Sustained Treatment of Paroxysmal Atrial Fibrillation Post-Approval Study (STOP AF PAS)
Phase: NA
Conditions: Paroxysmal Atrial Fibrillation (PAF)
Sponsor: Medtronic Cardiac Ablation Solutions

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Sustained Treatment of Paroxysmal Atrial Fibrillation Post-Approval Study 
(STOP AF PAS) 
 
 
Clinical Investigation Plan 
 
 
 
 
18 AUG 2011 
 
 
Medtronic, Inc. 
8200 Coral Sea Street NE 
Mounds View, MN U.S.A. 55112 
1-800-328-2518 
 

 
 
 
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Table of Contents 
Sustained Treatment of Paroxysmal Atrial Fibrillation Post-Approval Study .............................................. 1 
(STOP AF PAS) ................................................................................................................................... 1 
Clinical Investigation Plan .................................................................................................................. 1 
18 AUG 2011 ....................................................................................................................................... 1 
List of Appendices .............................................................................................................................. 4 
List of Tables ...................................................................................................................................... 4 
Table of Figures .................................................................................................................................. 4 
CONTACT INFORMATION ................................................................................................................ 5 
1 
INTRODUCTION ....................................................................................................................... 6 
1.1  Study Purpose ......................................................................................................... 6 
1.2  Study Scope ............................................................................................................ 6 
2 
BACKGROUND AND JUSTIFICATION ..................................................................................... 6 
3 
SYSTEM DESCRIPTION AND INTENDED USE ........................................................................ 6 
3.1  Product Used in the Study....................................................................................... 6 
4 
METHODOLOGY ...................................................................................................................... 7 
4.1  Study Design ........................................................................................................... 7 
4.2  Primary Effectiveness Objective ............................................................................. 9 
4.3  Primary Safety Objective ........................................................................................ 9 
4.4  Secondary Objectives ............................................................................................ 10 
4.5  Site Selection ........................................................................................................ 11 
4.6  Subject Selection ................................................................................................... 12 
4.7  Minimization of Bias ............................................................................................ 15 
5 
STUDY PROCEDURES ............................................................................................................ 16 
5.1  Equipment requirements ....................................................................................... 16 
5.2  Informed Consent Process .................................................................................... 16 
5.3  Data Collection Overview ..................................................................................... 18 
5.4  Subject Follow-Up Schedule ................................................................................ 19 
5.5  Baseline ................................................................................................................. 19 
5.6  Cryoablation Procedure ........................................................................................ 20 
5.7  Scheduled Follow-up Visits .................................................................................. 21 
5.8  Unscheduled Follow-up Visits .............................................................................. 23 
5.9  Termination Follow-up Visits ............................................................................... 23 
5.10  Visit Procedure Details ......................................................................................... 24 
5.11  Recurrence of Atrial Fibrillation ........................................................................... 26 
5.12  Permissible Retreatment of Study Subjects .......................................................... 26 
5.13  Study Exit.............................................................................................................. 26 
5.14  Lost to Follow-Up ................................................................................................. 27 
5.15  Subject Follow-up after Withdrawal ..................................................................... 27 
5.16  Medication Restrictions ........................................................................................ 27 
6 
STUDY DEVIATIONS.............................................................................................................. 28 
7 
ADVERSE EVENTS ................................................................................................................. 29 
7.1  Adverse Event Assessment ................................................................................... 29 
7.2  Adverse Event Definitions, Classification and Reporting .................................... 30 
7.3  Adverse Event Classification and Reporting ........................................................ 32 
7.4  Subject Death ........................................................................................................ 34 

 
 
 
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7.5  Adverse Event Adjudication Committee (AEAC) Review .................................. 35 
7.6  Medical Device Reporting Requirements for User Facilities ............................... 35 
7.7  Investigator Adverse Event Records and Reporting Requirements ...................... 36 
7.8  Medtronic Adverse Event Records and Reporting Requirements ........................ 37 
8 
RISK ANALYSIS ..................................................................................................................... 38 
8.1  Risk Minimization ................................................................................................ 38 
8.2  Potential Benefits .................................................................................................. 38 
9 
PLANNED STUDY CLOSURE, EARLY TERMINATION OR STUDY SUSPENSION ................ 38 
9.1  Planned Study Closure .......................................................................................... 38 
9.2  Early Termination or Suspension.......................................................................... 39 
9.3  Criteria .................................................................................................................. 39 
9.4  Procedures ............................................................................................................. 40 
10 
STATISTICAL METHODS AND DATA ANALYSIS ................................................................. 41 
10.1  Primary Effectiveness Endpoint ........................................................................... 41 
10.2  Primary Safety Endpoint ....................................................................................... 41 
10.3  Analysis Sets ......................................................................................................... 43 
10.4  Sample Size Justification ...................................................................................... 43 
10.5  Statistical Analysis Methods ................................................................................. 44 
10.6  Interim Patient Safety Monitoring ........................................................................ 48 
11 
DATA AND QUALITY MANAGEMENT .................................................................................. 48 
12 
WARRANTY/INSURANCE INFORMATION ............................................................................ 49 
12.1  Warranty ............................................................................................................... 49 
13 
MONITORING ......................................................................................................................... 49 
13.1  Monitoring Visits .................................................................................................. 49 
14 
REQUIRED RECORDS AND REPORTS ................................................................................... 50 
14.1  Investigator Records ............................................................................................. 50 
14.2  Investigator Reports .............................................................................................. 51 
14.3  Sponsor Records ................................................................................................... 53 
14.4  Sponsor Reports .................................................................................................... 53 
 

 
 
 
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List of Appendices 
 
Appendix A:  Protocol Acronyms and Abbreviations ....................................................................... 57 
Appendix B: Summary of STOP AF PAS Protocol Changes ............................................................ 59 
 
 
List of Tables 
 
Table 1:  Study Contact Information ................................................................................................... 5 
Table 2: Cryoablation Procedure Event ............................................................................................. 10 
Table 3: Major Atrial Fibrillation Events .......................................................................................... 11 
Table 4: Data Collection/Study Procedure Requirements at Subject Visits ...................................... 18 
Table 5: Subject Follow-up Windows .................................................................................................... 19 
Table 6: Adverse Event Definitions ....................................................................................................... 30 
Table 7: Adverse Event and Subject Death Classification Responsibilities ............................................... 33 
Table 8: Subject Death Classification Definitions ................................................................................... 34 
Table 9: Investigator Adverse Event Reports .......................................................................................... 36 
Table 10: Medtronic Adverse Event reporting ........................................................................................ 37 
Table 11: Cryoablation Procedure Events............................................................................................... 42 
Table 12: Major Atrial Fibrillation Events .............................................................................................. 47 
Table 13: Investigator Reports for all Geographies per Medtronic requirements ....................................... 51 
Table 14: Investigator Reports Applicable to the United States per FDA Regulations ............................... 52 
Table 15: Sponsor Reports for Canada ................................................................................................... 54 
Table 16: Sponsor Reports for the United States ..................................................................................... 55 
Table 17: Study Milestones/Timeline..................................................................................................... 56 
 
Table of Figures 
 
Figure 1: STOP AF PAS Overall Study Design .................................................................................. 8 

 
 
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CONTACT INFORMATION 
Medtronic contact information is provided below. This information is subject to change during 
the course of the clinical study. Periodic updates to study contact information will be sent to the 
centers. 
 
Table 1:  Study Contact Information 
  
 
 
 
Study Sponsor Contacts 
Worldwide Clinical Trial Leader 
 
Fred Ecklund, Prin. Clinical Research 
Specialist 
Direct Phone: (+1-763) 526-1860 
Direct Fax: +1-763-367-1727  
fred.l.ecklund@medtronic.com 
Clinical Director 
 
Linda Nelson, Director 
Direct Phone: +1-763- 526-2891 
Direct Fax: +1-763-367-1727 
linda.k.nelson@medtronic.com 
Study Monitor Contacts 
Worldwide Clinical Trial Monitor 
 
Cindy Prelli, Clinical Monitoring Manager 
Direct Phone: +1-763-526-2622 
Direct Fax: +1-763-367-1727 
cindy.m.prelli@medtronic.com 
 
Core Lab Contacts 
Worldwide 
 
Imaging Core Lab Name 
Phone 
Fax 
email 
 
 
 

 
 
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1 
INTRODUCTION 
1.1 Study Purpose 
The purpose of the Post-Approval Study (PAS) is to provide long-term safety and 
effectiveness of the Arctic Front® Cardiac Cryoablation Catheter System, including 
the Freezor® MAX Cardiac cryoablation catheter according to the Product Labeling. 
This PAS is a condition of the Pre-Market Approval order (P100010) by the Food and 
Drug Administration. 
 
1.2 Study Scope 
The study will be expected to be conducted at a minimum of 30 centers located in the 
United States and Canada. Up to 400 subjects will be enrolled to achieve the primary 
endpoint analyses. Subjects will be followed for 5 years from their cryoablation 
procedure date. It is expected to take 18-24 months to enroll 400 subjects. At least 
70% of the total subject enrollments are required to come from the new Arctic Front 
user investigational sites as defined in Section 4.5 of this protocol, while the 
remaining subject enrollments can come from the STOP AF/CAP AF investigational 
sites.  
 
2 
BACKGROUND AND JUSTIFICATION 
The pivotal trial of the Arctic Front® Cardiac Cryoablation Catheter System with the 
adjunctive use of the Freezor  MAX Cardiac Cryoablation Catheter to electrically 
isolate pulmonary veins (PV) in patients with paroxysmal atrial fibrillation (PAF), 
compared to a randomized drug control group demonstrated that 69.9% [62.3, 76.9% 
95% CI] of experimental subjects were free of atrial fibrillation at 12 months 
compared to 7.3% in the control group. The proportion of experimental subjects with 
serious adverse events related to the cryoablation procedure was 3.1% [6.3% 95% 
upper confidence bound] which was well within the pre-defined 95% upper 
confidence bound of 14.8%. 
 
3 
SYSTEM DESCRIPTION AND INTENDED USE 
 
3.1 Product Used in the Study 
For the purpose of this study the Arctic Front® Cardiac CryoAblation System is 
indicated for the treatment of subjects with drug refractory recurrent symptomatic 
paroxysmal atrial fibrillation.  
 
Arctic Front® Cardiac CryoAblation System, consisting of: 
 

 
 
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 Arctic Front® Cardiac CryoAblation Catheter in two balloon sizes  
 Manual Retraction Kit  
 The Freezor MAX Cardiac CryoAblation Catheter in two curves Ref # 
239F3 and 239F5  
 Medtronic CryoCath CryoConsole  
Medtronic may incorporate additional Medtronic CryoCath CryoConsoles, updated 
Freezor MAX and Arctic Front® Cardiac CryoAblation Catheters or updated 
CryoConsole software into this post-approval study as they receive appropriate 
license or regulatory approval and are released commercially by Medtronic, 
provided they do not affect the scientific soundness of the study. 
4 
 METHODOLOGY 
4.1  Study Design  
The PAS is a prospective multi-center, non-randomized, single arm, controlled, 
unblinded clinical study designed to provide long-term safety and effectiveness of 
the Arctic Front® Cardiac CryoAblation System. 
Safety and effectiveness will be evaluated against pre-specified performance 
criteria as determined by the sponsor and FDA. The criteria set in this study have 
been previously used to demonstrate safety and effectiveness in cryoablation and 
radio-frequency ablation for the treatment of paroxysmal atrial fibrillation. 
The analyses of the primary effectiveness objective will take place once all the 
subjects with a study cryoablation procedure attempt have reached 36 months of 
follow-up post-cryoablation procedure. The analysis of the primary safety objective 
will take place once all the subjects with a study cryoablation procedure attempt 
have reached 12 months of follow-up post-cryoablation procedure. The analyses for 
the secondary objectives will take place once all subjects with a study cryoablation 
attempt have reached 60 months of follow-up post-cryoablation procedure. The 
overall study design is summarized in Figure 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Figure 1: STOP AF PAS Overall Study Design 
400 Enrolled 
Subjects
Baseline Visit
Cryoablation 
Procedure
Discharge
3 Month Visit
6 Month Visit
12 Month Visit
Annual Follow-up 
through 5 years
Pre/Post Procedure 
Fluorscopy for PNP
CT/MRI within 
previous 6 months 
or at Baseline Visit
Chest X-ray for 
subjects with 
abnormal post-
procedure 
fluoroscopy
CT/MRI PV stenosis 
surveillance
CT/MRI PV stenosis 
surveillance for 
subjects identified 
with PV stenosis at 
6 months
CT/MRI PV stenosis 
surveillance for 
subjects identified 
with PV stenosis at 
6 months
Chest X-ray for subjects 
with abnormal post-
procedure fluoroscopy if 
not resolved at 3 months
Chest X-ray for subjects 
with abnormal post-
procedure fluoroscopy if 
not resolved at previous 
follow-up
 

 
 
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4.2  Primary Effectiveness Objective 
Demonstrate effectiveness (through 36 months) of  the Arctic Front® Cardiac 
CryoAblation Catheter System, including the Freezor®  MAX Cardiac 
Cryoablation Catheter by assessing the rate of subjects free of chronic treatment 
failure with paroxysmal atrial fibrillation who have failed one or more Atrial 
Fibrillation Drugs (AFDs). 
 
Chronic treatment failure is defined as: 
 Documented atrial fibrillation lasting longer than 30 seconds OR 
 Intervention for atrial fibrillation (except for repeat cryoablation during the 
90 day blanking period) 
 
Intervention for atrial fibrillation is defined as: An invasive procedure intended for 
the definitive treatment of AF, including any ablation of the PVs or atrial triggers 
(other than protocol-specified ablation), interruption of AV nodal function, 
procedures to alter left atrial conduction or function such as the Maze procedure, or 
the implantation of an atrial pacemaker or atrial defibrillator; whether approved by 
relevant regulatory authorities or not for such indications; excluding electrical or 
pharmacologic cardioversion of arrhythmias and excluding procedures solely 
directed at the treatment of atrial flutter or atrial tachycardias. A reablation 
permitted under Section 5.12 of this protocol is not an AF intervention. 
 
4.3 Primary Safety Objective 
Demonstrate safety (through 12 months) of Arctic Front® Cardiac CryoAblation 
Catheter System, including the Freezor®  MAX Cardiac Cryoablation Catheter by 
assessing the rate of subjects experiencing a Cryoablation Procedure Events (CPEs) 
with paroxysmal atrial fibrillation who have failed one or more Atrial Fibrillation 
Drugs (AFDs). 
 
Cryoablation procedure event is defined in Table 2 below. 

 
 
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Table 2: Cryoablation Procedure Event 
Cryoablation Procedure Events 
(CPE) 
With onset between Day 0 
and: 
Access site complications requiring: 
Transfusion of 3 or more units or 
Surgical intervention or 
Permanent loss or functional 
impairment 
Day 7 
Cardiac damage (including MI) 
Day 7 
Pulmonary vein stenosis* 
Through 12-months  
Atrio-esophogeal fistula 
Through 12-months 
Embolic complications (including 
stroke) 
Day 7 
Arrhythmias 
Day 7 
Persistent phrenic nerve palsy** 
Through 12-months 
Death 
Day 7 
* CPE will be assessed at the completion of the follow-up visit, as determined by 
CT/MRI Core Lab. 
** CPE will be assessed at the completion of the follow-up as determined by chest 
X-ray (insp/exp) 
 
4.4 Secondary Objectives 
The following are a list of secondary objectives, which are intended to provide 
additional information on the performance of the Arctic Front® Cardiac 
CryoAblation Catheter System. There will be no established performance 
requirements related to these secondary objectives required. The secondary 
objectives are as follows: 
  
Safety Objective: 
 
 Evaluate the proportion of subjects free from MAFE events at 1, 2, 3, 4 and 5 
years 
 
Major Atrial Fibrillation Event (MAFE):  A MAFE is a serious adverse event 
(SAE) — which has not been categorized as a CPE—as set out in the following 
Table: 

 
 
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Table 3: Major Atrial Fibrillation Events 
 
Major Atrial Fibrillation Events (MAFEs): 
Cardiovascular deaths 
Hospitalizations for (primary reason): 
   AF recurrence or ablation 
   Atrial flutter ablation (excluding Type I) 
   Systemic embolization (not stroke) 
   Congestive heart failure 
   Hemorrhagic event (not stroke) 
   Antiarrhythmic drug:  initiation, adjustment or 
complication 
Myocardial infarction (MI) 
Stroke 
 
Effectiveness Objective: 
 
 Evaluate the proportion of subjects free of chronic treatment failure at 1, 2,  4 and 
5 years 
 
Cryoablation Objectives: 
 
 Procedure parameters 
 
4.5 Site Selection 
Investigational sites that participated in the Continued Access Protocol for the 
Evaluation of Catheter Cryoablation in the Treatment of Paroxysmal Atrial 
Fibrillation (CAP-AF) will be invited to participate in the PAS. In addition, 
investigational sites that followed subjects with pulmonary vein (PV) stenosis or 
unresolved phrenic nerve injury (PNI) in STOP AF will be invited to participate. 
 
The sponsor will also invite at least 30 investigational sites that are new users (non-
STOP AF/CAP AF sites) of the Arctic Front® Cardiac CryoAblation Catheter 
System. The new user investigational sites will be selected from the pool of United 
States sites that have the following:  
o Medtronic CryoCath CryoConsole that is compatible with the Arctic 
Front® Cardiac CryoAblation Catheter System and have completed the 
required product training 
o Willingness to participate in protocol and precedural training, as 
requested, 
o Sufficient staff (at least one primary investigator, one radiologist and 
study coordinator) and Medtronic support to execute and maintain 

 
 
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compliance to the protocol, including data collection and record retention 
requirements 
o Acknowledgement of, and agreement to, comply with applicable 
regulatory and local requirements governing clinical study conduct 
o Site has the ability to submit data via Oracle Clinical database 
 
Additionally, Investigational sites must have the qualified personnel and equipment 
to perform the protocol specified surveillance for recurrent atrial fibrillation, 
pulmonary vein stenosis and phrenic nerve injury as described in Section 5.10 of 
this protocol as well as all other study related duties. All investigational sites will 
complete the required protocol training prior to enrolling subjects in the study. 
 
All applicable physicians will be asked to participate in the study.  
4.6 Subject Selection 
Subjects who have a diagnosis of paroxysmal atrial fibrillation will be considered 
for the study based on the inclusion and exclusion criteria. Subjects are considered 
enrolled upon signing the Informed Consent Form and must be consented prior to 
any study driven testing. The date the subject signed the consent form and privacy 
authorization (if required) must be recorded.  
 
Subjects that were enrolled and treated in CAP-AF will be asked to participate in 
the follow-up phase of this PAS and are exempt from the inclusion and exclusion 
criteria for this study.  
 
FDA requested the sponsor attempt to enroll STOP AF subjects into the STOP AF 
PAS that demonstrated PV stenosis or unresolved PNI at the conclusion of the 
STOP AF pivotal as defined in the STOP AF protocol. These subjects are exempt 
from the inclusion and exclusion criteria for this study.  
 
Sites will be required to document effort to enroll CAP AF and STOP AF subjects 
into the STOP AF PAS. 
 
Enrolled subjects may participate in other clinical trials that are not likely to impact 
the scientific soundness of this PAS. Sites are required to obtain written approval 
from Medtronic prior to enrolling subjects already participating in an ongoing 
clinical trial or enrolling an existing PAS subject in another clinical trial. 
4.6.1 Inclusion Criteria: 
For inclusion in the study, subjects must fulfill ALL of the following criteria: 
 
 Documented PAF: 
 Diagnosis of paroxysmal atrial fibrillation (PAF), AND 

 
 
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 2 or more episodes of AF during the 3 months preceding the 
Consent Date, at least 1 of which must be documented with a 
tracing 
 Age 18 years or older 
 Failure for the treatment of AF (effectiveness or intolerance) of one or 
more of the following drugs indicated in the treatment of PAF:  
flecainide, propafenone, sotalol or dofetilide. 
4.6.2 Exclusion Criteria: 
ANY of the following is regarded as a criterion for excluding a subject 
from the study: 
 
 Any previous left atrial (LA) ablation (except permissible retreatment 
subjects) 
 Any previous LA surgery 
 Current intracardiac thrombus (can be treated after thrombus is 
resolved) 
 Presence of any pulmonary vein stents 
 Presence of any pre-existing pulmonary vein stenosis 
 Pre-existing hemidiaphragmatic paralysis 
 Anteroposterior LA diameter > 5.5 cm by TTE 
 Presence of any cardiac valve prosthesis 
 Clinically significant mitral valve regurgitation or stenosis  
 Myocardial infarction, PCI / PTCA or coronary artery stenting which 
occurred during the 3 month interval preceding the Consent Date 
 Unstable angina 
 Any cardiac surgery which occurred during the 3 month interval 
preceding the Consent Date 
 Any significant congenital heart defect corrected or not (including atrial 
septal defects or pulmonary vein abnormalities but not including minor 
PFO) 
 NYHA class III or IV congestive heart failure 
 Left ventricular ejection fraction (LVEF) < 40% 
 2º (Type II) or 3º atrioventricular block 
 Presence of a permanent pacemaker, biventricular pacemaker, atrial 
defibrillator or any type of implantable cardiac defibrillator (with or 
without biventricular pacing function) 
 Brugada syndrome 
 Long QT syndrome 

 
 
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 Arrhythmogenic right ventricular dysplasia 
 Sarcoidosis 
 Hypertrophic cardiomyopathy 
 Known cryoglobulinemia 
 Uncontrolled hyperthyroidism 
 Any cerebral ischemic event (strokes or TIAs) which occurred during 
the 6 month interval preceding the Consent Date. 
 Any woman known to be pregnant 
 Life expectancy less than one (1) year 
 Current or anticipated participation in any other clinical trial of a drug, 
device or biologic during the duration of this study 
 Unwilling or unable to comply fully with study procedures and follow-
up 

 
 
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4.7 Minimization of Bias  
Potential sources of bias in this study may result from selection of subjects, 
treatment of subjects, and evaluation of study data.  The following methods have 
been incorporated into the study to minimize potential bias include (not limited to 
these): 
 Subjects will undergo a rigorous screening to confirm eligibility for 
enrollment with defined inclusion/exclusion criteria prior to enrollment  
 All centers and geographies will use the same version of the Clinical 
Investigational Plan and CRFs 
 Data collection requirements and study procedures will be standardized 
across all geographies 
 All investigational site personnel and Medtronic personnel will be trained 
on their respective aspects of the study using standardized training 
materials 
 All investigational site personnel will be trained on and required to follow 
the Clinical Investigational Plan  
 An independent adjudication committee will be utilized to regularly review 
and adjudicate reported adverse events and endpoints 
 All study investigators will be required to meet 21 CFR Part 54, Financial 
Disclosure by Clinical Investigators, to identify potential bias due to 
financial interest in the outcome of the study 
 

 
 
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5 
STUDY PROCEDURES 
All clinical investigators performing a cryoablation procedure must be trained in the 
handling of Arctic Front® Cardiac CryoAblation Catheter and must receive 
protocol training prior to any study procedures.  
Center personnel who consent patients and/or participate in the follow-up visits 
must be trained by Medtronic. 
5.1 Equipment requirements 
The following equipment must be available at each center to support study 
activities:  
 Medtronic CryoCath CryoConsole 
 Arctic Front® Cardiac CryoAblation Catheter in two balloon sizes  
 Manual Retraction Kit  
 Freezor MAX Cardiac CryoAblation Catheter in two curves  
 
The maintenance and calibration of the equipment as listed above will be assessed 
by the participating center following their normal processes.  Clinical monitors will 
not monitor maintenance or calibration schedules. 
5.2 Informed Consent Process  
Patient informed consent is defined as legally effective, documented confirmation 
of a subject’s (or their legally authorized representative or guardian) voluntary 
agreement to participate in a particular clinical investigation 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.  
When the patient has consented to participate in the trial, they are considered to be 
an enrolled subject. 
Each investigational center’s Ethics Board will be required to approve the Clinical 
Investigation Plan (CIP), Informed Consent (IC) and any subject recruitment 
materials.  Refer to for the sample patient informed consent form(s).  Any changes 
to the patient informed consent must be approved by Medtronic and the Ethics 
Board reviewing the application before being used to consent a prospective study 
subject.  The document(s) should be controlled (i.e. versioned and/or dated) to 
ensure it is clear which version(s) were approved by the Ethics Board. 
Prior to initiation of any study-specific procedures, subjects (or their legally 
authorized representative or guardian) must sign and date the HIPAA/data 
protection authorization/or other privacy language where required by law and the 
Ethics Board and Medtronic approved Informed Consent.  The Informed Consent 
form and HIPAA/data protection authorization/or other privacy language where 

 
 
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required by law, must be given to the subject (or their legally authorized 
representative or guardian) in a language he/she is able to read and understand.   
The process of obtaining patient informed consent shall: 
 Avoid coercion and undue influence of subjects to participate 
 Not waive or appear to waive subject’s legal rights 
 Use language that is non-technical and understandable to the subject 
 Provide ample time for the subject to consider participation 
 Include a dated signature of the subject acknowledging that their participation 
in the study is voluntary 
 
If the patient informed consent is obtained the same day the subject begins 
participating in study-related procedures, it should be documented in the subject’s 
case history that consent was obtained prior to participation in any study-related 
procedures.  
In the event the subject cannot read and/or write, witnessed (impartial third party) 
informed consent will be allowed, provided detailed documentation of the process 
is recorded in the subject’s case history and the witness signs and dates the patient 
informed consent.   
The original or a copy of the signed patient informed consent must be filed in the 
hospital/clinical chart or with the subject’s study documents.  A copy of the signed 
patient informed consent and authorization/or other privacy language where 
required by law must be provided to the subject.  When a patient signs and dates 
the STOP AF PAS informed consent, he/she is considered a subject enrolled in the 
study.  
The patient informed consent form and the signed patient informed consent and 
authorization/or other privacy language (where required by law) must be available 
for monitoring and auditing.   

 
 
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5.3 Data Collection Overview 
Clinical data will be collected at the time points detailed in Table 4. 
Table 4: Data Collection/Study Procedure Requirements at Subject Visits 
 
 
Cryoablation 
Procedure 
Repeat Cryoablation 
Procedure (0-90 days) 
3 month 
6 and 12 month 
2, 3, 4 and 5 year 
Termination  
Baseline 
Procedure 
Post-
procedure 
Discharge 
Baseline 
Procedure 
Post-
procedure 
Discharge 
Consent 
X 
 
 
 
X 
 
 
 
 
 
 
 
Incl/Excl 
Criteria 
X 
 
 
 
X 
 
 
 
 
 
 
 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
Anticoagulation 
Use 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
Arrhythmic Sx 
review 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Use of AFDs 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
12 lead ECG 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
TTE 
X(1) 
 
 
X 
X(1)
 
 
X 
 
 
 
 
MRI or CT 
X(1) 
 
 
 
 
 
 
 
 
X(3,4) X(3,4)
X(3,4)
24 hour Holter 
monitoring 
 
 
 
 
 
 
 
 
 
X 
 
 
48 hour Holter 
monitoring 
 
 
 
 
 
 
 
 
 
X(6) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-12 Health 
Survey 
X(7) 
 
 
 
 
 
 
 
 
X 
X 
X 
TEE 
 
X(2) 
 
X 
 
X(2)
 
X 
 
 
 
 
Chest X-ray 
(insp/exp) 
 
 
 
 
 
 
 
 
X(5) 
X(5) 
X(5) 
X(5) 
Fluoroscopy 
 
X 
X 
 
 
X 
X 
 
 
 
 
 
AE review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. Performed during the 6 month interval preceding the Consent Date, or between the 
Consent Date and Procedure Date 
2. Performed within 7 days prior to the Procedure 
3. Follow-up PV imaging technology (CT or MRI) performed at follow-up visits must be 
the same type as used for baseline 
4. Only if CT/MRI at 6 month follow-up demonstrated PV stenosis in one or more 
pulmonary veins 
5. Performed at the 3 month follow-up for subjects whose post-procedural fluoroscopy 
demonstrated study-related phrenic nerve palsy. If phrenic nerve palsy is present at 

 
 
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the 3 month visit, a chest X-ray (inspiration/expiration) is required at 12 month follow-
up visit. If phrenic nerve palsy persists at the 12 month visit, a chest x-ray is required 
at the each annual (24-60 months) follow-up until resolved. 
6. Performed at the 12 month follow-up visit. 
7. Only subjects that will be receiving their initial ablation procedure in the STOP AF 
PAS. 
 
5.4 Subject Follow-Up Schedule  
Regular follow-ups are necessary to monitor the condition of subjects. Subjects 
with a study procedure attempt will be followed through 60 months post study 
cryoablation procedure attempt.    
If a follow-up visit falls outside the prescribed window, a study deviation must be 
reported and the original follow-up window must be maintained for subsequent 
visits. Follow-up visits outside the window will be used in the final analysis. 
Follow-up visit windows are listed in Table 5. All windows are based on days post -
study cryoablation procedure attempt. 
Table 5: Subject Follow-up Windows 
 
Visit 
Window  
(Days post  study cryoablation procedure attempt)
  
Window Start 
(# of days) 
Target 
(# of days) 
Window End 
(# of days) 
Month 3 
76 
90 
104 
Month 6 
166 
180 
194 
Month 12 
365 
365 
395 
Month 24 
700 
730 
760 
Month 36 
1,095 
1,095 
1,125 
Month 48 
1,430 
1,460 
1,490 
Month 60 
1,795 
1,825 
1,855 
 
5.5 Baseline 
The following baseline evaluations will be performed after consent, unless 
previously performed as part of routine clinical evaluations within the specified 
windows: 
 
Within 6 months prior to the Consent Date: 
1. Documented Trans-thoracic Echocardiogram (TTE) performed during the 6 
month interval preceding the Consent Date, or between Consent and Start Dates 
2. An MRI or CT scan of the four PVs or their anomalous equivalent performed 
during the 6 month interval preceding the Consent Date, or between Consent and 
Start Dates  
 

 
 
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Performed within 1 month prior to the Consent Date: 
1. Medical history, including 
a. assessment of risk factors, NYHA cardiac function class, systemic history 
and cardiovascular medical history 
b. assessment of atrial fibrillation symptoms and other arrhythmic episodes 
that have occurred in the 3 month interval preceding the Consent Date 
c. history of AF with documentation, including date of onset 
d. number of cardioversions and AF-related hospitalizations that have 
occurred in the 12 months preceding the Consent Date. 
e. medication history regarding prior and current use of AFDs, including any 
of the following AFDs: flecainide, propafenone, sotalol, dofetilide, 
amiodarone. 
f. assessment of all factors specified for evaluation under Inclusion Criteria 
and  Exclusion Criteria 
2. Physical examination and vital signs 
3. 12 lead ECG 
Performed after Consent Date 
1. SF-12 Health Survey 
 
Performed within 7 days prior to the Start Date (procedure date): 
1. A transesophageal echocardiogram (TEE) assessing potential thrombus in the 
heart within 7 days prior to the Start Date 
 
5.6 Cryoablation Procedure 
 
Prior to the cryoablation procedure, the Investigator will review the procedural 
steps in this protocol and the relevant documentation for the Arctic Front® Cardiac 
CryoAblation Catheter, the Freezor  MAX Cardiac Cryoablation Catheter and the 
Cryoablation console. In addition, the Investigator will: 
 
1. Prior to the first cryoablation application, the Investigator will make a 
fluoroscopic recording of inspiratory and expiratory movement of the 
diaphragm. 
2. During the procedure the investigator will document the following: 
a. Catheter used for each cryoapplication (i.e. Arctic Front, Freezor Max or 
RF) 
b. Temperature for each cryoapplication 
c. Duration of each cryoapplication 
d. Vein location for each cryoapplication (e.g. Right superior pulmonary 
vein) 
e. Use of phrenic nerve pacing for each cryoapplication 
3. After the last cryoablation application, the investigator will make a fluoroscopic 
recording of the inspiratory and expiratory movement of the diaphragm. 
 

 
 
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5.6.1 Other Ablations  
1. Occasional subjects will have cardiac rhythm abnormalities requiring treatment 
detected during the cryoablation procedure.  Whenever possible, the 
experimental cryoablation devices will be used, however when necessary for 
subject welfare, other commercially available devices may be utilized at the 
Investigator’s discretion. This may include right / left atrial flutter or atrial 
fibrillation triggers. 
2. Such ablations will be fully documented in the relevant CRF.  Post Procedure 
Evaluations  
3. Before leaving the EP Lab: 
a. total procedure duration, total elapsed fluoroscopy duration and first 
cryocatheter insertion / last cryocatheter removal times (total cryocatheter 
insertion time) will be recorded. 
b. procedure duration and elapsed fluoroscopy duration during non-cryo 
applications will be recorded (if any). 
c. the use of any adjunctive mapping or visualization devices will be 
recorded on the relevant CRF. 
5.6.2 Discharge Procedures 
At or shortly before discharge: 
1. Assessments:  All subjects will have the following assessments prior to 
discharge: 
a. physical examination and vital signs  
b. 12 lead ECG 
c. Transthoracic echocardiogram within 72 hours post-procedure 
d. screening for adverse events 
2. Anticoagulation:  Subjects will have anticoagulation treatment determined by 
the Investigator according to established guidelines.  
3. Instructions:  The subject will be given written instructions on the handling and 
reporting of any symptomatic events throughout the follow-up period. 
4. Post ablation AF drug regimens: the use of AF drugs during this investigation is 
determined by the clinical judgment of the Investigator. Any use of membrane-
active AFDs (Class Ia, Ic, III) will be documented in the CRF. These drugs 
include quinidine, procainamide, disopyramide, flecainide, propafenone, 
moricizine, amiodarone, dofetilide, ibutilide and sotalol. 
 
5.7 Scheduled Follow-up Visits 
5.7.1 Three, Six and Twelve Month Follow-up Visits 
Subjects must be seen in person.  The following data/procedures will be 
completed at each follow-up visit.  
 Physical exam  

 
 
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 12 lead ECG 
 Medications  
 Adverse event collection 
 24 hour Holter monitoring (6 month) 
 48 hour Holter monitoring (12 month) 
 SF-12 Health Survey (6 and 12 month) 
 Signs/symptoms review for arrhythmias 
 Intercurrent episodes of medical care suggestive of arrhythmia 
including hospitalizations, office or ER visits, or any AF-related 
procedures such as cardioversion or additional ablation 
 Treatment with AFD 
 Anticoagulation use 
 For any subject whose post-procedural fluoroscopy demonstrated 
study-related phrenic nerve palsy, a follow up chest X-ray including 
inspiration / expiration films will be performed at the 3 month 
follow-up visit 
 12 month follow-up visit chest X-ray (inspiration / expiration) 
required if phrenic nerve palsy was unresolved at 3 month follow-
up visit 
 For any subject whose 6 month CT/MRI demonstrated PV stenosis, 
a CT/MRI scan will be performed at the 12 month follow-up. 
5.7.2 Two through Five Year Follow-up Visits 
Subjects must be seen in person.  The following data/procedures will be 
completed at each follow-up visit.  Subjects are exited from the study at the 
60 month visit. 
 Physical exam  
 12 lead ECG 
 Medications  
 Adverse event collection 
 48 hour Holter monitoring 
 SF-12 Health Survey 
 Signs/symptoms review for arrhythmias 
 Intercurrent episodes of medical care suggestive of arrhythmia 
including hospitalizations, office or ER visits, or any AF-related 
procedures such as cardioversion or additional ablation 
 Treatment with AFD 
 Anticoagulation use 

 
 
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 Chest X-ray (inspiration / expiration) required if phrenic nerve 
palsy unresolved at previous follow-up visit  
 For any subject whose 6 month CT/MRI demonstrated PV stenosis, 
a CT/MRI scan will be performed. 
 
5.8 Unscheduled Follow-up Visits 
For any subject performing an unplanned office visit, assessments will be 
performed as follows: 
 Physical exam  
 12 lead ECG 
 Medications  
 Adverse event collection 
 Signs/symptoms review for arrhythmias 
 Intercurrent episodes of medical care suggestive of arrhythmia 
including hospitalizations, office or ER visits, or any AF-related 
procedures such as cardioversion or additional ablation 
 Health care utilization 
 Treatment with AFD 
 Anticoagulation use 
 
5.9 Termination Follow-up Visits 
For any subject not completing 36 months of clinic follow-up (e.g., due to 
withdrawal) termination assessments will be performed as follows: 
 Physical exam  
 12 lead ECG 
 Medications  
 Adverse event collection 
 48 hour Holter monitoring 
 SF-12 Health Survey 
 Signs/symptoms review for arrhythmias 
 Intercurrent episodes of medical care suggestive of arrhythmia 
including hospitalizations, office or ER visits, or any AF-related 
procedures such as cardioversion or additional ablation 
 Treatment with AFD 
 Anticoagulation use 
 For any subject whose post-procedural fluoroscopy demonstrated 
study-related phrenic nerve palsy, a follow up chest X-ray 
(inspiration / expiration films) will be performed at the Termination 

 
 
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follow-up visit if phrenic nerve palsy was unresolved at the 3 month 
or previous follow-up visit. 
  
 For any subject whose 6 month CT/MRI demonstrated PV stenosis, 
a CT/MRI scan will be performed at the Termination follow-up 
visit. 
5.10 Visit Procedure Details 
5.10.1 
Physical exam 
The physical exam will include the following:   
 Vital signs (blood pressure/heart rate) 
 Check of body systems 
 Neck – JV pressure 
 Lungs – auscultation 
 Cardiovascular 
 Abdomen 
5.10.2 
12 lead ECG 
A 12 lead ECG must be completed and analyzed by the 
investigator. 
5.10.3 
Medications 
Information regarding medications will be collected including the 
purpose for their use and, start and stop dates and dosage.  
5.10.4 
 Adverse event collection 
If a subject presents with symptoms at or outside of their scheduled 
follow-up the center is required to report any unreported adverse 
events.  In addition, any changes (e.g. actions taken, change in 
outcomes) to previously reported unresolved adverse events must 
be reported.   
5.10.5 
Signs/symptoms review for arrhythmias 
Assess for signs/symptoms of arrhythmias since last visit. Subjects 
that present with symptoms believed to be due to atrial fibrillation, 
but was not captured on ECG, will be provided with an event 
recorder for 30 days to capture symptomatic atrial fibrillation 
 

 
 
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5.10.6 
24 Hour Holter monitoring   
At the 6 month (window ± 2 weeks) a 24 hour Holter monitor will 
be obtained.  
 
5.10.7 
48 Hour Holter Monitoring 
The annual follow-ups at months 12, 24, 36, 48 and 60, a 48 hour 
Holter monitor will be required.   
5.10.8 
SF-12 Health Survey 
At baseline, 6 month, 12 month and annual visits through 60 
months, subjects will be asked to complete the SF-12 Health 
Survey. 
5.10.9 
Health Care Utilization 
During the course of the study, Medtronic will ask investigational 
sites to provide certain elements from the UBO4 and 1500 forms 
for health care utilization analyses. The frequency of this data 
collection will be determined by the changes in subject health 
status that requires use of the health care system.  
5.10.10 CT/MRI Imaging for Pulmonary Vein Stenosis  
At the 6 month follow-up visit, subjects will undergo an MRI or 
CT scan (same technology as the baseline assessment) of all PVs 
or their anomalous equivalents. For any subject that has > 50% 
reduction in baseline PV area, as determined by a site radiologist, 
an additional review will be performed by an independent Core 
Lab to confirm protocol defined PV stenosis of > 75% reduction in 
baseline PV area. For those subjects with core lab confirmed PV 
stenosis an additional MRI or CT scan will be repeated at 12 
months and annually through 60 months. 
 
5.10.11 Chest X-ray for Phrenic Nerve Palsy  
For any subject whose post-procedural fluoroscopy demonstrated 
study-related phrenic nerve palsy, a follow up chest X-ray 
including inspiration / expiration films will be performed at the 3 
month follow-up and annually until resolved or subject has 
completed the 60 month follow-up. All chest X-rays for study 
related phrenic nerve palsy will be analyzed by a site radiologist. 
 
 

 
 
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5.11 Recurrence of Atrial Fibrillation 
If a subject presents with symptoms at or outside of the scheduled follow-up visits, 
the center is required to report any documented recurrence of AF.   This 
documentation must be provided to the sponsor and additional source documents 
may be requested. 
Documentation of AF must include at least one of the following per standard center 
procedures: 
 
ECG 
 
TTM 
 
Holter  
 
Rhythm strip 
 
5.12 Permissible Retreatment of Study Subjects 
All Study Subjects may have one repeat cryoablation procedure within Days 0 – 90 
under this protocol if all the following criteria are met: 
1. Informed Consent:  If the original Informed Consent does not cover this repeat 
cryoablation procedure, then Informed Consent will be obtained for this 
procedure. 
2. Inclusion / Exclusion criteria for repeat cryoablation procedure: 
a. The subject has either of the following: 
i. Failure to isolate one or more PVs during the initial cryoablation 
procedure or 
ii. Recurrent AF 
b. The subject has not had any other ablation procedure in the LA between 
the first cryoablation and the proposed repeat cryoablation. 
c. The subject continues to meet Study Exclusion Criteria, where the 
reablation procedure date is substituted for “Start Date” and “Consent 
Date”. 
3. Baseline reablation assessments are performed as follows: 
a. Baseline Evaluations. 
b. Assessment of NYHA cardiac function class 
c. If the TTE performed for the first cryoablation procedure was obtained 
more than 6 months prior to the proposed date for the second procedure, 
then another TTE 
d. Another TEE within 7 days prior to the reablation date 
4. Study Status post Reablation:  Reablated Subject’s Start Date and study-
specified intervals, procedures and assessments remain the same. A reablation 
of a study subject under this Section is not an AF Intervention. 
 
5.13 Study Exit 
Prior to an early exit of a subject from the study, all efforts should be made to 
continue following the subject until all unresolved serious, device  and procedure 

 
 
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related adverse events are resolved or they are considered to be unresolved, no 
further actions planned. Prior to exit every attempt should be made to determine and 
report the status of any unresolved adverse events. Prior to exit every attempt 
should be made to determine and report the status of the any recurrent atrial 
fibrillation. 
Once a subject has been exited from the study, there will be no further follow-up or 
attempts to collect data on the subject. All data available through the time of the 
subject’s exit will be used for analysis.  
Subjects are urged to remain in the study as long as possible, but may be exited 
from the trial for any of the following situations: 
 Subject has completed follow-up 
 Subject lost to follow-up 
 Subject death 
 Subject did not meet inclusion/exclusion criteria after consent 
 Subject chooses to withdraw (e.g., consent withdrawal, relocation to 
another geographic location)  
 Investigator deems withdrawal necessary (e.g., medically justified, 
inclusion/exclusion criteria not met, failure of subject to maintain 
adequate study compliance) 
 The sponsor decides the study will be closed or a particular center will 
be closed 
5.14 Lost to Follow-Up 
In the case that the subject is determined to be lost to follow-up, the following 
contact attempts should be made; one phone message to subject, one phone message 
to subject through a contact person and one letter. Regulations set forth by the 
governing IRB/MEC must be followed. 
 
5.15  Subject Follow-up after Withdrawal 
Investigational sites will notify the sponsor of a subject’s intention to withdraw 
from the study. The subject’s atrial fibrillation status will be collected prior to the 
subject exiting the study. If a subject is withdrawn from the study prior to their 60 
month visit, no further study visits will occur for the subject and no further study 
data will be collected after the date of withdrawing from the study.   
 
5.16 Medication Restrictions 
All medications are permitted in this study with following exceptions: 
 Investigational drugs that may confound the study results 
  

 
 
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6 
STUDY DEVIATIONS 
A study deviation is defined as an event within a study that did not occur according 
to the Clinical Investigation Plan or the Clinical Trial Agreement. 
Prior approval by the Medtronic Clinical Study Manager or designee is expected in 
situations where the investigator anticipates, contemplates, or makes a conscious 
decision to deviate.  Prior approval is not required when a deviation is necessary to 
protect the life or physical 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, etc.).  
For medically justifiable conditions which preempt a subject’s ability to complete a 
study-required procedure, it may be permitted to complete only one deviation CRF 
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 end point 
analysis, etc.).  However, prior approval from Medtronic is required for such 
situations.   
All study deviations must be reported to Medtronic regardless of whether medically 
justifiable, pre-approved by Medtronic, an inadvertent occurrence, or taken to 
protect the subject in an emergency.  The deviation must be recorded with an 
explanation for the deviation and corrective/ preventative action(s).   
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 Institutional Review Board (IRB) as well as Medtronic 
within five (5) working days.  Reporting of all other study deviations should 
comply with IRB policies and/or local laws and must be reported to Medtronic as 
soon as possible upon the center becoming aware of the deviation.  Reporting of 
deviations must comply with IRB/ MEC policies, local laws, and or regulatory 
agency requirements.   Refer to Investigator Reports, Table 13 for geography-
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 
Clinical Investigation Plan, conduct additional training, terminate the investigation, 
etc.).  Repetitive or serious investigator compliance issues may represent a need to 
initiate a corrective action plan with the investigator and site, and in some cases, 
necessitate suspension of enrollment until compliance is obtained 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 site on a periodic basis.   
 

 
 
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7 
ADVERSE EVENTS 
Timely, accurate, and complete reporting and analysis of safety information for 
clinical studies are crucial for the protection of subjects, investigators, and the 
sponsor. 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. This study is conducted in accordance with these procedures and 
regulations. 
  
7.1 Adverse Event Assessment 
All adverse events (AEs) and adverse device effects (ADE’s) will be reported in 
all geographies (i.e. US and Canada) throughout the study duration.   Exceptions 
include: 
 Documented pre-existing conditions unless the nature or severity of the 
condition has worsened.  
 Recurrence of AF event unless an action is taken.   
 Unavoidable AEs unless the AE worsens or is present outside the stated 
timeframe listed in Table 6 
 
Information reported about an AE will include date of onset, a description of the 
event, diagnosis, relationship of the event to a procedure, relationship of the 
event to each device, actions taken as a result of the event, and the outcome of 
the event.  Each diagnosis must be reported as a separate event. 
Subject deaths are also required to be reported. Refer to Section 7.4 for study 
requirements related to subject death. 
 
Managing AE updates and resolving AEs 
For any changes in status of a previously reported adverse event (i.e. change 
inactions taken, change in outcome, change in relatedness), an adverse event 
update must be completed. All AEs must be followed until the AE 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 
AEs are resolved or are considered unresolved with no further actions planned. 
At the time of study closure, all AEs with an outcome of “unresolved, further 
actions or treatment planned” must be reviewed and an AE update must be 
provided. At a minimum, if there are no changes to the description, relatedness, 

 
 
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or actions taken, the outcome must be updated to reflect that it is unresolved at 
time of study exit/death/study closure. 
 
7.2 Adverse Event Definitions, Classification and Reporting 
 
7.2.1 Adverse Event Definitions 
Definitions provided in Table 6 will be used throughout this study for the 
purpose of collecting, classifying and reporting adverse events: 
Table 6: Adverse Event Definitions 
General 
Adverse Event 
(AE) 
Any untoward medical occurrence in a subject 
NOTE: This definition does not imply that there is a relationship between the 
Adverse Event and the device under investigation.  
 
Hospitalization A hospital admission lasting more than 24 hours or which includes an 
overnight admission. 
Seriousness 
Serious 
Adverse Event 
(SAE) 
An Adverse Event that  
a) led to a death, or 
b) led to a serious deterioration in the health of the subject that  
 Resulted in a life-threatening illness or injury, or 
 Resulted in permanent impairment of a body structure or a body 
function, or 
 Required in-patient hospitalization >48 hours or prolongation of existing 
hospitalization, or 
 Resulted in medical or surgical intervention to prevent, permanent 
impairment to body structure or a body function, or 
c) led to fetal distress, fetal death or a congenital abnormality or birth defect 
 

 
 
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Complication 
An adverse event that results death, involves any termination of significant 
device function, or requires an invasive intervention 
 Noninvasive: Noninvasive, when applied to a diagnostic device or 
procedure, means one that does not by design or intention: (1) Penetrate or 
pierce the skin or mucous membranes of the body, the ocular cavity, or the 
urethra, or (2) enter the ear beyond the external auditory canal, the nose 
beyond the nares, the mouth beyond the pharynx, the anal canal beyond the 
rectum, or vagina beyond the cervical os. For purposes of this part, blood 
sampling that involves simple venipuncture is considered noninvasive, and 
the use of surplus samples of body fluids or tissues that are left over from 
samples taken for non-investigational purposes is also considered 
noninvasive. (21 CFR 812.3(k)) 
Observation 
Any adverse event that is not a complication. 
Relatedness 
Cryoablation 
Procedure 
related 
An Adverse Event that occurs due to any procedure related to the study 
cryoablation procedure.   
Procedure 
related  
An Adverse Event that occurs due to any other procedure related to the 
study (i.e. EP study). 
Device 
related 
 
Arctic Front® Cardiac CryoAblation Catheter System catheter related: 
An adverse event that results from the presence or performance (intended or 
otherwise) of the Arctic Front® Cardiac CryoAblation Catheter System  
 
 
Other related: An adverse event that results from the presence or 
performance (intended or otherwise) of any other device / tool used  
 
Timing 
Ablation 
Procedure  AE 
An adverse event that occurs during the ablation procedure, after 
introduction of the study catheter into the vasculature and prior to 
completion of skin closure. 
Post-ablation 
Procedure AE 
An adverse event that occurs after the completion of skin closure for the 
ablation procedure. 
Unavoidable 
AE  
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 the list provided below. 
Unavoidable AEs are not reportable AEs. Onset of any of these events 
occurring after the specified timeframes and/or events lasting longer than the 

 
 
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specified timeframe if onset is at the time of the surgery should be reported 
as adverse events under the above definitions. 
Unavoidable AEs 
Event Description 
Time (Hours) from the 
Surgical Procedure
Anesthesia related 
nausea/vomiting  
24 
Low-grade fever (<100°F or < 
37.8°C)  
48 
Incisional pain  
72 
Mild to moderate bruising / 
ecchymosis  
168 
Sleep problems (insomnia)  
72 
Back pain related to lying on the 
table  
72 
Shoulder 
pain/discomfort/stiffness related 
to shoulder immobilization 
during procedure 
72 
 
 
. 
7.3 Adverse Event Classification and Reporting 
AEs will be classified according to the definitions provided. In order to meet the 
requirements of the regulatory agencies, each event will be classified by the 
investigator according to standard regulatory definitions. 
Upon receipt of adverse events at Medtronic, a Medtronic representative will 
review the adverse event for completeness and accuracy and when necessary 
will request clarification and/or additional information from the Investigator. 
Medtronic will utilize MedDRA, the Medical Dictionary for Regulatory 
Activities, to assign a MedDRA term for each adverse event based on the 
information provided by the investigator. 
Regulatory reporting of AEs will be completed according to local regulatory 
requirements. Refer to Table 9 and Table 10 for a list of required investigator and 
Medtronic reporting requirements and timeframes. It is the responsibility of the 
Investigator to abide by the AE reporting requirements stipulated by the IRB or 
MEC. 
A listing (Foreseeable Adverse Event List (FAL)) of adverse events associated 
with the use of market-approved cryoablation systems or cryoablation procedure 
that have been observed in previous studies and may be experienced by subjects 
can be found in the product labeling. This list may help to assess if an AE is 
unexpected in nature.   

 
 
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Adverse Events and Deaths will be classified according to the standard 
definitions as outlined below: 
Table 7: Adverse Event and Subject Death Classification Responsibilities 
 
What is Classified 
 
Who Classifies 
 
Classification Parameters 
 
Timing of the 
Event 
 
Investigator 
 
During study cryoablation procedure, 
Post study cryoablation procedure 
Relatedness 
Investigator 
 
Arctic Front® Cardiac CryoAblation 
Catheter System, CryoConsole, study 
cryoablation procedure, other procedures 
Severity 
 
Investigator 
 
SAE  
Sponsor 
CPE, MAFE and Complication or 
Observation* 
Diagnosis 
 
 
Investigator 
Based on presenting signs and symptoms 
and other supporting data 
Sponsor 
MedDRA key term assigned based on the 
data provided by Investigator 
Death 
Classification1 
Investigator 
Sudden Cardiac, Non-sudden Cardiac, 
Non-cardiac, Unknown 
Event 
Adjudication2 
Adverse Event 
Adjudication 
Committee (AEAC)  
Adjudicates All of the Above 
  
1Deaths will only be adjudicated to relatedness and death classification. All other 
adjudication information will be taken from the corresponding AE with an 
outcome of ‘death’ 
2The AEAC may not adjudicate the following:  timing of the event or MedDRA 
key term. 
* Complication or Observation will apply to only system and procedure related 
adverse events 
  
 

 
 
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7.4 Subject Death  
7.4.1 Data Collection 
All subject deaths must be reported by the center to Medtronic as soon as 
possible after the center first learns of the death. The adverse event that lead 
to the death must be reported  
A copy of the death certificate, if available and allowed by state/local law, 
should be sent to the in-house Medtronic clinical study team.  When a death 
occurs in a hospital, a copy of the physician’s dictated death summary report 
and all relevant hospital records should be sent to the in-house Medtronic 
clinical study team, if available.  If an autopsy is conducted, the autopsy 
report should also be sent to the in-house Medtronic clinical study team.  
When the death occurs at a remote site, it is the investigative center’s 
responsibility to attempt retrieval of information about the death.  In 
summary, the following data will be collected: 
o Date of death 
o Detailed description of death 
o Cause of death  
o Relatedness to device 
o Relatedness to  procedures 
o Death certificate (if available and allowed by state/local law) 
o Death summary/hospital records (if available and allowed by 
state/local law) 
o Autopsy report (if available and allowed by state/local law) 
7.4.2 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 found in Table 8 Regulatory reporting of Subject Deaths 
will be completed according to local regulatory requirements.  Refer to Table 
9 and Table 10 for a list of required investigator and sponsor reporting 
requirements and timeframes. 
 
Table 8: Subject Death Classification Definitions 
Cardiac Death 
A death directly related to the electrical or mechanical 
dysfunction of the heart. 
Non-cardiac Death 
A death not classified as a cardiac death. 

 
 
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Sudden Cardiac 
Death (SCD) 
Natural death due to cardiac causes, heralded by abrupt loss of 
consciousness within one hour of the onset of acute symptoms; 
preexisting heart disease may have been known to be present, 
but the time and mode of death are unexpected.  If time of onset 
cannot be determined, SCD will alternatively be defined as any 
unexpected cardiac death occurring out of the hospital or in the 
emergency room as dead on arrival. 
Non-sudden Cardiac 
Death 
All cardiac deaths that are not classified as sudden deaths, 
including all cardiac deaths of hospitalized subjects on inotropic 
support. 
Unknown 
Unknown death classification is intended for use only when 
there is insufficient or inadequate information to classify the 
death. 
 
7.5 Adverse Event Adjudication Committee (AEAC) Review  
 At regular intervals, an independent Adverse Event Adjudication Committee 
(AEAC) will conduct a medical review of all adverse events and deaths for 
subjects participating in the study.  This committee will also adjudicate events 
for endpoint considerations (CPE and MAFE).   
The AEAC will consist of up to three non-Medtronic employed physicians, 
including an AEAC chairperson.  At least three AEAC members must 
adjudicate, at a minimum, all deaths, serious AEs, device / procedure related 
AEs and events for endpoints.  All other AEs must be adjudicated by at least one 
physician member of the AEAC.   
Medtronic personnel may facilitate and participate in an AEAC meeting but will 
be non-voting members. 
Medtronic will provide the AEAC with the Investigator’s description and 
classification of each AE in addition to the MedDRA key term.  The AEAC is 
responsible for reviewing the investigator’s assessment and classification of 
each event, and adjudicating a final classification.   
If the AEAC disagrees with the investigator’s classification of the event, the 
rationale will be provided to the investigator.  If the investigator agrees with the 
AEAC’s adjudication, the case report form documenting the AE or AE update 
will be updated accordingly. If the investigator does not agree with the AEAC’s 
adjudication, both determinations will be provided within the final report, 
however the AEAC’s adjudication will be used for data analysis purposes  
7.6 Medical Device Reporting Requirements for User Facilities 
Per FDA regulations, Device User Facilities are required to report Medical 
Device Reports (MDR) on market approved products (21 CFR 803, subpart C) 

 
 
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A Device User Facility is defined as a hospital, an ambulatory surgical facility, a 
nursing home, an outpatient treatment facility, or an outpatient diagnostic 
facility which is not a physician’s office.   
7.7 Investigator Adverse Event Records and Reporting 
Requirements 
Adverse Events will be recorded and reported according to local regulatory 
requirements. Refer to for investigator adverse event reporting requirements.  It 
is the responsibility of the Investigator to abide by the adverse event reporting 
requirements stipulated by the centers’ IRB/MEC.   
Table 9: Investigator Adverse Event Reports 
Report 
Submit To 
Description 
Serious 
Adverse Event 
Sponsor 
Immediately after the Investigator 
first learns of event 
MEC/IRB 
Reporting time frame as per local 
requirement 
Adverse 
Device Effect 
(ADE) 
Other Adverse 
Device Effect 
Sponsor 
Immediately after the Investigator 
first learns of event 
MEC/IRB 
Reporting time frame as per local 
requirement 
All Other 
Adverse 
Events 
Sponsor 
Submit in a timely manner after the 
investigator first learns of the event 
MEC/IRB 
Submit to MEC/IRB per local 
reporting requirement 
Medical Device 
Reporting 
(Marketed 
Product) 
FDA (US) 
A report must be submitted to the 
sponsor as soon as practicable but no 
more than 10 work days after the day 
that the investigator become aware of 
information, from any source, that 
reasonable suggests that a device has 
or may have caused or contributed to 
the death of a patient (21 CFR 803) 
Mandatory 
Problem 
Reporting 
Health 
Canada 
(Canada) 
The investigator must file a report 
with the Minister and notify the 
manufacturer (sponsor) within 72 
hours of an event that comes to their 
attention and meets the criteria. 
(Health Canada: Medical Device 
Regulation, PART 1 and PART 3) 
The requirement to report an incident 
that occurs outside Canada does not 
apply unless the manufacturer has 
indicated, to a regulatory agency of 

 
 
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the country in which the incident 
occurred, the manufacture’s intention 
to take corrective action, or unless the 
regulatory agency has required the 
manufacturer to take corrective 
action. (Health Canada: Medical 
Device Regulations, Part 1; Section 
59 (2)) 
 
7.8 Medtronic Adverse Event Records and Reporting 
Requirements 
Adverse Events will be recorded and reported according to local regulatory 
requirements. Refer to Table 10 for Medtronic adverse event reporting 
requirements.  
Table 10: Medtronic Adverse Event reporting 
Report 
Submit To 
Description 
 
 
Medical Device 
Reporting 
 
 
 
FDA  
 
 
US and Canada: An event about which 
manufacturers or importers have received or 
become aware of information that reasonably 
suggests that one of their marketed devices 
may have caused or contributed to a death or 
serious injury; or has malfunctioned and that 
the device or a similar device marketed by 
the manufacturer or importer would be likely 
to cause or contribute to a death or serious 
injury if the malfunction were to recur. (21 
CFR 803) 
 
 
 
 
Mandatory Problem 
Reporting 
 
 
 
 
Health 
Canada  
 
 
US and Canada: Required reporting by 
manufacturers concerning any incident that 
comes to their attention occurring inside or 
outside Canada and involving a device that is 
sold in Canada and that: 
a) Is related to a failure of the device or a 
deterioration in its effectiveness, or any 
inadequacy in its labeling or in its directions 
for use; AND 
b) 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. (Health Canada: Medical 
Device Regulation, PART 1 & PART 3) 
 

 
 
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8 
RISK ANALYSIS 
There are potential risks and side effects associated with participation in this study. 
Possible additional risks for participating in this study include the following 
(although others are possible): 
 Radiation exposure due to potential for additional CT scan or Chest X-
rays 
 Electrodes used with Holter recorder might cause mild skin discomfort or 
irritation, or some skin discomfort following electrode removal. 
8.1 Risk Minimization  
Medtronic has attempted to minimize the potential risks to subjects in this study 
by taking the following actions: 
 Selecting qualified investigators and training study personnel on the 
Clinical Investigation Plan.  
 Requiring careful assessment of each subject prior to, during, and after the 
ablation procedure. 
 Providing guidelines for subject selection and evaluation. 
 Providing adequate instructions and labeling.  
 After the ablation procedure, subjects in the clinical study will be followed 
at regular intervals to monitor for reoccurrence of AF and adverse events. 
8.2 Potential Benefits  
The Arctic Front® Cardiac CryoAblation Catheter System has been demonstrated 
to reduce paroxysmal atrial fibrillation in subjects, however some subjects may not 
receive this benefit. The information gained from this study could result in 
improved management of paroxysmal atrial fibrillation.  
9 
PLANNED STUDY CLOSURE, EARLY TERMINATION OR STUDY 
SUSPENSION  
9.1 Planned Study Closure 
Study Closure is a process initiated by distribution of an initial study closure 
letter.  Study closure is defined as closure of a clinical study that occurs when 
Medtronic and/or regulatory requirements have been satisfied per the Clinical 
Investigational Plan and/or by a decision by Medtronic or regulatory authority, 
whichever occurs first.  The study closure process is complete upon distribution 
of the Final Report or after final payments, whichever occurs last.  IRB/MEC re-
approvals are required until the overall study closure process is complete. 
 

 
 
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9.2 Early Termination or Suspension 
Early Termination of a study is the closure of a clinical study that occurs prior to 
meeting all enrollment and/or follow-up visits for all enrolled subjects.  This is 
possible for the whole study or a single center. 
Study Suspension is a temporary postponement of study activities related to 
enrollment and distribution of the product.  This is possible for the whole study 
or a single center. 
9.3 Criteria 
9.3.1 Study Termination or Suspension 
Possible reasons for considering study suspension or premature termination 
of the study may include: 
 Adverse events associated with the system or product under 
investigation which might endanger the safety or welfare of the 
subject 
 Observed/suspected performance different from the product’s design 
intent 
 Decision by Medtronic or regulatory body (where the study is 
operating under regulatory body authority) 
9.3.2 Investigator/Center Termination or Suspension 
Possible reasons for clinical investigator or center termination or suspension 
include but are not limited to: 
 Failure to obtain initial MEC/IRB/Head of Medical Institution 
approval or annual renewal of the study 
 Consistent non-compliance to the clinical investigation plan (e.g. 
failure to adhere to inclusion/exclusion criteria, failure to follow 
subjects per scheduled follow-ups, etc.) 
 Lack of enrollment 
 Noncompliance to regulations and the terms of the Clinical Trial 
Agreement (e.g. failure to submit data in a timely manner, failure to 
follow-up on data queries and monitoring findings in a timely 
manner, etc.) 
 IRB/ MEC suspension of the center 
 Fraud or fraudulent misconduct is discovered (as defined by local 
law and regulations) 
 Investigator request (e.g. no longer able to support the study) 

 
 
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9.4 Procedures 
9.4.1 If Medtronic terminates or prematurely suspends the study:  
 Medtronic will promptly inform the clinical investigators of the termination 
or suspension and the reasons and inform the regulatory authority (ies) 
(where required per regulatory requirements).  
 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.  
 In the case of study termination, the investigator must inform the subjects 
and may inform the personal physician of the subjects to ensure appropriate 
care and follow-up is provided. 
  In the case of a study suspension, subjects already enrolled should 
continue to be followed out of consideration of their safety, rights and 
welfare. 
9.4.2 If the investigator terminates or suspends the study without prior 
agreement of Medtronic: 
 The investigator will promptly inform Medtronic and provide a detailed 
written explanation of the termination or suspension. 
 The investigator will promptly inform the institution (where required per 
regulatory requirements). 
 The investigator will promptly inform the IRB/MEC.  
9.4.3 If the IRB/MEC terminates or suspends its approval of the study: 
 The investigator will promptly inform Medtronic and provide a detailed 
written explanation of the termination or suspension within 5 business 
days. 
 Subject enrollment must stop until the MEC/ IRB suspension is lifted. 
 Subjects already enrolled should continue to be followed in accordance 
with MEC/ IRB policy or its determination that an overriding safety 
concern or ethical issue is involved. 
 The investigator will inform his/her institution (where required per local 
requirements). 
 The investigator will promptly inform the subjects and/or the personal 
physician of the subjects, with the rationale for the study termination or 
suspension. 

 
 
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10 STATISTICAL METHODS AND DATA ANALYSIS  
10.1 Primary Effectiveness Endpoint 
The primary effectiveness endpoint is the rate of subjects free of chronic treatment 
failure at 36 Months. Chronic Treatment Failure is defined as: 
1. Detectable AF outside of the 90 day blanked follow-up period, OR 
2. The occurrence of an AF Intervention (except repeat cryoablation during the 
90 day blanking period) 
 
 
10.2 Primary Safety Endpoint 
 
1. Adverse event (AE) ascertainment and reporting:  AEs for all subjects will be 
ascertained for the full 5 year follow-up interval.  All AEs will be categorized 
using the MedDRA or similar system, tabulated and listed in decreasing 
frequency order. 
a. The primary safety endpoint is the rate of subjects experiencing one or more 
Cryoablation Procedure Event (CPE) through 12 months. The CPE is 
defined as:   
i. A CPE is a device-related or procedure-related serious adverse event 
(SAE) with onset between the time of the subject’s entry into the 
procedure room for the study-specified cryoablation procedure (Day 0) 
through the indicated onset intervals as set out in the following Table 
11: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table 11: Cryoablation Procedure Events 
 
Cryoablation Procedure Events 
(CPEs): 
Onset 
Interval 
Access site complications requiring: 
 Transfusion of 3 or more units or 
 Surgical intervention or 
 Permanent loss or functional 
impairment 
Through  7 
days 
Cardiac damage (including MI) 
except for 
Through  7 
days 
 Pulmonary vein stenosis* 
 
Through  12 
months 
 Atrio-esophageal fistula 
Through  12 
months 
Embolic complications (including 
stroke) 
Through  7 
days 
Arrhythmias 
Through  7 
days 
Persistent phrenic nerve palsy** 
 Through  12 
months 
Death 
Through  7 days 
* CPE will be assessed at the completion of the follow-up visit, as determined 
by CT/MRI Core Lab. 
** CPE will be assessed at the completion of the follow-up as determined by 
chest X-ray (insp/exp) 
 
ii. Pulmonary vein stenosis is defined as > 75% reduction in the baseline 
area at 12 month follow-up. 
iii. Phrenic nerve palsy is defined as abnormal diaphragm excursion as 
demonstrated during the post-cryoablation procedure fluoroscopy. 
iv. CPEs exclude  
1. adverse events that are normal and expected concomitants of 
catheterization and diagnostic and ablation EP procedures, 
such as induced arrhythmia and groin ecchymosis, but only 
IF that AE resolves completely AND involves only routine 
responses such as medication, fluids, compression, 
temporary pacing, or cardioversion. 
2. Atrial fibrillation or atrial flutter occurring during post-
procedural hospitalization. 
v. CPEs will be accrued for Retreated Subjects for the comparable 7 day 
period following a repeat cryoablation. 
 

 
 
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2. Primary safety endpoint:  The primary safety endpoint is the rate of subjects 
experiencing a CPEs through 12 months. 
3. Adjudication:  All potential CPEs, MAFEs, device-related AEs, procedure-
related AEs, SAEs and UADEs will be reviewed and adjudicated by the AEAC. 
 
 
10.3 Analysis Sets 
Enrolled Set: any patients who have a signed informed consent. 
Intent-To-Treat Set: any enrolled subjects who meet all inclusion and 
exclusion criteria. 
mITT (modified intent-to-treat) Set: any subjects with a Arctic Front® 
Cardiac CryoAblation Catheter System inserted into the vasculature for the 
purpose of this study. 
 
10.4 Sample Size Justification 
10.4.1 
Primary Effectiveness Endpoint 
Sample size was estimated using SAS V9.2 Proc Power. The sample size was 
calculated under an asymptotic z- test for a single binomial proportion with a 
continuity adjustment under the following assumptions: 
 
 Power = 90% 
 Significance level = 0.025 (one-sided) 
 Assumed underlying effectiveness rate = 55% 
 Performance goal = 45% 
 
Long-term (> 12 months) effectiveness of pulmonary vein isolation for the 
treatment of atrial fibrillation ranges from 44-70%, with 40% reported as the 
minimum goal by physicians.1 Shah et al reported that the annual rate of atrial 
fibrillation recurrence after one year was 8.8% and Tzou et al reported a similar 
annual rate of  7%.2,3 Based on the STOP AF results and assuming an annual rate 
of atrial fibrillation recurrence of 7-9%, the estimated effectiveness rate at 36 
months would be approximately 55%. The performance goal of 45% was 
determined from the lower bound of 95% CI for the primary effectiveness rate in 
STOP AF study. 
 
If the underlying effectiveness rate is assumed 55%, a total of 270 evaluable 
subjects will be required to provide 90% power to meet this effectiveness 
objective. 

 
 
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10.4.2 
Primary Safety Endpoint 
Sample size was estimated using SAS V9.2 Proc Power. The sample size was 
calculated under an asymptotic z- test for a single binomial proportion with a 
continuity adjustment under the following assumptions: 
 
 Power = 90% 
 Significance level = 0.025 (one-sided) 
 Assumed underlying primary safety event rate = 6% 
 Performance goal = 14.8% 
 
The performance goal 14.8% was determined on based on STOP AF study. If the 
underlying safety event rate is assumed 6%, a total of 141 mITT subjects will be 
required to provide 90% power to meet this safety objective. 
 
10.4.3 
Overall Sample Size 
In order to adequately power for both the primary effectiveness and safety 
hypotheses, we require a sample size of 270 evaluable subjects to complete 36 
months of follow-up. We estimate that the attrition rate will be approximately 
10% per year for the duration of the 5 year follow-up period. Therefore the final 
sample size required to achieve 270 subjects followed for 36 months and 
account for attrition (i.e. 10% per year) is 370 mITT subjects with procedure 
attempts. It is expected up to 400 subjects will need to be enrolled to ensure 370 
mITT subjects with procedure attempts assuming a small number of subjects 
who are enrolled will not undergo a procedure. 
 
10.5 Statistical Analysis Methods 
A Statistical Analysis Plan (SAP) will be developed to provide details for all 
planned statistical analysis. The primary analyses will be conducted when all 
subjects reach their required follow-up. 
10.5.1 
General Statistical Considerations 
All analyses will be performed using SAS statistical software (SAS Institute Inc, 
Cary, NC). It is planned that the data from all centers that participate in this 
protocol will be combined for analysis. 
Descriptive statistics includes but is limited to number of non-missing 
observations, mean, standard deviation, median, minimum, and maximum for 
continuous variables and count and percentage for categorical variables. Unless 
otherwise specified, the analysis will be performed using descriptive statistics.  

 
 
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10.5.2 
Pooling of Study Centers for Analysis 
A study center is defined as a treatment administration site or group of treatment 
administrative sites under the control and supervision of the same Principal 
Investigator. Each study center will be limited to enrolling no more than 50 
subjects into the mITT set.   Each center will be encouraged to enroll at least 10 
subjects into the mITT set. This will prevent any single center from contributing 
a significant proportion of the subjects to the study. While every effort will be 
made to acquire similar enrollment from all participating centers, it is likely that 
some centers may enroll small numbers of subjects.   Therefore the centers that 
enroll at most five subjects will be polled into a super center. The participating 
centers with more than five subjects enrolled will be reported individually. 
10.5.3 
Subject Disposition 
Subject disposition (screened, analysis set allocation, discontinued along with 
primary reason for discontinuation) will be summarized using frequency and 
percent.  A summary of patients enrolled by site will be provided.  
10.5.4 
Analysis of Baseline and Demographic Characteristics 
The baseline and demographic variables of interest will be summarized using 
descriptive statistics. The baseline and demographic characteristics include but 
not limited to age, sex, race, height, weight, body mass index, medical history, 
comorbid conditions, cardiovascular medication history and concomitant 
medications. Analysis of baseline and demographic characteristics will be 
conducted for all analysis sets. 
10.5.5 
Analysis of Primary Endpoints 
The study will be considered a success if both primary effectiveness and safety 
objectives are met at one-sided 0.025 level of significance in the final analysis. 
The analysis will conducted using the mITT set.  
 
Primary Effectiveness Analysis 
The following hypothesis will be tested in a one-sided test at the 0.025 
significance level. 
 
Ho: Pe ≤ 45% 
Ha: Pe > 45% 
 
Where Pe is the probability of chronic treatment success at 36 Months and 45% is 
the pre-specified performance goal based on the lower bound of 95% CI for the 
primary effectiveness rate in STOP AF study.  

 
 
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Kaplan-Meier method will be used to estimate the probability of chronic 
treatment success at 36 months follow-up.  The standard error will be 
approximated using Greenwood's formula. A two-sided 95% log-log confidence 
interval for the probability will be constructed.  The Kaplan-Meier estimate and 
its 95% log-log confidence interval will be constructed from the day of protocol 
specified ablation procedure (Day 1) through the end of follow-up. For subjects 
with a treatment failure, the days of follow-up will be computed as the days from 
Day 1 to the failure date. For subjects without failure events, days of follow-up 
will be computed as the days from Day 1 through the last follow-up. For subjects 
who are lost to follow-up, the last contact date will be used as the last follow-up 
date. If the lower bound of this 95% log-log confidence interval is greater than the 
performance goal of 45%, we can conclude the primary effectiveness objective is 
met. 
 
Primary Safety Analysis 
The primary safety endpoint is the occurrence of any cryoabalation procedure 
events (CPE) through 12 month follow-up. A CPE is a device-related or 
procedure-related serious adverse event (SAE) with onset between the time of the 
subject’s entry into the procedure room for the study specified cryoablation 
procedure (Day 1) through the indicated follow-up intervals as set out in Table 
Table 11. 
 
The parameter of interest is the probability of subjects experiencing one or more 
CPE through the 12 month follow-up. The following hypothesis will be tested in a 
one-sided test at the 0.025 significance level: 
 
Ho: Ps ≥ 14.8% 
Ha: Ps < 14.8% 
 
Where Ps is the probability of subjects with one or more CPE and 14.8% is the 
pre-specified performance goal based on the upper bound of 95% CI for the 
primary safety rate in the STOP AF study. 
Kaplan-Meier method will be used to estimate the probability of a subject 
experiencing one of more CPE at 12 months follow-up.  The standard error will 
be approximated using Greenwood's formula. A two-sided 95% log-log 
confidence interval for the probability will be constructed.  The Kaplan-Meier 
estimate and its 95% log-log confidence interval will be constructed from the day 
of study specified cryoablation procedure (Day 1) through the end of follow-up. 
For subjects with safety events, the days of follow-up will be computed as the 
days from Day 1 to the onset date of the first safety event. For subjects without 
safety events, days of follow-up will be computed as the days from Day 1 through 
the last follow-up. For subjects who are lost to follow-up, the last contact date will 
be used as the last follow-up date. If the upper bound of this 95% log-log 

 
 
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confidence interval is less than the performance goal 14.8%, we can conclude the 
primary safety objective is met. 
 
10.5.6 
Analysis of Secondary Endpoints 
The analyses of secondary endpoints are intended to provide additional 
information on the performance of Arctic Front® Cardiac CryoAblation 
Catheter System. All secondary analyses will be exploratory and no formal 
hypotheses tested.  
 
Effectiveness Objectives 
 The probability of subjects free of chronic treatment failure at the 1, 2, 4 
and 5 year follow-up visits will be estimated using Kaplan-Meier method.  
The standard error will be approximated using Greenwood's formula. A 
two-sided 95% log-log confidence interval for the proportion will be 
constructed. This calculation will be based on the mITT Set. 
 
Safety Objectives 
a. The probability of subjects free of MAFE at the 1, 2, 3, 4 and 5 year follow-
up visits will be estimated using Kaplan-Meier method.  The standard error 
will be approximated using Greenwood's formula. A two-sided 95% log-log 
confidence interval for the proportion will be constructed. The analysis will 
be conducted in the mITT set. 
. 
i. Major Atrial Fibrillation Event (MAFE):  A MAFE is a serious 
adverse event (SAE) — which has not been categorized as a CPE—
as set out in the following table: 
 
Table 12: Major Atrial Fibrillation Events 
 
Major Atrial Fibrillation Events (MAFEs): 
Cardiovascular deaths 
Hospitalizations for (primary reason): 
   AF recurrence or ablation 
   Atrial flutter ablation (excluding Type I) 
   Systemic embolization (not stroke) 
   Congestive heart failure 
   Hemorrhagic event (not stroke) 
   Antiarrhythmic drug:  initiation, adjustment or 
complication 
Myocardial infarction (MI) 
Stroke 

 
 
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b. Long Term Safety Outcomes:  Device and procedure related events, serious 
adverse events, unexpected adverse device effects and other safety 
categories will be collected through the 5 year follow-up, analyzed and 
reported descriptively.  
 
Cryoablation 
 Cryoablation procedure parameters such as total number of cryoablation 
attempts, mean number of cryoablation attempts per attempted subject and 
number of successful cryoablations per subject will be summarized using 
descriptive statistics. 
 Cryoablation temperature and ablation procedure time will be summarized 
using descriptive statistics. 
 
Procedure and Fluoroscopy Time 
 Total procedure time defined as the period from puncture of the skin 
performed to obtain venous access for catheter placement to final ECG at 
end of procedure will be analyzed using descriptive statistics. 
 Total fluoroscopy time will be analyzed using descriptive statistics. 
 
Other 
 All adverse events will be summarized by presenting the number and 
percentage of subjects having any AE, having an AE in each body system, 
and having each individual AE. Any other information collected (e.g., 
seriousness, severity or relatedness to device/procedure) will be presented 
as appropriate. 
 
10.6 Interim Patient Safety Monitoring 
No interim analysis of data for the primary endpoints is planned before the 
required primary safety and effectiveness follow-ups are completed.  
 
11 DATA AND QUALITY MANAGEMENT 
Data will be collected using an electronic data management system for clinical 
trials. CRF 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. Study 
management reports may be generated to monitor data quality and study progress. 
At the end of the study, the data will be frozen and will be retained indefinitely by 
Medtronic.  

 
 
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Procedures in the Clinical Investigation Plan require source documentation. In some 
cases, items on CRFs may be considered source as long as there is evidence of the 
visit in the subject’s record. Even when the CRF may be considered as source, an 
alternate method of source documentation is always strongly encouraged.  
CryoConsole data from transmissions may be uploaded to secure servers. Upon 
receipt, this data will be maintained with databases and retrieved for analysis and 
reporting. 
The sponsor or a regulatory authority may audit the study center to evaluate the 
conduct of the study. The clinical investigator(s)/institution(s) shall allow trial 
related monitoring, audits, Ethics Board review, and regulatory inspection(s) by 
providing direct access to source data/documents.  
 
12 WARRANTY/INSURANCE INFORMATION 
12.1 Warranty  
Warranty information is provided in the product packaging for the Arctic 
Front® Cardiac CryoAblation Catheter as well as the Freezor MAX catheter and 
Cryoconsole.  Additional copies are available upon request. 
13 MONITORING  
It is the responsibility of Medtronic to ensure proper monitoring of the study per 
regulations.  Appropriately trained Medtronic personnel or delegates appointed by 
Medtronic will perform study monitoring at the study center in order to ensure that 
the study is conducted in accordance with the Clinical Investigation Plan, the 
Clinical Trial Agreement, and applicable regulatory requirements. Medtronic must 
therefore be allowed access to the subjects’ case histories (clinic and hospital 
records, and other source data/documentation) when so requested as per the Subject 
Informed Consent, Privacy Authorization (US only) and Clinical Trial Agreement. 
 
13.1 Monitoring Visits 
Frequency of monitoring visits will occur based on subject enrollment, duration of 
the study, study compliance, findings from previous monitoring visits and any 
suspected inconsistency in data that requires investigation. Regulatory documents 
(e.g., IRB/MEC approval letters, etc.) may be reviewed at each study center.  
Monitoring visits will be conducted periodically to assess site study progress, the 
investigator’s adherence to the Clinical Investigation Plan, 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 facilitate site regulatory and study compliance by identifying 
findings of non-compliance and communicating those findings along with 

 
 
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recommendations for preventative/corrective actions to site personnel.   Monitors 
may work with study personnel to determine appropriate corrective action 
recommendations and to identify trends within the study or at a particular center.  
 
 
14 REQUIRED RECORDS AND REPORTS 
 
14.1 Investigator Records 
The investigator 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 case report forms, should be kept in the Investigator Site File (i.e., the study 
binder provided to the investigator) or Subject Study Binder. CRFs may be 
maintained and signed electronically within the electronic data capture system 
during the trial. The following records are subject to inspection and must be 
retained for a period of two years (or longer as local law or hospital 
administration requires) after product approval or the date on which the 
investigation is terminated or the date that the records are no longer required for 
purposes of supporting a pre-market approval application. 
 All correspondence between the IRB/MEC/HOMI, sponsor, monitor, FDA 
and/or other regulatory bodies, and/or the investigator that pertains to the 
investigation, including required reports 
 Subjects’ case history records, including:  
o Signed and dated informed consent form 
o Observations of adverse events/adverse device effects 
o Medical history 
o Procedure and follow-up data 
o Documentation of the dates and rationale for any deviation from 
the protocol 
o Documentation of the dates and rationale for any deviation from 
the protocol 
 Signed and dated CRFs 
 Device Disposition Records 
 All approved versions of the Clinical Investigation Plan  
 Report of Prior Investigation Summary (in geographies where distributed)  
 Signed and dated Clinical Trial Agreement 
 Current curriculum vitae of all participating investigators  
 Delegated Tasks List 

 
 
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 IRB/MEC approval documentation including written information that the 
investigator or other study staff, when member of the IRB/MEC, did not 
participate in the approval process 
 Study training records for center staff. 
 Any other records that FDA and local regulatory agencies require to be 
maintained. 
 Final Report of the clinical investigation prepared and distributed by the 
sponsor  
 Final investigator report prepared by center and submitted to their 
IRB/MEC Investigator Reports 
 
14.2 Investigator Reports 
The investigator is responsible for the preparation (review and signature) and 
submission to the sponsor of all case report forms, adverse events and adverse 
device effects (reported per the country-specific collection requirements), 
deaths, and any deviations from the investigation plan.  If any action is taken by 
an IRB/MEC with respect to this clinical study, copies of all pertinent 
documentation must be forwarded to Medtronic in a timely manner. Reports are 
subject to inspection and to the retention requirements as described above for 
investigator records.  
Investigator requirements for the reporting of safety data are listed in Section 7.  
The investigator shall prepare and submit in a complete, accurate and timely 
manner the reports listed in this section. 
 
Table 13: Investigator Reports for all Geographies per Medtronic requirements 
Report 
Submit To 
Description/Constraints 
Withdrawal of 
IRB/MEC approval 
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.  CFR 812.150(a)(2)) 
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.  

 
 
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Final Report 
IRBs/MECs 
Relevant 
Authorities 
This report must be submitted within 3 months of 
study completion or termination. 
Adverse Events 
 
Refer to Section 7 
 
 
Table 14: Investigator Reports Applicable to the United States per FDA Regulations 
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 (3)).   
Study deviations  
Sponsor and 
IRB/MEC 
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.  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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14.3 Sponsor Records 
Medtronic shall maintain the following accurate, complete, and current records: 
 All correspondence which pertains to the investigation 
 Investigational device traceability records 
 Signed Investigator Trial Agreements, financial disclosure and current 
investigator curriculum vitae (signed and dated Europe only), Delegated 
Tasks List 
 All case report forms and supporting documentation submitted by 
investigator, samples of consent forms, and other information provided to 
the subjects 
 Copies of all IRB/MEC approval letters and relevant IRB/MEC 
correspondence 
 Names of the institutions in which the clinical investigation will be 
conducted 
 Correspondence with authorities as required by national legislation 
 Forms for reporting any adverse events and adverse device effects 
 ECA/MEA only: Names/contact addresses of monitors  
 Statistical analyses and underlying supporting data. 
 Final report of the clinical investigation 
 The Clinical Investigation Plan, Investigator Brochure/Report of Prior 
Investigations Summary and study related reports 
 Study training records for site personnel and Medtronic personnel involved 
in the study 
 ECA/MEA only: Insurance certificates  
 Any other records that local regulatory agencies require to be maintained 
 
 
14.4 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. 
Safety data Medtronic reporting requirements are listed in Section 7.8. 
Medtronic records and reports will be stored in locked file cabinets at Medtronic 
during the course of the study. Electronic versions of the reports will be kept on 
a password-protected document management system.  After closure of the study, 
all records and reports will be archived indefinitely. 

 
 
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Table 15: Sponsor Reports for Canada 
Report 
Submit To 
Description 
Premature 
termination or 
suspension of the 
clinical 
investigation 
Investigators 
IRB/MEC Relevant 
authorities 
Head of the Institution
Provide prompt notification of termination or 
suspension and reason(s). (ISO 14155-
1:2003(E)(k))  
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)) 
Recall and device 
disposition 
Investigators Head of 
Institution IRB/MEC 
relevant authorities 
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)) 
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 14155-1:2003(E)(h)) 
Site specific study deviations will be submitted to 
investigators quarterly.   
 
 
 
 
 
 

 
 
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Table 16: Sponsor Reports for the United States 
Report 
Submit To 
Description 
Premature termination 
or suspension of the 
clinical investigation 
Investigators 
 IRB/MEC 
Relevant authorities 
Head of the Institution 
Provide prompt notification of termination or 
suspension and reason(s). (ISO 14155-
1:2003(E)(k)), (MHLW Ordinance 36, 
Article 32)  
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)) 
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 
FDA 
Progress reports will be submitted at least 
annually.  (21 CFR 812.150(b)(4)(5), 
812.36(f)   
Recall and device 
disposition 
Investigators 
Head of Institution 
IRB/MEC 
relevant authorities 
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.  
(ISO 14155-1:2003(E)(h)) 
Site specific study deviations will be 
submitted to investigators quarterly.   
 
 

 
 
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Table 17: Study Milestones/Timeline 
Milestone 
Timeline 
Estimated date of study initiation 
November 2011 
Estimated monthly number of study sites with IRB 
approval 
4-5* 
Estimated number of subjects enrolled per month 
35** 
Estimated date of enrollment completion 
March 2013 
Estimated date of study follow-up completion 
March 2018 
Estimated date for Final Report submission 
June 2018 
* Number of sites to obtain IRB approval per month during study initiation 
** This enrollment rate assumes all sites are approved to enroll.

 
 
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Appendix A:  Protocol Acronyms and Abbreviations 
 
AE 
adverse event 
AF 
atrial fibrillation 
AFD atrial fibrillation drug 
APS 
acute procedural success 
CPE 
cryoablation procedure event 
CRF 
case report form 
CT 
computed tomography 
CTF 
chronic treatment failure 
ECG electrocardiogram 
EP 
electrophysiology 
FDA Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption 
INR 
international normalized ratio 
IRB 
Institutional Review Board  
IVC  inferior vena cava 
LA  
left atrium or left atrial 
MAFE major atrial fibrillation event 
MRI  magnetic resonance imaging 
NYHA New York Heart Association 
PAF  paroxysmal atrial fibrillation 
PPM permanent pacemaker 
PV  
pulmonary vein 
RA  
right atrium 
RF 
radiofrequency 
TEE  trans-esophageal echocardiography 
TIA 
transient ischemic attack  
TTE  trans-thoracic echocardiography 

 
 
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SAE 
serious adverse event 
SVC  superior vena cava 
UADE unanticipated adverse device effect 
U.S. 
United States 

 
 
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Appendix B: Summary of STOP AF PAS Protocol Changes 
Sponsor 
Approved, Ver 4 18-Aug-2011 
FDA 
Not approved, 20-Jun-2011 
Prior 
Ver 3, 20-Jun-2011 
Section 1 
Section 1.2 Added proportion of total study enrollments required to 
come from new Arctic Front user investigational sites 
Section 2 
No change 
Section 3 
No change 
Section 4 
Section 4.5 Language updated to clarify the number of new Arctic Front 
user investigational sites to be included in the STOP AF PAS and added 
site selection criteria.  
 
Section 5 
No change 
Section 6 
No change 
Section 7 
No change 
Section 8 
No change 
Section 9 
No change 
Section 10 
No change 
Section 11 
No change 
Section 12 
No change 
Section 13 
No change 
Section 14 
No change 
Appendix A 
No change 
Appendix B 
Updated for changes made from Ver 3 to Ver 4. 
 
 
                                                
1 Katritsis D, Wood M, Giazitzoglou E, Shepard R, Kourlaba G, Ellenbogen K. 
Long-term follow-up after radiofrequency catheter ablation for atrial fibrillation. 
Europace. 2008;10:419-424. 
2 Shah A, Mittal S, Sichrovsky T, Cotiga D, Arshad A, Maleki K, Pierce W, 
Steinberg J. Long-term outcome following successful pulmonary vein isolation: 
pattern and prediction of very late recurrence. J Caridiovasc Electrophysiol. 
2008;19:661-667. 
3 Tzou W, Marchlinski F, Zado E, Lin D, Dixit S, Callans D, Cooper J, Bala R, 
Garcia F, Hutchinson M, Riley M, Verdino R, Gerstenfeld E. Long-term outcome 
after successful catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol. 
2010;3:237-242.