STOP Persistent AF
Phase: NA
Conditions: Atrial Fibrillation
Sponsor: Medtronic Cardiac Ablation Solutions

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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title 
STOP Persistent AF 
Study Product Name 
Arctic Front Advance™ Cardiac CryoAblation Catheter 
Freezor MAX® Cardiac CryoAblation Catheter 
Sponsor/Local Sponsor 
United States of America 
Medtronic, Inc. 
8200 Coral Sea Street NE 
Mounds View, MN 55112 
United States of America 
 
Canada 
Medtronic of Canada, Ltd. 
99 Hereford Street 
Brampton, Ontario, L6Y 0R3 
Canada 
 
Europe 
Medtronic, Bakken Research Center B.V. 
Endeplosdomein 5 
6229 GW Maastricht 
The Netherlands 
 
Japan 
Medtronic Japan Co. Ltd. 
1-2-70 Konan 
Minato-ku, Tokyo 108-0075 
Japan 
Document Version 
6, 01DEC2017 
Lead Co-Principal 
Investigator(s)/Coordinating Investigators 
Hugh Calkins, MD 
Address: Johns Hopkins, 1800 Orleans Street, Zayed 
Tower 712R, Baltimore, MD 21287 
Telephone: 410-955-7405 
Fax: 410-614-1345 
 

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Professional Position: Nicholas J. Fortuin Professor of 
Cardiology, Division of Cardiology, The Johns Hopkins 
University School of Medicine. Professor of Medicine, 
Department of Medicine, Division of Cardiology, The 
Johns Hopkins University School of Medicine. Professor 
of Pediatrics, Department of Pediatrics, Division of 
Pediatric Cardiology, The Johns Hopkins University 
School of Medicine. Director of the Arrhythmia Service, 
Clinical Electrophysiology Laboratory, and 
Arrhythmogenic Right Ventricular Dysplasia Program, 
The Johns Hopkins Hospital 
 
Vivek Reddy, MD 
Address: Mt. Sinai Heart, One Gustave L Levy Place, 
Box 1030, New York, NY 10029 
Telephone: 212-241-7114 
Fax: 646-537-9691 
 
Professional Position: The Leona M. and Harry B. 
Helmsley Charitable Trust Professor of Medicine in 
Cardiac Electrophysiology 
Coordinating Investigator 
Wilbur Su, MD 
Address: Banner-University Medical Group-Heart 
Center 
1300 North 12th Street, Suite 407, Phoenix, AZ 58006 
Telephone: 602-839-7393 
 
Professional Position: Clinical Assoc. Professor of 
Medicine, University of Arizona, Chief of Cardiac EP, 
Banner-University Medical Center-Phoenix, Director of 
EP Fellowship, Banner-University Medical Center-
Phoenix 
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 
1. 
Glossary ..................................................................................................................... 7 
2. 
Sponsor Contacts .................................................................................................... 10 
3. 
CROs/Core Laboratories ......................................................................................... 11 
4. 
Synopsis ................................................................................................................... 12 
5. 
Introduction ............................................................................................................. 16 
5.1. 
Background ....................................................................................................................... 16 
5.2. 
Purpose ............................................................................................................................. 20 
6. 
Objectives and Endpoints ........................................................................................ 21 
6.1. 
Objectives ........................................................................................................................ 21 
6.1.1. 
Primary Objectives .............................................................................................................. 21 
6.1.1.1. 
Primary Efficacy Objective .............................................................................................. 21 
6.1.1.2. 
Primary Safety Objective ................................................................................................ 21 
6.1.2. 
Secondary Objective ........................................................................................................... 21 
6.1.3. 
Ancillary Objectives ............................................................................................................. 21 
6.2. 
Endpoints ......................................................................................................................... 21 
6.2.1. 
Primary Endpoints ............................................................................................................... 21 
6.2.2. 
Secondary Endpoint ............................................................................................................ 22 
6.2.3. 
Ancillary Endpoints .............................................................................................................. 23 
7. 
Study Design ............................................................................................................ 24 
7.1. 
Duration ............................................................................................................................ 25 
7.2. 
Rationale ........................................................................................................................... 26 
8. 
Product Description................................................................................................. 26 
8.1. 
General ............................................................................................................................. 26 
8.1.1. 
Arctic Front Advance Cardiac CryoAblation Catheters ................................................... 27 
8.1.2. 
Freezor MAX Cardiac CryoAblation Catheters ................................................................. 27 
8.1.3. 
FlexCath Advance Steerable Sheath ................................................................................. 27 
8.1.4. 
Achieve and Achieve Advance Mapping Catheters .......................................................... 28 
8.1.5. 
CryoConsole ........................................................................................................................ 28 
8.1.6. 
Coaxial Umbilical .................................................................................................................. 28 
8.1.7. 
Electrical Umbilical .............................................................................................................. 28 
8.1.8. 
Manual Retraction Kit .......................................................................................................... 28 
8.1.9. 
 .......................................................................................... 28 
8.1.10. 
Additional Study Devices ................................................................................................ 29 
8.2. 
Packaging ......................................................................................................................... 29 
8.3. 
Product Receipt, Tracking and Storage ........................................................................... 29 

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9. 
Investigator/Investigational Center Selection ...................................................... 30 
10. 
Center Activation .................................................................................................... 30 
11. 
Selection of Subjects ............................................................................................... 31 
11.1. 
Study Population ........................................................................................................... 31 
11.2. 
Subject Enrollment ....................................................................................................... 31 
11.3. 
Inclusion Criteria ........................................................................................................... 31 
11.4. 
Exclusion Criteria .......................................................................................................... 32 
12. 
Minimization of Bias ................................................................................................. 33 
13. 
Study Procedures ..................................................................................................... 33 
13.1. 
Schedule of Events ........................................................................................................ 33 
13.2. 
Role of the Sponsor ....................................................................................................... 35 
13.3. 
Subject Consent ............................................................................................................ 35 
13.4. 
Enrollment, Baseline and Pre-ablation ......................................................................... 37 
13.5. 
Procedure ...................................................................................................................... 38 
13.5.1. 
Esophageal Visualization and Temperature Monitoring .............................................. 39 
13.5.2. 
Peri-procedural Anticoagulation .................................................................................... 39 
13.5.3. 
Diaphragm Movement .................................................................................................... 39 
13.5.4. 
Balloon Pulmonary Vein (PV) Cryoablation .................................................................... 39 
13.5.5. 
Other Ablations during Index Procedure ....................................................................... 40 
13.5.6. 
Cardioversion ................................................................................................................... 40 
13.5.7. 
Procedure Documentation ............................................................................................. 40 
13.6. 
Hospital Discharge ........................................................................................................ 40 
13.7. 
Medications ................................................................................................................... 41 
13.7.1. 
Class I and III antiarrhythmic medication use after the 90 day post-procedure 
blanking period ................................................................................................................................... 41 
13.8. 
Permissible Repeat Cryoablations ................................................................................ 41 
13.9. 
Cardioversions .............................................................................................................. 42 
13.10. 
Scheduled Follow-up Visits ....................................................................................... 42 
13.10.1. 
Six Week Phone Call ......................................................................................................... 43 
13.10.2. 
Three Month Office Visit ................................................................................................. 43 
13.10.3. 
Six Month Office Visit ...................................................................................................... 43 
13.10.4. 
Twelve Month Office Visit ............................................................................................... 43 
13.11. 
Unscheduled Office Visits ......................................................................................... 43 
13.12. 
Holter and TTM Management .................................................................................... 44 
13.13. 
12 lead Electrocardiograms ....................................................................................... 44 
13.14. 
 .................................................... 44 
13.15. 
Assessment of Efficacy ............................................................................................. 44 
13.16. 
Assessment of Safety ................................................................................................ 45 
13.17. 
Recording Data .......................................................................................................... 45 
13.18. 
Deviation Handling .................................................................................................... 45 
13.19. 
Subject Withdrawal or Discontinuation .................................................................... 46 

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14. 
Risks and Benefits .................................................................................................... 47 
14.1. 
Potential Risks .............................................................................................................. 47 
14.2. 
Risk Minimization .......................................................................................................... 50 
14.3. 
Potential Benefits ......................................................................................................... 50 
14.4. 
Risk-Benefit Rationale .................................................................................................. 50 
15.
Adverse Event and Device Deficiencies Assessment............................................. 50
15.1. 
Adverse Event and Device Deficiency Definitions ....................................................... 51 
15.2. 
Adverse Events ............................................................................................................. 53 
15.3. 
Device Deficiencies ....................................................................................................... 54 
15.4. 
Processing Updates and Resolution ............................................................................. 54 
15.5. 
Reporting of Adverse Events and Device Deficiencies ................................................. 54 
15.6. 
Subject Death ................................................................................................................ 61 
15.6.1. 
Death Classification and Reporting ............................................................................... 62 
15.7. 
Product Complaint Reporting ....................................................................................... 62 
16. 
Data Review Committees ........................................................................................ 63 
17. 
Statistical Design and Methods ............................................................................... 64 
17.1. 
General Considerations ................................................................................................ 64 
17.2. 
Analysis Timing ............................................................................................................. 64 
17.2.1. 
PMA-S Submission .......................................................................................................... 64 
17.2.2. 
PMDA Submission............................................................................................................ 64 
17.3. 
Primary Objectives ....................................................................................................... 64 
17.3.1. 
Primary Efficacy Objective .............................................................................................. 64 
17.3.2. 
Primary Safety Objective ................................................................................................ 70 
17.4. 
Secondary Objective ..................................................................................................... 73 
17.4.1. 
Secondary Objective: Quality of Life - Atrial Fibrillation Effect on QualiTy-of-life 
(AFEQT) and SF-12 Questionnaires ................................................................................................. 73 
17.4.1.1. 
Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) ................................................. 74 
17.4.1.2. 
Medical Outcome Study Short Form-12 (SF-12 ) ..................................................... 75 
17.5. 
Ancillary Objectives ...................................................................................................... 75 
17.5.1. 
 ....................................................... 75 
17.5.2. 
 ...................................... 76 
17.5.3. 
 ...................................................... 77 
17.5.4. 
 ......................... 77 
17.5.5. 
 ............................ 78 
17.5.6. 
 ................................ 79 
18. 
Ethics ........................................................................................................................ 79 
18.1. 
Statement(s) of Compliance ......................................................................................... 79 
19. 
Study Administration .............................................................................................. 81 
19.1. 
Monitoring ..................................................................................................................... 81 
19.2. 
Data Management ......................................................................................................... 82 
19.3. 
Confidentiality .............................................................................................................. 83 

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19.4. 
CIP Amendments .......................................................................................................... 83 
19.5. 
Record Retention .......................................................................................................... 83 
19.5.1. 
Investigator Records ....................................................................................................... 83 
19.5.2. 
Investigator Reports ....................................................................................................... 84 
19.5.3. 
Sponsor Records.............................................................................................................. 88 
19.5.4. 
Sponsor Reports .............................................................................................................. 89 
19.6. 
Publication and Use of Information ............................................................................... 94 
19.7. 
Suspension or Early Termination .................................................................................. 95 
19.7.1. 
Early Termination or Suspension ................................................................................... 95 
19.7.2. 
Study-wide Termination or Suspension ........................................................................ 96 
19.7.3. 
Investigator/Center Termination or Suspension ......................................................... 96 
19.7.4. 
Procedures for Termination or Suspension .................................................................. 97 
19.7.4.1. 
Medtronic-Initiated and Regulatory Authority-Initiated .......................................... 97 
19.7.4.2. 
Investigator-Initiated .................................................................................................. 97 
19.7.4.3. 
IRB/MEC Initiated ......................................................................................................... 98 
20. 
Liability/Warranty/Insurance Information ............................................................. 98 
20.1. 
Warranty ....................................................................................................................... 98 
20.2. 
Insurance (US) ............................................................................................................... 98 
20.3. 
Insurance (Canada) ....................................................................................................... 98 
20.4. 
Insurance (Europe) ........................................................................................................ 99 
20.5. 
Insurance (Japan) .......................................................................................................... 99 
21. 
References ............................................................................................................... 99 
22. 
Appendices ............................................................................................................. 102 
23. 
Version History…………………………………………………………………………………………………….. 121 
 

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1. Glossary 
Table 1:  Glossary 
Term 
Definition 
AE 
Adverse event 
AF 
Atrial fibrillation 
AAD 
Antiarrhythmic drug 
ACC 
American College of Cardiology 
ACT 
Activated clotting time 
ADE
Adverse device effect
AFL 
Atrial flutter 
AHA 
America Heart Association 
AT 
Atrial tachycardia 
AFEQT 
Atrial fibrillation effect on quality-of-life 
questionnaire 
BMI 
Body mass index 
C 
Celsius 
CT 
Computed tomography 
CV 
Curriculum vitae 
CEC 
Clinical Events Committee 
CFE 
Complex fractionated electrograms 
CFR 
Code of Federal Regulations 
CIP 
Clinical investigation plan 
CRF 
Case report form 
CRO 
Clinical Research Organization 

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CTA 
Clinical trial agreement 
DC 
Direct current 
DD 
Device deficiency 
e.g. 
For example 
ECG 
Electrocardiogram 
ECAS 
European Cardiac Arrhythmia Society 
ECRF 
Electronic case report form 
EHRA
European Heart Rhythm Association
F 
Fahrenheit 
FD 
Financial disclosure 
FAL 
Foreseeable adverse event list 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
GCP 
Good clinical practice 
GEE 
Generalized estimating equation 
HR 
Hazard ration 
HRS 
Heart Rhythm Society 
HOMI 
Head of medical institution 
ID 
Identification 
IDE 
Investigational device exemption 
Inc 
Incorporated 
IRB 
Institutional review board 
ISO 
International Organization for Standardization 
ICMJE
International Committee of Medical Journal Editors

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LAD 
Left atrial diameter 
LVEF 
Left ventricular ejection fraction 
MDD 
Medical device directive 
MEC 
Medical ethics committee 
MHLW 
Ministry of Health, Labour and Welfare 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAC 
Novel oral anticoagulant 
NYHA
New York Heart Association
N2O 
Nitrous Oxide 
OPC 
Objective performance criteria 
PV 
Pulmonary vein 
PAF 
Paroxysmal atrial fibrillation 
PCI  
Percutaneous coronary intervention 
PIC 
Patient informed consent 
PVI 
Pulmonary vein isolation 
PTCA 
Percutaneous transluminal coronary angioplasty 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PMA-S 
Premarket Approval Supplement 
RF 
Radiofrequency 
RI 
Right inferior 
RS 
Right superior 
SD 
Standard deviation 
SF 
Short form 
SAE
Serious adverse event

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SAP 
Statistical analysis plan 
SCD 
Sudden cardiac death 
SADE 
Serious adverse device effect 
TEE 
Transesophageal echocardiogram 
TIA 
Transient ischemic attack 
TTE 
Transthoracic echocardiogram 
TTM 
Trans-telephonic monitoring 
US
United States
UADE 
Unanticipated adverse device effect 
USADE 
Unanticipated serious adverse device effect 
2. Sponsor Contacts 
Regional contact information is provided below. This information may be subject to change during the course 
of the study. Periodic updates to study contact information will be sent to centers as needed.  
Table 2: Study Sponsor Contact Information 
Study Contacts 
Worldwide and US Clinical Study Leader 
Dana Wigert, Principal Clinical Research Specialist 
Direct Phone: 763-526-2802 
 
Direct Fax: 763-367-1727 
Email: dana.wigert@medtronic.com 
 
Europe 
Daniel Becker, Senior Clinical Research Specialist 
Direct Phone: 49 215981490 
Direct Fax: 49 21598149100 
Email: daniel.becker@medtronic.com 
 
Canada 
Mary McCann, Senior Clinical Research Specialist 
Direct Phone:  905-460-3639 
Direct Fax: 905-460-3998 
Email: mary.mccann@medtronic.com 
 

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Japan 
Yoshiko Ishiwatari, Senior Clinical Research Specialist 
Direct Phone: 81-3 6776-0105 
Direct Fax: 81-3 6774-4705 
Email: yoshiko.ishiwatari@medtronic.com 
Monitoring 
Contacts 
US, Canada 
Ian Schorn, Medical Research Manager 
North American Science Associates, Inc. 
 
Email: ischorn@namsa.com 
 
Europe 
Anja Hesse, Clinical Monitoring Manager 
Direct Phone: 49215981490 
Direct Fax: 4921027069069 
Email: anja.hesse@medtronic.com 
 
Japan 
Hitomi Yoshida, Senior Clinical Research Specialist 
Direct Phone: 81-3 6776-0775 
Direct Fax: 81-3 6774-4705 
Email: hitomi.yoshida@medtronic.com 
3. CROs/Core Laboratories 
This information may be subject to change during the course of the clinical study.  Periodic updates to 
contact information will be sent to centers as needed. 

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Table 3: CRO and Core Laboratory Information 
Contact Information  
Duties performed 
Cognizant Technology Solutions 
500 Frank W. Burr Blvd. 
Teaneck, NJ 07666 
Direct Phone: (201) 801-0233 
Direct Fax: (201) 801-0243 
x
Development of study electronic case report forms, edit 
checks, and study management reports. 
x
Review of electronic case report forms, management of 
discrepancies, and coding of medications and deviations. 
Biomedical Systems now part of 
eResearch Technology  
77 Progress Parkway 
St. Louis, MO 63043 
Direct Phone: (314) 576-6800 
x
Distribution of Holters, TTMs and 12-lead ECG machines 
x
Adjudication of atrial arrhythmias 
North American Science Associates, 
Inc. 
400 Highway 169 South, Suite 500 
Minneapolis, MN 55426 
Direct Phone: 320-282-6312  
x
Monitoring activities in the US and Canada
4. Synopsis 
Table 4: Study Synopsis 
Title 
STOP Persistent AF study 
Clinical Study Type 
Pivotal 
Product Name 
Arctic Front Advance™ Cardiac CryoAblation Catheter 
Freezor MAX® Cardiac CryoAblation Catheter 
Sponsor  
United States of America 
Medtronic, Inc. 
8200 Coral Sea Street NE 
Mounds View, MN 55112 
United States of America 

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Local Sponsor 
Canada 
Medtronic of Canada, Ltd. 
99 Hereford Street 
Brampton, Ontario, L6Y 0R3 
Canada 
 
Europe 
Medtronic, Bakken Research Center B.V. 
Endeplosdomein 5 
6229 GW Maastricht 
The Netherlands 
 
Japan 
Medtronic Japan Co. Ltd. 
1-2-70 Konan 
Minato-ku, Tokyo 108-0075 
Japan
Indication under 
investigation  
The proposed indication for the Arctic Front Advance CryoAblation Catheter is as 
follows: The Arctic Front Advance Cardiac CryoAblation Catheters are indicated for 
the treatment of drug refractory recurrent symptomatic paroxysmal and 
persistent atrial fibrillation.   
The proposed indication for the Freezor MAX Cardiac CryoAblation Catheter is as 
follows: The Freezor MAX Cardiac CryoAblation Catheters are indicated for use as 
an adjunctive device in the endocardial treatment of paroxysmal and persistent 
atrial fibrillation in conjunction with the Arctic Front Advance Cardiac CryoAblation 
Catheter for the following uses: gap cryoablation to complete electrical isolation of 
the pulmonary veins, cryoablation of focal trigger sites and creation of ablation line 
between the inferior vena cava and the tricuspid valve.  
These proposed indications are outside of the approved indications in the United 
States and Japan but are within the approved indications in Europe and Canada. 
Investigation 
Purpose 
To demonstrate safety and effectiveness of the Arctic Front Advance and Freezor 
MAX Cardiac CryoAblation Catheters for the treatment of drug refractory 
recurrent symptomatic persistent atrial fibrillation (AF). 

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Product Status 
Component 
Model 
Number  
Geography 
Manufacturer 
Arctic Front 
Advance Cardiac 
CryoAblation 
Catheter  
2AF234 
US (investigational)
Japan (investigational) 
Medtronic, 
Inc. 
2AF284 
2AF233 
Canada (non-investigational) 
Europe (non-investigational) 
Medtronic, 
Inc. 
2AF283 
Freezor MAX 
Cardiac 
CryoAblation 
Catheter 
239F3 
US (investigational) 
Japan (investigational) 
Medtronic, 
Inc. 
239F5 
209F3 
Canada (non-investigational) 
Europe (non-investigational) 
Medtronic, 
Inc. 
209F5 
Primary Objectives 
x
Demonstrate an acceptable efficacy success rate at 12 months after 
the pulmonary vein isolation (PVI) ablation procedure. 
x
Demonstrate an acceptable safety profile of the pulmonary vein 
isolation (PVI) ablation procedure. 
Secondary 
Objective 
1. Demonstrate an improvement in quality of life between baseline and 12 
months as measured by the Atrial Fibrillation Effect on QualiTy-of-life 
Questionnaire (AFEQT) and Medical Outcome Study Short Form-12 (SF-12) 
questionnaires 
Ancillary 
Objectives 

 

 

 
 

 
 

 
 

  
Study Design 
The study is prospective, interventional, multi-center, non-randomized, single 
arm, unblinded clinical study.  The study will be conducted at up to 25 centers 
located in the US, Canada, Europe and Japan.  The study objectives will be analyzed 
for a Premarket Approval Supplement (PMA-S) after all subjects from the US, 
Canada and Europe complete 12 months of follow-up after the index ablation 
procedure.   

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Study data from the Japanese centers will not be included in the PMA-S 
submission, but will be included in a submission to Japan Pharmaceuticals and 
Medical Device Agency (PMDA). 
The Japanese subjects are required by PMDA to support an expanded indication to 
the persistent AF population in Japan. The PMDA cohort will be analyzed separate 
to the PMA-S because participation and enrollment in Japan is anticipated to start 
later than the rest of the PMA-S cohort. 
Sample Size and 
Analysis Timing 
Up to 225 subjects will be enrolled world-wide.  In the US, Canada and Europe, up to 
200 subjects will be enrolled to ensure 150 subjects are treated with an Arctic Front 
Advance Cardiac CryoAblation Catheter.  The maximum number of subjects 
treated at Canadian and European centers combined is 45 subjects.   
Up to 25 subjects will be enrolled in Japan to ensure15 subjects are treated with an 
Arctic Front Advance Cardiac CryoAblation Catheter.  
At the completion, the last 12 month visit from the 150 enrolled and treated 
subjects from the US, Canada and Europe, a PMA-S will be submitted to the FDA.  
Study data from the Japanese centers will not be included in the PMA-S submission 
but will be made available. 
A final report will be submitted to Japan PMDA at the completion of the last 12 
month visit from the 15 treated Japanese subjects.  Study data from all 165 treated 
subjects will be included in this report.  
Inclusion/Exclusion 
Criteria 
Inclusion Criteria 
x
Documentation of symptomatic persistent AF 
R
Defined as having a continuous episode lasting longer than 7 days but 
less than 6 months documented by consecutive ECG recordings  
OR 
R
Defined as having a continuous episode lasting longer than 7 days but 
less than 6 months documented by an ECG recording and one doctor 
note indicating patient had symptoms consistent with AF 
x
Failure or intolerance of at least one Class I or III antiarrhythmic drug 
x
Age 18 or older (or older than 18 if required by local law)  
 
Exclusion Criteria 
x
Left atrial diameter > 5.0 cm (anteroposterior) 
x
Prior left atrial ablation or surgical procedure (including left atrial appendage 
closures) 
x
Presence or likely implant of a permanent pacemaker, biventricular pacemaker, 
loop recorder, or any type of implantable cardiac defibrillator (with or without 
biventricular pacing function) within 12 months 
x
Presence of any pulmonary vein stents 
x
Presence of any pre-existing pulmonary vein stenosis 
x
Pre-existing hemidiaphragmatic paralysis 
x
Presence of any cardiac valve prosthesis 

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x
+3 and +4 mitral valve regurgitation or stenosis 
x
Any cardiac surgery, myocardial infarction, PCI / PTCA or coronary artery 
stenting which occurred during the 3 month interval preceding the consent 
date 
x
Unstable angina 
x
NYHA Class III or IV congestive heart failure and/or documented left ventricular 
ejection fraction (LVEF) less than or equal to 35% measure by acceptable 
cardiac testing (e.g. TTE) 
x
Primary pulmonary hypertension 
x
Rheumatic heart disease 
x
Thrombocytosis, thrombocytopenia 
x
Any condition contraindicating chronic anticoagulation 
x
Active systemic infection 
x
Hypertrophic cardiomyopathy 
x
Cryoglobulinemia 
x
Uncontrolled hyperthyroidism 
x
Any cerebral ischemic event (strokes or TIAs) which occurred during the 6 
month interval preceding the consent date 
x
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 
x
Life expectancy less than one year 
x
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 
x
Known allergies or hypersensitivities to adhesives 
x
Known drug or alcohol dependency 
x
Unwilling or unable to comply fully with study procedures and follow-up 
Study Procedures 
and Assessments 
Subjects are assessed for eligibility at a baseline visits and then undergo a 
cryoablation procedure followed by hospital discharge.  All subjects are contacted 
by phone 6 weeks after the ablation procedure, are seen in the office at 3, 6 and 12 
months after the index ablation procedure, and are then exited from the study. 
5. Introduction  
5.1.
Background  
Atrial fibrillation 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.  AF can be clinically stratified based on whether episodes are self-terminating 
SDUR[\VPDORUSHUVLVWHQW3DUR[\VPDO$)3$)LVGHILQHGDVUHFXUUHQW$)ƨHSLVRGHVWKDWWHUPLQDWHV

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spontaneously within 7 days. Persistent AF is defined as continuous AF that is sustained for greater than 7 
days.1    
AF is the most common of the sustained arrhythmias affecting millions of people worldwide. In the US, AF 
affects between 2.7 million and 6.1 million adults2, and that number is expected to double over the next 25 
years.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 PAF, 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    
In the US, approved treatment options for patients with persistent AF are presently limited to 
pharmaceutical therapy and concomitant surgical ablation, which are unsatisfactory for many patients with 
AF.  Per the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation, 
“Antiarrhythmic drug (AAD) efficacy is modest and asymptomatic AF recurrences are common”.2  All AADs 
may result in adverse events requiring therapy discontinuation and, with the exceptions of amiodarone and 
propafenone, increase the likelihood of proarrhythmia.2  Side effects for AADs include bradycardia, 
palpitations, fatigue, dizziness, nausea and vomiting, stomach pain, constipation and diarrhea, rash, vision 
problems, and urinary retention. However, there is a growing body of evidence supporting catheter ablation 
as a reasonable option for treating persistent AF patients.  In 2012, the HRS/EHRA/ECAS Expert Consensus 
Statement on Catheter and Surgical Ablation of Atrial Fibrillation published a Class IIa Level B 
recommendation for catheter and surgical ablation of AF for persistent symptomatic AF (refractory or 
intolerant to at least one Class I or III AAD), stating “the benefits of an AF ablation procedure exceed the 

1 Calkins, H., et al., HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation of atrial fibrillation: 
recommendations for Patient selection, procedural techniques and follow-up, definitions, endpoints and research trial 
design.  A report of the Heart Rhythm Society (HRS) Task Force on catheter and surgical ablation of atrial fibrillation. 
Heart Rhythm. 2012; 9(4): p. 632-696.e20. 
2 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. 
3 Go A, Hylek E, Phillips K, et al. Prevalence of Diagnosed Atrial Fibrillation in Adults:  National Implications for Rhythm 
Management and Stroke Prevention: the AnTicoagulation and Risk Factors In Atrial Fibrillation (ATRIA) Study. JAMA. 
2001; 285(18): 2370-2375. 
4 Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clinical 
Epidemiology. 2014;6:213-220. doi:10.2147/CLEP.S47385. 
5 Wolf P, Abbott R, Kannel W. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 
1991;22(8):983-988. 
6 Ghanbari H, Baser K, Jongnarangsin K, et al. Mortality and cerebrovascular events after radiofrequency catheter 
ablation of atrial fibrillation. Heart Rhythm. 2014;11:1503-1511. 

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risks”.1  In the 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.2 
Catheter ablation treatment strategies for AF have evolved over time and currently include pulmonary vein 
isolation (PVI) as a cornerstone of ablation therapy in all types of AF (paroxysmal and persistent).7, 8  AF arises 
primarily from the left side of the heart in (or near) the atrium, particularly where the pulmonary veins (PVs) 
join the atrium.  The fundamental basis for the AF ablation procedure is the creation of myocardial lesions 
that block the propagation of AF wave fronts from the triggering source. The muscular sleeves within the PVs 
have been established as a critical source of AF triggers.9       
Historically, the stepwise approach was introduced over 10 years ago as the ablation strategy for patients 
with persistent AF.8,10  The stepwise strategy assumed that better outcomes were obtained when AF was 
organized and then broke due to additional ablation and substrate modification. The strategy was 
observational in nature and presumed better outcomes with a stepwise series of radiofrequency (RF) 
ablations. However, more recently the entire stepwise strategy has been the topic of reevaluation as 
outcomes may have been more biased by patient cohorts rather than ablation strategy.11   
Three recent studies call into question the stepwise ablation approach as each study reporting benefit using 
a minimal PVI-only type strategy.12,13,14,15  In the 2C3L study, an extensive ablation group which included 
complex fractionated electrograms (CFE) ablation had a trend towards worse outcomes compared to a 
control cohort with less extensive ablation.12 Similarly, in the Wynn et al. 2015 study, PVI alone had a trend 
towards better outcomes compared to PVI ablation with the addition of linear line ablation.  Finally, the 
pivotal STAR AF II results demonstrated the benefits of a PVI-only approach over that of additional linear 
ablation or CFE ablation. This trial compared the efficacy of three different AF ablation strategies in 589 

7 Raviele et al.  Venice Chart International consensus Document on Atrial Fibrillation:  2011 Update.  J Cardiovasc 
Electrophysiol, 2012;23:890-923. 
8 Jais P, O’Neill MD, Takahashi Y, 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. 
9 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.
10 Rostock T, Steven D, Hoffman B, et al. Chronic Atrial Fibrillation Is a Biatrial Arrhythmia Data from Catheter Ablation of 
Chronic Atrial Fibrillation Aiming Arrhythmia Termination Using a Sequential Ablation Approach. Circ Arrhythmia 
Electrophysiol. 2008;1:344-353. 
11 Winkle RA. How much ablation to eliminate atrial fibrillation: Is less more or is more more? Heart Rhythm. Epub ahead of 
print. DOI: http://dx.doi.org/10.1016/j.hrthm.2015.06.031
12 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. 
13 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. 
14 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. 
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.


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patients with persistent AF. Subjects were randomized to PVI alone, PVI plus complex fractionated 
electrograms (PVI+CFE), and PVI plus linear ablation (PVI+Lines). The STAR AF II trial outcomes were: 
x
Additional CFE or Lines ablation increased procedural time 
x
No benefit in AF reduction when additional substrate ablation (CFE or Lines) was performed in 
addition to PVI.  
x
PVI alone achieved freedom from recurrence in 59% of patients at 18 months 
The stepwise ablation studies may have suffered from the inability to create a robust and durable PVI as a 
foundational strategy (with historic focal RF ablation catheters), which could have adversely changed the 
data interpretation of the results. More recent studies have examined and compared the ability of 
cryoballoon technology to create a robust and durable PVI compared to RF catheters. Aryana et al. in a large, 
multicenter study demonstrated the superiority of the Arctic Front Advance catheter at creating durable PVI 
and better long-term outcomes as a result of the robust PVI (freedom from AF/AT/AFL at 12 months 
following a single procedure without AADs was 76.6% vs 60.4%, p<0.001 and less repeat ablations, 14.6% vs 
24.1%, p<0.001).16  Consequently, PVI remains an important foundational ablation strategy for the treatment 
of both paroxysmal and persistent AF, and previous ablations strategies, including stepwise, may have been 
hampered by the inability to create long-term PVI.   
The safety profile of cryoballoon ablation is also well established.  The STOP AF trial17was a prospective, 
multicenter, randomized, controlled investigation device exemption (IDE) study designed to compare 
outcomes of cryoballoon and antiarrhythmic drug therapies in patients with PAF. The cryoballoon arm met 
its primary safety objective with a serious procedure related event rate of 3.1%.  Comparing safety rates 
versus the AAD arm, 6.1% of cryoballoon subjects experienced a serious procedure-related event or major 
adverse event versus 8.5% of AAD subjects.  An analysis of 149 cryoballoon studies with 11,242 patients (see 
Appendix A for literature search methodology) showed similar complication rates to STOP AF for both PAF 
and persistent AF patients (see Table 5). 
 
 
 
 
 
 
 

16 Aryana A, Singh SM, Kowalski M, et al. Acute and Long-Term Outcomes of Catheter Ablation of Atrial Fibrillation Using 
the Second-Generation Cryoballoon versus Open-Irrigated Radiofrequency: A Multicenter Experience. J Cardiovasc 
Electrophysiol. 2015 Aug;26(8): 832-9.
17 Packer D, Kowal R, Wheelan K, Irwin J, Champagne J, Guerra P, Dubuc M, Reddy V, Nelson L, Holcomb R, Lehmann J, 
Ruskin J. J Am Coll Cardiol. 23 April 2013. 61(16):1713-1723. 

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Table 5: Safety Summary of Cryoballoon Literature 
 
 
 
  
 
 
*The complication definition may vary from study to study. 
Expanded indications in the US would fulfill an unmet clinical need for symptomatic persistent AF patients in 
which antiarrhythmic drugs fail or are not tolerated.       
5.2.
Purpose 
The purpose of the study is to provide data demonstrating the safety and effectiveness of the Arctic Front 
Advance and Freezor MAX Cardiac CryoAblation Catheters for the treatment of symptomatic drug 
refractory persistent AF.  The study is proposed by the sponsor as a result of feedback received from the US 
Food and Drug Administration (FDA) on pre-submission Q151184, regarding a proposal to expand the 
indications for use for the Arctic Front Advance to include patients with persistent AF.  The study is also 
designed to expand the indication for the Freezor MAX Cardiac CryoAblation Catheter.  The proposed 
indication for the Arctic Front Advance CryoAblation Catheter is as follows: The Arctic Front Advance 
Cardiac CryoAblation Catheters are indicated for the treatment of drug refractory recurrent symptomatic 
paroxysmal and persistent atrial fibrillation.  The proposed indication for the Freezor MAX Cardiac 
CryoAblation Catheter is as follows: The Freezor MAX Cardiac CryoAblation Catheters are indicated for use 
as an adjunctive device in the endocardial treatment of paroxysmal and persistent atrial fibrillation in 
conjunction with the Arctic Front Advance Cardiac CryoAblation Catheter for the following uses: gap 
cryoablation to complete electrical isolation of the pulmonary veins, cryoablation of focal trigger sites and 
creation of ablation line between the inferior vena cava and the tricuspid valve.   
 
 
Atrial Fibrillation Type (Number patients, studies) 
Complications %* 
Paroxysmal AF (n = 5736; 82 studies)
6.12%
Persistent AF (n= 843; 17 studies) 
4.63% 
Paroxysmal/persistent AF combined (n= 4663; 56 studies) 
6.26% 
All Atrial Fibrillation (n=11,242; 149 studies) 
6.07% 

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6. Objectives and Endpoints 
6.1.
Objectives 
6.1.1.
Primary Objectives 
6.1.1.1.
Primary Efficacy Objective 
Demonstrate an acceptable efficacy success rate at 12 months after the pulmonary vein isolation (PVI) 
ablation procedure. 
6.1.1.2.
Primary Safety Objective 
Demonstrate an acceptable safety profile of the pulmonary vein isolation (PVI) ablation procedure. 
6.1.2.
Secondary Objective 
Demonstrate an improvement in quality of life between baseline and 12 months after the index ablation 
procedure as measured by the AFEQT and SF-12 questionnaires. 
6.1.3.
Ancillary Objectives 

  

 

 
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
   

 
6.2.
Endpoints 
6.2.1.
Primary Endpoints 
1. Primary Efficacy: Demonstrate an acceptable efficacy success rate at 12 months after the pulmonary 
vein isolation (PVI) ablation procedure. 
 
Treatment success is defined as freedom from treatment failure.  Treatment failure is defined as any of 
the following components: 
R
Acute procedural failure  
R
Documented AF/AT/AFL on Holter/TTM/12-lead ECG after the 90 day blanking period 

Minimum of 30 seconds on Holter/TTM and 10 seconds on 12-lead ECG 
R
A reablation for the treatment of recurrent AF/AT/AFL after the 90 day blanking period 

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R
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, or re-
initiation of a previously failed or not tolerated Class I or III AAD after the 90 day blanking is not 
considered a failure. 
R
Ablation using RF in the left atrium 
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, cardioversion or one cryo re-ablation procedure of the pulmonary veins.  Titration of Class I and III 
antiarrhythmic medications are allowed during the blanking period. Subjects are allowed to remain on Class I 
or III antiarrhythmic medications at the historic maximum ineffective dose (on prior to the ablation 
procedure) after the 90 day post-procedure blanking period. 
Acute procedural failure is defined as: 
R
Inability to isolate all accessible targeted pulmonary veins (minimally assessed for entrance 
block and, where assessable, exit block) during the index procedure 
R
Left atrial non-PVI ablations including but not limited to, ablation of linear lesions complex 
fractionated electrograms or non-PV triggers 
 
2. Primary Safety: Demonstrate an acceptable safety profile of the pulmonary vein isolation (PVI) ablation 
procedure. 
 
A primary safety event is defined as a serious procedure-related or serious system-related adverse 
event including the following: 
x
Transient ischemic attack (within 7 days of ablation procedure) 
x
Cerebrovascular accident (within 7 days of ablation procedure)  
x
Major bleeding that requires transfusion (within 7 days of ablation procedure) 
x
Cardiac perforation, tamponade or pericardial effusion (within 7 days of ablation procedure) 
x
Pulmonary vein stenosis (> 75% reduction within 12-months of ablation procedure)  
x
Myocardial infarction (within 7 days of ablation procedure) 
x
Phrenic nerve injury (unresolved at 12-months) 
x
Atrio-esophageal fistula (within 12-months of ablation procedure) 
x
Death (within 7 days of ablation procedure) 
6.2.2.
Secondary Endpoint 
Demonstrate an improvement in quality of life between baseline and 12 months after the index ablation 
procedure as measured by the AFEQT and SF-12 questionnaires. 

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x
The (AFEQT) and (SF-12) questionnaires will be utilized for this objective. The AFEQT 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, where 0 corresponds to complete disability 
and 100 corresponds to no disability. The SF-12 questionnaire is a quality of life questionnaire that 
evaluates the subject’s mental and physical performance. Physical and mental health composite 
scores are calculated using responses to 12 questions with a response range from 0 to 100, where a 
0 score indicates the lowest level of health measured by the scale and 100 indicates the highest level 
of health. 
6.2.3.
Ancillary Endpoints 

  
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7. Study Design  
Medtronic, lnc. is sponsoring the STOP Persistent AF Study; a prospective, interventional, multi-center, non-
randomized, single arm, unblinded clinical study.  The study design diagram is shown in Figure 1.   
Up to 225 subjects will be enrolled world-wide.  In the US, Canada and Europe, up to 200 subjects will be 
enrolled to ensure 150 subjects are treated with an Arctic Front Advance Cardiac CryoAblation Catheter.  
The maximum number of subjects treated at Canadian and European centers combined is 45 subjects.   
Up to 25 subjects will be enrolled in Japan to ensure15 subjects are treated with an Arctic Front Advance 
Cardiac CryoAblation Catheter. The maximum number of subjects treated at Japanese centers is 15 
subjects.   
It is anticipated that at least 165 Arctic Front Advance Cardiac CryoAblation Catheters will be used in this 
study.  The maximum number of subjects that may be treated at a single center is 20 subjects (13% of the 
total treated in the PMA-S cohort). 

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Figure 1:  Study Design Flowchart 
 
 
7.1.
Duration 
Subjects from all geographies will be followed for 12 months after the index cryoballoon ablation procedure 
and then be exited from the study.  Accordingly, the expected total study duration is approximately 2 years 
and 2 months, representing 14 months of enrollment and 12 months of subject follow-up.  Subjects will not 
be replaced with newly enrolled subjects upon early study exit.  The objectives will be analyzed for a 
Premarket Approval Supplement (PMA-S) after all subjects from the US, Canada and Europe complete 12 
months of follow-up after the index ablation procedure.  Study data from the Japanese centers will not be 
included in the PMA-S submission.  A final report will be submitted to Japan PMDA at the completion of the 
study.   

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7.2.
Rationale  
The study has primary objectives designed to evaluate the safety and effectiveness of the Arctic Front 
Advance and Freezor MAX Cardiac CryoAblation Catheters for treatment of drug refractory symptomatic 
persistent AF.  In the United States, there are no ablation catheters approved to treat subjects with 
persistent AF.  The study will provide subjects with more options for treatment and the possibility of 
improving their health, quality of life and a decrease in stroke risk.  If successful, the STOP Persistent AF 
study will demonstrate meaningful therapeutic benefit in this underserved population.  This evaluation will 
support an indication expansion for the treatment of recurrent, symptomatic persistent AF.  The study will 
be considered successful if it meets the primary objectives, contingent upon FDA review and approval.   
8. Product Description 
8.1.
General 
In the US, Canada and Europe, centers will utilize the commercially released Arctic Front Advance Cardiac 
CryoAblation Catheters and Freezor MAX Cardiac CryoAblation Catheters (and future commercially released 
generations).  In Japan, the devices will be provided to the centers.  Instructions for use of the devices used in 
the study are provided in their respective manuals.  Device information is provided in Table 6 and described 
below.     
 
Any changes made to these devices 
during the investigation will be subject to IDE Modification Reporting Requirements as applicable. 
 
Table 6:  Device Information 
Component 
Model 
Number  
Geography 
Manufacturer 
Arctic Front 
Advance 
CryoAblation 
Catheter  
2AF234 
US (investigational) 
Japan (investigational) 
Medtronic, Inc. 
2AF284 
2AF233 
Canada (non-investigational) 
Europe  (non-investigational) 
Medtronic, Inc. 
2AF283 
Freezor MAX 
CryoAblation 
Catheter 
239F3 
US (investigational) 
Japan (investigational) 
Medtronic, Inc. 
239F5 
209F3 
Canada (non-investigational) 
Europe (non-investigational) 
Medtronic, Inc. 
209F5 

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8.1.1.
Arctic Front Advance Cardiac CryoAblation Catheters  
Approved indication in the US and Japan: The Arctic Front Advance Cardiac CryoAblation Catheters are 
indicated for the treatment of drug refractory recurrent symptomatic paroxysmal atrial fibrillation.   
Investigational indication in the US and Japan: The Arctic Front Advance Cardiac CryoAblation Catheters are 
indicated for the treatment of drug refractory recurrent symptomatic paroxysmal and persistent atrial 
fibrillation. 
Approved indication in Europe and Canada:  The Arctic Front Advance Cardiac CryoAblation Catheter is 
indicated for the treatment of patients with atrial fibrillation. 
The catheters are sterile, single use, minimally invasive intravascular balloon catheters specifically designed 
for tissue cryoablation.  The Arctic Front Advance Cardiac CryoAblation Catheter is used together with the 
CryoConsole and related devices.  Arctic Front Advance catheters are percutaneously advanced to the heart 
chamber from the femoral access via a transseptal sheath in the vasculature. Once the catheter reaches the 
left atrium, the balloon is inflated and the cooling segment creates circumferential lesions at the antrum of 
the targeted pulmonary veins. 
8.1.2.
Freezor MAX Cardiac CryoAblation Catheters 
Approved indication in the US and Japan: The Freezor MAX Cardiac CryoAblation Catheter is used as an 
adjunctive device in the endocardial treatment of paroxysmal atrial fibrillation in conjunction with the Arctic 
Front Advance Cardiac CryoAblation Catheter. 
Investigational indication in the US and Japan: The Freezor MAX Cardiac CryoAblation Catheters are 
indicated for use as an adjunctive device in the endocardial treatment of paroxysmal and persistent atrial 
fibrillation in conjunction with the Arctic Front Advance Cardiac CryoAblation  Catheter for the following 
uses: gap cryoablation to complete electrical isolation of the pulmonary veins, cryoablation of focal trigger 
sites and creation of ablation line between the inferior vena cava and the tricuspid valve. 
Approved indication in Europe and Canada: The Freezor MAX Cardiac CryoAblation Catheter is intended for 
use in treatment of cardiac arrhythmias. 
The Freezor MAX Cardiac CryoAblation Catheter is a flexible, steerable catheter used to ablate cardiac 
tissue.  It is used together with the CryoConsole and related components.  The 8mm tip of the focal Freezor 
MAX Cryocatheter reaches cryoablation temperatures when refrigerant is injected from the CryoConsole to 
the tip of the catheter.  The catheter tip has an integrated thermocouple for temperature reading capability.  
The catheter is introduced into the vasculature by traditional minimally invasive techniques. 
8.1.3.
FlexCath Advance Steerable Sheath 
The FlexCath Advance Steerable Sheath is a percutaneous introducer fitted with a hemostasis valve to allow 
for introduction, withdrawal and swapping of catheters and wires while minimizing blood loss.  A side-port 
with stopcock is integrated into the hemostasis valve to allow continuous drip infusion, injection through the 
center lumen, flushing, aspiration, blood sampling and pressure monitoring.  The FlexCath Advance 

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Steerable Sheath is intended to allow sheath deflection to facilitate catheter positioning.  It is supplied sterile 
and packaged together with a dilator. 
8.1.4.
Achieve and Achieve Advance Mapping Catheters  
The Achieve and Achieve Advance Mapping Catheters are an intra-cardiac electrophysiology diagnostic 
catheter indicated for multiple electrode electrophysiological mapping of the cardiac structures of the heart, 
i.e., recording or stimulation only. The Achieve and Achieve Advance Mapping Catheters are designed to 
obtain electrograms in the atrial regions of the heart.  
8.1.5.
CryoConsole 
The console houses the electronics and software for controlling and recording the ablation procedure, stores 
and controls delivery of liquid refrigerant under high pressure through the co-axial umbilical to the catheter, 
recovers the expanded refrigerant vapor from the catheter under vacuum, and disposes of the refrigerant 
through the hospital scavenging system. 
The hardware controls the safety monitoring system while the software provides the user interface subject 
information, procedure temperature, time set point in automatic mode and procedure data information. 
8.1.6.
Coaxial Umbilical 
The sterile coaxial umbilical delivers the Nitrous Oxide (N2O) gas from the console to the catheter and 
transports refrigerant vapors from the catheter to the console, which is then vented into the hospital 
scavenging system. 
8.1.7.
Electrical Umbilical 
The sterile electrical umbilical is an electrical extension cable that transports: 
x
Temperature feedback from the catheter to the console  
x
Leak detection signals from the catheter to the console  
x
Blood sensor signals from the catheter to the console  
x
Pressure sensor form the catheter to the console 
8.1.8.
Manual Retraction Kit 
The Manual Retraction Kit contains one large syringe, one 3-way stopcock and a coaxial-to-luer adaptor. The 
kit is used during the rewrap procedure of the Arctic Front Advance catheter if the Investigator cannot 
retract the catheter using the normal catheter retraction cycle. 
8.1.9.
 
 
 

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8.1.10.
Additional Study Devices 
Medtronic may incorporate additional components, software, and devices into this clinical study as they 
receive appropriate license or regulatory approval and are released commercially by Medtronic in the region 
where they will be used providing that the scientific soundness of the study is not adversely affected as 
evaluated by Medtronic.   
8.2.
Packaging 
In the US, Canada and Europe, the Arctic Front Advance and Freezor MAX CryoAblation Catheters and 
Manual Retraction Kits will not be labeled as investigational, as these devices will be considered 
investigational upon opening per the CIP.  Commercially available products will be used for the study.   
 
In Japan, the devices will be labeled “Exclusively for Clinical Research” and provided to the centers. 
8.3.
Product Receipt, Tracking and Storage 
In the US, Canada and Europe, the study will utilize the market-released Arctic Front Advance and Freezor 
MAX Cardiac CryoAblation Catheters and Manual Retraction Kits with no study driven changes to the product 
or labeling.  These devices will not be provided to the centers. 
In Japan, the devices including the Manual Retraction Kits will be labeled “Exclusively for Clinical Research” 
and will be provided to the centers.  These devices must be kept in a secure and locked location and only used 
for the study. 
The Arctic Front Advance and Freezor MAX Cardiac CryoAblation Catheters will be considered 
investigational in the US and Japan when opened with the intent to use in the study; however non-
investigational in Canada and Europe.  The Manual Retraction Kits will be considered investigational only in 
Japan when opened with the intent to use in the study. 
Arctic Front Advance and Freezor MAX distribution logs will be provided to the US and Japanese centers and 
will be used for tracking of all investigational product throughout the entire study.  The logs must be 
maintained and updated when disposed of or returned to Medtronic.  A Manual Retraction Kit distribution log 
will be provided only to Japanese centers and will be used for tracking this product throughout the entire 
study. 
NOTE: this is an exception to the ISO standard because device accountability for Arctic Front Advance and 
Freezor MAX Cardiac CryoAblation Catheters and Manual Retraction Kits will not be performed in Europe or 
Canada and only upon package opening in the US (full device accountability will take place in Japan starting 
with distribution from Medtronic).   
 

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In Japan, the Arctic Front Advance and Freezor MAX Cardiac CryoAblation Catheters and the Manual 
Retraction Kit must be stored in a secure location at the center.  It is the responsibility of the Investigator to 
correctly handle, store, and track the investigational devices.  These devices will be used only in the study 
according to the CIP.  Investigational product disposition logs will be provided to the center and used for 
tracking the Arctic Front Advance and Freezor MAX Cardiac CryoAblation Catheters and the Manual 
Retraction Kits during the study.  The logs must be maintained at each center and updated when the Arctic 
Front Advance and Freezor MAX Cardiac CryoAblation Catheters and Manual Retraction Kits are received, 
opened, used/attempted, disposed of or returned to Medtronic. 
9. Investigator/Investigational Center Selection 
All clinical Investigators managing the subject’s arrhythmia must be qualified practitioners and experienced in 
the diagnosis and treatment of subjects with atrial arrhythmias.  Investigators performing the cryoablation 
procedure must have been trained in the handling of Arctic Front Advance Cardiac CryoAblation Catheters. 
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 Principal Investigator and proposed investigational center shall: 
x
Be qualified by Medtronic AF Solutions training & education, and has gained relevant experience 
having performed at least 20 ablation procedures with Arctic Front Advance and associated 
products  
x
Have adequate time and resources to conduct the study throughout the duration of the study  
x
Have access to an adequate number of subjects in the persistent AF population to enroll 1-3 
subjects per month 
x
Have the ability to comply with applicable IRB/MEC/HOMI and regulatory requirements 
x
Not be debarred, disqualified or working under sanctions in applicable regions 
x
Be willing to perform pulmonary vein isolation only for the treatment of persistent AF 
Center personnel training will be completed prior to participation in this clinical study.   
10. Center Activation 
During the activation process (prior to subject enrollment), Medtronic will train center personnel on the CIP, 
relevant standards and regulations, informed consent, and on data collection and reporting tools. If new 
members join the study center 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:  

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x
IRB/MEC approval (and membership roster/voting list, as required by local law) of the current version 
of the CIP, Patient Informed Consent Form, subject facing materials, Report of Prior Investigation, 
Investigator Brochure as required by local laws and other materials, as necessary  
x
Regulatory authority approval or notification (as required per local law)  
x
Fully executed Clinical Trial Agreement (CTA) and Investigator Statement where applicable 
x
Financial Disclosure of Investigators 
x
Curriculum Vitae (CV) of Investigators and key members of the investigation center team (as 
required by local law) (in Europe, CVs are required for all center members who have been delegated 
tasks) 
x
Documentation of delegated tasks 
x
Documentation of study 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 IRB/MEC and regulatory authority shall be followed.  
In addition, all participating center 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 center with documentation of study center/Investigator readiness in the 
form of a center readiness letter; this letter must be received prior to subject enrollment.  Additional center 
personnel included after the initial activation will be notified when all requirements have been completed. 
11. Selection of Subjects 
11.1. Study Population 
The study population being studied is one that has documented persistent atrial fibrillation with generally 
good cardiovascular health.   
11.2. 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 this CIP 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. 
11.3. Inclusion Criteria 
x
Documentation of symptomatic persistent AF 
R
Defined as having a continuous episode lasting longer than 7 days but less than 6 months 
documented by consecutive ECG recordings  
OR 

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Defined as having a continuous episode lasting longer than 7 days but less than 6 months 
documented by an ECG recording and one doctor note indicating patient had symptoms 
consistent with AF 
x
Failure or intolerance of at least one Class I or III antiarrhythmic drug 
x
Age 18 or older (or older than 18 if required by local law)  
11.4. Exclusion Criteria 
x
Left atrial diameter > 5.0 cm (anteroposterior) 
x
Prior left atrial ablation or surgical procedure (including left atrial appendage closures) 
x
Presence or likely implant of a permanent pacemaker, biventricular pacemaker, loop recorder, or any  
type of implantable cardiac defibrillator (with or without biventricular pacing function) within 12 
months 
x
Presence of any pulmonary vein stents 
x
Presence of any pre-existing pulmonary vein stenosis 
x
Pre-existing hemidiaphragmatic paralysis 
x
Presence of any cardiac valve prosthesis 
x
+3 and +4 mitral valve regurgitation or stenosis 
x
Any cardiac surgery, myocardial infarction, PCI / PTCA or coronary artery stenting which occurred  
during the 3 month interval preceding the consent date 
x
Unstable angina 
x
NYHA Class III or IV congestive heart failure and/or documented left ventricular ejection fraction 
(LVEF) less than or equal to 35% measure by acceptable cardiac testing (e.g. TTE) 
x
Primary pulmonary hypertension 
x
Rheumatic heart disease 
x
Thrombocytosis, thrombocytopenia 
x
Any condition contraindicating chronic anticoagulation 
x
Active systemic infection 
x
Hypertrophic cardiomyopathy 
x
Cryoglobulinemia 
x
Uncontrolled hyperthyroidism 
x
Any cerebral ischemic event (strokes or TIAs) which occurred during the 6 month interval preceding  
the consent date 
x
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 
x
Life expectancy less than one year 
x
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 
x
Known allergies or hypersensitivities to adhesives 
x
Known drug or alcohol dependency 
x
Unwilling or unable to comply fully with study procedures and follow-up 

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12. 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): 
x
Subjects will be screened to confirm eligibility for enrollment with defined inclusion/exclusion criteria 
prior to enrollment 
x
Subject demographics will be collected at baseline in order to later assess possible characteristics that 
may influence endpoints  
x
A statistical analysis plan will be developed prior to analyzing data which will document all pre-specified 
analyses and analysis methods 
x
All centers and geographies will use the same version of the CIP  
x
All study clinicians and Medtronic personnel will be trained on their respective aspects of the study using 
standardized training materials 
x
All study clinicians will be trained on and required to follow the CIP 
x
An independent Clinical Events Committee (CEC) will be utilized to regularly review and adjudicate at a 
minimum, all system (cryoablation and 
) related and all procedure related 
adverse events, as well as all deaths in the study. 
x
An independent core lab will be utilized to regularly review and adjudicate the arrhythmia component of 
the primary endpoint, recurrent AF/AT/AFL. 
x
Monitoring will be conducted to review adherence to the CIP and perform source data verification per 
the Monitoring Plan 
x
A maximum of 20 treated subjects will be allowed at a single center to ensure an even distribution of total 
subjects across centers. 
x
 
 
In summary, potential sources of bias that may be encountered in this clinical study have been considered 
and minimized by careful study design. 
13. Study Procedures  
13.1. Schedule of Events
Data collection requirements are summarized in Table 7. 
 
 

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Table 7: Study Procedures and Data Collection per Subject Visit 
Baseline 
Cryoablation 
Procedure
Hospital 
Discharge 
Repeat Ablation 
in Blanking 
6 week phone 
call 
3 Month Visit 
6 and 12 Month 
Visit 
Repeat Ablation 
out of Blanking
Unscheduled 
Visit 
Exit 
Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X1 
 
 
 
 
 
 
 
 
 
Review Medications 
X 
 
X 
 
X 
X 
X 
 
X 
 
Pregnancy Screen (if applicable)2 
X 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
X1 
 
X 
 
 
X 
X 
 
X 
 
Trans-thoracic Echocardiogram (TTE)3 
X
SF-12 Health Survey and AFEQT 
Questionnaire 
X 
 
 
 
 
 
X 
 
 
 
Trans-esophageal Echocardiogram (TEE)4 
X 
 
 
X 
 
 
 
 
 
 
Sub-study 
5 
 
 
 
 
 
 
 
Ablation Procedure Data 
 
X 
 
X 
 
 
 
X 
 
 
24h Continuous Monitoring with Holter 
 
 
 
 
 
 
X 
 
 
 
Trans-telephonic monitoring 
 
 
 
 
 
Weekly and upon symptoms 
Review symptoms suggestive of recurrent 
AF/AT/AFL 
 
 
 
 
X 
X 
X 
 
X 
 
Device Deficiencies 
As they occur 
Adverse Events (incl. AE with outcome of 
death) 
As they occur
Study Deviation  
As they occur 
Study Exit Information 
 
 
 
 
 
 
 
 
 
X6 
1Only required if data not available from within prior 30 days from consent date. 
2Female subjects of child bearing potential only.  3Only required if data not available from within prior 6 months from consent 
date.  
4TEE to assess for LA thrombus as indicated by the 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and 
Surgical Ablation of Atrial Fibrillation. 
5Subjects need to sign the sub-study patient informed consent form 
 
 
  See Appendix B for additional details. 
6A review of medications, adverse event assessment and a 12-lead ECG should be attempted if the subject exits the study 
outside of a study visit. 

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13.2. Role of the Sponsor 
Sponsor representatives may provide support as required for the study under supervision of the Principal 
Investigator, including: 
x
Provide study training relevant and pertinent to the involvement of personnel conducting study 
activities and Investigator responsibilities 
x
Technical support during the procedures under the supervision of a study Investigator, but no data 
entry, shall be performed by Medtronic personnel or their representatives at centers 
x
Monitoring and auditing activities  
13.3. Subject Consent 
Patient informed consent (PIC) is defined as a legally effective documented confirmation of a subject’s (or 
their legally authorized representative except in Europe) 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 a PIC Form and an 
Authorization to Use and Disclose Personal Health Information that has been approved by the study center’s 
IRB/MEC and signed and dated by the subject or their legally authorized representative (except in Europe).   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. Informed consent may be given by 
their legally authorized representative (except in Europe) only if a subject is unable to make the decision to 
participate in a clinical investigation. In such cases, the subject shall also be informed about the clinical 
investigation within his/her ability to understand. 
Prior to enrolling subjects, the PIC Form must have been approved by each center’s IRB/MEC.  Each site must 
also use an Authorization to Use and Disclose Personal Health Information/Research Authorization/other 
privacy language as required by law.  The PIC Form must be controlled (i.e. versioned and/or dated) to ensure 
it is clear which version(s) were approved by the IRB/MEC.  Any adaptation of the sample PIC Form must be 
reviewed and approved by Medtronic and the IRB reviewing the application prior to enrolling subjects.  
The Investigator must notify the subject (or their legally-authorized representative) of any significant new 
findings about the study that become available during the course of 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 (or their legally authorized representative). Likewise, privacy or health information protection 
regulation may require subjects to sign additional forms to authorize centers 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 PIC Form and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law must be given to the subject 
(or their legally authorized representative) 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 center personnel. The informed 
consent process shall not waive or appear to waive the subject’s legal rights. The language used shall be as 

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non-technical as possible and must be understandable to the subject and the impartial witness, where 
applicable.  
The subject must have ample time and opportunity to read and understand the PIC Form, to inquire about 
details of the study, and to decide whether or not 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 PIC Form and the Authorization to Use and 
Disclose Personal Health Information/Research Authorization/other privacy language as required by law 
must be signed and personally dated by the subject (or their legally authorized representative) and either the 
Investigator or the Investigator’s authorized designee, as required by local law.  If applicable, witness shall 
also sign and personally date the consent form to attest that the information in the PIC Form was accurately 
explained and clearly understood by the subject, and that informed consent was freely given. 
In Europe and Japan, include a personally dated signature by the Principal Investigator or authorized 
designee responsible for conducting the informed consent process.  The Principal Investigator or designee 
must conduct the informed consent discussion. 
A copy of the PIC Form and the Authorization to Use and Disclose Personal Health Information/Research 
Authorization/other privacy language as required by law, 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) PIC 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 PIC Form.  In Europe, when a subject cannot read and/or write, an independent witness 
shall be present throughout the process, the written PIC Form and any other information shall be read aloud 
and explained to the prospective subject. The subject should “make his mark” (sign or otherwise physically 
mark the document so as to indicate consent) on the PIC Form as well. The PIC Form should document the 
method used for communication with the prospective subject and the specific means by which the 
prospective subject communicated agreement to participate in the study.  
The original of the signed PIC Form and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law must be filed in the 
hospital/clinical chart and/or with the subject’s study documents. PIC Form (in Japan, the signature page 
only) and the Authorization to Use and Disclose Personal Health Information/Research Authorization/other 
privacy language as required by law 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 PIC Form 
and verify its completeness prior to proceeding with the procedure. In the event the Medtronic Field 
personnel identify a PIC 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.  In Japan, only the monitor assigned to 
the study may be able to review the signed PIC Form prior to the study procedure. 

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13.4. Enrollment, Baseline and Pre-ablation 
When a patient and the Principal Investigator or authorized designee, as required, have signed and dated the 
PIC Form, the patient is considered a subject enrolled in the study.  The date the subject signed the PIC 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 cryoablation 
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: 
x
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. 
Within 30 days prior to consent date: 
x
12-lead ECG and physical exam.  A repeat 12-lead ECG and physical exam for the purpose of the 
study after the consent date is not required if a 12-lead ECG and physical exam were performed 
within 30 days of the consent date and all data are available. 
After consent date but prior to procedure:  
Note: The time between the consent date and the procedure should not exceed 30 days. 
x
Final assessment of all factors specified for evaluation under Inclusion Criteria and Exclusion Criteria 
(Section 11) 
x
Demographics 
x
Medical history 
x
Pregnancy screen (female subjects of child bearing potential only)  
x
Review of AF and anticoagulation medications  
x
SF-12 health survey and AFEQT Questionnaire 
x
Transesophageal Echocardiogram (TEE)  

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x
When performed, the TEE should occur within one day (on the day of or within the day prior 
to) the planned ablation procedure. 
x
A TEE should be performed in all subjects with atrial fibrillation more than 48 hours in 
duration or of an unknown duration if adequate systemic anticoagulation has not been 
maintained for at least 3 weeks prior to the ablation procedure. 
x
Performance of a TEE in subjects who are in sinus rhythm at the time of ablation or eligible 
subjects that have been in AF for 48 hours or less prior to AF ablation may be considered but 
is not mandatory. 
x
The subject will not proceed with the study ablation procedure and will be exited from the 
study if a left atrial thrombus is visualized. 
x
 if enrolled in the sub-study (see Appendix B) 
13.5. Procedure 
Perform the pulmonary vein isolation procedure using Arctic Front Advance Cardiac CryoAblation Catheter.  
If needed, a Freezor MAX Cardiac CryoAblation Catheter may also be utilized for gap ablation to complete 
electrical isolation of the pulmonary veins and creation of ablation lines between the inferior vena cava and 
the tricuspid valve.  The Investigator is to perform the procedure according to the procedural steps in this 
CIP and the Instructions for Use for the Arctic Front Advance and Freezor MAX Cardiac CryoAblation 
Catheters.  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.  
Current recommendations for anticoagulation are found in the 2012 HRS/EHRA/ECAS Expert Consensus 
Statement on Catheter and Surgical Ablation of Atrial Fibrillation1, 2014 Focused Update on the Canadian 
Cardiovascular Society Guidelines for the Management of Atrial Fibrillation18 and Guidelines for indications 
and procedural techniques of catheter ablation.19 
Only the Medtronic FlexCath sheath family should be used with the Arctic Front Advance Cardiac 
CryoAblation Catheter.  The use of other sheaths may damage the device.  The Investigator may choose 
compatible guidewires and mapping catheters at his or her discretion. 

 Verma, A, MD, et al. 2014 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of 
Atrial Fibrillation. Canadian Journal of Cardiology. 30 (2014) 1114-1130. 
Okumura. Guidelines for indications and procedural techniques of catheter ablation.  Japan Circulation Society. 2012. 

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13.5.1.
Esophageal Visualization and Temperature Monitoring 
a. Ensure an esophageal temperature monitor is used for each cryoablation application.  Cease 
FU\RDEODWLRQLIWKHWHPSHUDWXUHUHDFKHVƧ& 
13.5.2.
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 an ACT of 300 to 400 seconds or 
per standard center guidelines. 
b. Performance of AF ablation in a subject systemically anticoagulated with warfarin or novel oral 
anticoagulants (NOACs) does not alter the need for intravenous heparin to maintain a 
therapeutic ACT during the procedure. 
c. Administration of protamine following ablation to reverse heparin should be considered. 
13.5.3.
Diaphragm Movement 
a. Continuous phrenic nerve pacing must be performed for all right sided pulmonary vein 
cryoapplications and should be considered for all cryoapplications.  Additional methods of 
phrenic nerve monitoring are recommended. 
13.5.4.
Balloon Pulmonary Vein (PV) Cryoablation 
a. Every effort consistent with subject welfare should be made to treat all PVs or their anomalous 
equivalents. 
b. The Arctic Front Advance will be advanced into the left atrium over the Achieve catheter or 
guidewire and inflated.  Once inflated, the catheter will be tracked over the Achieve catheter or 
guidewire and positioned at the entrance of the PV. 
c. Assess the positioning, contact and occlusion of the PV by the catheter’s balloon by injection 
of contrast material, ultrasound imaging, or other technique.  Reposition as needed. 
d. Each pulmonary vein should be minimally assessed for entrance block and, where assessable, 
exit block to demonstrate electrical isolation.   
e. It is recommended that the Investigator use cryoapplications of three (3) minutes each.  Once 
PV isolation has been achieved, one (1) additional application of three (3) minutes at the same 
PV should be performed; however, it is up to the operator’s discretion to assess application 
time and necessity of a bonus freeze given factors such as time to isolation of first application, 
temperature of first application, risk of collateral damage, etc. 
f.
Upon the Investigator’s assessment of procedure completion, Isoproterenol and/or adenosine 
may be used to assess pulmonary vein isolation. 

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13.5.5.
Other Ablations during Index Procedure 
a. Ablation of the cavotricuspid isthmus, with the goal of achieving bi-directional isthmus block, 
is required 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. Left atrial non-PVI ablations including but not limited to, ablation of linear lesions, complex 
fractionated electrograms or non-PV triggers will be treated as a primary endpoint failure.  
Ablation using RF in the left atrium will be treated as a primary endpoint failure. 
c. Additional right atrial ablations may be performed if clinically necessary. 
13.5.6.
Cardioversion 
a.
Electrical or pharmacological cardioversion to sinus rhythm must be attempted following the 
PVI portion of the procedure if sinus rhythm wasn’t restored. 
13.5.7.
Procedure Documentation  
During the procedure the Investigator will document the following:  
x
Catheters used (i.e. Arctic Front Advance, Freezor MAX and Achieve Mapping Catheter, etc.) 
x
Minimum temperature for each cryoapplication 
x
Minimum esophageal temperature for each PV 
x
Duration of each cryoapplication 
x
Vein location for each cryoapplication (e.g. right superior PV) 
x
Use of phrenic nerve pacing or other phrenic nerve monitoring technique for each 
cryoapplication, specifically those cryoapplications surrounding the RS and RI PVs 
x
Demonstrated electrical block and, if real-time signals are available, time to isolation 
x
Adjunctive catheters, mapping or visualization devices, sedation type, procedure information, 
esophageal temperature, ACT, cardioversion use and fluoroscopy time will be collected 
13.6. Hospital Discharge 
At or shortly before hospital discharge, the following will be performed and collected: 

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x
Adverse event assessment 
x
Review medications 
x
12-lead ECG 
x
Review study requirements with the subject to help ensure compliance with follow-up 
procedures 
Systemic anticoagulation with warfarin or a direct thrombin or Factor Xa inhibitor is recommended for at 
least two months following the AF ablation procedure, however the anticoagulation treatment will be at the 
Investigator’s discretion according to established guidelines.  Decisions regarding the continuation of 
systemic anticoagulation agents more than two months following ablation should be based on the subject’s 
risk factors for stroke and not on the presence of AF.1,21,22 
13.7. Medications 
It is recommended to discontinue the use of Class I and III antiarrhythmic medication by the end of the 90 day 
post-procedure blanking period.  Up-titration of the dose is allowed only in the 90 day post-procedure 
blanking period. 
Information regarding medications prescribed for anticoagulation or to treat atrial arrhythmias, including the 
medication name, purpose for use, start and stop dates, and route of administration, will be collected from 
subject enrollment through study exit.   
13.7.1.
Class I and III antiarrhythmic medication use after the 90 day post-procedure 
blanking period 
x
Subjects are allowed to remain on Class I or III antiarrhythmic medications at the historic 
maximum ineffective dose (on prior to the ablation procedure) after the 90 day post-procedure 
blanking period. 
x
Subjects may re-initiate, at any point during follow-up, a Class I or III antiarrhythmic medication 
that failed or was not tolerated prior to the ablation procedure at the same or lower dose. 
x
Initiation of a new Class I or III antiarrhythmic medication after the 90 day post-procedure 
blanking period will be treated as a primary endpoint failure. 
x
Remaining on a dose higher than the historic maximum ineffective dose (on prior to the ablation 
procedure) after the 90 day post-procedure blanking period will be treated as a primary endpoint 
failure. 
All medications are permitted in the study with the exception of investigational drugs that may confound the 
study results. 
13.8. Permissible Repeat Cryoablations 
Pulmonary vein isolation using Arctic Front Advance following the same procedure described in 13.5 is 
allowed one time in the 90 day post-procedure blanking period.  Right atrial ablations may be performed 
using any catheter deemed appropriate for the procedure.   

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Left atrial ablations of non-PV triggers, complex fractionated electrograms and ablation of linear lesions will 
be treated as a primary endpoint failure.  Ablation using RF in the left atrium will be treated as a primary 
endpoint failure. 
Repeat ablation procedures will be documented on an electronic case report form (eCRF).  The subject’s 
procedures and follow-up windows will continue based on the index cryoballoon ablation procedure date.   
13.9. Cardioversions 
Electrically and pharmacologically cardioverting the subject to sinus rhythm is allowed within the 90 day 
post-procedure blanking period at the discretion of the Investigator. 
13.10. Scheduled Follow-up Visits 
After receiving notice of completed study procedure, Medtronic will provide the target dates and windows 
for each visit to the center. 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 8 and are based on days after the index ablation procedure.   
Table 8:  Follow-up Schedule 
Occurrence/ 
Visit 
Window 
(Calculated days after the ablation procedure) 
Window Start 
Target
Window End 
Enrollment/Baseline 
-30 days 
-15 days 
Day 0 
Index Cryoablation Procedure 
Day 0 
Day 0 
Day 0 
6 week phone call 
35 days 
39 days 
42 days
3 month office 
91 days 
91 days 
121 days 
6 month office 
165 days
180 days 
195 days 
12 month office 
365 days
365 days 
395 days 
The following information is required to be collected at the follow-up visits: 

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13.10.1.
Six Week Phone Call  
x
Review medications  
x
Adverse event assessment 
x
Review symptoms suggestive of recurrent AF/AT/AFL 
13.10.2.
Three Month Office Visit 
x
Review medications  
x
Adverse event assessment 
x
Review symptoms suggestive of recurrent AF/AT/AFL 
x
12-lead ECG 
R
Send to the core lab 
x
Review the TTM system and begin transmitting weekly and upon symptoms 
13.10.3.
Six Month Office Visit
x
Review medications  
x
Adverse event assessment 
x
Review symptoms suggestive of recurrent AF/AT/AFL 
x
12-lead ECG 
R
Send to the core lab 
x
24h continuous monitoring with Holter 
R
Send to the core lab 
x
SF-12 Health Survey and AFEQT Questionnaire 
13.10.4.
Twelve Month Office Visit 
x
Review medications 
x
Adverse event assessment 
x
Review symptoms suggestive of recurrent AF/AT/AFL 
x
12-lead ECG 
R
Send to the core lab 
x
24h continuous monitoring with Holter 
R
Send to the core lab 
x
SF-12 Health Survey and AFEQT Questionnaire 
13.11. Unscheduled Office Visits 
An unscheduled visit is defined as any unplanned cardiovascular-related office visit or early study exit at the 
study center that occurs between CIP required visits.  If the subject exits the study early, an unscheduled 
office visit should occur.  The following information is required to be collected at unscheduled follow-up 
visits: 

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x
Review medications 
x
Adverse event assessment 
x
Review symptoms suggestive of recurrent AF/AT/AFL 
x
12-lead ECG 
R
Send to the core lab 
13.12. Holter and TTM Management 
Market-released Holters will be distributed by a core lab to centers after activation has occurred.  All subjects 
will wear a Holter in conjunction with their 6 and 12 month office visits.  Holters will then be sent back to the 
center 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.  
Holter distribution logs will be provided to European centers.  The logs must be maintained and updated 
when Holters are received and returned to the core lab. 
Market-released TTMs will be distributed by a core lab to centers after activation has occurred.  All subjects 
will transmit weekly and symptomatic ECGs via the TTM system following their 3 month office visit.  The TTM 
system will be sent back to the core lab at the end of the study.  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 TTMs.  
TTM distribution logs will be provided to European centers.  The logs must be maintained and updated when 
TTMs are received and returned to the core lab. 
13.13. 12 lead Electrocardiograms 
Market-released 12-lead ECG machines will be distributed by a core lab to centers after activation has 
occurred.  All 12-lead ECGs starting with the one occurring at the 3 month office visit will be sent to the core 
lab.  The 12-lead ECG machine will be sent back to the core lab at the end of the study. The core lab will be 
responsible for adjudication of atrial arrhythmias for the primary objective of the study.  Copies of additional 
source documents may be requested.  The core lab will manage maintenance, calibration and tracking of the 
12-lead ECG machine.  
12-lead ECG distribution logs will be provided to European centers.  The logs must be maintained and 
updated when 12-lead ECG machines are received and returned to the core lab. 
13.14.
 
Follow Appendix B if the subject is enrolled in the sub-study
 
 
13.15. Assessment of Efficacy 
The primary efficacy objective is based on the ECG data collected as discussed in Section 17.  

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13.16. Assessment of Safety 
The primary safety objective is based on the Adverse Event data collected. Further information on the 
collection of Adverse Events is discussed in Section 17.  
13.17. Recording Data 
The study will collect data using Oracle Clinical, an electronic data management system for clinical studies. 
Centers will enter data onto case report forms (CRFs) within an Oracle Clinical database. The 
Holter/TTM/12-lead ECG core lab will also enter data onto CRFs within a separate Oracle Clinical database.  
Data reported on the CRFs shall be derived from source documents, which may include worksheets, quality 
of life questionnaires, patient medical records and ECG data. These source documents must be created and 
maintained by the center personnel. Further detail on data management is provided in Section 19.2. 
13.18. 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.  In countries following ISO 14155:2011, prior 
approval for study deviations will be reported to local authorities and ethics boards per local requirements.  If 
the deviation affects subject’s rights, safety and well-being, or the scientific integrity of the study, prior 
approval from ethics board and/or competent authority is also required, depending on local legislations.  
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).  A study deviation is not required if a subject misses a weekly 
TTM transmission. 
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/MEC as well as 
Medtronic within five (5) working days.  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 study deviations 
should comply with IRB/MEC policies, local laws and/or regulatory agency requirements and must be 
reported to Medtronic as soon as possible upon the center becoming aware of the deviation.  Refer to 

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Investigator Reports, Section 19.5.2, for specific deviation reporting requirements and timeframes for 
reporting to Medtronic and/or regulatory bodies.  
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 center, 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 center-specific reports to Investigators summarizing information on deviations that occurred at the 
investigational center on a periodic basis. 
13.19. Subject Withdrawal or Discontinuation  
A subject can withdraw from the study or the 
 sub-study at any time.  If the 
subject wishes to exit from the study (i.e. the subject revokes consent), the center is required to document 
the reason for exit on an eCRF.  In addition, centers shall follow the regulations set forth by their IRB/MEC.  It 
is recommended to follow the subject until all ongoing device and/or procedure-related adverse events are 
resolved or unresolved with no further actions planned.  For countries following ISO, permission may be 
requested to follow-up with the subject outside of the study due to withdrawal based on problems related to 
the study device safety or performance.  Following exit, subjects will continue to receive standard medical 
care.  All data available through the time of the subject’s exit will be used for analysis. 
Reasons for study exit include: 
x
Subject lost to follow-up 
x
Subject did not meet inclusion/exclusion criteria after consent and did not undergo an ablation 
procedure 
x
An Arctic Front Advance catheter was not used during the subject’s ablation procedure 
x
Subject did not provide consent or data use protection authorization 
x
Subject chooses to withdraw (e.g., consent withdrawal, relocation to another geographic location)  
x
Investigator deems withdrawal necessary (e.g., medically justified, inclusion/exclusion criteria not 
met, failure of subject to maintain adequate study compliance) 
x
The sponsor decides the study will be closed or a particular center will be closed   
The following information is required to be collected at study exit: 
x
Reason for exit must be documented on the eCRF and in the subject’s medical record 
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. 

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14. Risks and Benefits 
14.1. 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 
residual risks associated with the Arctic Front Advance and Freezor MAX Cardiac CryoAblation Catheters 
have been found to be acceptable and have been mitigated to the fullest extent possible. The potential 
benefits related to the use of the Arctic Front Advance and Freezor MAX Cardiac CryoAblation Catheters 
have been determined to outweigh any potential risks.  Neither device has been recalled. 
There are potential risks and side effects associated with ablation procedures.  The Investigator shall 
describe risks in further detail when asked by the subject.  The risks must be continuously monitored, 
assessed and documented by the Investigator.  The current Arctic Front Advance Instructions for Use 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): 
x
Anemia-deficiency of red blood cells or of hemoglobin in the blood resulting in weariness 
x
Anxiety-a feeling of worry, nervousness, or unease 
x
Back pain-pain felt in the lower or upper back 
x
Bronchitis, cough, pneumonia-inflammation of the lungs can be caused by a virus or bacteria 
x
Cardiac tamponade-pressure on the heart as a result of fluid collecting in the sac surrounding the 
heart 
x
Cardiopulmonary arrest-cessation of blood circulation and/or respiration due to dysfunction of the 
heart and/or lungs 
x
Chest discomfort/pain/pressure-includes a range of feeling from sharp stabbing to dull ache in the 
chest 
x
Cold feeling-having a low or inadequate temperature 
x
Complications associated with contrast agents-adverse effects of contrast agents used during the 
procedure (e.g. allergic reaction or radio contrast nephropathy) 
x
Complications associated with medications commonly utilized during the procedure-known risks of 
medications commonly used during the procedure (e.g. narcotics, anxiolytics, other pain 
medications, anti-vasospasm agents) 
x
Complications at catheter insertion site in the groin: 
R
AV fistula-an abnormal connection between an artery and a vein (i.e., cause by needle 
insertion through the femoral artery and vein) 
R
Hematoma/Bruising/Ecchymosis-a collection of blood in the tissue surrounding the 
catheter insertion site 

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R
Infection-localized redness, heat swelling and pain at the catheter insertion site 
R
Pain-discomfort at the catheter insertion site that can range from mild to severe 
R
Pseudoaneurysm-a collection of blood in the tissue surrounding the catheter insertion site 
due to ongoing leaking of blood from a blood vessel 
R
Significant bleeding-blood loss from the catheter insertion site requiring surgery or 
transfusion of 2 or more units of packed red blood cells (PRBCs) 
x
Coronary artery spasm, vasospasm-constriction of a blood vessel 
x
Death-a complication or deterioration of health ultimately leading to a patient’s death 
x
Diarrhea-feces are discharged from the bowels frequently and in a liquid form 
x
Difficulty swallowing-narrowing of the esophagus 
x
Digestive discomfort-pain in the abdomen 
x
Dissection of a blood vessel-tear within the wall of a blood vessel 
x
Dizziness, lightheadedness-feeling faint, woozy, weak or unsteady 
x
Embolism-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. 
x
Endocarditis –inflammation of the inner surface of the heart 
x
Esophageal injury –damage to your swallowing tube, atrio-esophageal fistula - abnormal 
passageway between the heart and esophagus, hematemesis (vomiting blood) 
x
Fatigue-extreme tiredness 
x
Fever-abnormally high body temperature 
x
Headache-pain in the head 
x
Heart rhythm disturbances-disruption of normal heart rate or rhythm e.g. atrial flutter, tachycardia, 
bradycardia, heart block 
x
Hemothorax–collection of blood around the lungs 
x
Hiccups-involuntary spasm of the diaphragm and respiratory organs 
x
Hypertension-high blood pressure 
x
Hypotension-low blood pressure 
x
Hypoxia-deficiency in the amount of oxygen reaching the tissues 

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Infection (e.g. pericarditis-infection of the sac that surrounds the heart, sepsis-infection throughout 
the body, urinary-infection of the urinary system) 
x
Injury to lung- (e.g. bronchial lesion, hemoptysis, constriction, pulmonary hemorrhage, bronchia 
fistula) 
x
Mild skin discomfort or irritation-redness sensitivity of the skin cause during or after the procedures 
(e.g. electrodes used with the ECG and Holter recorder might cause mild skin discomfort or irritation 
or some skin discomfort following electrode removal or tape removal). 
x
Nausea-a sensation of unease and discomfort in the upper stomach with an urge to vomit 
x
Perforation of a blood vessel or cardiac tissue-unintended puncture through the wall of a blood 
vessel or cardiac tissue 
x
Pericardial effusion- fluid collecting in the sac that surrounds the heart 
x
Nerve injury e.g. damage to the phrenic nerve that controls breathing 
x
Pleural effusion–collection of extra fluid around the lungs 
x
Pulmonary edema-excess fluid in the lungs 
x
Pulmonary hypertension-high blood pressure that affects the arteries in the lungs and the right side 
of the heart 
x
Pulmonary vein hematoma-trauma to the pulmonary vein 
x
Pulmonary vein stenosis –blockage in the blood vessels takes blood from the lungs to the heart 
x
Pneumothorax – collapsed lung 
x
Renal dysfunction-kidneys fail to adequately filter waste products from the blood 
x
Bleeding e.g. bleeding into the retroperitoneal space 
x
Right sided heart failure-right side of the heart is not pumping blood to the lung normally 
x
Shivering-body shaking 
x
Shortness of breath-difficulty breathing 
x
ST elevation-the ST segment of an ECG is abnormally high above the baseline 
x
Sore throat-pain in the throat 
x
Vagal nerve injury (e.g. gastroparesis-delayed gastric emptying) 
x
Vascular complications requiring surgery-damage to an artery (e.g. femoral) or vein requiring 
surgical repair 
x
Vasovagal reaction-reflex of the involuntary nervous system that causes the heart to slow down and 
blood pressure drops 
x
Visual changes (e.g. blurred vision) 

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Vomiting-forceful expulsion of stomach contents through the mouth and/or nose 
14.2. Risk Minimization 
Medtronic has attempted to minimize the potential risks to subjects in the study by taking the following 
actions: 
x
Selecting qualified Investigators and training study personnel on the CIP 
x
Requiring that Investigators be actively involved in the procedure and follow-up of the subjects who 
undergo a study procedure 
x
Providing guidelines for subject selection and evaluation 
x
Requiring that subjects be followed at regular intervals following the ablation procedure to monitor 
for recurrence of atrial arrhythmias and to assess for adverse events 
14.3. Potential Benefits 
The Arctic Front Advance Cardiac CryoAblation Catheter may reduce or eliminate persistent atrial fibrillation 
in subjects; however, some subjects may not receive this benefit.  The information gained from the study 
could result in improved management of atrial fibrillation. 
14.4. Risk-Benefit Rationale 
The cohort of subjects for inclusion in the study is symptomatic as a result of their persistent atrial fibrillation 
and the failure of Class I or III antiarrhythmic drug therapy.  Cryoablation therapy offers the opportunity to 
reduce the episodes of atrial fibrillation and therefore reduce the subject’s risk of stroke and symptoms.  
In the United States, there are no ablation catheters approved to treat subjects with persistent atrial 
fibrillation.  If successful, the STOP Persistent AF study could demonstrate meaningful therapeutic benefit in 
this underserved population. 
In Japan, there are limited options for physicians to choose for the treatment of persistent atrial fibrillation.  
If successful, the STOP Persistent AF study could demonstrate meaningful therapeutic benefit in this 
underserved population. 
In Canada and Europe, the Arctic Front Advance ablation catheters are approved to treat subjects with 
persistent atrial fibrillation.  If successful, the STOP Persistent AF study could confirm meaningful 
therapeutic benefit in this underserved population. 
15. Adverse Event and Device Deficiencies Assessment 
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. 

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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.  
15.1. Adverse Event and Device Deficiency Definitions 
Where the definition indicates “device”, it refers to any device used in the study. This might be the catheter, 
or any other component of the system under investigation, or any market-released component of the 
system. 
Table 9:  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 
that encompasses cryoablation.   
Cryoablation system related 
An Adverse Event that results from the presence or performance 
(intended or otherwise) of the cryoablation system (including the 
Arctic Front Advance, Freezor MAX, FlexCath Sheath, Achieve 
Mapping Catheter, CryoConsole, Manual Retraction Kit) 

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Cardiovascular related 
An Adverse Event relating to the heart and the blood vessels or the 
circulation. 
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 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) 
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) 
Other 

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15.2. Adverse Events 
For the purposes of the study, the following Adverse Events will be collected starting at the time of signing 
the PIC Form through the duration of the subject’s participation in the study: 
x
All procedure related AEs 
x
All system related AEs (cryoablation and 
) 
x
All cardiovascular related AEs 
x
All Serious Adverse Events (SAEs), regardless of relatedness 
Reporting of these 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 center, treatment, resolution, assessment of both the 
seriousness and the relatedness to the investigational device. Each AE must be recorded on a separate AE 
eCRF.  Exceptions include: 
x
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. 
x
Unavoidable Adverse Events, listed in Table 9 need not be reported unless the adverse event 
worsens or is present outside the stated timeframe after the ablation procedure. 
x
Cardioversions (DC or Drug) for recurrent symptomatic atrial fibrillation and other atrial arrhythmias 
are not considered serious adverse events 
Subject deaths are also required to be reported. Refer to section 15.6 for Subject Death collection and 
reporting requirements. 
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.    
Event Description 
Timeframe 
(hours) from 
the Surgical 
Procedure 
Anesthesia related nausea / vomiting  
24 
Low-JUDGHIHYHU)RU& 
48 
Mild to moderate bruising / ecchymosis in 
groin area / groin pain 
168 
Sleep problems (insomnia) 
72 
Back pain related to laying on table 
72 

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15.3. Device Deficiencies 
Device deficiency (DD) information will be collected throughout the study and reported to Medtronic. 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 AEs/DDs that require immediate reporting, initial 
reporting may be done by contacting the study sponsor per the sponsor contact information. 
15.4. Processing Updates and Resolution 
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 resolved, is unresolved with no further actions planned, 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 unresolved procedure or system related adverse events, as classified 
by the Investigator, are resolved or they are unresolved with no further actions planned.  
At the time of study exit, all adverse events with an outcome of “Unresolved, further actions or treatment 
planned” must be reviewed and an update to the original AE must be reported.  At a minimum, if there are no 
changes to the description, relatedness, test and procedures or actions taken, the outcome must be 
updated to reflect “Unresolved at time of study closure.” 
15.5. Reporting of Adverse Events and Device Deficiencies 
All reported adverse events and device deficiencies 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/device deficiency 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 and device deficiencies that could have led to a SADE will be completed 
according to local regulatory requirements. Refer to Section 19.5 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 G.  This is a list of adverse events related 
to the Arctic Front Advance CryoAblation Catheter or procedure that have been observed in previous 
studies and may be experienced by subjected.  This list may help to assess if an adverse event is unexpected 
in nature. 

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For emergency contact regarding a SAE, 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 as outlined below: 
 
 
Table 10:  Adverse Event Classification Responsibilities 
What is classified? Who classifies? Classification Parameters 
Relatedness 
Investigator 
Cryoablation procedure related, Cryoablation system 
related, 
, 
Cardiovascular related 
Sponsor 
Cryoablation procedure related, Cryoablation system 
related, 
 
Seriousness 
Investigator 
SAE 
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 
An independent Clinical Events Committee (CEC) will at a minimum, review all system (cryoablation and 
) related and all procedure related adverse events, as well as all deaths and 
provide a final adjudication and death classification.   
Adverse Event and Device Deficiency Reporting Requirements 
Regulatory reporting of AEs/DDs will be completed according to local regulatory requirements.  It is the 
responsibility of the Investigator to abide by any additional AE/DD reporting requirements stipulated by the 
IRB/MEC responsible for oversight of the study.  Investigators should report Serious Adverse Events to 
Medtronic immediately after the Investigator learns of the event. In case that the Adverse Event 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 compliant via the regulator channels for 
market-released products. 
Table 11: Adverse Event and Device Deficiency Report Requirements 
Serious Adverse Events (SAEs) 
Investigator submit to:

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Medtronic 
Europe: Immediately after the Investigator first learns of the event or of new 
information in relation with an already reported event. (ISO 14155 and local law) 
Japan: All serious, adverse events must be reported, whether or not there exists a 
cause and effect relationship with the investigational device.  The Principal 
Investigator shall immediately report all serious, adverse events to the sponsor, 
unless emergency reports are stipulated as being unnecessary in such documents 
as the CIP and investigational device summary.  The Principal Investigator shall 
promptly submit a detailed written report after submitting and emergency report 
(MHLW Ordinance 36, 2005 Article 68) 
All geographies: Report to the sponsor, without unjustified delay, all serious 
adverse events. (ISO 14155:2011) 
MEC/IRB 
All geographies: Submit to MEC/IRB per local reporting requirement. 
Regulatory 
Authorities 
All geographies: Submit to regulatory authority per local reporting requirement. 
HOMI 
Japan: All serious, adverse events must be reported, whether or not there exists a 
cause and effect relationship with the investigational device.  The principal shall 
immediately report in writing all serious, adverse events to HOMI.  In this case, the 
Principal Investigator shall identify serious, unpredictable adverse device effects out 
of the reported serious, adverse events.  (MHLW Ordinance 36, 2005 Article 68) 
Sponsor submit to: 
Investigators 
Japan: All SAEs classified as reportable events follow the applicable reporting 
requirements. (MHLW Ordinance 36, 2005 Article 28) 
MEC/IRB 
All geographies: Submit to MEC/IRB per local reporting requirement. 
Japan: in the case where there is a prior agreement with the IRB and HOMI, all SAEs 
classified as reportable events follow the applicable reporting requirements.  (MHLW 
Ordinance 36, 2005 Article 28) 
Regulatory 
Authorities 
All geographies: Submit to regulatory authority per local reporting requirement. 
Japan: All SAEs classified as reportable events follow the applicable reporting 
requirements.  (Pharmaceutical and Medical Device Act Enforcement Regulations, 
Article 274, Paragraph 2) 
HOMI 
Japan: All SAEs classified as reportable events follow the applicable reporting 
requirements. (MHLW Ordinance 36, 2005 Article 28) 
Serious Adverse Device Effects (SADEs) 
Investigator submit to: 

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Medtronic 
 
Europe: Immediately after the Investigator first learns of the event or of new 
information in relation with an already reported event. (ISO 14155 and local law) 
Japan: the Principal Investigator shall immediately report to the sponsor. (MHLW 
Ordinance 36, 2005, Article 68) 
All other geographies: Submit as soon as possible after the Investigator first learns 
of the event, and per local requirements 
MEC/IRB
All geographies:  Submit to MEC/IRB per local reporting requirement.
Regulatory 
authorities 
All geographies:  Submit as soon as possible after the Investigator first learns of the 
event, and per local requirements 
HOMI 
Japan: The Principal Investigator shall immediately report to HOMI.  (MHLW 
Ordinance 36, 2005 Article 68) 
Sponsor submit to: 
Investigator 
Japan: All SADEs classified as reportable events follow the applicable reporting 
requirements.  (MHLW Ordinance 36, 2005 Article 28) 
MEC/IRB
All geographies:  Submit to MEC/IRB per local reporting requirement.
Japan: in the case where there is a prior agreement with the IRB and HOMI, all 
SADEs classified as reportable events follow the applicable reporting requirements.  
(MHLW Ordinance 36, 2005 Article 28) 

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Regulatory 
authorities 
Canada: All SADEs on the patient, the user or any other person: these must be 
reported by Medtronic to the regulatory within 10 days from the date the first 
person becomes aware.  Preliminary and final reporting to the Canadian Ministry of 
Health (Health Canada) of events occurring inside (always) or outside Canada (in 
case of corrective actions) that is related to a failure of the device or a deterioration 
in its effectiveness, or any inadequacy in its labeling or its directions for use and has 
led to the death or a serious deterioration in the state of health of a patient, user or 
other person or could do so were it to recur. Report a) within 10 days after 
awareness, if incident has led to death or a serious deterioration in the state of 
health of a patient, user or other person b) within 30 days, if incident has not led to 
death or a serious deterioration in the state of health of a patient, user or other 
person, but could do so were it to recur c) as soon as possible, if incident occurred 
outside of Canada and is related to a corrective action. (Medical Devices Regulation 
Mandatory Problem Reporting 59(1) , 59(2), 60 (1)) 
Japan: All SADEs classified as reportable events follow the applicable reporting 
requirements. (Pharmaceutical and Medical Device Act Enforcement Regulations, 
Article 274, Paragraph 2) 
All geographies: Submit to regulatory authority per local reporting requirement. 
HOMI 
Japan: All SAEs classified as reportable events follow the applicable reporting 
requirements. (MHLW Ordinance 36, 2005 Article 28) 
Unanticipated Adverse Device Effects (UADEs) and Unanticipated Serious Adverse Device Effects 
(USADEs) 
Investigator submit to: 
Medtronic 
US: Submit as soon as possible, but no later than within 10 working days after the 
Investigator first learns of the event. (21 CFR 812.150(a)(1))  
Europe: Immediately after the Investigator first learns of the event or of new 
information in relation with an already reported event. 
Japan: The Principal Investigator shall immediately report to the sponsor.  (MHLW 
Ordinance 36, 2005 Article 68) 
MEC/IRB 
US: Submit as soon as possible, but no later than within 10 working days after the 
Investigator first learns of the event. (21 CFR 812.150(a)(1))  
All geographies: Submit to MEC/IRB per local reporting requirement. 
Regulatory 
authorities 
Europe: Submit to regulatory authority per local reporting requirement. 
HOMI 
Japan: The Principal Investigator shall immediately report to HOMI.  (MHLW 
Ordinance 36, 2005 Article 68) 
Sponsor submit to 

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Investigator 
All geographies: Notification as soon as possible and not later than 10 working days 
after the sponsor first learns of the effect. (21 CFR 812.150(b)(1)) 
Japan: Report to the Principal Investigator per reporting requirements (MHLW 
Ordinance 36, 2005 Article 28) 
MEC/IRB 
All geographies: Notification as soon as possible and not later than 10 working days 
after the sponsor first learns of the effect. (21 CFR 812.150(b)(1)) 
Japan: Report to the IRB per reporting requirements in the case where there is a 
prior agreement with the IRB and HOMI.  (MHLW Ordinance 36, 2005 Article 28) 
Regulatory 
authorities 
US: Notification as soon as possible to FDA, but not later than 10 working days after 
the sponsor first learns of the effect. (21 CFR 812.150(b)(1))  
Canada: All USADEs on the patient, the user or any other person; these must be 
reported by Medtronic to the regulatory within 10 days from the first person at 
Medtronic that becomes aware. Preliminary and final reporting to the Canadian 
Ministry of Health (Health Canada) of events occurring inside (always) or outside 
Canada (in case of corrective actions) that is related to a failure of the device or a 
deterioration in its effectiveness, or any inadequacy in its labeling or its directions 
for use and has led to the death or a serious deterioration in the state of health of a 
patient, user or other person or could do so were it to recur. Report a) within 10 days 
after awareness, if incident has led to death or a serious deterioration in the state of 
health of a patient, user or other person b) within 30 days, if incident has not led to 
death or a serious deterioration in the state of health of a patient, user or other 
person, but could do so were it to recur c) as soon as possible, if incident occurred 
outside of Canada and is related to a corrective action. (Canada Medical Device 
Regulations, SOR/98-282; Mandatory Problem Reporting 59(1) , 59(2), 60 (1)) 
Europe: Submit to regulatory authorities per local reporting requirement. 
Japan: Report to the regulatory authorities per reporting requirements. 
(Pharmaceutical and Medical Device Act Enforcement Regulations, Article 274, 
Paragraph 2) 
HOMI 
Japan: Report to HOMI per reporting requirements (MHLW Ordinance 36, 2005 
Article 28) 
Adverse Device Effects
Investigator submit to: 
Medtronic 
Europe: Immediately after the Investigator first learns of the effect. (ISO 14155 and 
local law) 
All other geographies: Submit in a timely manner after the Investigator first learns 
of the effect. 
MEC/IRB 
All geographies: Submit to MEC/IRB per local reporting requirement. 

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Regulatory 
authorities 
All geographies: Submit to regulatory authority per local reporting requirement. 
Sponsor submit to: 
MEC/IRB 
All geographies: Submit to MEC/IRB per local reporting requirement. 
Regulatory 
authorities 
All geographies: Submit to regulatory authority per local reporting requirement. 
All other reportable Adverse Events  
Investigator submit to: 
Medtronic 
All geographies: Submit in a timely manner after the Investigator first learns of the 
event. 
Regulatory 
authorities 
All geographies: Submit to regulatory authority per local reporting requirement. 
MEC/IRB 
All geographies: Submit to MEC/IRB per local reporting requirement. 
Sponsor submit to: 
Regulatory 
authorities 
All other geographies: Submit to regulatory authority per local reporting 
requirement. 
Device Deficiencies and SADE Potential 
Investigator submit to: 
Medtronic 
Europe: Immediately after the Investigator first learns of the deficiency or of new 
information in relation with an already reported deficiency.  
All geographies: Report to the sponsor, without unjustified delay, all device 
deficiencies that could have led to a serious adverse device effect (ISO 14155:2011) 
Regulatory 
authorities 
All geographies:  Submit to regulatory authority per local reporting requirement. 
MEC/IRB 
All geographies:  Submit to regulatory authority per local reporting requirement. 
Sponsor submit to: 
MEC/IRB 
All geographies: Submit to EC/IRB per local reporting requirement. 
Regulatory 
authorities 
Canada:  Any Device Deficiency that:  

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x
has resulted in any of the consequences characteristic of an SAE on the patient, 
the user or any other person; These must be reported by Medtronic to the 
Regulator within 10 days from the date Medtronic becomes aware. 
or 
x
could do so were it to reoccur. These must be reported by Medtronic to the 
Regulator within 30 days from the date Medtronic becomes aware. 
Preliminary and final reporting to the Canadian Ministry of Health (Health Canada) of 
events occurring inside (always) or outside Canada (in case of corrective actions) 
that is related to a failure of the device or a deterioration in its effectiveness, or any 
inadequacy in its labeling or its directions for use and has led to the death or a 
serious deterioration in the state of health of a patient, user or other person or could 
do so were it to recur. Report a) within 10 days after awareness, if incident has led to 
death or a serious deterioration in the state of health of a patient, user or other 
person b) within 30 days, if incident has not led to death or a serious deterioration in 
the state of health of a patient, user or other person, but could do so were it to recur 
c) as soon as possible, if incident occurred outside of Canada and is related to a 
corrective action. (Canada Medical Device Regulations, SOR/98-282; Mandatory 
Problem Reporting 59(1) , 59(2), 60 (1))  
Europe: Submit to regulatory authorities per local reporting requirement.  
All geographies: Submit to regulatory authority per local reporting requirement. 
All Other Device Deficiencies 
Investigator submit to: 
Medtronic
All geographies: Submit in a timely manner after the Investigator first learns of the 
event. 
MEC/IRB 
All geographies: Submit to Ethics Committee per local reporting requirement. 
Regulatory 
authorities 
All geographies: Submit to regulatory authority per local reporting requirement. 
15.6. Subject Death 
All subject deaths must be reported by the Investigator to Medtronic on an adverse event eCRF (AE with 
outcome of death) as soon as possible after the Investigator first learns of the death.  There should be one AE 
with the outcome of death.  
A 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 the Medtronic clinical study team, if available. If an autopsy is conducted, 
the autopsy report should also be sent to the Medtronic clinical study team if available and allowed by 

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state/local law. When the death occurs at a remote center, it is the investigative center’s responsibility to 
attempt retrieval of information about the death. In summary, the following data will be collected: 
x
Date of death 
x
Detailed description of death 
x
Cause of death  
x
Relatedness to device and/or procedure 
x
Death summary/hospital records (if available and allowed by state/local law) 
x
Autopsy report (if available and allowed by state/local law) 
x
Death certificate (if available and/or allowed by state/local law) 
15.6.1.
Death Classification and Reporting 
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: 
x
Cardiac Death: A death directly related to the electrical or mechanical dysfunction of the heart. 
x
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. 
x
Non-sudden Cardiac Death: All cardiac deaths that are not classified as sudden deaths, including all 
cardiac deaths of hospitalized subjects on inotropic support. 
x
Non-cardiac Death: A death not classified as a cardiac death. 
x
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 deaths and provide a final adjudication of the primary cause of death and cardiac 
classification. 
Regulatory reporting of Subject Deaths will be completed according to local regulatory requirements.  
15.7. Product Complaint Reporting 
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 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: 
x
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. 
x
Any technical or medical reason resulting in withdrawal of a device from the market by the 
manufacturer. 
x
A serious deterioration in the state of heath includes: 
R
Life-threatening illness or injury 
R
Permanent impairment of a body function or permanent damage to a body structure 
R
A condition necessitating medical or surgical intervention to prevent permanent 
impairment of a body function or permanent damage to a body structure 
The Investigator and Medtronic must abide by the reporting requirements shown in Section 19.5. 
16. Data Review Committees  
At regular intervals, an independent Clinical Events Committee (CEC) will review and adjudicate, at a 
minimum, all system (cryoablation and 
) related and all procedure related 
adverse events, as well as all deaths for subjects participating in the study.  
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.  Associated imaging studies (i.e. CT, MRI, x-ray, etc.) may be 
requested, if available, for all serious adverse events with possible relatedness to the system or procedure 
listed in Section 18.3.2 to support adjudication.  Additionally, the CEC will provide an adjudication of the 
death classification for all reported deaths including primary cause of death and cardiac classification. 
If the CEC disagrees with the Investigator’s classification of the event, the rationale 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/MECs and regulatory authorities, if required. 

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17. Statistical Design and Methods 
17.1. General Considerations 
Two analysis cohorts have been defined for this study: 
x
PMA-S cohort (US/Canada/Europe cohort) – subjects from US, Canada, and Europe centers 
x
PMDA cohort (US/Canada/Europe/Japan cohort) –subjects from US, Canada, Europe, and Japan 
centers  
Analysis methods are detailed for all objectives in sections 17.1- 17.5.  The same methods will be used for 
both the PMA-S cohort, and also the PMDA cohort.  The estimated sample sizes are 150 subjects for the 
PMA-S cohort, and 165 subjects for the PMDA cohort.  The PMDA cohort will have a slight increase in 
statistical power given 165 subjects will be utilized versus 150. 
The Statistical Analysis Plan (SAP) will be created prior to data analysis and include a comprehensive 
description of the statistical methods to be included in study reports.  Any change to the data analysis 
methods described in the CIP will require an amendment 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.  Medtronic employees or their designated representatives will 
perform all statistical analyses. 
17.2. Analysis Timing 
17.2.1.
PMA-S Submission 
At the completion the last 12 month visit from the enrolled and treated US, Canada and Europe subjects, a 
PMA-S will be submitted to the FDA.  Study data from the Japanese centers will not be included in the PMA-S 
submission but will be made available. 
17.2.2.
PMDA Submission 
At the completion the last 12 month visit from the enrolled and treated Japan subjects, a report will be 
submitted to Japan PMDA.  Study data from all enrolled and treated subjects (US, Canada, Europe, and 
Japan) will be included. 
17.3. Primary Objectives 
17.3.1.
Primary Efficacy Objective 
Demonstrate an acceptable efficacy success rate at 12 months after the pulmonary vein isolation (PVI) 
ablation procedure. 
Hypothesis 
The following hypothesis will be tested in a one-sided test at the 0.025 significance level: 

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+R36Ƨ40% 
Ha: PS > 40% 
Where PS is the probability of treatment success at 12 months.   
Endpoint Definition 
Treatment success is defined as freedom from treatment failure.  Treatment failure is defined as any of 
the following components: 
R
Acute procedural failure  
R
Documented AF/AT/ AFL on Holter/TTM/12-lead ECG after the 90 day blanking period 

Minimum of 30 seconds on Holter/TTM and 10 seconds on 12-lead ECG 
R
A reablation for the treatment of recurrent AF/AT/AFL after the 90 day blanking period 
R
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, or re-
initiation of a previously failed or not tolerated Class I or III AAD after the 90 day blanking is 
not considered a failure. Subjects are allowed to remain on Class I or III antiarrhythmic 
medications at the historic maximum ineffective dose (on prior to the ablation procedure) 
after the 90 day post-procedure blanking period. 
R
 Ablation using RF in the left atrium 
 
 
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, cardioversion or one cryo re-ablation procedure of the pulmonary veins.  Titration of Class I and III 
antiarrhythmic medications are allowed during the blanking period. 
Acute procedural failure is defined as: 
R
Inability to isolate all accessible targeted pulmonary veins (minimally assessed for entrance 
block and, where assessable, exit block) during the index procedure 
R
Left atrial non-PVI ablations including but not limited to, ablation of linear lesions, complex 
fractionated electrograms or non-PV triggers 
 
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 cryoablation 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 

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recorded on CRF which may include the last study visit, 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. 
Performance Requirements 
If the lower bound of the 95% confidence interval at 12 months is greater than the performance goal of 40%, 
the objective will be considered met. 
Rationale for Performance Criteria 
The choice of twelve month follow-up and acceptable success rate of 40% performance criteria was selected 
based on the 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, provides recommendations for success rates 
in clinical trials. The recommendation for evaluating the efficacy 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%.”1 
 
Additionally, there is mounting evidence in published literature on the use of catheter ablation in the 
treatment of persistent AF.  Table 12 displays a summary of published literature where the publications 
reported on utilizing Arctic Front and Arctic Front Advance catheters for the treatment of patients with 
persistent AF.  The summary includes results published as manuscripts in peer reviewed medical journals.  
The search criteria were publications on studies where the therapy was the use of the Cryoballoon for a PVI-
only approach for persistent AF.  There were variations in endpoint definitions and use of antiarrhythmic 
medications in the reported studies, but on average the data support the criteria from the 2012 
HRS/EHRA/ECAS Expert Consensus Statement.  A weighted average was calculated at the bottom of the 
table, resulting in an average efficacy rate of 59.3%. None of the studies utilized weekly TTMs, so due to the 
additional arrhythmia monitoring, the point estimate for this study has been set to 54%.  The weighted 
average lower 95% confidence bound is 43.8%, and in combination of additional arrhythmia monitoring, 
support the lower confidence bound OPC of 40%.  

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Table 12: Summary of Published Literature on Catheter Ablation for Persistent AF 
Reference 
Design 
Sites 
Subjects 
Subject Monitoring  
(When/How) 
Efficacy 
Arrhythmia 
Assessment  
12M Efficacy* 
Off 
AADs? 
Acute 
Procedural 
Success 
Aytemir K, et al 
J Interv Card Electrophysiol 
2013;38(3):187-195. i 
Prospective, 
observational, 
consecutive patients, 
PVI-only 
1 
48 
ECG and 24hr Holter @ 3M,6M,12M and 
symptomatic event recorder 
AF > 30s 
0.62 (0.47, 0.76) 
YES 
99.50% 
Ciconte G, et al 
Heart Rhythm. 2014; 12(1):60-
6.ii 
Prospective, 
consecutive patients, 
PVI-only 
3 
63 
ECG and 24hr Holter @ 1M,3M,6M,12M 
Any AF/AT > 30s 
0.60 (0.47, 0.72) 
YES 
100% 
Ferrero-De Loma-Osorio A., 
et al 
J. Intervent. Card. 
Electrophysiol. August 1 
2013;37(2):189-196.iii 
Prospective, 
consecutive patients, 
PVI-only 
1 
23 
3M and every 6 thereafter (72h Holter + 
ECG) 
AF > 30s 
0.49 (0.27, 0.69) 
YES 
96.80% 
Jackson N, et al Heart Lung 
Circ 2012;21(8):427-432.iv   
Consecutive patients, 
PVI-only 
1 
61 
3M,6,12 (unspecified duration Holter + 
ECG) 
AF > 30s 
0.59 (0.46, 0.71) 
YES 
97.70% 
Kojodjojo P, et al 
Heart 2010;96(17):1379-1384. 
v 
Prospective, 
consecutive patients 
1 
34 
3M,6,12 and every 6 thereafter (24h 
Holter + ECG +symptomatic event 
recorder) 
Any AF/AT > 30s 
0.48 (0.30, 0.65) 
YES 
83% 
Kubala M, et al 
Clin Electrophysiol 
2011;34(7):837-843. vi 
Prospective, 
consecutive patients, 
PVI-only 
1 
33 
ECG and 24hr Holter @ 1M,3M,6M,12M 
and symptomatic event recorder 
AF > 30s 
0.52 (0.34, 0.69) 
YES 
Not reported 

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*Confidence interval calculated with binomial Fisher’s exact methods
Malmborg H,et al 
Europace 2013;15(11):1567-
1573. vii 
Prospective, 
randomized, PVI-only 
1 
15 
ECG @ 3M,6,12 and 7 day Holter @ 
6M,12M 
AF > 30s 
0.60 (0.32, 0.84) 
NO 
98% 
Neumann T, et al 
J Am Coll Cardiol 
2008;52(4):273-278viii 
Prospective, 
consecutive patients, 
PVI-only 
3 
53 
7 day Holter @ 3M,6M,9M,12M 
AF > 30s 
0.42 (0.28, 0.56) 
YES 
97% 
Schmidt M, et al 
Int J Cardiol 2013;167(1):114-
120ix 
Consecutive patients, 
PVI-only 
3 
44 
ECG and 72hr Holter @ 
1M,3M,6M,9M,12M and symptomatic 
event recorder 
AF or Flutter >30s 
0.77 (0.62, 0.89) 
YES 
100% 
Schmidt M, et al 
Clin Res Cardiol 
2012;101(10):777-785. x 
Prospective, 
consecutive patients, 
PVI-only 
1 
33 
ECG and 72hr Holter @ 
1M,3M,6M,9M,12M and symptomatic 
event recorder 
AF > 30s 
0.70 (0.51, 0.84) 
NO 
98.40% 
Lemes C, et al 
Europace. 2015 May 19. [Epub 
ahead of print].xi 
Retrospective, PVI-only 
2 
49 
Holter and ECG and telephonic 
interviews @ 3M,6M,12M 
Any AF/AT > 30s 
0.69 (0.57, 0.83) 
YES 
100% 
Weighted average (weights 
based on study sample size) 
 
 
 
 
 
59.3% (43.8, 
74.4%) 
 
 

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Sample Size Calculation 
For the US/Canada/Europe cohort, 150 treated subjects affords 90% power based on the following 
assumptions: 
x
One analysis at 12-months 
x
12-month efficacy rate = 54% 
x
OPC = 40% at 12-months 
x
Overall alpha = 0.025, one-sided 
x
10% attrition through 12 months 
x
Binomial exact methods 
Table 12 summarizes the published literature of 12-month efficacy rates for Cryoballoon PVI ablation.  The 
summary estimates 12-month efficacy to be 59.3%.  Due to more stringent endpoint definition, increased 
monitoring, and the potential for publication bias, this study protocol assumes a 12 month efficacy rate of 
54% for the sample size calculation.  With 150 enrolled and treated subjects, minus an assumed 10% attrition 
rate, the expected number of subjects with 12 months of follow-up at the final analysis is 135.   
For the US/Canada/Europe/Japan cohort, 165 treated subjects affords 92% power to test the primary 
endpoint based on the same assumptions.  With 165 enrolled and treated subjects, minus an assumed 10% 
attrition rate, the expected number of subjects with 12 months of follow-up at the final analysis is 148. 
Determination of Subjects/Data for Analysis 
All enrolled subjects who have the Arctic Front Advance Cardiac CryoAblation Catheter inserted into 
vasculature will be included.  
   
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 10%. 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 40% OPC is crossed by the lower 95% 
confidence bound.  
 

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17.3.2.
Primary Safety Objective 
Demonstrate an acceptable safety profile of the pulmonary vein isolation (PVI) ablation procedure. 
Hypothesis 
The following hypothesis will be tested in a one-sided test at the 0.025 significance level: 
Ho: PS ƨ 13% 
Ha: PS < 13% 
Where PS is the probability of a safety event through 12 months.   
Endpoint Definition 
A primary safety event is defined as a serious procedure-related or serious system-related adverse event 
including the following: 
x
Transient ischemic attack (within 7 days of ablation procedure) 
x
Cerebrovascular accident (within 7 days of ablation procedure)  
x
Major bleeding that requires transfusion (within 7 days of ablation procedure) 
x
Cardiac perforation, tamponade or pericardial effusion (within 7 days of ablation procedure) 
x
Pulmonary vein stenosis (>75% reduction within 12-months of ablation procedure)  
x
Myocardial infarction (within 7 days of ablation procedure) 
x
Phrenic nerve injury (unresolved at 12-months) 
x
Atrio-esophageal fistula (within 12-months of ablation procedure) 
x
Death (within 7 days of ablation procedure) 
Analysis Methods 
The probability of a safety event 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 cryoablation procedure.  For subjects with a 
safety event, the survival date will be set to the 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.   
For subjects with a repeat ablation within 12 months, the start of the survival analysis will not reset. Day 0 will 
remain the day of the index cryoablation procedure.  Safety events related to the repeat ablation procedure 
occurring on or prior to 365 days post the index cryoablation procedure will be counted as safety events and 
count against the primary safety objective. 
Performance Requirements 
If the upper bound of the two-sided 95% confidence interval at 12 months is less than the performance goal 
of 13%, the objective will be considered met. 

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Determination of Subjects/Data for Analysis 
All enrolled subjects who have the Arctic Front Advance Cardiac CryoAblation Catheter inserted into 
vasculature will be included.  
Sample Size Calculation 
For the US/Canada/Europe cohort, 150 treated subjects affords 86% power based on the following 
assumptions: 
x
One analysis at 12-months 
x
12-month safety rate = 5% 
x
Clinically important difference = 8% (i.e., if the safety rate of the cryoballoon in this population is 5%, 
the study will have adequate power to demonstrate a difference from 13%)  
x
Overall alpha = 0.025, one-sided 
x
10% attrition 
With 150 enrolled and treated subjects, minus an assumed 10% attrition rate, the expected number of 
subjects with 12 months of follow-up at the final analysis is 135.   
For the US/Canada/Europe/Japan cohort, 165 treated subjects affords 93% power to test the primary 
endpoint based on the same assumptions.  With 165 enrolled and treated subjects, minus an assumed 10% 
attrition rate, the expected number of subjects with 12 months of follow-up at the final analysis is 148.  
 
Rationale for Performance Criteria 
The safety endpoint definition is based on the Guidance for Industry and FDA Staff20.  The estimated safety 
rate of 5% was selected based on current rate observed in the STOP AF Post Approval Study (PAS).  Table 13 
summarizes the safety event rate in STOP AF PAS.  The safety event rate is 2.3% in STOP AF PAS based on 
the 2015 FDA Annual Report.  The study was not complete and follow-up was ongoing at the time of the 2015 
annual report.  Therefore the event rate may be slightly higher when the study is completed due to additional 
events reported, the persistent AF population being studied under this protocol has further advanced AF 
disease, and therefore the estimated rate for the STOP Persistent AF study has been estimated to be 5%.  
The OPC of 13% is based on the meaningful clinical difference of 8% (i.e., if the safety rate of the cryoballoon 
in this population is 5%, the study will have adequate power to demonstrate a difference from 13%)     

Clinical Study Designs for Percutaneous Catheter Ablation for Treatment of Atrial Fibrillation. January 9, 
2004.

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Table 13:  Safety Event Rate in STOP AF PAS 
Study 
Observed Safety Event Rate1 
STOP AF PAS (n=347)21 
8 safety events in 8 subjects 
Safety event rate = 2.3% 
PNI Unresolved at 12 months   (3) 
Cerebrovascular accident (1) 
Pericardial Effusion (1) 
Cardiac tamponade (1) 
PV Stenosis (1) 
Incision site hematoma (1) 
1Based on the primary safety endpoint definition in this STOP Persistent AF protocol

60 Month Interim Post Approval Study Status Report.  PMA P100010/R Arctic Front Cardia CryoAblation System.  STOP AF PAS. Version 2, 10DEC2015.

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17.4. Secondary Objective 
The secondary objective, Quality of Life, will be evaluated to gain additional information about the 
performance of the Arctic Front Advance Cardiac CryoAblation catheter.   
There are three hypotheses tested in the objective, hypothesis tests for AFEQT questionnaire, the physical 
component score of the SF-12 questionnaire, and the mental component score of the SF-12 questionnaire.  
A Hommel multiple testing procedure will be utilized to maintain an overall type I error rate of 0.025 for this 
objective22.   
The Hommel procedure is a stepwise procedure and will be implemented following the below. 
The three hypothesis will be defined as H(1), H(2), and H(3).  For each of the hypotheses, p-values will be 
calculated and sorted p(1) < p(2) < p(3).  The decision rule to accept or reject each hypothesis will follow the 
step-XSDOJRULWKPZKHUH˩  
6WHS,IS!˩DFFHSW+DQGJRWR6WHSRWKHUZLVHUHMHFWDOOK\SRWKHVHVDQGVWRS 
6WHS,IS!˩DFFHSW+DQGJRWR6WHSotherwise reject all remaining hypotheses and stop 
6WHS,I˩SƧ˩DQGSƧ˩RUSƧ˩UHMHFW+RWKHUZLVHDFFHSW+ 
 
17.4.1.
Secondary Objective: Quality of Life - Atrial Fibrillation Effect on QualiTy-of-life 
(AFEQT) and SF-12 Questionnaires 
Demonstrate an improvement in quality of life between baseline and 12 months as measured by the AFEQT 
and SF-12 questionnaires. 

Hommel, G.A stagewise rejective multiple test procedure based on a modified Bonferroni test. Biometrika 1988; 75, 
383-386.

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17.4.1.1. Atrial Fibrillation Effect on QualiTy-of-life (AFEQT)  
Hypothesis 
The following hypothesis will be tested in a one-sided test at the 0.025 significance level: 
+Rƛ$)(47  
+Dƛ$)(47! 
:KHUHƛ$)(47LVWKHFKDQJHLQ$)(47VFRUHIURPEDVHOLQHWRPRQWKV 
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 corresponds to complete disability and 100 corresponds to no disability. 
Analysis Methods 
Change in AFEQT score is defined as 12-month AFEQT score minus baseline AFEQT score.  Change in 
AFEQT scores will be assessed utilizing a one-sample t-test.   A two-sided 95% confidence interval will be 
calculated based on the t-distribution. 
Additionally, summary statistics (e.g. mean, SD, median, range) and graphical methods will be used to 
summarize the change in AFEQT scores from baseline through 12 months. 
Performance criteria 
If the p-value from the one-sample t-test after adjusting for the Hommel procedure is < 0.025, the objective 
will be considered met. 
Determination of Subjects/Data for Analysis 
All enrolled subjects who have the Arctic Front Advance Cardiac CryoAblation Catheter inserted into 
vasculature and have completed baseline and 12 month questionnaires will be included. 
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. 
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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17.4.1.2. Medical Outcome Study Short Form-12 (SF-12 ) 
The following hypotheses will be tested.  Each will be tested in a one-sided test at the 0.025 significance 
level: 
+Rƛ6)-12mental = 0 
 
 
+Rƛ6)-12physical= 0 
+Dƛ6)-12mental  > 0 
 
 
+Dƛ6)-12physical > 0 
 
:KHUHƛ6)-12mental LVWKHFKDQJHLQƛ6)-PHQWDOVFRUHIURPEDVHOLQHWRPRQWKVDQGƛ6)-12physical is the 
FKDQJHLQƛ6)-12 physical score from baseline to 12 months   
Endpoint Definition 
The Medical Outcome Study Short Form-12 (SF-12) questionnaire will be utilized for this objective. The SF-
12 questionnaire is a health-related quality of life questionnaire to evaluate the subject’s mental and physical 
performance.  Physical and mental health component scores are calculated using responses to 12 questions 
with a response range from 0 – 100, with 0 corresponds to lowest level of health and 100 indicates highest 
level of health. 
Analysis Methods 
Change in SF-12 component score is defined as 12-month SF-12 score minus baseline SF-12 score.  Change 
in SF-12 scores will be assessed utilizing a one-sample t-test.   A two-sided 95% confidence interval will be 
calculated based on the t-distribution. 
Additionally, summary statistics (e.g. mean, SD, median, range) and graphical methods will be used to 
summarize the change in SF-12 scores from baseline through 12 months. 
Performance criteria 
If the p-value from the one-sample t-test after adjusting for the Hommel procedure is < 0.025, the objective 
will be considered met. 
Determination of Subjects/Data for Analysis 
All enrolled subjects who have the Arctic Front Advance Cardiac CryoAblation Catheter inserted into 
vasculature and have completed baseline and 12 month questionnaires will be included. 
17.5. Ancillary Objectives 
Ancillary objectives been defined to provide additional information about the performance of the Arctic Front 
Advance Cardiac CryoAblation Catheter.  No hypotheses are defined for regulatory or labeling purposes.   

  

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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18. Ethics 
18.1. 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)/Medical Ethics Committee (MEC)/Head of Medical Institution (HOMI) 
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 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 

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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.  The ISO standard also informed study design in the areas of device 
deficiency reporting and risk evaluation, with the exception (to the ISO standard) that only those Adverse 
Events (AEs) which are cardiovascular, serious, system (cryoablation and 
) 
related and procedure related will be collected.  This ensures any AEs which could potentially be relevant will 
be collected.  There is a second exception (to the ISO standard) that device accountability will not be 
performed in Europe or Canada and only upon package opening in the US (full device accountability will take 
place in Japan starting with distribution).  
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.  In Europe, the study will 
also be conducted in accordance with the Declaration of Helsinki 2013.  For all geographies, the principles of 
the Declaration of Helsinki have been implemented through the patient informed consent (IC) process, 
Ethics Board/IRB/MEC approval, study training, clinical trial registration, preclinical testing, risk-benefit 
assessment and publication policy. 
Ultimately, all centers in all geographies will follow and comply with: 
x
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 
x
21 CFR Part 11 (Electronic Records, Electronic Signatures) 
x
21 CFR Part 54 (Financial Disclosure by Clinical Investigators) 
x
The procedures described with in this CIP 
x
Local Ethics Board requirements 
All participating geographies will make study data available to the regulatory body such as FDA or competent 
authority if the regulatory body deems an onsite inspection necessary.  The regulatory body will be able to 
inspect records at clinical centers around the world to resolve any uncertainties about whether the study was 
conducted in accordance with good clinical practice. 
In addition to the regulatory requirements outlined above, the study will be conducted in compliance with 
relevant local laws.  These include but are not limited to: 

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x
In the United States, US FDA 21 CFR Parts  
R
50: Protection of Human subjects, 56: Institutional Review Boards and 812: Investigational 
Device Exemptions 
x
In Europe, Declaration of Helsinki 2013, the Competent Authority requirements, the Medical Device 
Directive (MDD) 93/42/EEC and ISO 14155:2011 with the exception stated earlier in this Section 
x
In Canada, the Medical Devices Regulations, Mandatory Medical Device Problem Reporting 59(1), 
59(2), 60(1) 
x
In Japan, the study will be conducted in compliance with MHLW Ordinance No. 36, 2005 and related 
laws and regulations 
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)). 
Approval of the Clinical Investigation Plan (CIP) is required from the following groups prior to any study 
procedures at a study center:  
x
US Food and Drug Administration (FDA) or regulatory authority 
x
Pharmaceuticals and Medical Device Agency (PMDA) (if applicable) 
x
Medtronic  
x
Principal Investigators (where required by local law) 
x
An independent IRB/MEC 
Similarly, approval of subsequent revisions to the CIP is required at each study center from the above 
mentioned groups prior to implementation of the revised CIP at that center. 
19. Study Administration 
19.1. 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 center 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 access to the 
subjects’ case histories (clinic and hospital records, and other source data/documentation) upon request as 
per the PIC 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 center. Monitoring for the study may include, but not limited to, site qualification visits, site 

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initiation visits, interim monitoring visits, and closeout visits, will be done in accordance to the study-specific 
monitoring plan. 
Monitoring visits may be conducted periodically to assess center study progress, the Investigator’s 
adherence to the CIP, regulatory compliance including but not limited to IRB/MEC approval and review of the 
study, maintenance of records and reports, and review of source documents against subject CRFs. Monitors 
review center regulatory and study compliance by identifying findings of non-compliance and 
communicating those findings along with recommendations for preventative/corrective actions to center 
personnel.  Monitors may work with study personnel to determine appropriate corrective action 
recommendations and to identify trends within the study or at a particular center. 
19.2. 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 centers for resolution.   
Data collected by Holters, TTMs and 12-lead 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. 
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 indefinitely by Medtronic. 
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 
center. Source documents, which may include worksheets, subject medical records, console files, must be 
created and maintained by the investigational center 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: 

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x
Time of isolation of the cryoablation catheter 
x
Esophageal temperature 
x
Investigator assessment of adverse event or death relatedness and severity 
x
Date center became aware of the adverse event, device deficiency or death 
x
Reason for study deviation 
x
Database generate patient reference ID 
When copies or print-outs of the source documents are made, center personnel must sign and date any 
copies or printouts of original source documents with a statement that this is complete and true 
reproduction of the original source document. 
The sponsor or a regulatory authority may audit or inspect the study center to evaluate the conduct of the 
study. The clinical Investigator(s)/institution(s) shall allow study related monitoring, audits, IRB/MEC review 
and regulatory inspection by providing direct access to source data/documents. 
19.3. Confidentiality
All records and other information about subjects participating in the study will be treated as confidential. See 
Section 19.2 for further information.  
19.4. CIP Amendments 
Approval of subsequent revisions to the CIP is required at each study center from the following groups prior 
to implementation of the revised CIP at the center: 
x
Medtronic 
x
Principal Investigators (where required by local law) 
x
Geography-specific regulatory authorities (if regulatory approval is required) 
x
An independent MEC or IRB 
If a CIP amendment occurs, center personnel will need to be re-trained as necessary, and will need to submit 
any changes to their IRB/MEC as required by the committee. CIP amendments will also be reported to and 
approved by the FDA. 
19.5. Record Retention 
19.5.1.
Investigator Records 
The Investigator, or in Japan, the record keeping manager at the study center 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 

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be retained for a period of two years (or longer as local law 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. 
x
All correspondence between the IRB/MEC, sponsor, monitor, FDA, local regulatory agencies and the 
Investigator that pertains to the investigation, including required reports 
x
Subject’s case history records, including:  
x
Signed and dated PIC Form signed by subject (In Europe and Japan, signed by subject, subject’s 
legally authorized representative except in Europe and Investigator.  In Japan, it is acceptable to retain 
only the signature page with the version number of the PIC Form.) 
x
Observations of adverse events and device deficiencies 
x
Medical history 
x
Procedure and follow-up data 
x
Documentation of the dates and rationale for any deviation from the CIP 
x
Reports of adverse events 
x
Subject screening logs (if used) and subject identification logs (Europe only) 
x
List of investigation centers 
x
Financial disclosure of Investigators 
x
Device Disposition Logs (US and Japan) 
x
All approved versions of the CIP, PIC, and Investigator’s Brochure/Report of Prior Investigation 
Summary 
x
Signed and dated Clinical Trial Agreement and Investigator Statement 
x
Current curriculum vitae (signed and dated in Europe) of Investigators and key members of 
investigation center team (Europe only) 
x
Documentation of delegated tasks 
x
Blank case report forms (Europe only) 
x
IRB/MEC approval documentation. Written information that the Investigator or other study staff, 
when member of the IRB/MEC, did not participate in the approval process. Approval documentation 
must include the IRB/MEC composition, in Europe and where required per local law.  
x
Regulatory authority notification, correspondence and approval, where required per local law 
x
Study training records for center staff 
x
Insurance certificates (where requested by the IRB/MEC) 
x
Any other records that FDA and local regulatory agencies require to be maintained 
x
Final Study Report including the statistical analysis 
19.5.2.
Investigator Reports 
The Investigator is responsible for the preparation (review and signature) and submission to the sponsor of 
all eCRFs, adverse events, device deficiencies, deaths, and any deviations from the CIP.  If any action is taken 
by an IRB/MEC with respect to this clinical study, copies of all pertinent documentation must be forwarded to 

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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. 
Table 14:  Investigator reports applicable for all geographies per Medtronic requirements 
Report  
Submit to 
Description/Constraints 
Withdrawal of 
IRB/MEC approval  
Sponsor and 
Relevant 
Authorities 
The Investigator must report a withdrawal of approval by the 
reviewing IRB/MEC of the Investigator’s part of the 
investigation within 5 working days. 
Study deviations  
Sponsor and 
IRB/MEC 
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. 
Final report
Sponsor 
IRB/MECs 
Relevant 
Authorities 
This report must be submitted within 3 months of study 
completion or termination. 
Refer to Section15 for adverse event, complaint, and device deficiency reporting.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 15: Additional Investigator reports applicable to the United States  
Report  
Submit to 
Description/Constraints 
Withdrawal of 
IRB/MEC approval 
(either suspension or 
termination) 
Sponsor 
The Investigator must report a withdrawal of approval by the 
reviewing IRB/MEC of the Investigator’s part of the 
investigation within 5 working days.  (21 CFR 812.150(a)(2)) 
Progress report  
Sponsor and 
IRB/MEC 
The Investigator must submit this report to the sponsor and 
IRB/MEC at regular intervals, but in no event less than yearly. 
(21 CFR 812.150 (a)(3)).   
Study deviations  
Sponsor and 
IRB/MEC 
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 IRB/MEC, 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 
IRBs/MECs 
If an Investigator uses a device without obtaining informed 
consent, the Investigator shall report such use within 5 
working days after device use.  (21 CFR 812.150(a)(5)) 
Final report 
Sponsor 
IRBs/MECs 
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 
IRB/MEC and FDA 
An Investigator shall, upon request by a reviewing IRB/MEC, 
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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Table 16: Investigator reports applicable to Europe 
Report  
Submit to 
Description/Constraints 
Withdrawal of 
IRB/MEC approval 
Sponsor 
Report if required by local law. 
Progress Report  
Sponsor and 
IRB/MEC 
Provide if required by local law or IRB/MEC.  
Study Deviations  
Sponsor and 
IRB/MEC 
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 
IRBs/MECs 
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 17: 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) 
19.5.3.
Sponsor Records 
Medtronic shall maintain the following accurate, complete, and current records: 
x
All correspondence which pertains to the investigation 
x
Investigational Device Disposition Logs (US and Japan) 
x
Signed Investigator Trial Agreements, financial disclosure of Investigators and current signed and 
dated (Europe only) curriculum vitae of principal Investigator and key members of the investigation 
center team (as required by local law), delegated task list 

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x
All approved versions of the PIC Form, and other information provided to the subjects and 
advertisements, including translations 
x
Copies of all IRB/MEC approval letters and relevant IRB/MEC correspondence and IRB/MEC voting 
list/roster/letter of assurance 
x
Names of the institutions in which the clinical study will be conducted 
x
Regulatory authorities correspondence, notification and approval as required by national legislation 
x
Insurance certificates (where requested by the IRB/MEC) 
x
Names/contact addresses of monitors 
x
Monitoring visit reports and follow-up letters 
x
Statistical analyses and underlying supporting data 
x
Final report of the clinical study 
x
All approved versions of the Clinical Investigation Plan and study related reports, Investigator’s 
Brochure/Report of Prior Investigation Summary 
x
Study training records for center personnel and Medtronic personnel involved in the study 
x
Hospital names and evidence of hospital existence (i.e. Web page address of the institution, hospital 
pamphlet, etc.) and the name of the HOMI 
x
Any other records that local regulatory agencies require to be maintained 
19.5.4.
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 
IRB/MEC, regulatory agency or FDA, provide accurate, complete and current information about any aspect of 
the investigation.  
Table 18: Sponsor reports for the United States 
Report  
Submit to 
Description/Constraints 
Withdrawal of 
IRB/MEC approval 
Investigators, 
IRB/MEC, 
FDA, and 
relevant 
authorities 
Notification within five working days.  (21 CFR 812.150(b)(2))   
Withdrawal of FDA 
approval 
Investigators, 
IRB/MEC, and 
relevant 
authorities 
Notification within five working days.  (21 CFR 812.150(b)(3)) 

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Report  
Submit to 
Description/Constraints 
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 
IRB/MEC 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, 
IRB/MEC, 
relevant 
authorities, and  
FDA 
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  
FDA 
Investigator’s report will be submitted to FDA within five 
working days of notification.  (21 CFR 812.150(b)(8)) 
Final report 
Investigators, 
IRB/MEC,  
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/MECs 
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.  
Center specific study deviations will be submitted to 
Investigators periodically.  
Other 
IRB, FDA 
Accurate, complete, and current information about any 
aspect of the investigation. (21 CFR 812.150(b)(10)) 

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Table 19:  Sponsor reports for Canada 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, 
IRB/MEC, 
Relevant 
authorities, and  
Head of the 
Institution 
Provide prompt notification of termination or suspension and 
reason(s).  
Recall and device 
disposition 
Investigators, 
Head of 
Institution, 
IRB/MEC, 
relevant 
authorities, and  
FDA 
Notification within 30 working days and will include the 
reasons for any request that an Investigator return, repair, or 
otherwise dispose of any devices.   
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.  
Center specific study deviations will be submitted to 
Investigators periodically.  
Device Deficiency  
Health Canada  
 
Any DD that: 
R
has resulted in any of the consequences 
characteristic of an SAE on the patient, the user or 
any other person; these must be reported by 
Medtronic to the Regulator within 10 days from the 
date Medtronic becomes aware. 
or 
R
could do so were it to reoccur. These must be 
reported by Medtronic to the Regulator within 30 
days from the date Medtronic becomes aware. 

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Table 20: Sponsor reports for Europe 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, 
IRB/MEC, 
Relevant 
authorities and 
Head of the 
Institution 
Provide prompt notification of termination or suspension and 
reason(s). (ISO 14155:2011) 
Withdrawal of 
IRB/MEC approval 
Investigators, 
Head of 
Institution, 
IRB/MEC and  
relevant 
authorities 
Investigators, IRBs/MECs will be notified only if required by 
local laws or by the IRB/MEC. 
Withdrawal of CA 
approval 
Investigators, 
Head of 
Institution, 
IRB/MEC, and 
relevant 
authorities 
Investigators, IRBs/MECs will be notified only if required by 
local laws or by the IRB/MEC. 
Progress Reports 
IRB/MEC and 
regulatory 
authorities 
This will be submitted to the IRB/MEC only if required by the 
IRB//MEC). 
Final report 
Investigators,  
IRB/MEC, and 
Regulatory 
authorities upon 
request 
For studies with centers complying to ISO 14155: 
x
The Investigator shall have the opportunity to 
review and comment on the final report.   
x
If a clinical Investigator does not agree with the final 
report, his/her comments shall be communicated 
to the other Investigator(s).   
x
The coordinating Investigators 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) 
Center specific study deviations will be submitted to 
Investigators periodically.   

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Table 21: 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. (Pharmaceutical and Medical Device Act 
Enforcement Regulations) 
The sponsor shall submit the list of Investigators to PMDA 
and HOMI when making any changes in the list. 
(Pharmaceutical and Medical Device Act Enforcement 
Regulations) 
Important 
information 
concerning the 
quality, efficacy, 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) Center 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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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 indefinitely. 
19.6. Publication and Use of Information 
Publications from the STOP Persistent AF 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 STOP Persistent 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 appendix, 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.   
The committee may decide that no publications, including abstracts, will be published prior to the end of the 
study or with individual center 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).  

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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: 
x
Substantial contribution to conception and design, or acquisition of data, or analysis and 
interpretation of data 
x
Drafting the article or revising it critically for important intellectual content 
x
Final approval of the version to be published 
x
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 STOP Persistent AF Clinical 
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: 
x
a final report, describing the results of all objectives and analysis, will be distributed to all 
Investigators, IRBs/MECs and Competent Authorities of participating countries when required by 
local law 
x
registering and posting the study results on ClinicalTrials.gov based on the posting rules stipulated  
x
submitting for publication the primary study results after the study ends  
x
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  
x
making an individual center’s study data accessible to the corresponding Investigator after the 
completion of the study, if requested 
19.7. Suspension or Early Termination 
19.7.1.
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 center.  Suspension is a temporary postponement of study activities 
related to enrollment.  This is possible for the whole study or a single center.  If suspension is lifted, the 
Investigator shall assess whether or not to continue the clinical study at their center. 

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19.7.2.
Study-wide Termination or Suspension 
Possible reasons for considering study suspension or termination of the study include but are not limited to: 
x
Adverse events associated with the system or product under investigation which might endanger 
the safety or welfare of the subject 
x
Observed/suspected performance different from the product’s design intent 
x
Decision by Medtronic or regulatory body (where the study is operating under regulatory body 
authority)  
x
Technical issues during the manufacturing process 
19.7.3.
Investigator/Center Termination or Suspension
Possible reasons for clinical Investigator or center termination or suspension include but are not limited to: 

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x
Failure to obtain IRB/MEC annual renewal of the study 
x
Persistent non-compliance to the Clinical Investigation Plan (e.g. failure to adhere to 
inclusion/exclusion criteria, failure to follow subjects per scheduled follow-ups)  
x
Lack of enrollment 
x
Noncompliance to regulations and the terms of the Clinical Trial Agreement (e.g. failure to submit 
data in a timely manner, failure to follow-up on data queries and monitoring findings in a timely 
manner, etc.)  
x
IRB/MEC suspension of the center 
x
Fraud or fraudulent misconduct is discovered (as defined by local law and regulations)  
x
Investigator request (e.g. no longer able to support the study) 
19.7.4.
Procedures for Termination or Suspension 
19.7.4.1. Medtronic-Initiated and Regulatory Authority-Initiated 
x
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 
x
In the case of study termination or suspension for reasons other than a temporary IRB/MEC approval 
lapse, the Investigator will promptly inform the IRB/MEC/Head of Medical Institution.  In Japan, the 
HOMI will promptly inform the Investigator and Ethics Board. 
x
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 
x
In the case of a study suspension, subject enrollment must stop until the suspension is lifted by 
Medtronic 
x
In the case of a study suspension, enrolled subjects should continue to be followed out of 
consideration of their safety, rights and welfare 
19.7.4.2. Investigator-Initiated 
x
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. 
x
The Investigator will promptly inform the institution (where required per regulatory requirements)  
x
The Investigator will promptly inform the IRB/MEC 
x
The Investigator will promptly inform the regulatory authorities (where required per regulatory 
requirements) 
x
The Investigator will promptly inform the subjects and/or the personal physician of the subjects to 
ensure appropriate care and follow-up is provided 
x
In the case of a study suspension, subjects enrolled should continue to be followed out of 
consideration of their safety, rights and welfare 

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19.7.4.3. IRB/MEC Initiated 
x
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. 
x
Subject enrollment must stop until the suspension is lifted 
x
Subjects already enrolled should continue to be followed in accordance with IRB/MEC policy or its 
determination that an overriding safety concern or ethical issue is involved 
x
The Investigator will inform his/her institution (where required per local requirements). 
x
The Investigator will promptly inform the subjects , (or legally-authorized designees or guardians 
except in Europe)and/or the personal physician of the subjects, with the rationale for the study 
termination or suspension 
x
The Investigator will promptly inform the regulatory authorities (where required per regulatory 
requirements) 
20. Liability/Warranty/Insurance Information 
20.1. Warranty
Warranty information is provided in the product packaging for the Arctic Front Advance and Freezor MAX 
Cardiac CryoAblation Catheters.  Additional copies are available upon request. 
20.2. Insurance (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 center Clinical Trial Agreements. 
20.3. Insurance (Canada) 
Medtronic of Canada is a wholly owned subsidiary of Medtronic, Inc., which as the parent company of such 
entity 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. 

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20.4. Insurance (Europe) 
Medtronic Bakken Research Center B.V. is a wholly owned subsidiary of Medtronic, Inc., which as the parent 
company of such entity 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. 
20.5. Insurance (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. 
21.
References
x
Aryana A, Singh SM, Kowalski M, et al. Acute and Long-Term Outcomes of Catheter Ablation of Atrial 
Fibrillation Using the Second-Generation Cryoballoon versus Open-Irrigated Radiofrequency: A 
Multicenter Experience. J Cardiovasc Electrophysiol. 2015 Aug;26(8): 832-9. 
x
 
 
x
 
 
 
x
 
 
x
 
 
x
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. 
x
Calkins, H., et al., HRS/EHRA/ECAS expert Consensus Statement on catheter and surgical ablation 
of atrial fibrillation: recommendations for Patient selection, procedural techniques and follow-up, 
definitions, endpoints and research trial design.  A report of the Heart Rhythm Society (HRS) Task 
Force on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2012; 9(4): p. 632-696.e20. 
x
Channer KS, Birchall A, Steeds RP, et al. A randomized placebo-controlled trial of pre-treatment and 
short- or long-term maintenance therapy with amiodarone supporting DC cardioversion for 
persistent atrial fibrillation. EurHeart J. 2004;25:144-50.  
x
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. 
x
Fetsch T, Bauer P, Engberding R, et al. Prevention of atrial fibrillation after cardioversion: results of 
the PAFAC trial. EurHeart J. 2004;25:1385-94.  

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x
Ghanbari H, Baser K, Jongnarangsin K, et al. Mortality and cerebrovascular events after 
radiofrequency catheter ablation of atrial fibrillation. Heart Rhythm. 2014;11:1503-1511. 
x
 
 
x
 
 
x
Go A, Hylek E, Phillips K, et al. Prevalence of Diagnosed Atrial Fibrillation in Adults:  National 
Implications for Rhythm Management and Stroke Prevention: the AnTicoagulation and Risk Factors 
In Atrial Fibrillation (ATRIA) Study. JAMA. 2001; 285(18): 2370-2375. 
x
 
 
x
 
 
x
Hommel, G.  A stagewise rejective multiple test procedure based on a modified Bonferroni test. 
Biometrika 1988; 75, 383-386. 
x
 
 
 
x
Jais P, O’Neill MD, Takahashi Y, 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. 
x
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. 
x
 
 
 
x
 
 
 
x
Karl-Heinz Kuck, M.D., Josep Brugada, M.D., Alexander Fürnkranz, M.D., Andreas Metzner, M.D., 
Feifan Ouyang, M.D., K.R. Julian Chun, M.D., Arif Elvan, M.D., Ph.D, Thomas Arentz, M.D., Kurt 
Bestehorn, M.D., Stuart J. Pocock, Ph.D., Jean-Paul Albenque, M.D., Ph.D., and Claudio Tondo, M.D., 
Ph.D., for the FIRE AND ICE Investigators. N Engl J Med 2016;374:2235-45.  
x
Ken Okumura, MD, Kazuo Matsumoto, MD, Yoshinori Kobayashi, MD, Akihiko Nogami, MD, Robert B. 
Hokanson, BA and Fred Kueffer, MS. Circulation Journal. Released June 30, 2016. CJ-16-0285.  
Presented at HRS 2016 (Abstract). 
x
Knight BP, Novak PG, Sangrigoli R, et al. 12-Month Clinical Outcomes Following Pulmonary Vein 
Isolation (PVI) Using the Arctic Front Advance™ Cryoballoon: Interim Results from the STOP-AF 
Post Approval Study. Presented at HRS 2016 (Abstract). 
x
 
 
x
Le Heuzey JY, De Ferrari GM, Radzik D, Santini M, Zhu J, Davy JM. A short-term, randomized, 
double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus 

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amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc 
Electrophysiol. 2010 Jun 1;21(6):597-605. 
x
Okumura. Guidelines for indications and procedural techniques of catheter ablation.  Japan 
Circulation Society. 2012. 
x
 
 
 
x
 
 
 
x
Packer D, Kowal R, Wheelan K, Irwin J, Champagne J, Guerra P, Dubuc M, Reddy V, Nelson L, 
Holcomb R, Lehmann J, Ruskin J. J Am Coll Cardiol. 23 April 2013. 61(16):1713-1723. 
x
 
 
 
x
 
 
x
 
 
x
 
 
 
x
Raviele et al.  Venice Chart International consensus Document on Atrial Fibrillation:  2011 Update.  J 
Cardiovasc Electrophysiol, 2012;23:890-923. 
x
Rostock T, Steven D, Hoffman B, et al. Chronic Atrial Fibrillation Is a Biatrial Arrhythmia Data from 
Catheter Ablation of Chronic Atrial Fibrillation Aiming Arrhythmia Termination Using a Sequential 
Ablation Approach. Circ Arrhythmia Electrophysiol. 2008;1:344-353. 
x
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. 
x
 
 
x
 
 
x
Winkle RA. How much ablation to eliminate atrial fibrillation: Is less more or is more more? Heart 
Rhythm. Epub ahead of print. DOI: http://dx.doi.org/10.1016/j.hrthm.2015.06.031 
x
Wolf P, Abbott R, Kannel W. Atrial fibrillation as an independent risk factor for stroke: the 
Framingham Study. Stroke. 1991;22(8):983-988. 
x
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. 
x
Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European 
perspective. Clinical Epidemiology. 2014;6:213-220. doi:10.2147/CLEP.S47385. 

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22. Appendices  
APPENDIX A: CRYOBALLOON SAFETY DATA LITERATURE SEARCH
The following pertains to Medtronic cryoablation products and/or related devices and includes reports 
identified in the scientific literature that were published from June 14, 2005 to March 15, 2015. 
Search Methodology  
Three literature searches were conducted in the following databases to ensure comprehensive coverage of 
globally published clinical evidence for medical device products and therapies. All searches were conducted in 
the STN database platform. 
EMBASE, published by Elsevier, contains over 11 million records with over 500,000 citations added annually. 
EMBASE’s international journal collection contains over 5,000 biomedical journals from 70 countries. 
MEDLINE is the U.S. National Library of Medicine's premier bibliographic database covering the fields of 
medicine, nursing, dentistry, veterinary medicine, the health care system, and the preclinical sciences. 
MEDLINE contains bibliographic citations and author abstracts from more than 5,000 biomedical journals 
published in the United States and 80 other countries. The database contains over 15 million citations. 
 
Search Results 
Search #1 – Medtronic Cryocath Arctic Front Brands and Models 
A search was conducted for the Medtronic Cryocath Arctic Front brands and models as outlined in the table 
below. The search was limited to English language, human only, clinical trials, case reports, registries, 
editorials or meta analyses for the time period of June 14, 2005 to March 15, 2015. All notes, comments, 
letters, books, conference papers, practice guidelines and patents were removed from the search results. A 
total of 56 unique articles were located. Note that as Arctic Front Advance ST was not released to the market 
at the time of this search it was not included as a search term. 
Literature Search Specifications 
Search Terms 
(MEDTRONIC OR ARCTIC()FRONT) AND (ARCTIC()FRONT OR 2AF231 OR 
2AF281 OR 2AF232 OR 2AF282) 
LIMITED TO: 
Study Types: clinical trials, meta analyses, case reports, registries, editorials 
Databases Searched 
MEDLINE, EMBASE 
Specified Timeframe 
June 14, 2005 – March 15, 2015 
Search #2 – Medtronic Cryocath Arctic Front Advance Brands and Models 

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A search was conducted for the Medtronic Cryocath Arctic Front Advance brands and models as outlined in 
the table below. The search was limited to English language, human only, clinical trials, case reports, 
registries, editorials or meta analyses for the time period of June 14, 2005 to March 15, 2015. All notes, 
comments, letters, books, conference papers, practice guidelines and patents were removed from the 
search results. A total of 14 unique articles were located for this search.  
Literature Search Specifications 
Search Terms 
(MEDTRONIC OR ARCTIC()FRONT()ADVANCE) AND 
(ARCTIC()FRONT()ADVANCE OR 2AF234 OR 2AF284 OR 2AF283 OR 2AF233) 
LIMITED TO: 
Study Types: clinical trials, meta analyses, case reports, registries, editorials 
Databases Searched 
MEDLINE, EMBASE 
Specified Timeframe 
June 14, 2005 – J March 15, 2015 
Search #3 – Cryoballoon Literature 
A search was conducted for industry-wide literature on cryoballoons. The search was limited to English 
language, human only, clinical trials, case reports, registries, editorials or meta analyses for the time period of 
June 14, 2005 to March 15, 2015. All notes, comments, letters, books, conference papers, practice guidelines 
and patents were removed from the search results. A total of 173 unique articles were located.  
Literature Search Specifications 
Search Terms 
CRYOBALLOON OR CRYOBALLOONS 
LIMITED TO: 
Study Types: clinical trials, meta analyses, case reports, registries, 
editorials 
Databases 
Searched 
MEDLINE, EMBASE 
Specified 
Timeframe
June 14, 2005 to March 15, 2015 
Final Result 
Results from Search #1, Search #2 and Search #3 were combined and duplicates were removed. A total of 
182 unique articles were located. Of these 182 articles, 54 articles were excluded per the following: 
• 
2 editorials 
• 
7 reviews with no new specific information  
• 
3 duplicates within the search 
• 
1 expert consensus statement 

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• 
2 meta-analyses 
• 
3 were study design papers with no results 
• 
1 case report with no adverse events reported 
• 
6 did not include the Arctic Front or Arctic Front Advance cryoballoon or Atrial Fibrillation 
• 
4 abstracts only (unable to access full article) with no new information  
• 
25 articles were excluded as they did not report safety  
 
Additional articles Medtronic was aware of or that were published after the searches were conducted were 
included. 
 
 

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APPENDIX B:
 SUB-STUDY 
Note: Data from this sub-study will not be required to be included in standard FDA reports, including the PMA-S 
and final report (except as described in Section 16.5 Reporting of Adverse Events and Device Deficiencies). 
All elements of the Clinical Investigation Plan (CIP) above also apply when executing this sub-study.  The 
elements detailed in this sub-study appendix are intended to be applied in addition to the elements described 
in the main CIP.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX C: DRAFT DATA COLLECTION ELEMENTS (CASE REPORT FORMS) 
Draft Case Report Forms for the STOP Persistent AF study will be provided under separate cover.  Final CRFs 
will be provided to centers via the electronic data management system after the center has fulfilled all 
requirements for database access. 
APPENDIX D: INFORMED CONSENT TEMPLATE 
The Patient Informed Consent Template will be distributed under separate cover. 
APPENDIX E: PARTICIPATING INVESTIGATOR AND INSTITUTIONS 
A final list of participating Investigators and institutions has not been finalized prior to development of the 
Clinical Investigator Plan and will be distributed under separate cover. 
APPENDIX F: IRB/MEC LIST 
A final IRB/MEC list has not been finalized prior to development of the Clinical Investigator Plan and will be 
distributed under separate cover 
 

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APPENDIX G: 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 foreseeable adverse events information consists of two parts: a listing of 
potential adverse events associated with cryoablation therapy/procedure and adverse event rates reported 
in published literature for same therapy/procedure (see Appendix A).  An evaluation of potentially anticipated 
events and reported events in literature may be used in combination with device labeling/IFU, current event 
reporting information, and other published data to assess for an unexpected occurrence.  
The cryoablation 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, etc.). 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 Arctic 
Front Advance CryoAblation Catheter under investigation.  
Additional potential risks associated with the Arctic Front Advance CryoAblation Catheter, as well as risk 
minimization are discussed within Section 14.2. 
Treatment required for procedure and/or 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 Arctic 
Front Advance CryoAblation Catheter include but are not limited to those in Table 23 and Table 24. 
Table 23 pertains to the foreseeable/anticipated adverse events that may be observed in the study and may 
assist in identifying those adverse events that are unexpected in nature. 
Table 23: Foreseeable adverse events 
Anemia 
Feeling cold 
Pseudoaneurysm 
Anxiety 
Fever 
Pulmonary edema 
Arrhythmia 
Gastrointestinal 
discomfort 
Pulmonary embolism 
Arteriovenous fistula 
Gastroparesis 
Pulmonary 
hemorrhage 
Atrial fibrillation 
Headache 
Pulmonary 
hypertension 
Atrial flutter 
Heart block 
Pulmonary infarction 

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Atrio-esophageal fistula  
Heart failure 
Pulmonary 
infiltration 
Back pain 
Hematemesis 
Pulmonary vein 
stenosis 
Bleeding 
Hematoma 
Renal impairment 
Blurred vision 
Hemoptysis 
Respiratory arrest or 
pulmonary arrest 
Bronchial fistula 
Hemothorax 
Right bundle branch 
block 
Bronchitis 
Hiccups 
Sepsis 
Bruising 
Hypertension 
Shivering 
Cardiac arrest or 
cardiopulmonary arrest 
Hypotension 
Shortness of breath 
Cardiac perforation or 
cardiac vein perforation or 
perforation of surrounding 
tissue 
Hypoxia 
Sore throat 
Cardiac tamponade 
Infection 
ST segment 
elevation
Cerebral embolism
Injury to pulmonary vein 
e.g. pulmonary vein 
dissection, pulmonary 
vein hematoma  
Stroke or 
cerebrovascular 
accident 
Chest discomfort or pain 
or pressure 
Lightheadedness 
Syncope 
Coronary artery spasm 
Lung injury 
Tachycardia 
Cough 
Myocardial infarction 
Thrombosis or 
thrombus 

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Death 
Nausea 
Transient ischemic 
attack 
Diarrhea 
Nerve injury e.g. phrenic 
nerve injury 
Urinary infection 
Dizziness 
Neurological impairment 
Vagal nerve injury 
Dressler's syndrome 
Paralysis or paresis 
Vascular access site 
complication 
Dysphagia 
Pericardial effusion or 
pericardial tamponade 
Vasospasm 
Embolism 
Pericarditis 
Vasovagal reaction 
Ecchymosis 
Pleural effusion 
Visual changes or 
visual impairment 
Esophageal injury/damage 
(including atrio-
esophageal fistula) 
Pneumonia 
Vomiting 
Fatigue 
Pneumothorax or 
collapse of lung 
 
Table 24 is a summary of reported procedure and Arctic Front Advance Cardiac CryoAblation Catheter 
related adverse events reported in a Medtronic Clinical Evaluation Report for The Arctic Front Family of 
Catheters Recertification (Rev 1A, 19MAY2015).  The observed rate is based on the study populations that 
included a total of 11,242 patients. 
Table 24: Arctic Front and Arctic Front Advance complications reported in literate for paroxysmal and 
persistent AF patients 
Events 
N=11,242 
Rate (95% CI*) 
Transient phrenic nerve injury (resolved prior to 
procedure end) 
4.26% (3.89-4.65%) 

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Events 
N=11,242 
Rate (95% CI*) 
Phrenic nerve injury 
2.18% (1.92-2.47% 
Groin hematoma 
0.58% (0.45-0.74%) 
Pericardial effusion/pericardial tamponade 
0.53% (0.41-0.69%) 
Pseudoaneurysm 
0.36% (0.25-0.48%) 
Hemoptysis 
0.27% (0.18-0.38%) 
Femoral arterio-venous fistula 
0.21% (0.14-0.32%) 
Cardiac tamponade 
0.20% (0.13-0.31%) 
Bleeding 
0.14% (0.08-0.23%) 
Gastroparesis 
0.14% (0.08-0.23%) 
Hematoma 
0.14% (0.08-0.23%) 
Atrial flutter 
0.13% (0.07-0.22%) 
Atrial tachycardia 
0.12% (0.06-0.20%) 
Esophageal damage/ulceration 
0.12% (0.06-0.20%) 
Transient ischemic attack 
0.12% (0.06-0.20%) 
Stroke or cerebral vascular accident 
0.10% (0.05-0.18%) 
Myocardial infarction 
0.05% (0.02-0.12%) 
Atrio-esophageal fistula 
0.04% (0.01-0.10%) 
Guidewire dissection 
0.04% (0.01-0.10%) 
Pulmonary vein stenosis 
0.04% (0.01-0.10%) 

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Events 
N=11,242 
Rate (95% CI*) 
ST elevation 
0.04% (0.01-0.10%) 
Accidental femoral artery puncture 
0.03% (0.01-0.09%) 
Inguinal aneurysm 
0.03% (0.01-0.09%) 
Pulmonary edema 
0.03% (0.01-0.09%) 
Difficulty swallowing/dysphagia 
0.02% (0.002-0.06%) 
Hemothorax 
0.02% (0.002-0.06%) 
Pericarditis 
0.02% (0.002-0.06%) 
Pulmonary vein hematoma 
0.02% (0.002-0.06%) 
Thrombosis or thrombus 
0.02% (0.002-0.06%) 
Vasovagal reaction 
0.02% (0.002-0.06%) 
Chest discomfort or pain or pressure 
0.01% (0.0002-0.5%) 
Cough 
0.01% (0.0002-0.5%) 
Death 
0.01% (0.0002-0.5%) 
Headache 
0.01% (0.0002-0.5%) 
Hemoptysis-clinically important 
0.01% (0.0002-0.5%) 
Inappropriate sinus tachycardia 
0.01% (0.0002-0.5%) 
Lightheadedness 
0.01% (0.0002-0.5%) 
Nausea 
0.01% (0.0002-0.5%) 
Odynophagia 
0.01% (0.0002-0.5%) 

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Events 
N=11,242 
Rate (95% CI*) 
Pneumonia 
0.01% (0.0002-0.5%) 
Pneumothorax or collapsed lung 
0.01% (0.0002-0.5%) 
Pulmonary infarction 
0.01% (0.0002-0.5%) 
Pulmonary infiltration 
0.01% (0.0002-0.5%) 
Sinus arrest/3rd degree AV block 
0.01% (0.0002-0.5%) 
Transient AV block 
0.01% (0.0002-0.5%) 
*95% CI calculated with binomial exact methods 
 

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APPENDIX H: PRE-CLINICAL TESTING 
A summary of results from pre-clinical testing with the Arctic Front Advance and Freezor MAX Cardiac 
CryoAblation Catheters is provided in the Report of Prior Investigations Summary. 

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x
i Aytemir K, Oto A, Canpolat U, et al. Immediate and medium-term outcomes of cryoballoon-
based pulmonary vein isolation in patients with paroxysmal and persistent atrial fibrillation: 
single-centre experience. J Interv Card Electrophysiol. 2013;38(3):187-195.   
x
ii Ciconte G, Ottaviano L, de Asmundis C, et al. Pulmonary Vein Isolation as Index Procedure for 
Persistent Atrial Fibrillation: One-Year Clinical Outcome After Ablation Using The Second-
Generation Cryoballoon. Heart Rhythm. 2014; 12(1):60-6. 
x
iii Ferrero-De Loma-Osorio A, Izquierdo-De Francisco M, Martinez-Brotons A, et al. Medium-
term results of cryoballoon ablation of the pulmonary veins in patients with paroxysmal and 
persistent atrial fibrillation. First experience of a Spanish center.  J. Intervent. Card. 
Electrophysiol. August 1 2013;37(2):189-196. 
x
iv Jackson N, Barlow M, Leitch J, Attia J. Treating atrial fibrillation: pulmonary vein isolation with 
the cryoballoon technique. Heart Lung Circ. 2012;21(8):427-432.   
x
v Kojodjojo P, O'Neill MD, Lim PB, et al. Pulmonary venous isolation by antral ablation with a large 
cryoballoon for treatment of paroxysmal and persistent atrial fibrillation: medium-term 
outcomes and non-randomised comparison with pulmonary venous isolation by radiofrequency 
ablation. Heart. 2010;96(17):1379-1384.   
x
vi Kubala M, Hermida JS, Nadji G, et al. Normal pulmonary veins anatomy is associated with 
better AF-free survival after cryoablation as compared to atypical anatomy with common left 
pulmonary vein. Pacing Clin Electrophysiol. 2011;34(7):837-843.   
x
vii Malmborg H, Lönnerholm S, Blomström P, Blomström-Lundqvist C. Ablation of atrial 
fibrillation with cryoballoon or duty-cycled radiofrequency pulmonary vein ablation catheter: a 
randomized controlled study comparing the clinical outcome and safety; the AF-COR study. 
Europace. 2013;15(11):1567-1573.   
x
viii Neumann T, Vogt J, Schumacher B, et al. Circumferential pulmonary vein isolation with the 
cryoballoon technique results from a prospective 3-center study. J Am Coll Cardiol. 
2008;52(4):273-278. 
x
ix Schmidt M, Dorwarth U, Straube F, et al. Cryoballoon in AF ablation: impact of PV ovality on AF 
recurrence. Int J Cardiol. 2013;167(1):114-120. 
x
x Schmidt M, Dorwarth U, Straube F, et al. A novel double cryoballoon strategy in persistent atrial 
fibrillation: a pilot study. Clin Res Cardiol. 2012;101(10):777-785. 
x
xi Lemes C, Wissner E, Reissmann B, et al. One-year clinical outcome after pulmonary vein 
isolation using the second-generation 28mm cryoballoon in patients with persistent atrial 
fibrillation. Europace. 2015; 18(2):201-5. 

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9HUVLRQ+LVWRU\
Version 
Summary of Changes 
Rationale 
Author(s)/Title 
1.0 
Not Applicable, New 
Document 
Not Applicable, New 
Document 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Synopsis, Sections 7.1, 
7.2 and 18: Modified the 
primary efficacy OPC and 
changed the atypical 
flutter treatment failure 
to any recurrence of atrial 
flutter 
FDA feedback 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Synopsis, Sections 7.1, 
7.2 14.16 and 18.3.2: 
Changed the secondary 
safety objective to a 
primary safety objective 
with a pre-specified 
hypothesis 
FDA feedback 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Synopsis, Sections 7.1, 
7.2 and 18.5: Added an 
ancillary objective
 
 
 
 
 
 
 
 
 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Synopsis, Sections 7.1, 
7.2 and 18.5: Added and 
ancillary objective 
 
 
 
 
 
 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Synopsis, Sections 7.1, 
7.2 and 18.5: Removed 
 
 
 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 

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
 
 ancillary 
objective 
Fred Kueffer, Pr. Statistician 
2.0
Synopsis, Sections 5, 8 
and 18: Study data from 
the Japanese centers will 
not be included in the 
PMA-S submission, but 
will be included in a 
submission to Japan 
Pharmaceuticals and 
Medical Device Agency 
(PMDA) 
Participation and enrollment in 
Japan is anticipated to start 
later than the other 
geographies 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Table 5: Noted the 
complication definition 
may vary from study to 
study 
Clarification 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Sections 14 and 20.2: 
Added weekly and 
symptom driven event 
monitoring 
FDA feedback and consistent 
with the 2012 HRS Expert 
Consensus Statement on 
Catheter and Surgical Ablation 
of AF 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Sections 7.2.1, 14.7 and 
18.3: Modified the 
antiarrhythmic dose 
allowed after the blanking 
period to historic 
maximum 
FDA feedback 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Sections 7.2.1 and 18: 12-
lead ECGs need to 
demonstrate at least 10 
seconds of an atrial 
arrhythmia to be 
considered a treatment 
failure 
Aligns with standard practice 
and FDA feedback 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 

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
2.0 
Section 8.2: Rationale was 
updated 
Consistent with the addition 
of a primary safety objective 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0
Section 14.1: Added 
review of symptoms 
suggestive of recurrent 
AF/AT/AFL to the study 
procedures and data 
collection table 
Clarification 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Section 14.4: Added 
When performed, the TEE 
should be occur within 1 
day (on the day of or 
within the day prior to) 
the planned ablation 
procedure 
Clarification 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Section 14.5.5: Require 
CTI ablation if typical 
flutter has been 
documented or was 
induced.  Recommend 
induction if not in the 
documented history. 
FDA feedback 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Sections 7.2.1, 7.2.3, 
14.5.5, 14.8, 18.3, and 
18.5: removed the 
limitation that only CTI 
ablations are allowed in 
the right atrium 
Allows for treatment of pre-
existing right atrial 
arrhythmias that may 
contribute to the primary 
objective if left untreated 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Section 14.18: Added that 
a study deviation is not 
required if a subject 
misses a weekly TTM 
transmission. 
Compliance percentage will be 
managed by the core lab 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 

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
2.0 
Section 17: Added that 
associated imaging 
studies may be 
requested, if available, for 
all serious adverse events 
with possible relatedness 
to the system or 
procedure 
To support adverse event 
adjudication 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Section 18: Provided 
details regarding the 
determination of subjects 
for data analysis 
FDA feedback 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Section 18.4: Provided 
details on the Hommel 
stepwise procedure for 
the secondary objectives 
FDA feedback 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Section 18.5: Stated that 
ancillary objectives been 
defined to provide 
additional information 
about the performance of 
the Arctic Front Advance 
Cardiac CryoAblation 
Catheter.  No hypotheses 
are defined for regulatory 
or labeling purposes. 
FDA feedback 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
2.0 
Section 21.3: Removed 
Ltd reference. 
Typo 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
3.0 
Section 18.3.2: Revised 
primary safety hypothesis 
statement and endpoint 
definition 
Typo 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Pr. Statistician 
4.0 
Sections 5, 8 and 18.2: 
Included additional details 
about the sample size in 
FDA feedback 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 

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relation to Japanese data 
and how Japanese data 
will be reported 
Fred Kueffer, Pr. Statistician 
5.0
Page 2: Removed Dr. 
Robert Kowal from the list 
of Coordinating 
Investigators 
Dr. Robert Kowal no longer 
functions as a practicing 
physician 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
5.0 
Section 3: Updated Japan 
Monitoring contact 
New information 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
5.0 
Table 4 and 6: Removed 
model number 990063-
020 
Typo 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
5.0 
Sections 5 and 12.4:  
Increased the BMI cut off 
to 40 
Insufficient patient population 
to support enrollment 
requirement 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
5.0 
Section 9.1.4: Added the 
Achieve Advance Mapping 
Catheter 
Device is now commercially 
available 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
5.0 
Sections 9.2 and 9.3: The 
Manual Retraction Kits will 
be investigational in 
Japan and tracked 
accordingly 
PMDA feedback 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
5.0 
Section 14.19: Removed 
Subject has completed 
follow up as an exit choice 
Completed follow up will be 
documented by completion of 
the 12 month office visit 
requirements 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 

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Version 6, 01DEC2017 
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5.0 
Section 15.1: Changed 
pelvic to phrenic 
Typo 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
5.0
Table 11: Changed Article 
273 to 274.2 for Japan 
Regulatory Authorities 
Sponsor responsibility 
reporting of SAEs and 
UADEs/USADEs 
Typo 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
6.0 
Table 2: Added the 
Monitoring contacts 
information 
New information 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
6.0 
Table 3: Added the core 
lab and monitoring 
contact information 
New information 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
6.0 
Section 4 and 11: 
Inclusion and exclusion 
criteria modified 
Insufficient patient population 
to support enrollment 
requirement 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
6.0 
Section 7 and 12: Allow up 
to 20 treated subjects at a 
single center 
Enrollment barrier 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
6.0 
Section 8.1.3: Removed 
“providing a barrier 
preventing air ingress into 
the valve and” from the 
FlexCath Advance device 
description. 
To reflect the product 
description language that was 
recently updated in the 
FlexCath Advance 4FC12 
Instructions for Use 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 

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Version 6, 01DEC2017 
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6.0 
Section 8.3 and 18.1: 
changed the words 
deviation and exemption 
to exception 
Typo 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
6.0
Table 7 and Section 13.4:  
Allow a 12-lead ECG and 
physical exam that 
occurred within 30 days of 
consent for the baseline 
requirement 
Performing a second 12-lead 
ECG and physical exam after 
consent is often not feasible if 
they were performed prior to 
consent 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
6.0 
Section 14.1 and 
Appendix G: Modified 
risks to align with the 
current Arctic Front 
Advance IFU and added 
that the current Arctic 
Front Advance IFU should 
be referenced with 
respect to the possible 
risks 
Updated to reflect recently 
approved labeling for the 
commercialized device 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
6.0 
Table 11: updated Japan 
regulatory references 
Typo 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
6.0 
Section 20: Added 
Liability to the section 
heading 
Template change 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 
6.0 
Header/Footer: Content 
was modified 
Template change 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician 

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Version 6, 01DEC2017 
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6.0 
Version History: Moved to 
the end of the document 
Template change 
Dana Wigert, Sr. Prin. Clinical 
Research Specialist 
Fred Kueffer, Sr. Prin. 
Statistician