AF recurrence) occur either in the 3-6 month period or in the 6-12 month 
period, based on the assumed 68% and 79% numbers above. 
• 
A patient with a chronic failure in the 3-6 month period has an equal chance of that failure 
occurring any day between 91 and 182 days post-ablation procedure 
• 
A patient with a chronic failure in the 6-12 month period has an equal chance of that failure 
occurring any day between 184 and 364 days post-ablation procedure 
• 
5% attrition from ablation (drop out) procedure to 12 months 
• 
Attrition occurs uniformly from 1-364 days post-ablation procedure 
 
 
 
  
 
Given the above assumptions, for the Paroxysmal AF arm of the study, a sample size of 165 Primary 
Analysis Cohort subjects is required. 
 
To ensure proper characteristics of the study, especially alpha-level, the simulation program was 
rerun with all of the above assumptions (including the sample size of 165 subjects) the same, except 
that the assumed 12-month effectiveness rate was set to the null hypothesis rate of 55% (and 6-
month effectiveness rate to 66%).  
 
  This meets the goal of having overall 
alpha being less than 2.5%. 

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Assumptions (Persistent Arm) 
• 
The overall alpha will be 0.025, 
 
 
• 
Power=90% 
• 
The number of Primary Analysis Cohort subjects enrolled per month will average 5 (1st 
month), 7 (2nd month), 11, 24, 35, 43, 51, 56, 60, 60, 60…   
• 
Daily enrollments follow a Poisson distribution with an average of x/30, where x is the 
average number of enrollments in that month.  This allows multiple ablation procedures in a 
day. 
• 
50% of enrollments are persistent AF subjects, and the other 50% are paroxysmal AF 
subjects 
• 
12-month effectiveness rate = 54% (A weighted average 12-month effectiveness was 
calculated at the bottom of Table 17, resulting in an average effectiveness rate of 59.5%. 
Due to the additional arrhythmia monitoring and more stringent endpoint definition in 
PULSED AF, the 12-month persistent AF effectiveness point estimate for this study has 
been set to 54%.) 
• 
6-month effectiveness rate = 72% (based on past studies (Table 17), the 6-month rate is 
approximately 18% higher than 12-month rate) 
• 
2% of patients will have an acute failure and these will occur on the first day post-ablation 
procedure 
• 
Chronic failures (AF recurrence) occur either in the 3-6 month period or in the 6-12 month 
period, based on the assumed 54% and 72% numbers above. 
• 
A patient with a chronic failure in the 3-6 month period has an equal chance of that failure 
occurring any day between 91 and 182 days post-ablation procedure 
• 
A patient with a chronic failure in the 6-12 month period has an equal chance of that failure 
occurring any day between 184 and 364 days post-ablation procedure 
• 
5% attrition from ablation (drop out) procedure to 12 months 
• 
Attrition occurs uniformly from 1-364 days post-ablation procedure 
 
 
 
  
 
Given the above assumptions, for the Persistent AF arm of the study, a sample size of 150 Primary 
Analysis Cohort subjects is required. 
 
To ensure proper characteristics of the study, especially alpha-level, the simulation program was 
rerun with all of the above assumptions (including the sample size of 150 subjects) the same, except 
that the assumed 12-month effectiveness rate was set to the null hypothesis rate of 40% (and 6-
month to 58%).  
 
  This meets the goal of having overall alpha 
being less than 2.5%. 

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12.2.4. 
Overall Study Sample Size Rationale 
The effectiveness sample sizes (165 for Paroxysmal AF and 150 for Persistent AF) are higher than 
the sample size of 138 for the safety objective. Therefore, a total of 315 Primary Analysis Cohort 
subjects are needed to have adequate power. 
 
Overall, up to 475 subjects will be enrolled to ensure there are 20 Pilot Phase subjects, up to 80 
Pivotal Phase roll-in subjects, and 315 Pivotal Phase primary analysis subjects treated with the PFA 
system, and to account for subjects not treated prior to exit. 
 
 
 

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12.3. Secondary Objective 
The secondary objective will be evaluated to gain additional information about the performance of 
the PFA system. The secondary objective will be reported separately by paroxysmal AF and 
persistent AF. 
Within each arm, testing for the two QOL hypothesis tests will be performed if the primary 
effectiveness and primary safety objectives are met. A Hochberg multiple testing procedure will be 
utilized to maintain an overall type I error rate of 0.025. 
 
The Hochberg procedure is a stepwise procedure and will be implemented as follows: 
The two null hypotheses will be defined as H(1) (AFEQT) and H(2) (EQ-5D). For each of the 
hypotheses, p-values will be calculated and sorted p(1) < p(2). The decision rule to accept or reject 
each hypothesis will follow the step-up algorithm, where α=0.025: 
Step 1: If p(2) ≥ α, accept H(2) and go to Step 2, otherwise reject both hypotheses and stop 
Step 2: If p(1) < α/2 reject H(1); otherwise accept H(1) 
12.3.1. 
Secondary Objective: Quality of Life  
Assess changes in quality of life from baseline through 12 months after the index ablation 
procedure 
 
This objective has two parts, the AFEQT questionnaire, and the EQ-5D questionnaire. 
 
 

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12.3.1.1. Atrial Fibrillation Effect on Quality-of-Life (AFEQT) 
 
Hypothesis 
The following hypothesis will be tested: 
Ho: ∆AFEQT = 0 
Ha: ∆AFEQT > 0 
Where ∆AFEQT is the mean change in AFEQT score from baseline to 12 months.   
 
Endpoint Definition 
The AFEQT questionnaire will be utilized for this objective. The questionnaire is an atrial fibrillation 
specific health-related quality of life questionnaire to assess the impact of AF on a subject’s life.  
The overall score ranges from 0 – 100, with 0 corresponding to complete disability and 100 
corresponding to no disability. 
The endpoint for each subject is change in AFEQT score, which is the AFEQT score at 12 months 
minus the AFEQT score at baseline. 
Analysis Methods 
The mean change in AFEQT score will be calculated, along with a two-sided 95% confidence 
interval.  The hypothesis will be tested using the one-sample t-test. 
 
  The p-value based on the final dataset will be compared to the Hochberg alpha level (Section 
12.3) to determine significance. 
Additionally, summary statistics (e.g. mean, SD) will be used to summarize the change in AFEQT 
scores from baseline through 12 months, including values collected at 6 months. 
Performance criteria 
If the p-value from the one-sample t-test is less than the Hochberg-criteria alpha level, then the 
objective will be considered met. 
Determination of Subjects/Data for Analysis 
Primary Analysis Cohort subjects who have completed baseline and 12-month follow-up 
questionnaires will be included. 

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Additional Analyses 
The AFEQT questionnaire has three subscale scores, Daily Activities Subscale, Treatment 
Concern, and Treatment satisfaction.  Each subscale ranges from 0 – 100, where 0 corresponds to 
low quality-of-life and 100 corresponds to high quality of life.  An additional analysis will be 
conducted to summarize these subscales through 12 months. 
Change in AFEQT subscale score is defined as 12-month AFEQT subscale score minus baseline 
AFEQT subscale score.  A two-sided 95% confidence interval will be calculated based on the t-
distribution.   
 
 

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12.3.1.2. EQ-5D Questionnaire 
Hypothesis 
The following hypothesis will be tested: 
Ho: ∆EQ-5D = 0 
Ha: ∆EQ-5D > 0 
Where ∆EQ-5D is the change in mean composite EQ-5D score from baseline to 12 months.  
Endpoint Definition 
The Euroqol EQ-5D questionnaire (5L version) will be utilized for this objective. The EQ-5D 
questionnaire is a standardized instrument for measuring generic health status. The EQ-5D has 
two sections. The first section is a descriptive section where the subject checks a box by the most 
appropriate statement. The second section is a visual analog scale. Composite scores will be 
indexed against a US reference population. (Shaw, Johnson and Coons 2004). 
The endpoint for each subject is change in EQ-5D composite score, which is the EQ-5D composite 
score at 12 months minus the EQ-5D composite score at baseline. 
Analysis Methods 
The mean change in EQ-5D composite score and a two-sided 95% confidence interval will be 
calculated based on the t-distribution. 
 
  The p-value based on the final dataset will be compared to the Hochberg alpha level (Section 
12.3) to determine significance. 
Summary statistics (e.g. mean, SD) will be used to summarize the change in EQ-5D composite 
scores from baseline through 12 months, including values collected at 6 months. In addition, the 
visual analog scale of the EQ-5D will be summarized through 12 months using summary statistics. 
Performance criteria 
If the p-value from the one-sample t-test is less than the Hochberg-criteria alpha level, then the 
objective will be considered met. 
Determination of Subjects/Data for Analysis 
Primary Analysis Cohort subjects who have completed baseline and 12-month follow-up 
questionnaires will be included. 
 
 
 

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13. Ethics 
13.1. Statement(s) of Compliance  
The study will be conducted in compliance with international ethical and scientific quality 
standards, known as good clinical practice (GCP). GCP includes review and approval by an 
independent Ethics Board/Institutional Review Board (IRB)/Research Ethics Board (REB)/Medical 
Ethics Committee (MEC)/Head of Medical Institution (HOMI)/Human Research and Ethics 
Committee (HREC) before initiating a study, continuing review of an ongoing study by an Ethics 
Board, and obtaining and documenting the freely given informed consent of a subject before 
initiating the study. The term Ethics Committee will henceforth be used collectively in reference to 
an Institutional Review Board (IRB)/Medical Ethics Committee (MEC)/Human Research Ethics 
Committee (HREC)/Research Ethics Board (REB)/Head of Medical Institution (HOMI) unless 
otherwise stated. 
The study was designed to reflect the GCP principles outlined in ISO 14155:2011 and other 
international clinical requirements outlined below. These include the protection of the rights, 
safety and well-being of human subjects, controls to ensure the scientific conduct and credibility of 
the clinical investigation and the definition of responsibilities of the sponsor and Investigators. In 
accordance with ISO standard, the sponsor shall avoid improper influence on, or inducement of, 
the subject, monitor, any Investigator(s) or other parties participating in or contributing to the 
clinical investigation.  All Investigators shall avoid improper influence on or inducement of the 
subject, sponsor, monitor, other Investigator(s) or other parties participating in or contributing to 
the clinical investigation.  Adverse Event and Device Deficiency handling in this study is ISO 
14155:2011 compliant for all participating geographies.   
The study will be conducted according to federal, national and local laws, regulations, standards, 
and requirements of the countries/geographies where the study is being conducted.  For all 
geographies, the principles of the Declaration of Helsinki have been implemented through the 
patient informed consent (IC) process, Ethics Committee approval, study training, clinical trial 
registration, preclinical testing, risk-benefit assessment and publication policy. 
 
 

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Ultimately, all sites in all geographies will follow and comply with: 
• 
Principles of Declaration of Helsinki (including privacy and data protection laws), or the laws 
and regulations of each participating country, whichever affords greater protection for the 
study subjects 
• 
21 CFR Part 11 (Electronic Records, Electronic Signatures) 
• 
21 CFR Part 54 (Financial Disclosure by Clinical Investigators) 
• 
The procedures described within this CIP 
• 
Local Ethics Committee requirements 
• 
The Clinical Trial Agreement 
 
In addition to the regulatory requirements outlined above, the study will be conducted according to 
federal, national and local laws, regulations, standards and requirements of the 
countries/geographies where the study is being conducted.  These include but are not limited to: 
• 
In Australia, local laws will be complied with and below will be followed:  
o Declaration of Helsinki 2013 and ISO 14155:2011  
• 
In Canada, the below will be followed: 
o Medical Devices Regulations, 1998 (SOR/98-282), 59(1), 59(2), 60(1), and the 
Canadian Regulatory Guidelines for Mandatory Medical Device Problem Reporting 
for Medical Devices, 2011.  
• 
In Europe, the study will be conducted in compliance with: 
o Declaration of Helsinki 2013, the Competent Authority requirements, the Medical 
Device Directive (MDD) 93/42/EEC and ISO 14155:2011  
• 
In Japan, the study will be conducted in compliance with:  
o MHLW Ordinance No. 36, 2005 and related laws and regulations 
• 
In the United States, the study will be conducted under an FDA Investigational Device 
Exemption (IDE) in compliance with US FDA 21 CFR Parts:  
o 50: Protection of Human subjects, 56: Institutional Review Boards and 812: 
Investigational Device Exemptions 
 
Any additional requirements imposed by an Ethics Committee or regulatory authority shall be 
followed, if appropriate. All participating geographies will make study data available to the 
regulatory body such as FDA, Health Canada or competent authority if the regulatory body deems 
an onsite inspection necessary.  The regulatory body will be able to inspect records at clinical study 
sites around the world to resolve any uncertainties about whether the study was conducted in 
accordance with good clinical practice. 
The study will be publicly registered prior to first enrollment in accordance with the 2007 Food and 
Drug Administration Amendments Act (FDAAA) and Declaration of Helsinki on 
http://clinicaltrials.gov (PL 110-85, Section 810(a)). In addition, the study may be registered in local 
regulatory databases where required by local law. 

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Approval of the Clinical Investigation Plan (CIP) is required from the following groups prior to any 
study procedures at a study site:  
• 
Medtronic  
• 
Principal Investigators (where required by local law) 
• 
An independent Ethics Committee 
• 
Geography-specific regulatory authorities (if regulatory approval is required) 
 
Similarly, approval of subsequent revisions to the CIP is required from the above-mentioned 
groups prior to implementation of the revised CIP at the study sites. 
 
 

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14. Study Administration 
14.1. Monitoring  
It is the responsibility of Medtronic to ensure proper monitoring of this clinical study.  Trained 
Medtronic personnel or delegates appointed by Medtronic may perform study monitoring at the 
study site in order to ensure that the study is conducted in accordance with the CIP, the Clinical 
Trial Agreement, and applicable regulatory and local requirements. Medtronic, or delegates, must 
therefore be allowed direct access to the subjects’ case histories (clinic and hospital records, and 
other source data/documentation) upon request as per the IC Form, Research Authorization 
(where applicable) and Clinical Trial Agreement. The Principal Investigator should also be available 
during monitoring visits. 
Frequency of monitoring visits may be based upon subject enrollment, duration of the study, study 
compliance, number of adverse events, number of deviations, findings from previous monitoring 
visits and any suspected inconsistency in data that requires investigation. Regulatory documents 
may be reviewed at each study site. Monitoring for the study may include, but not limited to, site 
qualification visits, site initiation visits, interim monitoring visits, and closeout visits, and will be 
done in accordance to the study-specific monitoring plan. 
Monitoring visits may be conducted periodically to assess site study progress, the Investigator’s 
adherence to the CIP, regulatory compliance including but not limited to Ethics Committee 
approval and review of the study, maintenance of records and reports, and review of source 
documents against subject CRFs. Monitors review regulatory and study compliance of study sites 
by identifying findings of non-compliance and communicating those findings along with 
recommendations for preventative/corrective actions to site personnel.  Monitors may work with 
study personnel to determine appropriate corrective action recommendations and to identify 
trends within the study or at a particular site. 
14.2. Data Management 
Data will be collected using an electronic data management system for clinical studies.  eCRF data 
will be stored in a secure, password-protected database which will be backed up nightly.  Data will 
be reviewed using programmed and manual data checks.  Data queries will be made available to 
sites for resolution.   
Data collected by Holters, Patient Activated Ambulatory Monitors and ECGs will be managed and 
over-read by a core lab.  Final classification of recurrent AF/AT/AFL will be stored in the study 
database. 

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Study management reports may be generated to assess data quality and study progress.  At the 
end of the study, the data will be frozen and will be retained per Medtronic standards and applicable 
regulations. 
All records and other information about subjects participating in the study will be treated as 
confidential. Data will be transferred and processed by Medtronic or a third party designated by 
Medtronic in a key coded form, unless it’s impossible to make it anonymous, for instance, where 
the subject’s name cannot be removed from the data carrier, such as fluoroscopy images.  In the 
case that de-identifying is impossible or involves a disproportionate effort, files containing 
personal data of subjects shall only be made accessible to authorized persons (secured role-based 
access). 
Procedures in the CIP require source documentation.  Source documentation will be maintained at 
the study site. Source documents, which may include worksheets, quality of life questionnaires, 
subject medical records, log files, must be created and maintained by the investigational site team.  
The data reported on the eCRFs shall be derived from source documents and be consistent with 
these source documents, and any discrepancies shall be explained in writing.  The eCRF may be 
considered source for the following data collection elements: 
• 
Database generated subject reference ID 
• 
Esophageal temperature 
• 
Investigator assessment of adverse event or death relatedness and severity 
• 
Date site became aware of the adverse event, non-subject adverse event, device 
deficiency or death 
• 
Reason for study deviation 
• 
Investigator’s assessment of conduction block 
 
When copies or printouts of the source documents are made, site personnel must ensure that all 
copies or printouts of original source documents are certified copies (i.e., signed and dated 
including a statement of true reproduction). 
The sponsor or a regulatory authority may audit or inspect the study site to evaluate the conduct 
of the study. The clinical Investigator(s)/institution(s) shall allow study related monitoring, audits, 
Ethics Committee review and regulatory inspection by providing direct access to source 
data/documents.  
Copies of source documents will be requested to support event adjudication by the Clinical Events 
Committee. In Japan, availability of source documentation may be limited due to hospital policies. 
If a specific source document is not available, necessary information may be transcribed onto the 
relevant CRF page. 

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14.3. Confidentiality 
All records and other information about subjects participating in the study will be treated as 
confidential. See Section 14.2 for further information. 
14.4. Liability 
Australia: Medtronic Australasia Pty Ltd is an indirectly owned subsidiary of Medtronic, Inc., which 
maintains appropriate clinical study liability insurance coverage as required under applicable laws 
and regulations and will comply with applicable local law and custom concerning specific insurance 
coverage. If required, a Clinical Study insurance statement/certificate will be provided to the Ethics 
Committee. 
 
Canada: Medtronic Canada ULC is an indirectly owned subsidiary of Medtronic, Inc., which 
maintains appropriate general liability insurance coverage as required under applicable laws and 
regulations and will comply with applicable local law and custom concerning specific insurance 
coverage. If required, a General Liability insurance statement/certificate will be provided to the 
Ethics Committee. 
 
Europe: Medtronic Bakken Research Center B.V. is an indirectly owned subsidiary of Medtronic, 
Inc., which maintains appropriate clinical study liability insurance coverage as required under 
applicable laws and regulations and will comply with applicable local law and custom concerning 
specific insurance coverage. If required, a Clinical Trial insurance statement/certificate will be 
provided to the Ethics Committee and/or Competent Authority (CA). 
Japan: Medtronic Japan Co. Ltd. Maintains appropriate clinical trial liability insurance coverage as 
required under applicable laws and regulations.  Documentation explaining compensation to the 
subjects in the event of study-related injuries will be submitted to Ethics Board.  Information 
regarding insurance, warranty and compensation will be provided under separate cover. 
US: Medtronic, Inc. maintains appropriate clinical study liability insurance coverage as required 
under applicable laws and regulations and will comply with applicable law and custom concerning 
specific insurance coverage. If required, a Clinical Trial Insurance statement/certificate will be 
provided to the IRB. 
 
The study is conducted in multiple countries; therefore, reimbursement and indemnification will be 
addressed on a country specific basis in the study documents and site Clinical Trial Agreements. 
14.5. CIP Amendments 
Approval of subsequent revisions to the CIP is required at each study site from the following 
groups prior to implementation of the revised CIP at the site: 

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• 
Medtronic 
• 
Principal Investigators (where required by local law) 
• 
Geography-specific regulatory authorities (if regulatory approval is required) 
• 
An independent Ethics Committee 
 
If a CIP amendment occurs, site personnel will need to be re-trained as necessary, and will need to 
submit any changes to their Ethics Committee as required by the committee.  
14.6. Record Retention and Reports 
Medtronic records and reports will be maintained in a password-protected document management 
system, and paper documents (where applicable) will be stored in secured file cabinets at 
Medtronic during the course of this study. After closure of the study Medtronic will archive records 
and reports per Medtronic standards and applicable regulations. 
14.6.1. 
Investigator Records 
The Investigator, or in Japan, the record keeping manager at the study site, is responsible for the 
preparation and retention of the records cited below.  All of the below records, with the exception 
of case history records and eCRFs, should be kept in the Investigator Site File (i.e., the study binder 
provided to the Investigator) or Subject Study Binder.  CRFs must be maintained and signed 
electronically within the electronic data capture system during the study.   
The following records are subject to inspection and must be retained for a period of two years (or 
longer as local law, regulations, or hospital administration requires) after the date on which the 
investigation is terminated or the date that the records are no longer required for purposes of 
supporting a pre-market approval application. 
• 
All correspondence between the Ethics Committee, sponsor, monitor, local regulatory 
agencies and the Investigator that pertains to the investigation, including required reports 
• 
Subject’s case history records, including:  
o IC Form signed and dated by subject  
 
In Europe and Japan, personally signed by subject and Investigator.   
 
In Japan, it is acceptable to retain only the signature page with the version 
number of the IC Form.) 
o Observations of adverse events and device deficiencies 
o Medical history 
o Procedure and follow-up data 
o Documentation of the dates and rationale for any deviation from the CIP 
• 
Reports of adverse events 

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• 
Electronically signed and dated CRFs 
• 
Blank case report forms (Australia and Europe only) 
• 
Subject screening logs (if used) and subject identification logs 
• 
List of investigation sites 
• 
Financial disclosure of Investigators 
• 
Device Disposition Logs 
• 
Shipping records of investigational devices 
• 
Investigational device accountability logs 
• 
All approved versions of the CIP, IC, and Investigator’s Brochure 
• 
Signed and dated Clinical Trial Agreement and Investigator Statement 
• 
Current signed and dated curriculum vitae of: 
o Investigators (all countries/geographies) 
o Key members of investigation site team (Australia and Europe only) 
• 
Documentation of delegated tasks 
• 
Ethics Committee approval documentation. Written information that the Investigator or 
other study staff, when member of the Ethics Committee, did not participate in the 
approval process. Approval documentation must include the Ethics Committee 
composition, in Europe and where required per local law.  
• 
Regulatory authority notification, correspondence and approval, where required per local 
law 
• 
Study training records for site staff 
• 
Insurance certificates (where requested by the Ethics Committee or CA) 
• 
Any other records that FDA or local regulatory agencies require to be maintained 
• 
Final Study Report including the statistical analysis 
14.6.2. 
Investigator Reports 
The Investigator is responsible for the preparation (review and signature) and submission to the 
sponsor of all case report forms, adverse events, device deficiencies, deaths, and any deviations 
from the CIP.  If any action is taken by an Ethics Committee with respect to this clinical study, 
copies of all pertinent documentation must be forwarded to Medtronic in a timely manner. Reports 
are subject to inspection and to the retention requirements as described above for Investigator 
records.  
The Investigator shall prepare and submit in a complete, accurate and timely manner the reports 
listed in this section and per local regulations. 

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Table 18: Investigator Reports Applicable for All Geographies per Medtronic Requirements 
Report  
Submit to 
Description/Constraints 
Withdrawal of Ethics 
Committee approval  
Sponsor and  
Relevant Authorities 
The Investigator must report a withdrawal 
of approval by the reviewing Ethics 
Committee of the Investigator’s part of 
the investigation within 5 working days. 
Study deviations  
Sponsor,  
Ethics Committee and 
Relevant Authorities 
Any deviation from the clinical 
investigational plan shall be recorded 
together with the explanation of the 
deviation. Notice of deviations from the 
CIP to protect the life or physical well-
being of a subject in an emergency shall be 
given as soon as possible, but no later than 
5 working days after the emergency 
occurred.  Except in such emergency, 
prior approval is required for changes in 
the plan or deviations. 
Australia: Report any suspected breaches 
to the sponsor and confirmed serious 
breaches to their institution (research 
governance office) within 72 hours of 
being aware or notified of the same; 
provide any follow up information as 
required and work with the institution or 
sponsor, as appropriate, to implement any 
corrective and preventative actions. 
Final report 
Sponsor,  
Ethics Committee and 
Relevant Authorities 
This report must be submitted per local 
requirements. 
Refer to Section 10 for adverse event, complaint, and device deficiency reporting.   
 
Table 19: Additional Investigator Reports Applicable to Australia 
Report  
Submit to 
Description/Constraints 
Progress Report  
Sponsor and 
Ethics 
Committee 
Per HREC requirements, but at least annually.  
Other  
Sponsor and 
Ethics 
Committee 
Provide any other reports if required by local law or 
Ethics Committee.  

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Table 20: Additional Investigator Reports Applicable to Europe 
Report  
Submit to 
Description/Constraints 
Withdrawal of Ethics 
Committee approval 
Sponsor 
Report if required by local law. 
Progress Report  
Sponsor and 
Ethics Committee/CA 
Provide if required by local law or Ethics 
Committee / CA.  
Study Deviations  
Sponsor and 
Ethics Committee 
Any deviation from the CIP shall be 
recorded together with an explanation for 
the deviation.  Deviations shall be 
reported to the sponsor who is 
responsible for analyzing them and 
assessing their significance.   
Note: When relevant, ethics committees, 
competent authorities or the appropriate 
regulatory bodies should be informed. 
(ISO 14155:2011) 
Failure to obtain 
informed consent 
Sponsor and 
Ethics Committee 
Informed consent shall be obtained in 
writing and documented before a subject 
is enrolled into the clinical investigation.  
(ISO 14155:2011) 

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Table 21: Additional Investigator Reports Applicable to Japan 
Report  
Submit to 
Description/Constraints 
Co-Investigator/ 
Clinical Trial 
Collaborator List 
HOMI 
When the principal Investigator assigns important parts 
of the clinical trial duties to co-Investigators and/or 
clinical trial collaborators, he or she shall prepare a list of 
the assigned duties and the individual performing the 
assigned duties, submit the list to the HOMI on the list, 
and receive the appointments of such individuals. 
(MHLW Ordinance 36, 2005 Article 63) 
Study Deviations 
Sponsor and 
HOMI 
The Investigator may implement a deviation from, or a 
change in, the protocol to eliminate an immediate 
hazard(s) to study subjects without prior Ethics Board 
approval. In this case, the Investigator shall immediately 
submit to the sponsor, the HOMI, and to the Ethics 
Board via the HOMI, the description and reason for the 
deviation and the proposed revision to the protocol, if 
one is necessary, to receive agreement. All deviations, 
regardless of the reason, shall be submitted to the 
sponsor. (MHLW Ordinance 36, 2005 Article 66) 
Summary of the 
Clinical Study 
Status 
HOMI 
The principal Investigator shall submit a summary of the 
clinical study status to the HOMI in writing once a year, 
or more frequently if requested by the Ethics Board, to 
receive the continuation review by the institutional 
review board. (MHLW Ordinance 36, 2005 Article 68) 
Premature 
Termination or 
Suspension of the 
Clinical 
Investigation 
HOMI 
When the principal Investigator discontinues or 
suspends the clinical study, he or she shall promptly 
notify the HOMI thereof in writing, and explain in detail in 
writing the discontinuation or suspension. (MHLW 
Ordinance 36, 2005 Article 69) 
Completion of the 
Clinical 
Investigation 
HOMI 
When the clinical study is completed, the principal 
Investigator shall notify the HOMI thereof in writing and 
report on a summary of the clinical study results in 
writing. (MHLW Ordinance 36, 2005 Article 69) 
 

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Table 22: Additional Investigator Reports Applicable to the United States  
Report  
Submit to 
Description/Constraints 
Withdrawal of Ethics 
Committee approval 
Sponsor 
The Investigator must report a withdrawal of 
approval by the reviewing Ethics Committee of 
the Investigator’s part of the investigation 
within 5 working days.  (21 CFR 812.150(a)(2)) 
Progress report  
Sponsor and 
Ethics Committee 
The Investigator must submit this report to 
the sponsor and Ethics Committee at regular 
intervals, but in no event less than yearly. (21 
CFR 812.150 (a)(3)).   
Study deviations  
Sponsor and 
Ethics Committee 
Notice of deviations from the CIP to protect 
the life or physical wellbeing of a subject in an 
emergency shall be given as soon as possible, 
but no later than 5 working days after the 
emergency occurred.  Except in such 
emergency, prior approval is required for 
changes in the plan or deviations.  If the 
deviation may affect the scientific soundness 
of the plan or the rights, safety and welfare of 
the subjects, the deviation must be approved 
by Medtronic, the Ethics Committee, and the 
FDA/applicable regulatory authorities.  If the 
deviation does not affect these issues, then 
only Medtronic must approve it.  (21 CFR 
812.150(a)(4)) 
Failure to obtain 
informed consent prior 
to investigational device 
use 
Sponsor and 
Ethics Committee 
If an Investigator uses a device without 
obtaining a signed Informed Consent Form, 
the Investigator shall report such use within 5 
working days after device use.  (21 CFR 
812.150(a)(5)) 
Final report 
Sponsor, 
Ethics Committee, and 
Relevant Authorities 
This report must be submitted within 3 months 
of study completion or termination of the 
investigation or the Investigator’s part of the 
investigation.  (21 CFR 812.150(a)(6)) 
Other 
Ethics Committee and 
FDA 
An Investigator shall, upon request by a 
reviewing Ethics Committee, FDA or any other 
regulatory agency, provide accurate, 
complete, and current information about any 
aspect of the investigation. (21 CFR 
812.150(a)(7)) 
 

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14.6.3. 
Sponsor Records 
Medtronic shall maintain the following accurate, complete, and current records: 
• 
All correspondence which pertains to the investigation 
• 
Investigational Device Disposition Logs 
• 
Signed Clinical Trial Agreements, financial disclosure of Investigators, and delegated task 
list  
• 
Current signed and dated curriculum vitae of  
o Investigators (all countries/geographies) 
o Key members of the investigation site team (Australia and Europe only) 
• 
All approved versions of the IC Form, and other information provided to the subjects and 
advertisements, including translations 
• 
All approved versions of the Clinical Investigation Plan, study related reports, and 
Investigator’s Brochure 
• 
All case report forms and supporting documentation submitted by investigator, samples of 
Informed Consent Forms, and other information provided to the subjects 
• 
Copies of all Ethics Committee approval letters and relevant Ethics Committee 
correspondence and Ethics Committee voting list/roster/letter of assurance 
• 
Names of the institutions in which the clinical study will be conducted 
• 
Regulatory authorities correspondence, notification and approval as required by national 
legislation 
• 
Insurance certificates (where requested by the Ethics Committee) 
• 
Shipping records of investigational devices 
• 
Investigational device accountability logs 
• 
Names/contact addresses of monitors 
• 
Monitoring visit reports and follow-up letters 
• 
Forms for reporting any adverse events and adverse device effects 
• 
Statistical analyses and underlying supporting data 
• 
Final report of the clinical investigation 
• 
Study training records for site personnel and Medtronic personnel involved in the study 
• 
Any other records that local regulatory agencies require to be maintained 
14.6.4. 
Sponsor Reports 
Medtronic shall prepare and submit the following complete, accurate, and timely reports listed in 
the tables below (by geography).  In addition to the reports listed below, Medtronic shall, upon 
request of reviewing Ethics Committee, regulatory agency or FDA, provide accurate, complete and 
current information about any aspect of the investigation. Safety data reporting requirements are 
listed in Section 10. 

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Table 23: Sponsor Reports for Australia 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical study 
Investigators,  
Ethics Committee, 
and relevant 
authorities 
Provide prompt notification of termination or 
suspension and reason(s). 
Recall and device 
disposition 
Investigators, 
Ethics Committee, 
and relevant 
authorities 
Notification as per local requirements in Australia.  
Study deviation  
Investigators,  
Ethics Committee, 
and relevant 
authorities 
Ensure that all deviations from the Clinical Investigation 
Plan are reviewed with the appropriate clinical 
Investigator(s), are reported on the case report forms 
and the final report of the clinical investigation.  
Site specific study deviations will be submitted to 
Investigators per local requirements. Serious breaches 
should be reported to the reviewing HREC and PI within 7 
calendar days of confirming a serious breach has 
occurred and provide follow-up reports when required.  
 
Table 24: Sponsor Reports for Canada 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical 
investigation 
Investigators, Ethics 
Committee, 
Health Canada, and  
Head of the Institution 
Provide prompt notification of termination or  
suspension and reason(s).  
Recall and device 
disposition 
Investigators, Ethics 
Committee, Health 
Canada 
Notification as per local requirements in Canada. 
Study deviation  
Investigators 
Ensure that all deviations from the Clinical Investigation 
Plan are reviewed with the appropriate clinical 
Investigator(s), are reported on the case report forms 
and the final report of the clinical investigation.  
Site specific study deviations will be submitted to 
Investigators periodically.   
Final report 
Investigators, 
Ethics Committee, 
Health Canada 
A final report will be submitted to Health Canada, 
Investigators, and Ethics Committees after completion 
or termination of this study.  

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Table 25: Sponsor Reports for Europe 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical 
investigation 
Investigators, 
Ethics Committee, 
relevant authorities 
 
Provide prompt notification of termination or 
suspension and reason(s). (ISO 14155:2011) 
Withdrawal of 
Ethics Committee 
approval 
Investigators, 
Ethics Committee, 
relevant authorities  
Investigators, other Ethics Committees and relevant 
authorities will be notified only if required by local laws or 
by the Ethics Committee. 
Withdrawal of CA 
approval 
Investigators, 
Ethics Committee, 
relevant authorities  
Investigators, Ethics Committees and relevant 
authorities will be notified only if required by local laws or 
by the Ethics Committee. 
Progress Reports 
Ethics Committee 
and regulatory 
authorities 
This will be submitted to the Ethics Committee and 
regulatory authorities only if required by local laws or by 
the Ethics Committee. 
Final report 
Investigators,  
Ethics Committee, 
and regulatory 
authorities upon 
request 
For sites complying with ISO 14155: 
• 
The Investigator shall have the opportunity to 
review and comment on the final report.   
• 
If a clinical Investigator does not agree with the 
final report, his/her comments shall be 
communicated to the other Investigator(s).   
• 
The coordinating Investigator shall sign the 
report. If no coordinating Investigator is 
appointed, then the signature of the principal 
Investigator in each center should be 
obtained.    (ISO 14155:2011) 
Study deviation  
Investigators 
Ensure that all deviations from the Clinical Investigation 
Plan are reviewed with the appropriate clinical 
Investigator(s), are reported on the case report forms 
and the final report of the clinical investigation.  (ISO 
14155:2011) 
Site specific study deviations will be submitted to 
Investigators periodically.   
 

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Table 26: Sponsor Reports for Japan 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical 
investigation 
HOMI 
PMDA 
When the sponsor suspends or discontinues the clinical trial, 
he or she shall promptly notify the heads of all the medical 
institutions and regulatory authorities thereof and the 
detailed reason therefor in writing. (MHLW Ordinance 36, 
2005 Article 32) 
Suspension of 
development of 
investigational 
device 
HOMI 
PMDA 
When the sponsor decides not to attach the documents 
concerning clinical trial records collected in the clinical trial to 
the authorization application, he or she shall promptly notify 
the heads of all the medical institutions other facilities 
engaged in the clinical trial thereof and the detailed reason 
therefor in writing. (MHLW Ordinance 36, 2005 Article 32) 
Investigator List 
HOMI 
PMDA 
The sponsor shall beforehand submit the list of Investigators 
to PMDA and HOMI. (MHLW Ordinance 36, 2005 Article 32) 
The sponsor shall submit the list of Investigators to PMDA 
and HOMI when making any changes in the list. (MHLW 
Ordinance 36, 2005 Article 32) 
Important 
information 
concerning the 
quality, 
effectiveness, and 
safety of the 
investigational 
device 
Investigators 
HOMI 
PMDA 
When new, important information is obtained, the sponsor 
shall revise the Investigator’s brochure. In addition, prior to 
revising the Investigator’s brochure, the sponsor shall report 
the information to the principal Investigator, HOMI, and 
regulatory authorities. (MHLW Ordinance 36, 2005 Article 28) 
Clinical Trial Report PMDA upon 
request 
The sponsor shall prepare, according to the procedure, a 
clinical study report that summarizes the results, etc., of a 
clinical study when it is completed or discontinued. (MHLW 
Ordinance 36, Article 33) 
Study deviation 
Investigators 
HOMI as 
necessary 
Ensure that all deviations from the Clinical Investigation Plan 
are reviewed with the appropriate clinical Investigator(s), are 
reported on the case report forms and the final report of the 
clinical investigation. (ISO 14155:2011) Site specific study 
deviations will be submitted to Investigators quarterly. When 
the monitor confirms deviation as a result of monitoring, the 
monitor shall notify the principal Investigator and, as 
necessary, the HOMI thereof. The monitor shall also request 
for appropriate measures to be taken to prevent such 
deviation in the future. (MHLW Ordinance 36, 2005 Article 30) 
 

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Table 27: Sponsor Reports for the United States 
Report  
Submit to 
Description/Constraints 
Withdrawal of 
Ethics Committee 
approval 
Investigators, 
Ethics Committee, 
FDA, and 
relevant 
authorities 
Notification within five working days.  (21 CFR 
812.150(b)(2))   
Withdrawal of FDA 
approval 
Investigators, 
Ethics Committee, 
FDA, and relevant 
authorities 
Notification within five working days.  (21 CFR 
812.150(b)(3)) 
Investigator List 
FDA 
Submit at 6-month intervals, a current list of the names 
and addresses of all Investigators participating in the 
investigation.  (21 CFR 812.150(b)(4)) 
Progress Reports 
Ethics Committee 
and FDA 
Progress reports will be submitted at least annually.  (21 
CFR 812.150(b)(5), 812.36(f)   
Recall and device 
disposition 
Investigators, 
Head of 
Institution, 
Ethics Committee, 
FDA, and relevant 
authorities 
Notification within 30 working days and will include the 
reasons for any request that an Investigator return, repair, 
or otherwise dispose of any devices.  (21 CFR 
812.150(b)(6)) 
Failure to obtain 
Informed Consent 
Form 
FDA 
Investigator’s report will be submitted to FDA within five 
working days of notification.  (21 CFR 812.150(b)(8)) 
Final report 
Investigators, 
Ethics Committee,  
Regulatory 
authorities upon 
request, and FDA 
Medtronic will notify FDA within 30 working days of the 
completion or termination of the investigation.  A final 
report will be submitted to the FDA, Investigators, and 
IRBs/Ecs within six months after completion or 
termination of this study.  (21 CFR 812.150(b)(7)) 
Study deviation  
Investigators 
Ensure that all deviations from the Clinical Investigation 
Plan are reviewed with the appropriate clinical 
Investigator(s), are reported on the case report forms and 
the final report of the clinical investigation.  
Site specific study deviations will be submitted to 
Investigators periodically.   
Other 
Ethics Committee, 
and FDA 
Accurate, complete, and current information about any 
aspect of the investigation. (21 CFR 812.150(b)(10)) 
 

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Medtronic records and reports will be maintained in a password-protected document management 
system, and paper documents (where applicable) will be stored in stored in secured file cabinets at 
Medtronic during the course of the study.  
After closure of the study Medtronic will archive records and reports per Medtronic standards and 
applicable regulations. 
14.7. Publication and Use of Information 
Publications from the study will be handled according to Medtronic Global Standard Operating 
Procedures and as indicated in the Clinical Trial Agreement. 
Publication Committee 
Medtronic may form the PULSED AF Publication Committee from the Steering Committee and/or 
study Investigators.  Medtronic personnel may serve as members of the committee. This 
committee will manage study publications with the goal of publishing findings from the data. The 
Publication Committee will develop the final Publication Plan as a separate document.   
The Publication Committee’s role is to: 1) manage elements addressed in the publication plan as 
outlined in this section, 2) develop the final Publication Plan under separate cover, 3) execute the 
Publication Plan, 4) oversee the publication of primary, secondary and ancillary study results, 5) 
review and prioritize publication proposals, 6) provide input on publication content, and 7) 
determine authorship.  In addition, the committee will apply and reinforce the authorship guidelines 
set forth in the Publication Plan.   
Membership in the Publication Committee does not guarantee authorship.  The committee will 
meet as needed. 
Management of Primary, Secondary and Ancillary Publications 
The Publication Committee reviews, prioritizes, and manages all publications including primary, 
secondary and ancillary publications.  Primary and secondary publications are those that address 
analyses of any or all primary objectives or secondary objectives, respectively, as specified in the 
Clinical Investigation Plan.  
An ancillary publication is any publication that does not address the study objectives identified in 
the Clinical Investigation Plan.  They include publications proposed and developed by other 
Medtronic departments or entities, clinicians participating in this clinical study, and clinicians not 
participating in this clinical study.  The committee will work with Medtronic to ensure that requests 
do not present conflicts with other proposals, are not duplicative, and to determine which ancillary 
publication proposals, if any, will be supported.   

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The committee may decide that no publications, including abstracts, will be published prior to the 
end of the study or with individual site data.  Requests for publications on study objectives utilizing 
subset data (e.g., regional) will be evaluated for scientific validity and the ability of Medtronic to 
provide resources.   
Criteria for Determining Authorship 
Publications will adhere to authorship criteria defined by the International Committee of Medical 
Journal Editors (ICMJE, Uniform requirements for manuscripts submitted to biomedical journals, 
www.icmje.org).  Individual authorship criteria defined by the target journal or conference will be 
followed when it differs from ICMJE criteria. 
Authors, including Medtronic personnel, must at a minimum meet all of the conditions below: 
• 
Substantial contribution to conception and design, or acquisition of data, or analysis and 
interpretation of data 
• 
Drafting the article or revising it critically for important intellectual content 
• 
Final approval of the version to be published 
• 
Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved 
 
Decisions regarding authorship and contributor-ship will be made by the committee. The selected 
authors will be responsible for drafting the publication. All selected authors must fulfill the 
authorship conditions stated above to be listed as authors, and all contributors who fulfill the 
conditions must be listed as authors. 
All Investigators not listed as co-authors will be acknowledged as the “Medtronic PULSED AF Study 
Investigators” and will be individually listed according to the guidelines of the applicable scientific 
journal when possible and affiliation. Any other contributors will be acknowledged by name with 
their specific contribution indicated. 
Transparency 
Transparency of study results will be maintained by the following means: 
• 
A final report, describing the results of all objectives and analysis, will be distributed to all 
Investigators, Ethics Committees and Regulatory Authorities of participating countries 
when required by local law 
• 
Registering and posting the study results on public registries (e.g., ClinicalTrials.gov, UMIN) 
based on the posting rules stipulated, as required by local law  
• 
Submitting for publication the primary study results after the study ends  

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• 
Disclosing conflicts of interest (e.g., financial) of the co-authors of publications according 
to the policies set forth by the corresponding journals and conferences  
• 
Making an individual site’s study data accessible to the corresponding Investigator after the 
completion of the study, if requested 
14.8. Investigator / Site Selection 
The role of the Principal Investigator is to implement and manage the day-to-day conduct of the 
clinical investigation as well as ensure data integrity and the rights, safety and well-being of the 
subjects involved in the clinical investigation. 
The minimum required criteria for a Principal Investigator and proposed investigational center are 
listed below: 
• 
Principal investigator has an MD degree, or equivalent, with a Fellowship in 
Electrophysiology and a minimum of 2 years of experience treating atrial fibrillation in 
patients using endocardial techniques. 
• 
Principal Investigator must participate in a Medtronic physician engagement event with 
hands on use of the Pulsed Field Ablation System, prior to enrolling a subject. 
• 
Principal Investigator has adequate time and resources to conduct the study throughout 
the duration of the study, including, as applicable, facilities, and qualified staff. 
• 
Principal Investigator has access to an adequate number of subjects in the study specific 
patient population to enroll 1-2 subjects per month. 
• 
Principal Investigator has the ability to comply with the Clinical Investigation Plan, and 
applicable REB/EC/IRB and regulatory requirements. 
• 
Principal Investigator is not debarred, disqualified or working under sanctions. 
14.9. Site Activation 
During the activation process (prior to subject enrollment), Medtronic will train site personnel on 
the CIP, relevant standards and regulations, informed consent, and on data collection and 
reporting tools. If new members join the study site team, they will receive training on the applicable 
clinical study requirements relevant to their role before contributing to the clinical study. 
Prior to performing study related activities, all local regulatory requirements shall be fulfilled, 
including, but not limited to the following: 
• 
Ethics Committee approval (and membership roster/voting list) of the current version of 
the CIP, Informed Consent Form, subject facing materials, Investigator Brochure as 
required by local laws and other materials, as necessary. 
• 
Regulatory authority approval or notification (as required per local law) 
• 
Fully executed Clinical Trial Agreement (CTA) and Investigator Statement where applicable 
• 
Financial Disclosure of Investigators 

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• 
Curriculum Vitae (CV) of Investigators and key members of the investigation site team (as 
required by local law) (in Australia and Europe, CVs are required for the Principal 
Investigator and all site personnel who have been delegated tasks) 
• 
Documentation of delegated tasks 
• 
Documentation of study training (including CIP, IB if available, informed consent process, 
data collection tools, regulations and product training) 
 
Documentation of delegated tasks must be completed prior to any person other than the Principal 
Investigator performing study activities. 
Additional requirements imposed by the Ethics Committee and regulatory authority shall be 
followed. 
Medtronic contracts with participating institutions/investigators through a Clinical Trial 
Agreement that defines the scope and responsibilities and associated compensation related to 
carrying out the obligations under a clinical study sponsored by Medtronic. 
In addition, all participating site staff must be trained on the current version of the CIP and must be 
delegated by the Principal Investigator to perform study related activities. 
Medtronic will provide each study site with documentation of study site/Investigator readiness in 
the form of a site readiness letter; this letter must be received prior to subject enrollment. 
Additional site personnel included after the initial activation will be notified when all requirements 
have been completed. 
14.10. 
Suspension or Early Termination 
14.10.1. Early Termination or Suspension 
Early termination is the closure of a clinical study that occurs prior to meeting defined endpoints. 
This is possible for the whole study or a single site.  Suspension is a temporary postponement of 
study activities related to enrollment.  This is possible for the whole study or a single site.  If 
suspension is lifted, the Investigator shall assess whether or not to continue the clinical study at 
their site. 
14.10.2. Study-wide Termination or Suspension 
Possible reasons for considering study termination or suspension of the study include but are not 
limited to: 

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• 
Adverse events associated with the system or product under investigation which might 
endanger the safety or welfare of the subject 
• 
Observed/suspected performance different from the product’s design intent 
• 
Decision by Medtronic or regulatory body (where the study is operating under regulatory 
body authority)  
• 
Technical issues during the manufacturing process 
14.10.3. Investigator/Center Termination or Suspension 
Possible reasons for clinical Investigator or center/site termination or suspension include but are 
not limited to: 
• 
Failure to obtain Ethics Committee annual renewal of the study 
• 
Persistent non-compliance to the Clinical Investigation Plan (e.g. failure to adhere to 
inclusion/exclusion criteria, failure to follow subjects per visit schedule)  
• 
Lack of enrollment 
• 
Noncompliance to regulations and the terms of the Clinical Trial Agreement (e.g. failure to 
submit data in a timely manner, failure to resolve data queries and monitoring findings in a 
timely manner)  
• 
Ethics Committee suspension of the site 
• 
Fraud or fraudulent misconduct is discovered (as defined by local law and regulations)  
• 
Investigator request (e.g. no longer able to support the study) 
14.10.4. Procedures for Termination or Suspension 
14.10.4.1. 
Medtronic-Initiated and Regulatory Authority-Initiated 
• 
Medtronic will promptly inform the clinical Investigators, or in Japan the HOMI, of the 
termination or suspension and the reasons and inform the regulatory authority(ies) where 
required. 
• 
In the case of study termination or suspension for reasons other than a temporary Ethics 
Committee approval lapse, the Investigator will promptly inform the Ethics Committee.  In 
Japan, the HOMI will promptly inform the Investigator and Ethics Board. 
• 
In the case of study termination, the Investigator must inform the subjects and may inform 
the personal physician of the subjects to ensure appropriate care and follow-up is provided 
• 
In the case of a study suspension, subject enrollment must stop until the suspension is 
lifted by Medtronic. 
• 
In the case of a study suspension, enrolled subjects should continue to be followed out of 
consideration of their safety, rights and welfare. 

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14.10.4.2. 
Investigator-Initiated 
• 
The Investigator will inform Medtronic and provide a detailed written explanation of the 
termination or suspension.  In Japan, the Investigator will promptly inform the HOMI and 
the HOMI will inform Medtronic in writing. 
• 
The Investigator will promptly inform the institution (where required per regulatory 
requirements). 
• 
The Investigator will promptly inform the Ethics Committee. 
• 
The Investigator will promptly inform the regulatory authorities (where required per 
regulatory requirements). 
• 
The Investigator will promptly inform the subjects and/or the personal physician of the 
subjects to ensure appropriate care and follow-up is provided. 
• 
In the case of a study suspension, subjects enrolled should continue to be followed out of 
consideration of their safety, rights and welfare. 
 
14.10.4.3. 
Ethics Committee-Initiated 
• 
The Investigator, or in Japan the HOMI, will inform Medtronic and provide a detailed written 
explanation of the termination or suspension within 5 business days.  In Japan, HOMI will 
also inform the Investigator. 
• 
Subject enrollment must stop until the suspension is lifted. 
• 
Subjects already enrolled should continue to be followed in accordance with Ethics 
Committee policy or its determination if an overriding safety concern or ethical issue is 
involved. 
• 
The Investigator will inform his/her institution (where required per local requirements). 
• 
The Investigator will promptly inform the subjects and/or the personal physician of the 
subjects, with the rationale for the study termination or suspension. 
• 
The Investigator will promptly inform the regulatory authorities (where required per 
regulatory requirements). 
 
 

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15. References 
1. Calkins H, et al., 2017 HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement 
on Catheter and Surgical Ablation of Atrial Fibrillation, Heart Rhythm (2017), 
doi:10.10106/j.hrthm.2017.05.012. 
2. Chugh, S. S., et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 
2010 Study. Circulation 129, 837-847, doi:10.1161/circulationaha.113.005119 (2014). 
3. Naccarelli, G. V., Varker, H., Lin, J. & Schulman, K. L. Increasing prevalence of atrial 
fibrillation and flutter in the United States. The American journal of cardiology 104, 1534-
1539, doi:10.1016/j.amjcard.2009.07.022 (2009). 
4. Zoni-Berisso M, et al. Epidemiology of atrial fibrillation: European perspective. Clinical 
Epidemiology. 2014;6:213-220. Doi:10.2147/CLEP.S47385. 
5. Wolf P, et al. Atrial fibrillation as an independent risk factor for stroke: the Framingham 
Study. Stroke. 1991;22(8):983-988. 
6. Ghanbari H, et al. Mortality and cerebrovascular events after radiofrequency catheter 
ablation of atrial fibrillation. Heart Rhythm. 2014;11:1503-1511. 
7. Calkins H, et al. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and 
Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural 
Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial 
Design. Heart Rhythm 2012 ;9 :632-696. 
8. January C, Wann L, Alpert J, Calkins H, et al. 2014 AHA/ACC/HRS guideline for the 
management of patients with atrial fibrillation: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart 
Rhythm Society. J Am Coll Cardiol. 2014. 
9. Raviele, et al. Venice Chart International consensus Document on Atrial Fibrillation : 2011 
Update. J Cardiovasc Electrophysiol, 2012;23:890-923. 
10. Jais P, et al. Stepwise Catheter Ablation of Chronic Atrial Fibrillation: Importance of 
Discrete Anatomic Sites for Termination. J Cardiovasc Electrophysiol. 2006;17: S28-S36, 
Suppl. 3. 
11. Dong JZ, Sang CH, Yu RH, et al. Prospective randomized comparison between a fixed 
“2C3L” approach vs. stepwise approach for catheter ablation of persistent atrial fibrillation. 
Europace. Doi:10.1093/europace/euv067.  
12. Wynn GJ, Panikker S, Morgan M, et al. Effect of linear ablation in substrate-based AF: 
Results of the substrate modification with ablation and antiarrhythmic drugs in non-
permanent atrial fibrillation trial. Heart Rhythm. 2015;12:1715. 
13. Verma A, Jiang CY, Betts TR, et al, STAR AF II Investigators. Approaches to Catheter 
Ablation for Persistent Atrial Fibrillation. N Engl J Med. 2015;372:1812-1822. 
14. Scott P, Silberbauer J, Murgatroyd F. The impact of adjunctive complex fractionated atrial 
electrograms ablation and linear lesions on outcomes in persistent atrial fibrillation: a meta-
analysis. Europace 2016; 18, 359-367. 
15. Calkins H, et al. HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical 
Ablation of Atrial Fibrillation: Recommendations for personnel, Policy, Procedures and 
Follow-Up. Europace. 2007;9(6):335-379. 

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16. Avitall, B. et al. The safety and efficacy of multiple consecutive cryo lesions in canine 
pulmonary veins-left atrial junction. Heart rhythm 1, 203-209, 
doi:10.1016/j.hrthm.2004.03.058 (2004).  
17. Dinerman, J. L., Berger, R. D. & Calkins, H. Temperature monitoring during radiofrequency 
ablation. Journal of cardiovascular electrophysiology 7, 163-173 (1996).  
18. Harrison, L. et al. Cryosurgical ablation of the A-V node-His bundle: a new method for 
producing A-V block. Circulation 55, 463-470 (1977). 
19. Georgiopoulos, G., Tsiachris, D. & Manolis, A. S. Cryoballoon ablation of atrial fibrillation: a 
practical and effective approach. Clinical cardiology 40, 333-342, doi:10.1002/clc.22653 
(2017). 
20. Stewart, Mark T., et al. “Intracardiac pulsed field ablation: proof of feasibility in a chronic 
porcine model.” Heart rhythm. 16.5 (2019): 754-764. 
21. Howard, Brian T., et al. “Pulsed Field Ablation Reduces Pulmonary Vein Stenosis Risk: An 
Advanced Model for Assessment of PV Stenosis.” Circulation 138.Suppl_1 (2018): A16516-
A16516. 
22. Verma, A., et al. “Pulsed field ablation-feasibility, safety and comparison to 
radiofrequency.” EUROPEAN HEART JOURNAL. Vol. 39. GREAT CLARENDON ST, 
OXFORD OX2 6DP, ENGLAND: OXFORD UNIV PRESS, 2018. 
23. Attanasio, P. et al. Pain Reactions during Pulmonary Vein Isolation under Deep Sedation: 
Cryothermal versus Radiofrequency Ablation. Pacing and clinical electrophysiology: PACE 
39, 452-457, doi:10.1111/pace.12840 (2016). 
24. P100010/R017 “STOP AF PAS Final Post-Approval Study Report”. 
25. Kuck, K. H., Brugada, J., Fürnkranz, A., et al. Cryoballoon or Radiofrequency Ablation for 
Paroxysmal Atrial Fibrillation. New England Journal of Medicine 374, 2235-2245 (2016). 
26. Squara, F., Zhao, A., Marijon, E., et al. Comparison between radiofrequency with contact 
force-sensing and second-generation cryoballoon for paroxysmal atrial fibrillation catheter 
ablation: a multicentre European evaluation. Europace 17, 718-724 (2015). 
27. Schmidt, M., Dorwarth, U., Straube, F., et al. Cryoballoon in AF ablation: impact of PV ovality 
on AF recurrence. Int J Cardiol 167, 114-120 (2013). 
28. Providencia, R., Defaye, P., Lambiase, P., et al. Results from a multicentre comparison of 
cryoballoon vs. radiofrequency ablation for paroxysmal atrial fibrillation: is cryoablation 
more reproducible? Europace 19, 48-57 (2017). 
29. Dukkipati, S., Cuoco, F., Kutinsky, I., et al. Pulmonary Vein Isolation Using the Visually 
Guided Laser Balloon: A Prospective, Multicenter, and Randomized Comparison to 
Standard Radiofrequency Ablation. Journal of the American College of Cardiology 66, 1350-
1360 (2015). 
30. Boveda, S., Metzner, A., Nguyen, D., et al. Single-Procedure Outcomes and Quality-of-Life 
Improvement 12 Months Post-Cryoballoon Ablation in Persistent Atrial Fibrillation: Results 
From the Multicenter CRYO4PERSISTENT AF Trial. Journal of the American College of 
Cardiology, doi:10.1016/j.jacep.2018.07.007 (2018). 
31. Tondo, C., Iacopino, S., Pieragnoli, P., et al. Pulmonary Vein Isolation Cryoablation for 
Persistent and Long-Standing Persistent Atrial Fibrillation Patients. Clinical Outcomes from 
Real Word Multicentric Observational Project. Heart Rhythm 15, 363-368, 
doi:10.1016/j.hrthm.2017.10.038 (2017). 

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32. Aryana, A., Baker, J., Espinosa Ginic M., et al. Posterior wall isolation using the cryoballoon in 
conjunction with pulmonary vein ablation is superior to pulmonary vein isolation alone in 
patients with persistent atrial fibrillation: A multicenter experience. Heart Rhythm 15, 1121-
1129 (2018). 
33. Deneke T et al. Silent cerebral events/lesions to AF ablation. J Cardiovasc Electrophysiol, 
2015; 26: 455-463. 
34. Di Biase, Luigi, et al. “Does periprocedural anticoagulation management of atrial fibrillation 
affect the prevalence of silent thromboembolic lesion detected by diffusion cerebral 
magnetic resonance imaging in patients undergoing radiofrequency atrial fibrillation 
ablation with open irrigated catheters? Results from a prospective multicenter 
study.” Heart Rhythm 11.5 (2014): 791-798. 
35. Neumann, Thomas, et al. “MEDAFI-Trial (Micro-embolization during ablation of atrial 
fibrillation): comparison of pulmonary vein isolation using cryoballoon technique vs. 
radiofrequency energy.” Europace 13.1 (2010): 37-44. 
36. Gaita, Fiorenzo, et al. “Incidence of silent cerebral thromboembolic lesions after atrial 
fibrillation ablation may change according to technology used: comparison of irrigated 
radiofrequency, multipolar nonirrigated catheter and cryoballoon.” Journal of cardiovascular 
electrophysiology 22.9 (2011): 961-968. 
37. Siklódy, Claudia Herrera, et al. “Incidence of asymptomatic intracranial embolic events after 
pulmonary vein isolation: comparison of different atrial fibrillation ablation technologies in a 
multicenter study.” Journal of the American College of Cardiology 58.7 (2011): 681-688. 
38. Nakamura, Tomofumi, et al. “Incidence of silent cerebral infarctions after catheter ablation 
of atrial fibrillation utilizing the second-generation cryoballoon.” Ep Europace 19.10 (2016): 
1681-1688. 
39. Tokuda, Michifumi, et al. “Effect of air removal with extracorporeal balloon inflation on 
incidence of asymptomatic cerebral embolism during cryoballoon ablation of atrial 
fibrillation.” Heart rhythm 14.9 (2017): 1291-1296. 
40. Miyazaki, Shinsuke, et al. “Thromboembolic risks of the procedural process in second-
generation cryoballoon ablation procedures: analysis from real-time transcranial Doppler 
monitoring.” Circulation: Arrhythmia and Electrophysiology10.12 (2017): e005612. 
41. Nakamura, Kohki, et al. “Postablation cerebral embolisms in balloon‐based atrial fibrillation 
ablation with periprocedural direct oral anticoagulants: A comparison between cryoballoon 
and HotBalloon ablation.” Journal of cardiovascular electrophysiology 30.1 (2019): 39-46. 
42. Miyazaki, Shinsuke, et al. “Silent cerebral events/lesions after second-generation 
cryoballoon ablation: How can we reduce the risk of silent strokes?.” Heart rhythm 16.1 
(2019): 41-48. 
43. Gaita, Fiorenzo, et al. “Radiofrequency catheter ablation of atrial fibrillation: a cause of 
silent thromboembolism? Magnetic resonance imaging assessment of cerebral 
thromboembolism in patients undergoing ablation of atrial fibrillation.” Circulation 122.17 
(2010): 1667-1673. 
44. Doi, Atsushi, et al. “Incidence and predictors of silent cerebral thromboembolic lesions 
after catheter ablation for atrial fibrillation in patients treated with direct oral 
anticoagulants.” Heart and Vessels 32.10 (2017): 1227-1235. 

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45. Neuzil, et al. Electrical reconnection after pulmonary vein isolation is contingent on contact 
force during initial treatment: results from the EFFICAS I study. Circ Arrhythm 
Electrophysiol. (2):327-33. 
46. Kautzner J, et al. EFFICAS II: optimization of catheter contact force improves outcome of 
pulmonary vein isolation for paroxysmal atrial fibrillation. Europace. 2015; 2015 
Aug;17(8):1229-1235. 
47. Ahmed, et al. The permanency of pulmonary vein isolation using a balloon cryoablation 
catheter. J Cardiovasc Electrophysiol. 2010;21(7):731-737. 
48. Williems, et al. Persistence of pulmonary vein isolation after robotic remotenavigated 
ablation for atrial fibrillation and its relation to clinical outcome. J Cardiovasc Electrophysiol. 
2010; 21(10):1079-1084. 
49. Reddy VY, et al. Durability of Pulmonary Vein Isolation with Cryoballoon Ablation: Results 
from the Sustained PV Isolation with Arctic Front Advance (SUPIR) Study. J Cardiovasc 
Electrophysiol. 2015 May;26(5):493-500. 
50. Kuck KR,et al. Impact of Complete Versus Incomplete Circumferential Lines Around the 
Pulmonary Veins During Catheter Ablation of Paroxysmal Atrial Fibrillation Results From 
the Gap-Atrial Fibrillation–German Atrial Fibrillation Competence Network 1 Trial. Circ 
Arrhythm Electrophysiol. 2016; 9e003337. 
51. Medicare Physician/Supplier Procedure Summary data. Available at: 
https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-
Reports/Physician-Supplier-Procedure-Summary/index.html 
 
 
 

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16. Appendices  
 
Appendix A: Study-Specific Requirements by Country 
Regulations for the conduct of clinical trials vary by country. Study-specific requirements in each 
country not outlined in the Clinical Investigational Plan will be provided under separate cover. 
 
 
 

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Appendix C: Foreseeable Adverse Events 
The information provided in this section pertains to foreseeable adverse events that may be 
observed in study subjects and may collectively assist in identifying those events for a given device 
or therapy that are unexpected in nature. 
The PVI ablation procedure involves surgery, therefore, standard adverse events associated with a 
surgical procedure may be experienced (e.g. anesthesia complications, injury, infections, bleeding, 
exacerbation of pre-existing conditions, healing complications). The focus of this section is to 
specifically address in more detail, those events that are foreseeable due to the use, performance, 
and/or presence of the PFA system under investigation.  
Treatment required for procedure and/or PFA system related adverse events that are experienced 
may include medication or other surgical and medical remedies. The adverse events associated 
with the use of the PFA system include but are not limited to those in Table C- 1. 
Table C- 1: Foreseeable Adverse Events 
Adverse Event/Risk  
Definition 
Access site complications (e.g. 
bruising, ecchymosis, AV fistula, 
hematoma, pseudoaneurysm) 
Complications at catheter insertion site in the groin 
Allergic reaction to x-ray contrast 
media 
Moderate to severe symptoms (for example: nausea, 
vomiting, hives, swelling, anaphylaxis) due to infusion of 
iodinated contrast media via IV 
Anesthesia reactions 
Moderate to severe side effects due to general anesthesia 
use, e.g. prolonged fatigue, transient confusion or memory 
loss, dizziness, urinary retention, nausea, vomiting, chills, and 
sore throat. In older patients, this can also include persistent 
confusion, memory loss, heart attack, pneumonia, 
thromboembolism and cerebrovascular accident. 
Anemia 
Deficiency of red blood cells or of hemoglobin in the blood 
resulting in weariness 
Arrhythmias, proarrhythmia (e.g. 
atrial flutter, bradycardia, heart 
block, tachycardia) 
Disruption of normal heart rate or rhythm 
Back pain 
Pain felt in the lower or upper back 
Bleeding, possibly requiring 
transfusion 
Loss of blood, including loss resulting in transfusion 
Body temperature elevation 
Sustained or continued fever, e.g. increase in body’s set point 
temperature greater than 1°C above normal diurnal body 
temperature 

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Perforation of the heart or other 
organs during transseptal 
puncture or other procedures 
Creation of a dissection or tear in myocardial tissue or other 
non-cardiac tissues during the ablation procedure that 
compromises hemodynamic stability 
Cardiac tamponade 
Pressure on the heart as a result of a significant pericardial 
effusion 
Chest discomfort 
Includes a range of feeling from sharp stabbing to dull ache in 
the chest 
Cough 
Rapid expulsion of air from the lungs 
Embolism 
Introduction of air, formation and dislodgement of a blood 
clot (thrombus) or dislodgement of cholesterol/plaque within 
the blood vessel, which travels downstream into small 
vessels, blocking blood flow and causing temporary or 
permanent damage to organs distal to blockage. Emboli are 
known to cause myocardial infarction, transient ischemic 
attack, stroke/cardiovascular accident, blurred vision, visual 
changes, paralysis, paresis, or kidney damage, peripheral 
ischemia and may ultimately lead to incapacitation or death. 
Symptomatic and non-symptomatic. 
Catheter entrapment in cardiac 
structures requiring intervention  
Tangling of the catheter with heart tissues which requires 
invasive intervention, including surgical repair 
Cerebrovascular accident (CVA) 
Blockage of blood flow, or rupture of an artery, to the brain 
which causes sudden death of brain cells 
Transient ischemic attack (TIA) 
New focal neurological deficit with rapid symptom resolution 
(usually 1 to 2 hours), no more than 24 hours 
Collateral damage to the 
conduction system or coronary 
vasculature 
Coronary artery injury due to occlusion or stenosis of the 
coronary arteries that may require balloon dilation, 
nitroglycerin use, or stenting. Prolonged injury may lead to 
myocardial infarction. 
Collateral damage to the conduction system includes 
unintended damage to the cardiac conduction system (e.g., 
atrioventricular node or sinus node). 
Death 
Complication or deterioration of health ultimately leading to a 
patient’s death 
Esophageal damage (including 
atrial esophageal fistula) 
Damage to the esophagus, including ulcer and 
atrioesophageal fistula (an abnormal passageway between 
the heart and esophagus) 
Hemoptysis 
Coughing up blood or blood-stained mucus 
Hypotension/ hypertension 
Low/high blood pressure 
Infections 
Invasion and multiplication of microorganisms (e.g. bacteria, 
virus) not normally present within the body 
Myocardial infarction or ischemia 
Blockage of blood flow to the heart muscle (i.e. heart attack) 

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Nerve injury or nerve damage 
(e.g. phrenic nerve injury) 
Phrenic Nerve Injury: Absent phrenic nerve function as 
assessed by diaphragmatic fluoroscopy/sniff test. 
Vagal Nerve Injury: an injury to the vagal nerve that results in 
esophageal dysmotility or gastroparesis 
Obstruction, perforation, 
damage, or spasm of the vascular 
system including the coronary 
circulation system 
Collateral damage to the vascular system includes 
unintended damage to the peripheral vascular system (ex: 
superior vena cava). 
Pericarditis or endocarditis 
Inflammation of the sac-like tissue that surrounds the heart, 
or vegetative growth inside the heart. 
Pleural effusion  
Collection of extra fluid around the lungs 
Pericardial effusion 
Fluid collecting in the pericardial sac that surrounds the heart 
Pneumonia 
Lung infection that inflames air sacs in one or both lungs 
Pneumothorax 
Collapsed lung 
Pulmonary vein stenosis 
Shrinkage of one or more pulmonary veins that carry blood 
from the lungs to the left atrium of the heart. 
Pulmonary edema 
Excess fluid accumulation in the lungs 
Radiation injury or damage and 
late malignancy 
Delayed effect of the radiation received by the patients, 
including acute and subacute skin injury, malignancy, and 
genetic abnormalities. 
Respiratory depression 
Suppression of normal breathing ability. 
Sore throat 
Pain in throat 
Unintended complete or 
incomplete atrioventricular node 
(AV-Node) or sinus node block or 
damage 
AV block has been defined by the occurrence of a complete 
AV block lasting ≥3 s during either catheter manipulation or 
the administration of RF pulses.  
Sinus node dysfunction: abnormality of cardiac impulse 
formation that may be caused by pacemaking dysfunction of 
the SA node, which may manifest on an electrocardiogram as: 
sinus bradycardia, sinus arrest or exit block, combinations of 
sino-atrial and atrioventricular nodal conduction 
disturbances, atrial tachyarrhythmias, with symptoms of: 
syncope, pre-syncope, palpitations, or dizziness. 
Valvular insufficiency or damage 
Damage to heart valve (e.g. tricuspid, mitral), including 
backward flow of blood through the valve 
Vasovagal reaction 
Reflex of the involuntary nervous system that causes the 
heart to slow down and blood pressure drops; may result in 
fainting 
 
 
 
 

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Appendix D: Endpoint-Related Adverse Event Definitions 
Table D- 1 describes definitions for a subset of endpoint-related adverse events that may be 
observed in the study. 
Table D- 1: Adverse Event Definitions 
Adverse Event 
Definition 
Atrioesophageal fistula 
Connection between the atrium and the lumen of the 
esophagus. Evidence supporting this diagnosis includes 
documentation of esophageal erosion combined with 
evidence of a fistulous connection to the atrium such as air 
emboli, an embolic event, or direct observation at the time of 
surgical repair. 
Cardiac tamponade/perforation  
Development of a significant pericardial effusion during or 
within 30 days of undergoing the study ablation procedure. A 
significant pericardial effusion is one that results in 
hemodynamic compromise, requires elective or urgent 
pericardiocentesis, or results in a 1-cm or more pericardial 
effusion as documented by echocardiography. 
Cerebrovascular accident  
Rapid onset of a focal or global neurological deficit with at 
least one of the following: change in level of consciousness, 
hemiplegia, hemiparesis, numbness or sensory loss affecting 
one side of the body, dysphasia or aphasia, hemianopia, 
amaurosis fugax, or other neurological signs or symptoms 
consistent with stroke. Confirmed by neurology assessment 
and/or radiographic confirmation. 
Major bleeding requiring 
transfusion 
Bleeding that requires and/or is treated with transfusion or 
results in a 20% or greater fall in hematocrit. 
Myocardial infarction  
Presence of any one of the following criteria: 
1) detection of ECG changes indicative of new ischemia 
(new ST-T changes or new LBBB), which persist for more 
than one hour; 
2) development of new pathological Q waves on an ECG; 
3) imaging evidence of new loss of viable myocardium or 
new regional wall motion abnormality. 
Pericarditis requiring intervention 
Pericardial effusion that leads to pericarditis with 
hemodynamic compromise or requires pericardiocentesis, 
prolongs hospitalization by more than 48 hours, requires 
hospitalization, or persists for more than 30 days following 
the ablation procedure. 
Phrenic nerve 
injury/diaphragmatic paralysis 
Absent phrenic nerve function as assessed by diaphragmatic 
fluoroscopy/sniff test that is ongoing from hospital 
discharge. Phrenic nerve injury documented to be present 6 

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months or longer following ablation will be considered against 
the primary safety endpoint. 
Pulmonary vein stenosis 
Reduction of the diameter of a PV or PV branch. PV stenosis 
can be categorized as mild <50%, moderate 50%–70%, and 
severe ≥70% reduction in the diameter of the PV or PV 
branch. A severe PV stenosis will be considered against the 
primary safety endpoint. 
Transient ischemic attack 
New focal neurological deficit with rapid symptom resolution 
(usually 1 to 2 hours), no more than 24 hours. Confirmed by 
neurology assessment and/or radiographic confirmation. 
Vagal nerve injury resulting in 
esophageal dysmotility or 
gastroparesis  
Injury to the vagal nerve that results in esophageal 
dysmotility or gastroparesis (i.e. delayed gastric emptying) 
that prolongs hospitalization, requires hospitalization, or 
results in ongoing symptoms for more than 30 days following 
the ablation procedure 
Vascular access complications 
requiring intervention  
Development of a hematoma (excluding minor hematomas 
not requiring surgical treatment), AV fistula or 
pseudoaneurysm that requires intervention, prolongs the 
hospital stay, or requires hospital admission. 
Any PFA system-related or PFA 
procedure-related cardiovascular 
and/or pulmonary adverse event 
that prolongs or requires 
hospitalization for more than 48 
hours (excluding recurrent 
AF/AFL/AT)  
Any PFA system-related or PFA procedure-related 
cardiovascular and/or pulmonary adverse event that 
prolongs or requires hospitalization for more than 48 hours. 
Because early recurrences of AF/AFL/AT are to be expected 
following AF ablation, recurrent AF/AFL/AT within 90 days 
that requires or prolongs a patient’s hospitalization will not be 
considered against the primary safety endpoint. 
 
 
 
 

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Appendix E: Instructions For Use 
Always reference the current version of the Instructions For Use document as provided by 
Medtronic under separate cover. 
 
Appendix F: Data Collection Elements (Case Report Forms) 
Draft CRFs for the study will be provided under separate cover. Final CRFs will be provided to sites 
via the electronic data management system after the site has fulfilled all requirements for database 
access. 
 
Appendix G: Informed Consent Template 
The Informed Consent Template will be distributed under separate cover. 
 
Appendix H: Participating Investigators and Institutions 
A final list of participating Investigators and institutions has not been finalized prior to 
development of the Clinical Investigation Plan and will be distributed under separate cover. 
 
Appendix I: IRB/REB/EC List 
A final IRB/REB/EC list has not been finalized prior to development of the Clinical Investigation 
Plan and will be distributed under separate cover if required or upon request. 
 
Appendix J: Pre-Clinical Testing 
A summary of results from pre-clinical testing with the PFA system is provided in the Investigator’s 
Brochure under separate cover. 
 
 
 

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Appendix K: Centers for Medicare and Medicaid Services (CMS) IDE Study 
Criteria 
Applicability of PFA to the Medicare Population 
There is a high prevalence of atrial fibrillation in the Medicare population as evidenced by the most 
recently available claims data for pulmonary vein isolation (PVI) ablation procedures. According to 
Medicare Physician/Supplier Procedure Summary data51, there were 41,906 PVI ablation 
procedures performed on Medicare beneficiaries in CY2017.  
Although study participation will be open to patients between the ages of 18-80, it is anticipated 
that approximately 50% of the patients enrolled will be age 65+. This enrollment pattern mirrors 
the age distribution of the general population of patients with atrial fibrillation (AF)1,2,3,4 and 
therefore results from this trial may be both relevant and generalizable to the Medicare beneficiary 
population. 
 
 
                                                            
51 Medicare Physician/Supplier Procedure Summary data. Available at: https://www.cms.gov/Research-Statistics-Data-
and-Systems/Statistics-Trends-and-Reports/Physician-Supplier-Procedure-Summary/index.html  

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17. Version History 
Version 
Summary of Changes 
Author(s)/Title 
1.0 
• 
Not Applicable, New Document 
Jeff Cerkvenik, Distinguished 
Statistician 
Josh Treadway, Clinical 
Research Specialist 
2.0 
• 
Updated details of study contact for 
Japan and monitoring contact for 
Europe/Australia. 
• 
Added new vendor details to Table 3. 
• 
Sections 2 and 12, and Appendix D: 
changed “and” to “and/or” in last bullet 
of each safety endpoint to clarify that 
the PFA system-related or PFA 
procedure-related AEs will be included 
in the endpoint if adjudicated as any of 
the following: cardiovascular, 
pulmonary, or both cardiovascular and 
pulmonary.  
• 
Section 2: updated Safety 
Assessments language to require 
collection of all adverse events. 
• 
Section 3.1 and Section 15: Added 
missing reference; Corrected broken 
links to references.  
• 
Section 6.1: corrected broken link to 
Figure 3. 
• 
Sections 6.1, 9.1, 14.6, 14.9 and 
Appendix J: removed references to 
Report of Prior Investigation (RPI) for 
US sites. Investigator Brochure (IB) 
only will be provided for this study. 
• 
Section 6.14: removed details of 
investigational labeling of market 
released components for each 
geography, instead referencing 
Appendix A where those details will be 
listed. 
• 
Section 10.4: removed duplicative 
links to Table 10 and Table 11. 
 
 
Jeff Cerkvenik, Distinguished 
Statistician 
Josh Treadway, Clinical 
Research Specialist 

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2.0 
• 
Sections 10 and 12.2.2: updated 
language throughout to require 
collection of all adverse events; 
removed definition of “cardiovascular 
related” AE and instructions for 
Investigator to classify cardiovascular 
relatedness for AEs. 
 
 
 
 
 
 
• 
Section 13: updated to remove the 
language claiming an exception to the 
ISO14155:2011 requirement to collect 
all adverse events.  
Jeff Cerkvenik, Distinguished 
Statistician 
Josh Treadway, Clinical 
Research Specialist 
3.0 
• 
Updated study contact details for 
Worldwide Clinical Study Leader. 
• 
Added new vendor details to Table 3. 
• 
Section 12.2.3: within “rationale for 
performance criteria” paragraphs, 
clarified definitions of primary 
effectiveness for paroxysmal AF and 
persistent AF to match the primary 
endpoint definitions. 
• 
Sections 6.14 and 6.16: modified 
language for product packaging and 
return requirements to allow better 
compliance to local laws and 
regulations in all study countries. 
• 
Section 8.4.4: added further guidelines 
for PFA therapy delivery and Table 8. 
• 
Section 8.1, Table 7, Section 8.5: 
added physical exam at discharge, with 
requirement to perform 
cardiopulmonary exam at a minimum. 
• 
Table of Contents (adding sub-header 
under 8.9), Section 2, Section 5, Figure 
1, Section 8.1, Table 7, Section 8.9, 
Table 9, Section 12.1.1, Table 14, 
Appendix B- Figure B-1: added 7-day 
telephone or office visit including an 
AE assessment and medication 
review. 
Jeff Cerkvenik, Distinguished 
Statistician 
Josh Treadway, Clinical 
Research Specialist 

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3.0 
• 
Section 8.1, Table 7, Section 8.9: at the 
30-day visit, added NIHSS assessment 
and physical exam with requirement to 
perform cardiopulmonary exam at a 
minimum.  
• 
Section 8.6: added sentence and 
reference to consult the 2014 
Guidelines for the Management of 
Patients with AF for AAD 
prescriptions. 
• 
Sections 2, 12.1.2, 12.2.3, 12.4.1: 
clarified definition of acute procedural 
success. 
• 
Sections 9.2, 9.3, Table 10, Appendix 
C: added pulmonary edema as a 
potential risk. 
Jeff Cerkvenik, Distinguished 
Statistician 
Josh Treadway, Clinical 
Research Specialist