Clinical trial NCT03118518
Conditions: Atrial Fibrillation Atrial Fibrillation New Onset
Sponsor: Medtronic Cardiac Ablation Solutions
Start date: 2017-06-23; Completion date: 2020-06-25
Enrollment: 225 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To provide data demonstrating the safety and effectiveness of the Arctic Front Advance™ Cardiac CryoAblation Catheter for the treatment of recurrent symptomatic paroxysmal atrial fibrillation, without the requirement that the subjects be drug refractory.

Detailed description:
Subjects with paroxysmal atrial fibrillation with no history of treatment with anti-arrhythmic drugs are randomized 1:1 to either an anti-arrhythmic drug or pulmonary vein isolation using the cryoballoon catheter.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Cryoablation intervention 2: Antiarrhythmic drug
Intervention descriptions: intervention 1: Pulmonary vein isolation via ablation with cryoballoon catheter intervention 2: Antiarrhythmic drug initiation

Protocol documents:
Prot_005.pdf: 
 
 
Clinical Investigation Plan Title 
STOP AF First 
Clinical Investigation Plan Identifier 
MDT16012AFS001 
Study Product 
Arctic Front Advance™ Cardiac CryoAblation Catheter 
Application Number 
IDE #G1160219 
ClinicalTrials.gov Identifier 
NCT03118518 
Sponsor 
Medtronic 
8200 Coral Sea St NE 
Mounds View, MN  55112 
Document Title 
STOP AF First Clinical Investigation Plan 
Document Version (Date) 
5.0 (05-DEC-2017) 
 


056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 1 of 130 
 
 
Version 5.0  
STOP AF First 
Page 1 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
 
 
Clinical Investigation Plan 
Clinical Investigation Plan/Study Title STOP AF First 
Clinical Investigation Plan Identifier MDT16012AFS001 
Study Product Name Arctic Front AdvanceTM  Cardiac CryoAblation 
Catheter 
Sponsor/Local Sponsor United States of America 
Medtronic, Inc. 
8200 Coral Sea St NE 
Mounds View, MN U.S.A. 55112 
 
Europe 
Medtronic, Bakken Research Center B.V. 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
Document Version Version 5.0, 05DEC2017 
Lead Principal Investigator Oussama Wazni, MD 
Cleveland Clinic 
9500 Euclid Ave, 
Cleveland, OH 44195 
Coordinating Investigators Gopi Dandmudi, MD 
Indiana University Krannert Institute of Cardiology 
1801 N. Senate Blvd, Suite 4000 
Indianapolis, IN  46202 
 
Steve Nissen, MD 
Cleveland Clinic 
9500 Euclid Avenue 
Cleveland, OH  44195 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Medtronic.  
Any distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly 
prohibited.  Persons to whom the information is disclosed must know that it is confidential and that it 
may not be further disclosed by them. 
 
 














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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 13 of 130 
 
 
Version 5.0  
STOP AF First 
Page 13 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
Table 13: Sponsor reports for Europe ............................................................................................... 110 
Table 14: Foreseeable Adverse Events ............................................................................................. 125 
Table 15: Arctic Front and Arctic Front Advance™ Complications Reported in Literate for Paroxysmal and 
Persistent AF Patients ...................................................................................................................... 127 
 
Listing of Figures 
Figure 1:  Study Design ..................................................................................................................... 32 
Figure 2: Arctic Front AdvanceTM Cardiac Cryoablation Catheter ........................................................... 37 
Figure 3: FlexCath AdvanceTM Steerable Sheath with Cryoablation Catheter .......................................... 38 
Figure 4: Achieve™ Mapping Catheter ................................................................................................ 39 
Figure 5: CryoCath CryoAblation Console ............................................................................................ 39 
Figure 6: Coaxial Umbilical Cable ....................................................................................................... 40 
Figure 7: Electrical Umbilical Cable ..................................................................................................... 40 
Figure 8: Manual Retraction Kit .......................................................................................................... 41 
 
Listing of Appendices 
Appendix A: CRYOBALLOON SAFETY DATA LITERATURE SEARCH...................................................... 118 
Appendix B: DRAFT DATA COLLECTION ELEMENTS (CASE REPORT FORMS) ...................................... 121 
Appendix C: INFORMED CONSENT FORM TEMPLATE ........................................................................ 122 
Appendix D: PARTICIPATING INVESTIGATOR AND INSTITUTIONS .................................................... 123 
Appendix E: IRB LIST ...................................................................................................................... 124 
Appendix F: FORESEEABLE ADVERSE EVENTS .................................................................................. 125 
Appendix G: PRE-CLINICAL TESTING ............................................................................................... 130 
 
 
 












056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 19 of 130 
 
 
Version 5.0  
STOP AF First 
Page 19 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
3. Synopsis 
Title 
STOP AF First 
Clinical Study Type 
Pivotal (US)/ Post-market interventional (Europe) 
Product Name 
Arctic Front AdvanceTM Cardiac CryoAblation Catheter 
Sponsor  
United States of America 
Medtronic, Inc. 
8200 Coral Sea St NE  
Mounds View, MN U.S.A. 55112 
Local Sponsor 
Europe 
Medtronic, Bakken Research Center B.V. 
Endeplosdomein 5 
6229 GW Maastricht 
The Netherlands 
Indication Under 
Investigation  
Current indication in the US:  The Arctic Front Advance™ Cardiac 
CryoAblation Catheter is indicated for the treatment of drug refractory 
recurrent symptomatic paroxysmal atrial fibrillation. 
Indication under investigation for the US:  The Arctic Front Advance™ 
Cardiac CryoAblation Catheter is indicated for the treatment of recurrent 
symptomatic paroxysmal atrial fibrillation. 
The indication under investigation is within the approved indication in 
Europe. 
Investigation Purpose 
The purpose of the study is to provide data demonstrating the safety 
and effectiveness of the Arctic Front Advance™ Cardiac CryoAblation 
Catheter for the treatment of recurrent symptomatic paroxysmal AF, 
without the requirement that the subjects be drug refractory.  
Product Status 
The Arctic Front Advance™ Cardiac CryoAblation Catheter is market 
released and will become investigational when used as indicated in the 
study in the US.  The catheter is market released and will be used within 
the approved indications in Europe, therefore is not considered 
investigational for the intended patient population in Europe.   
Primary Objective 
Primary Efficacy Objective: 
Demonstrate the superiority of cryoballoon ablation as compared to 
antiarrhythmic drug (AAD) therapy in terms of the rate of freedom from 
AF/AT/AFL in a non-drug refractory paroxysmal AF population. 
 


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Primary Safety Objective: 
Demonstrate an acceptable safety profile of the cryoballoon ablation 
procedure as a first line therapy in a non-drug refractory paroxysmal AF 
population. 
Secondary Objectives 
Secondary Objectives are as follows: 
1. Assess changes in quality of life (QoL) between baseline and 12 
months in the cryoballoon ablation arm.     
2. Compare health care utilization (HCU) between the treatment 
and control arms.   
 
 
 
 
 
  
 
 
 
 
 
 
 
  
Primary Endpoint 
Primary Efficacy Endpoint: 
The primary endpoint is treatment success at 12 months after AAD 
initiation (control arm) or after the pulmonary vein isolation ablation 
procedure utilizing the Arctic Front Advance™ Cardiac CryoAblation 
Catheter (treatment arm).  A treatment success is the opposite of a 
treatment failure. 
Treatment failure is defined as any of the following components: 
• Acute procedural failure (treatment arm only) 
• Documented AF/AT/AFL on ambulatory monitoring/12-lead 
ECG after the 90 day post-ablation blanking period 
(treatment arm)/AAD optimization period (control arm) 
o 
Minimum of 30 seconds on ambulatory monitoring or 10 
seconds on 12-lead ECG. 
o 
Note: Documented occurrence and treatment of typical 
right-sided cavotricuspid isthmus dependent atrial flutter 
is not considered a failure if confirmed by entrainment 
maneuvers during EP testing. 
• Any subsequent AF surgery or ablation in the left atrium.   
• Any subsequent cardioversion after the 90 day post-ablation 
blanking period (treatment arm)/AAD optimization period 
(control arm). 
• Class I or III antiarrhythmic drug (or sotalol) use after the 90 
day blanking period (treatment arm only). 
The AAD optimization period is defined as the first 90 days after AAD 
initiation (control arm).  The post-ablation blanking period is defined as 
the first 90 days after the index ablation procedure (treatment arm).  


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Recurrences of atrial arrhythmias during the AAD optimization/blanking 
periods will not be counted in the determination of the first clinical 
failure for the primary endpoint.   
Within the AAD optimization period/post-ablation blanking period, 
recurrent arrhythmias can be managed with medications or 
cardioversions.  Reablation will be considered a primary endpoint failure 
at all times, including during the 90 day post-ablation blanking period. 
Acute procedural failure (treatment arm only) is defined as: 
a) Inability to isolate all accessible targeted pulmonary veins 
(assessed for entrance block and, where assessable, exit block) 
during the index ablation procedure. 
b) Left atrial non-PVI ablations including but not limited to, ablation 
of linear lesions  
c) Use of a non-study device in the left atrium. 
 
Primary Safety Endpoint: 
The following adverse events will be counted towards the primary safety 
endpoint:  
• 
Transient Ischemic Attack (TIA)within 7 days 
• 
Cerebrovascular accident within 7 days 
• 
Major bleeding that requires transfusion or results in a 20% or 
greater fall in hematocrit (HCT) within 7 days 
• 
Development of a significant pericardial effusion within 30 days.   
A significant pericardial effusion is one that results in 
hemodynamic compromise, requires elective or urgent 
pericardiocentesis, or results in a 1-cm or more pericardial 
effusion as documented by echocardiography.  
• 
Symptomatic PV stenosis within 12 months; accompanied by 
one of the following: 50%-70% reduction in diameter of the 
pulmonary vein, with symptoms not explained by other 
conditions; OR >70% reduction in diameter of the pulmonary 
vein  
• 
MI within 7 days 
• 
PNI unresolved at 12 months 
• 
AE fistula within 12 months 
• 
Major vascular complication that requires intervention, prolongs 
the hospital stay, or requires hospital admission (within 7 days).   
Secondary Endpoints 
1. The difference in composite scores from the AFEQT 
questionnaire taken at baseline and 12 month visits, and the 
difference in composite scores for the EQ-5D questionnaire 
taken at baseline and 12-month visits.  
2. 12-month rates of cardiovascular HCU events, and 12-month 
rates of cardioversion (either electrical or pharmacological).  
 
 
 
 
 


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Study Design 
Prospective, interventional, multi-center, randomized, controlled, 
unblinded clinical study. 
The study will be conducted at up to 30 sites in the US and up to 10 in 
Europe. 
Study Duration 
All randomized study subjects will be followed from the time of consent 
through 12 months post-index cryoballoon ablation procedure 
(treatment arm), or AAD initiation (control arm). 
Subjects will be exited from the study at the conclusion of the 12 month 
follow-up visit.  The expected total study duration is approximately 30 
months, representing 18 months of enrollment and 12 months of subject 
follow-up.  
Sample Size 
210 enrolled subjects in the US and Europe. 
Inclusion/Exclusion 
Criteria 
The following is a list of inclusion/exclusion criteria: 
Inclusion criteria 
• 
A diagnosis of symptomatic paroxysmal AF with the following 
documentation: (1) physician’s note indicating recurrent self- 
terminating AF or paroxysmal AF; and (2) any ECG documented 
AF within 6 months prior to enrollment.  
• 
Age 18-80 
Exclusion criteria 


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• 
History of AF treatment with class I or III antiarrhythmic drug, 
including sotalol, with the intention to prevent an AF recurrence.  
However, patients pretreated with above AAD for less than 7 
days with the intention to convert an AF episode are allowed.  
• 
Prior persistent AF (continuous AF that is sustained  >7 days) 
• 
Left atrial diameter greater than 5.0 cm 
• 
Prior left atrial ablation or left atrial surgical procedure 
• 
Presence or likely implant of a permanent pacemaker, 
biventricular pacemaker, loop recorder, or any type of 
implantable cardiac defibrillator (with or without biventricular 
pacing function) 
• Presence of any pulmonary vein stents 
• 
Known presence of any pre-existing pulmonary vein stenosis 
• 
Pre-existing hemidiaphragmatic paralysis 
• 
Presence of any cardiac valve prosthesis 
• 
Moderate or severe mitral valve regurgitation or stenosis  
• 
Any cardiac surgery, myocardial infarction, PCI / PTCA or 
coronary artery stenting which occurred during the 90 day 
interval preceding the date the subject signed the Informed 
Consent Form 
• 
Unstable angina 
• 
NYHA class III or IV congestive heart failure and/or known left 
ventricular ejection fraction (LVEF) less than 45%  
• 
Diagnosis of primary pulmonary hypertension 
• 
Rheumatic heart disease 
• 
Thrombocytosis, thrombocytopenia 
• 
Contraindication to anticoagulation therapy 
• 
Active systemic infection 
• 
Hypertrophic cardiomyopathy 
• 
Cryoglobulinemia 
• 
Known reversible causes of AF, including but not limited to 
uncontrolled hyperthyroidism, severe obstructive sleep apnea, 
and acute alcohol toxicity. 
• 
Any cerebral ischemic event (strokes or TIAs) which occurred 
during the 180 day interval preceding the date the subject 
signed the Informed Consent Form, or any known unresolved 
complications from previous stroke/TIA 
• 
Existing thrombus 
• 
Pregnancy 
• 
Patient with life expectancy that makes it unlikely 12 months of 
follow-up will be completed.   
• 
Current or anticipated participation in any other clinical trial of a 
drug, device or biologic during the duration of this study not 
pre-approved by Medtronic 
• 
Patients with contraindications to a Holter monitor 
• 
Unwilling or unable to comply fully with study procedures and 
follow-up 


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before ablation may be attempted.  Pharmacological therapy for AF (paroxysmal and persistent) has 
limited antiarrhythmic efficacy, with recurrence of AF reported at 44% to 67% within one year, based on 
a systematic review of 45 randomized controlled clinical trials (Lafuente-Lafuente, Mouly, et al. 2006).  
Treatment with AADs may also result in an increased risk for adverse events. Results of an AFFIRM sub 
study showed that adverse events resulting in discontinuation of the treatment were common for AADs, 
occurring in 11.1% to 28.1% of patients, depending on the AAD used (AFFIRM First Antiarrhythmic Drug 
Substudy Investi. 2003).  The RAAFT-2 study found that AAD’s had a success rate of 42% at one year in 
61 previously treatment-naive paroxysmal AF patients; meanwhile, the 2014 AHA/ACC/HRS guideline for 
the management of patients with AF stated that “much like other antiarrhythmic drugs, with the 
exception of amiodarone, the rates of maintaining sinus rhythm at 1 year for sotalol are 30 -50%” 
(January et. al. 2014) (Morillo, et al. 2014). 
Atrial fibrillation is known to cause electrical remodeling of the atria as well as structural changes that 
promote perpetuation and progression of symptoms (Wijesurendra and Casadei 2015) (Shulka and Curtis 
2014) (Jalife and Kaur 2015).  Untreated PAF can give rise to persistent or permanent forms of the 
disease (De Vos, et al. 2010), which may be more resistant to contemporary AF treatments (Oral, et al. 
2002) (Romero, et al. 2015).  As such, early and effective intervention is key for normalizing sinus rhythm 
(SR) and preventing further remodeling and disease progression (Nattel, et al. 2014) (Cosio, et al. 2008).  
AAD treatments have little to no effect on remodeling (Nattel, et al. 2014) and although may restore SR 
in the short-term, have high long-term relapse rates (45-90%) (Cosio, et al. 2008) making this treatment 
largely ineffective at preventing progression of AF.  By contrast, early evidence seems to indicate that 
catheter ablation may reverse indicators of structural remodeling associated with AF (Walters, et al. 
2016) (Wu, et al. 2016).  Furthermore, catheter ablation, particularly using the Arctic Front Advance™ 
Cardiac CryoAblation Catheter, hereafter also referred to as the cryoballoon, has a much higher efficacy 
rate and may be even more effective when provided earlier after AF onset (Arena, et al. 2016) (Tanner, 
et al. 2011). 
Catheter ablation treatment strategies for AF have evolved over time and currently include pulmonary 
vein isolation (PVI) as a cornerstone of ablation therapy in all types of AF (paroxysmal and persistent) 
(Raviele 2012) (Jais, et al. 2006).  AF arises primarily from the left side of the heart in (or near) the 
atrium, particularly where the pulmonary veins (PVs) join the atrium.  The fundamental basis for the AF 
ablation procedure is the creation of myocardial lesions that block the propagation of AF wave fronts from 
the triggering source.  The muscular sleeves within the PVs have been established as a critical source of 
AF triggers (Caulkins and et. al. 2007). 
The safety profile of cryoballoon ablation is also well established. The STOP AF trial (Packer, et al. 2013) 
was a prospective, multicenter, randomized, controlled investigation device exemption (IDE) study 
designed to compare outcomes of cryoballoon and antiarrhythmic drug therapies in patients with PAF.  
Six point one percent (6.1%) of cryoballoon subjects experienced a procedure-related event or major 
adverse event versus 8.5% of AAD subjects.  An analysis of 149 cryoballoon studies with 11,242 patients 
(see Appendix A for literature search methodology) showed similar complication rates to STOP AF. 
The STOP AF Post Approval Study was designed to provide long-term safety and effectiveness of the 
Arctic Front and Arctic Front Advance™ Cardiac Cryoablation Catheter System, including the Freezor® 
MAX Cardiac cryoablation catheter according to the Product Labeling.  Inexperienced users were selected 
as study Investigators in order to understand complication rates in a real world setting.  There were 402 
subjects enrolled.  The study is currently in the follow-up phase, with all enrolled subjects having been 
followed for one year post-ablation procedure.  Major procedure related events occurred in 20/341 
patients (5.9% of patients and 5.7% of procedures).  No device or procedure related deaths were 
reported (Knight, et al. 2016). 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
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Page 29 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
5.1.4.2. 
Primary Safety Endpoint 
The following adverse events will be counted towards the primary safety endpoint:  
• 
TIA within 7 days 
• 
Cerebrovascular accident within 7 days 
• 
Major bleeding that requires transfusion or results in a 20% or greater fall in hematocrit (HCT) 
within 7 days 
• 
Development of a significant pericardial effusion within 30 days.   A significant pericardial 
effusion is one that results in hemodynamic compromise, requires elective or urgent 
pericardiocentesis, or results in a 1-cm or more pericardial effusion as documented by 
echocardiography.  
• 
Symptomatic PV stenosis within 12 months; accompanied by one of the following: 50%-70% 
reduction in diameter of the pulmonary vein, with symptoms not explained by other conditions; 
OR >70% reduction in diameter of the pulmonary vein  
• 
MI within 7 days 
• 
PNI unresolved at 12 months 
• 
Atrial-esophageal fistula within 12 months 
• 
Major vascular complication that requires intervention, prolongs the hospital stay, or requires 
hospital admission (within 7 days).   
 
 


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05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
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Page 42 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
NOTE: this is a deviation to Section 9.8 of the ISO standard because device accountability for the Arctic 
Front Advance™ Cardiac CryoAblation Catheters will not be performed in Europe and only upon package 
opening with the intent of using the catheter for a study subject in the US. 
 
 


056-F275, Clinical Investigation Plan Template, Version 2.0 
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05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
8. Investigator/Investigator Center Selection 
All clinical Investigators managing the subject’s arrhythmia must be qualified practitioners and 
experienced in the diagnosis and treatment of subjects with atrial arrhythmias. Investigators performing 
the cryoablation procedure must have been trained in the handling of Arctic Front Advance™ Cardiac 
CryoAblation Catheters. 
 
The role of the Principal Investigator is to implement and manage the day-to-day conduct of the clinical 
investigation as well as ensure data integrity and the rights, safety and well-being of the subjects 
involved in the clinical investigation. 
 
The minimum required criteria for a Principal Investigator and proposed investigational center are listed 
below: 
• 
Investigator/site is qualified by training, education, and relevant experience appropriate to the 
use of the product and associated procedures.   
• 
Investigator/site expects to have adequate time and resources to conduct the study throughout 
the duration of the study. 
• 
Investigator/site has access to an adequate number of eligible subjects.  
• 
Ability to comply with applicable Institutional Review Board (IRB)/Ethics Committee (EC) and 
regulatory requirements. 
• 
Investigator is not debarred, disqualified, or working under sanctions in applicable regions. 
 
Center personnel training will be completed prior to participation in this clinical study. 
 
 


056-F275, Clinical Investigation Plan Template, Version 2.0 
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Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
9. Center Activation 
During the activation process (prior to subject enrollment), Medtronic will train center personnel on the 
CIP, relevant standards and regulations, informed consent, and on data collection and reporting tools. If 
new members join the study center team, they will receive training on the applicable clinical study 
requirements relevant to their role before contributing to the clinical study. 
 
Prior to performing study related activities, all local regulatory requirements shall be fulfilled, including, 
but not limited to the following: 
 
• 
IRB/MEC approval (and membership roster/voting list) of the current version of the CIP, Patient 
Informed Consent Form, subject facing materials, Report of Prior Investigation, Investigator 
Brochure as required by local laws and other materials, as necessary. 
• 
Regulatory authority approval or notification (as required per local law) 
• 
Fully executed Clinical Trial Agreement (CTA) and Investigator Statement where applicable 
• 
Financial Disclosure of Investigators 
• 
Curriculum Vitae (CV) of Investigators and key members of the investigation center team (as 
required by local law) (in Europe, CVs are required for the Principal Investigator and all center 
members who have been delegated tasks) 
• 
Documentation of delegated tasks 
• 
Documentation of study training 
 
Documentation of delegated tasks must be completed prior to any person other than the Principal 
Investigator performing study activities. 
 
Additional requirements imposed by the IRB/MEC and regulatory authority shall be followed. 
 
In addition, all participating center staff must be trained on the current version of the CIP and must be 
delegated by the Principal Investigator to perform study related activities. 
 
Medtronic will provide each study center with documentation of study center/Investigator readiness in the 
form of a center readiness letter; this letter must be received prior to subject enrollment. Additional 
center personnel included after the initial activation will be notified when all requirements have been 
completed. 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 46 of 130 
 
 
Version 5.0  
STOP AF First 
Page 46 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
• Diagnosis of primary pulmonary hypertension 
• Rheumatic heart disease 
• Thrombocytosis, thrombocytopenia 
• Contraindication to anticoagulation therapy 
• Active systemic infection 
• Hypertrophic cardiomyopathy 
• Cryoglobulinemia 
• Known reversible causes of AF, including but not limited to uncontrolled hyperthyroidism, 
severe obstructive sleep apnea, and acute alcohol toxicity. 
• Any cerebral ischemic event (strokes or TIAs) which occurred during the 180 day interval 
preceding the date the subject signed the Informed Consent Form, or any known unresolved 
complications from previous stroke/TIA 
• Existing thrombus 
• Pregnancy 
• Patient with life expectancy that makes it unlikely 12 months of follow-up will be completed. 
• Current or anticipated participation in any other clinical trial of a drug, device or biologic during 
the duration of this study not pre-approved by Medtronic 
• Patients with contraindications to a Holter monitor 
• Unwilling or unable to comply fully with study procedures and follow-up 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 50 of 130 
 
 
Version 5.0  
STOP AF First 
Page 50 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
participate in the study. If relevant, approval may be requested from subjects to confirm their continued 
participation. 
 
Prior to initiation of any study-specific procedures, documented IC must be obtained from the subject (or 
their legally authorized representative, US ONLY). Likewise, privacy or health information protection 
regulation may require subjects to sign additional forms to authorize centers to submit subject 
information to the study sponsor. The IC process must be conducted by the principal Investigator or an 
authorized designee, and the ICF and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law must be given to the 
subject (or their legally authorized representative, US ONLY) in a language he/she is able to read and 
understand. The process of IC must be conducted without using coercion, undue or improper influence 
on, or inducement of the subject to participate by the Investigator or other center personnel. The 
informed consent process shall not waive or appear to waive the subject’s legal rights. The language 
used shall be as non-technical as possible and must be understandable to the subject and the impartial 
witness, where applicable. 
 
The subject must have ample time and opportunity to read and understand the ICF to inquire about 
details of the study, and to decide whether or not to participate in the clinical study. All questions about 
the study should be answered to the satisfaction of the subject. When the subject decides to participate 
in the clinical study, the ICF and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law must be signed and 
personally dated by the subject (or their legally authorized representative, except in Europe) and either 
the Investigator or the Investigator’s authorized designee, as required by local law. If applicable, witness 
shall also sign and personally date the consent form to attest that the information in the ICF was 
accurately explained and clearly understood by the subject, and that IC was freely given. 
 
In Europe, include a personally dated signature by the Principal Investigator or authorized designee 
responsible for conducting the informed consent process. The Principal Investigator or designee must 
conduct the informed consent discussion. 
 
A copy of the ICF and the Authorization to Use and Disclose Personal Health Information/Research 
Authorization/other privacy language as required by law, signed and dated as required by law, must be 
provided to the subject. 
 
If consent is obtained the same day the subject begins participating in study-related procedures, it must 
be documented in the subject’s case history that consent was obtained prior to participation in any study 
related procedures. It is best practice for the IC process to be documented in the subject’s case history, 
regardless of circumstance. In the event the subject cannot read and/or write, a witnessed (impartial 
third party) ICF will be allowed, provided detailed documentation of the process is recorded in the 
subject’s case history and the witness signs and dates the ICF to attest that the information was 
accurately explained and that informed consent was freely given. In Europe, when a subject cannot read 
and/or write, an independent witness shall be present throughout the process, the written ICF and any 
other information shall be read aloud and explained to the prospective subject. The subject should “make 
his mark” (sign or otherwise physically mark the document so as to indicate consent) on the ICF as well. 
The ICF should document the method used for communication with the prospective subject and the 
specific means by which the prospective subject communicated agreement to participate in the study. 
 
 
 


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Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
11.5.3.4. Post-procedure Anticoagulation 
Systemic oral anticoagulation should be initiated on the day of the procedure and is recommended for at 
least two months following an AF ablation procedure.  Decisions regarding the continuation of systemic 
anticoagulation agents more than two months following ablation should be based on the patient’s risk 
factors for stroke as estimated by the CHA2DS2-VASc score and not on the presence or type of AF. 
Discontinuation of systemic anticoagulation therapy post ablation is not recommended in patients who 
are at high risk of stroke as estimated by the CHA2DS2-VASc score. 
11.5.3.5. Diaphragm Movement  
a. Prior to the first cryoablation application, the Investigator will make a fluoroscopic recording 
of inspiratory and expiratory movement of the diaphragm. 
b. Continuous phrenic nerve pacing with abdominal palpitation must be performed for all right 
pulmonary vein cryoapplications and should be considered for all cryoapplications.  
Additional methods of phrenic nerve monitoring are encouraged, such as diaphragmatic 
compound motor action potential (CMAP). 
c. After the last cryoablation application, the Investigator will make a fluoroscopic recording of 
inspiratory and expiratory movement of the diaphragm. 
11.5.3.6. Balloon Pulmonary Vein (PV) Cryoablation 
a. Every effort consistent with subject welfare will be made to treat all PVs or their anomalous 
equivalents. 
b. The catheter will be advanced into the left atrium over the mapping catheter or guidewire 
and inflated.  Once inflated, the catheter will be tracked over the Achieve™ catheter and 
positioned at the entrance of the PV. 
c. Assess the positioning, contact and occlusion of the PV by the catheter’s balloon by 
injection of contrast material, ultrasound imaging, or other technique.  Reposition as 
needed. 
d. Each pulmonary vein must be assessed for entrance block and, where assessable, exit block 
to demonstrate electrical isolation. 
e. It is recommended that the Investigator use cryoapplications of three (3) minutes each.  
Once PV isolation has been achieved, one (1) additional application of three (3) minutes at 
the same PV should be performed; however, it is up to the operator’s discretion to assess 
application time and necessity of the additional freeze given factors such as time to 
isolation of prior application(s), temperature of prior application(s), risk of collateral 
damage, etc. 
f. 
Upon the Investigator’s assessment of procedure completion, isoproterenol and/or 
adenosine may be used to assess pulmonary vein isolation. 


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Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
11.5.3.7. Other Ablations During Index Procedure 
a. Ablation of the cavotricuspid isthmus is required in subjects with a history of typical atrial 
flutter or inducible cavotricuspid isthmus depend atrial flutter.  Complete an assessment for 
bi-directional block if this procedure is performed.  Any commercially released catheter 
deemed appropriate for the procedure may be used. 
 
b. The following are not allowed: 
• Left atrial non-PVI ablations including but not limited to, ablation of linear lesions, complex 
fractionated electrograms or non-PV triggers 
• Ablation using any non-study device in the left atrium 
11.5.3.8. Cardioversion 
a. Electrical or pharmacological cardioversion to sinus rhythm must be attempted following the 
PVI portion of the procedure if sinus rhythm wasn’t restored.  Cardioversion may be 
performed prior to PVI if needed. 
11.5.3.9. Procedure Documentation  
During the procedure the investigator will document the following:  
• Catheters used (i.e. Arctic Front Advance™, Freezor® MAX and Achieve™ Mapping Catheter, 
etc.) 
• Minimum temperature for each cryoapplication 
• Duration of each cryoapplication 
• Vein location for each cryoapplication (e.g. right superior PV) 
• Use of phrenic nerve pacing or other phrenic nerve monitoring technique for each 
cryoapplication, specifically those cryoapplications surrounding the RS and RI PVs 
• Demonstrated electrical block and, if real-time signals are available, time to isolation 
• Adjunctive catheters, mapping or visualization devices, sedation type, procedure information, 
esophageal temperature, ACT, cardioversion use and fluoroscopy time will be collected. 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 59 of 130 
 
 
Version 5.0  
STOP AF First 
Page 59 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
11.5.8.2. Three Month Office Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
Health care utilization assessment- collect information about hospitalizations or emergency 
department visits experienced by the subject since the last visit 
• 
12 lead ECG 
• 
Provide the subject with patient-activated ambulatory monitoring equipment; provide instructions 
for and weekly and symptomatic transmissions. 
• 
Chest X-ray 
o 
For any subject whose post-procedural fluoroscopy demonstrated study-related PNI, a 
follow-up chest X-ray, including inspiration and expiration films, will be performed if the 
PNI was unresolved at the one month visit 
• 
In the case of suspected PV stenosis, Magnetic Resonance Imaging (MRI) or Computerized 
Tomography Scanning (CT scan) is required.  It is not required at this visit if it was already 
completed at an earlier visit and PV stenosis was confirmed.   
11.5.8.3. Six Month Office Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
Health care utilization assessment- collect information about hospitalizations or emergency 
department visits experienced by the subject since the last visit 
• 
12 lead ECG 
• 
24h continuous ECG monitoring with ambulatory monitoring equipment  
• 
EQ-5D and AFEQT Questionnaires 
• 
Review the patient-activated ambulatory monitoring instructions with the subject.   
• 
Chest X-ray, including inspiration and expiration films, is required for subjects whose PNI was 
unresolved at the 3 month visit 
• 
In the case of suspected PV stenosis, Magnetic Resonance Imaging (MRI) or Computerized 
Tomography Scanning (CT scan) is required.  It is not required at this visit if it was already 
completed at an earlier visit and PV stenosis was confirmed.   
 
 


056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 60 of 130 
 
 
Version 5.0  
STOP AF First 
Page 60 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
11.5.8.4. Twelve month Office Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
Health care utilization assessment- collect information about hospitalizations or emergency 
department visits experienced by the subject since the last visit 
• 
12 lead ECG 
• 
24h continuous ECG monitoring with ambulatory monitoring equipment.  The subject will be 
instructed to apply the continuous monitoring patches and complete the 24 hours of continuous 
monitoring within 7 days prior to the 12 month visit.   It is recommended that the study 
personnel call the subject to remind them of this requirement.  If the subject is not able to apply 
the device prior to the visit, it may be applied by study personnel at the 12 month visit.   
• 
EQ-5D and AFEQT Questionnaires 
• 
Collect the ambulatory monitoring equipment and return to Medtronic (or designee).  If the 
subject did not perform the continuous monitoring prior to the 12 month visit, apply the device to 
the subject to complete 24 hour continuous monitoring.  Give the subject instructions on how to 
return the equipment.   
• 
Chest X-ray, including inspiration and expiration films, is required for subjects whose PNI was 
unresolved at the 6 month visit 
• 
In the case of suspected PV stenosis, Magnetic Resonance Imaging (MRI) or Computerized 
Tomography Scanning (CT scan) is required.  It is not required at this visit if it was already 
completed at an earlier visit and PV stenosis was confirmed.   
• 
Inform the subject they have completed the study 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 66 of 130 
 
 
Version 5.0  
STOP AF First 
Page 66 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
o 
Pain-discomfort at the catheter insertion site that can range from mild to severe. 
o 
Pseudoaneurysm-a collection of blood in the tissue surrounding the catheter insertion site 
due to ongoing leaking of blood from a blood vessel. 
o 
Significant bleeding-blood loss from the catheter insertion site requiring surgery or 
transfusion of 2 or more units of packed red blood cells (PRBCs). 
• 
Coronary artery spasm, vasospasm-constriction of a blood vessel. 
• 
Death-a complication or deterioration of health ultimately leading to a patient’s death. 
• 
Dissection of a blood vessel-a tear within the wall of a blood vessel. 
• 
Dizziness, lightheadedness-feeling faint, woozy, weak or unsteady. 
• 
Embolism-formation and dislodgement of a blood clot (thrombus) or dislodgement of 
cholesterol/plaque within the blood vessel, which travels downstream into small vessels, blocking 
blood flow and causing temporary or permanent damage to organs distal to blockage.  Emboli 
are known to cause myocardial infarction, transient ischemic attack, stroke/cardiovascular 
accident, blurred vision, visual changes, paralysis, paresis, or kidney damage, peripheral ischemia 
and may ultimately lead to incapacitation or death.  Symptomatic and non-symptomatic. 
• 
Endocarditis –inflammation of the inner surface of the heart. 
• 
Esophageal injury –damage to your swallowing tube, atrio-esophageal fistula - abnormal 
passageway between the heart and esophagus, hematemesis (vomiting blood). 
• 
Fatigue- extreme tiredness. 
• 
Fever- abnormally high body temperature. 
• 
Gastroparesis- delayed gastric emptying. 
• 
Headache- pain in the head. 
• 
Heartblock requiring permanent pacemaker implantation 
• 
Heart rhythm disturbances-disruption of normal heart rate or rhythm (e.g. atrial flutter, 
tachycardia, bradycardia). 
• 
Hemothorax –collection of blood around the lungs. 
• 
Hiccups- involuntary spasm of the diaphragm and respiratory organs. 
• 
Hypertension-high blood pressure. 
• 
Hypotension-low blood pressure. 
• 
Infection (e.g. sepsis) 
• 
Injury to lung- (e.g. bronchial lesion, hemoptysis, constriction, pulmonary hemorrhage, bronchia 
fistula). 
• 
Mild skin discomfort or irritation-redness sensitivity of the skin cause during or after the 
procedures (e.g. electrodes used with the ECG and Holter recorder might cause mild skin 
discomfort or irritation or some skin discomfort following electrode removal or tape removal). 
• 
Nausea-a sensation of unease and discomfort in the upper stomach with an urge to vomit. 


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• 
Perforation of a blood vessel or cardiac tissue-unintended puncture through the wall of a blood 
vessel or cardiac tissue. 
• 
Pericardial effusion- fluid collecting in the sac that surrounds the heart. 
• 
Pericarditis –inflammation of the sac that surrounds the heart. 
• 
Phrenic nerve injury –damage to the nerve that controls breathing. 
• 
Pleural effusion –collection of extra fluid around the lungs. 
• 
Pneumothorax – collapsed lung.Pulmonary edema- excess fluid in the lungs. 
• 
Pulmonary hypertension- high blood pressure that affects the arteries in the lungs and the right 
side of the heart.Pulmonary vein hematoma- trauma to the pulmonary vein. 
• 
Pulmonary vein stenosis –blockage in the blood vessels takes blood from the lungs to the heart. 
• 
Renal dysfunction-kidneys fail to adequately filter waste products from the blood. 
• 
Right sided heart failure- right side of the heart is not pumping blood to the lung normally. 
• 
Shivering- body shaking. 
• 
Shortness of breath- difficulty breathing. 
• 
Small ischemic cerebral (brain) lesions not accompanied by clinically apparent symptoms have 
been found on brain imaging performed after an AF ablation procedure.  So far, the relationship 
between these lesions and an increased incidence of stroke or transient ischemic attack (a mini 
stroke) has not been established.  However, whether these lesions will result in long term 
cognitive decline (e.g. loss of memory and trouble thinking) is unclear. 
• 
ST elevation- the ST segment of an ECG is abnormally high above the baseline. 
• 
Sore throat- pain in the throat. 
• 
Urinary infection- an infection in the urinary system. 
• 
Vascular complications requiring surgery-damage to an artery (e.g. femoral) or vein requiring 
surgical repair. 
• 
Vasovagal reaction- reflex of the involuntary nervous system that causes the heart to slow down 
and blood pressure drops. 
• 
Vomiting-forceful expulsion of stomach contents through the mouth and/or nose. 
The risks of participating in this clinical study are the same as the cryoablation procedure risks, and also 
include: 
• 
Risks/discomforts associated with sedation/anesthesia: 
o 
Hoarseness. 
o 
Myalgia (pain in the muscles). 
o 
Numbness and tingling of the fingers. 
o 
Diarrhea. 
o 
Dry mouth. 
o 
Sleepiness. 


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Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
13.3.1.2. Death Classification and Reporting 
Sufficient information will be required in order to properly classify the subject’s death.  The Investigator 
shall classify each subject death per the following definitions: 
• 
Cardiac Death: A death directly related to the electrical or mechanical dysfunction of the heart. 
• 
Sudden Cardiac Death (SCD): Natural death due to cardiac causes, indicated by abrupt loss of 
consciousness within one hour of the onset of acute symptoms; preexisting heart disease may 
have been known to be present, but the time and mode of death are unexpected. If time of 
onset cannot be determined, SCD will alternatively be defined as any unexpected cardiac death 
occurring out of the hospital or in the emergency room as dead on arrival. 
• 
Non-sudden Cardiac Death: All cardiac deaths that are not classified as sudden deaths, including 
all cardiac deaths of hospitalized subjects on inotropic support. 
• 
Non-cardiac Death: A death not classified as a cardiac death. 
• 
Unknown Classification: Unknown death classification is intended for use only when there is 
insufficient or inadequate information to classify the death. 
The CEC will review deaths and provide a final adjudication of the primary cause of death and cardiac 
classification. 
Regulatory reporting of subject deaths will be completed according to local regulatory requirements. 
 
 


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


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15. Statistical Design and Methods 
Medtronic employees will perform all statistical analyses. 
Additionally, a separate Statistical Analysis Plan (SAP) will be developed to further describe statistical 
methods, pre-specified data handling rules (including how missing data will be handled), and pre-
specified analyses, including subgroup analyses, that will be included in study reports (e.g. PMA report, 
final study report).  Any deviation from the pre-specified statistical analyses will be noted in the study 
report.  
The SAP will include a comprehensive description of the statistical methods and analyses to be included 
in reports that include analysis of endpoints.  Any change to the data analysis methods described in the 
CIP will require an amendment to the CIP only if it changes a principal feature of the CIP.  Any other 
change to the data analysis methods described in the CIP, and the justification for making the change, 
will be described in the clinical study report. 
Additional exploratory analyses of the data may be conducted as deemed appropriate. 
All objectives will be analyzed once all treated subjects complete the 12 month follow-up visit, or have 
exited the study.  A final report will be completed after all subjects complete the final follow-up visit, or 
have exited the study. No interim analyses are planned. 
The primary analysis will be conducted using a modified intent-to-treat protocol; all subjects for whom 
either AAD or cryoballoon ablation therapy is initiated will be analyzed according to their randomization 
status. Subjects who withdraw consent between randomization and initiation of therapy will be excluded 
from the primary efficacy analysis. 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 90 of 130 
 
 
Version 5.0  
STOP AF First 
Page 90 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
15.3.1.2. Endpoint Definition 
The AFEQT questionnaire will be utilized for this objective.  The questionnaire is an atrial fibrillation 
specific health-related quality of life questionnaire to assess the impact of AF on a subject’s life.  The 
overall score ranges from 0 – 100, with 0 corresponding to complete disability and 100 corresponding to 
no disability.  The absolute difference between each subject’s baseline and 12 month scores is the 
endpoint of interest. 
15.3.1.3. Analysis Methods 
The difference in mean AFEQT scores will be assessed utilizing a paired t-test.   
15.3.1.4. Performance Criteria 
If the p-value from the two-sample t-test procedure is less than the alpha level determined by the 
Hochberg procedure described above, the objective will be considered met. 
15.3.1.5. Rationale for Performance Criteria 
If this analysis shows that scores from the AFEQT, a validated instrument for measuring quality of life in 
subjects with atrial fibrillation (Spertus, et al. 2011), are significantly higher 12 months after the 
procedure compared to before the procedure, it will show a documented association between the 
cryoballoon ablation procedure and QoL improvement in a non-drug refractory paroxysmal AF population. 
. While this hypothesis test will not be between randomized groups, in the context of a secondary 
objective that will only be tested if efficacy has been established, such results would provide evidence of 
a QoL improvement in cryoballoon ablation-treated patients. 
15.3.1.6.  Determination of Subjects/Data for Analysis 
All subjects randomized to the cryoballoon ablation group who have completed both baseline and 12-
month questionnaires will be included and analyzed. 
 
Comparison to the AAD arm is not planned as it is expected that a large percentage of AAD arm subjects 
will have a cryoballoon procedure during the 12 months of follow-up.  Having a cryoballoon procedure 
prior to 12 months will bias the AAD arm’s 12-month QOL results. 
15.3.1.7.  Additional analyses 
The AFEQT questionnaire has three subscale scores, Daily Activities Subscale, Treatment Concern, and 
Treatment satisfaction.  Each subscale ranges from 0 – 100, where 0 corresponds to low quality-of-life 
and 100 corresponds to high quality of life. 
 
Change in AFEQT subscale score is defined as 12-month AFEQT subscale score minus baseline AFEQT 
subscale score.  A two-sided 95% confidence interval will be calculated based on the t-distribution. 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 94 of 130 
 
 
Version 5.0  
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Page 94 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
15.3.4.5. Rationale for Performance Criteria 
If the test specified above indicates a statistically significant increase in the time to the first cardioversion 
between cryoballoon ablation and AAD-treated subjects, this is sufficient evidence to say that the 
treatment has a lower rate of cardioversions within a year of treatment initiation, due to the randomized 
and intention-to-treat nature of the comparison. 
15.3.4.6. Determination of Subjects/Data for Analysis 
The modified intent-to-treat cohort will be utilized.  All subjects who initiate either AAD therapy or 
cryoballoon ablation will be analyzed according to the group to which they were randomized in the 
assessment of this objective. 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 100 of 130 
 
 
Version 5.0  
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Page 100 of 130 
05DEC2017 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
In addition to the regulatory requirements outlined above, the study will be conducted in compliance with 
relevant local laws. These include but are not limited to: 
 
• 
In the United States, US FDA 21 CFR Parts 
o 
50: Protection of Human subjects,  
o 
56: Institutional Review Boards  
o 
812: Investigational Device Exemptions 
• 
In Europe, Declaration of Helsinki 2013, the Competent Authority requirements, the Medical 
Device Directive (MDD) 93/42/EEC and ISO 14155:2011 with the exceptions stated earlier in this 
Section 
 
The study will be publicly registered prior to first enrollment in accordance with the 2007 Food and Drug 
Administration Amendments Act (FDAAA) and Declaration of Helsinki on http://clinicaltrials.gov (PL 110 
85, Section 810(a)). 
 
Approval of the Clinical Investigation Plan (CIP) is required from the following groups prior to any study 
procedures at a study center: 
 
• 
US Food and Drug Administration (FDA) or regulatory authority 
• 
Medtronic 
• 
Principal Investigators (where required by local law) 
• 
An independent IRB/EC 
 
Similarly, approval of subsequent revisions to the CIP is required at each study center from the above 
mentioned groups prior to implementation of the revised CIP at that center. 
 
Medtronic maintains appropriate clinical study liability insurance coverage as required under applicable 
laws and regulations and will comply with applicable local law and custom concerning specific insurance 
coverage.  If required, a clinical insurance statement/certificate will be provided to the IRB/EC. 
The study is conducted in multiple countries, therefore reimbursement and indemnification will be 
addressed on a country specific basis in the study documents and center Clinical Trial Agreements. 
 
 


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• 
The Investigator will promptly inform the subjects (or legally authorized designees or guardians, 
except in Europe),  and may inform the personal physician of the subjects, with the rationale for 
the study termination or suspension 
• 
The Investigator will inform local regulatory authority, where required per regulatory 
requirements 
 
 


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18. References 
AFFIRM First Antiarrhythmic Drug Substudy Investi. 2003. "Maintenance of sinus rhythm in patients with 
atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug." J Am Coll Cardiol 42: 20-
9. 
Arena, G, C Tondo, G Cattafi, and et. al. 2016. "Cryoballoon ablation as treatment of recent paroxysmal 
atrial fibrillation. Data from a large cohort of patients followed in a real world multicenter 
experience." Heart Rhythm 13: S375-76. 
Calkins, et. al. 2017. "2017 HRS/EHRA/ECAS expert Consensus Statement on catether and surgical 
ablation of AF." Heart Rhythm 14 (10): 275-444. 
Caulkins, H, and et. al. . 2007. "HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical 
Ablation of Atrial Fibrillation: Recommendations for Personnel, Policy, Procedures and Follow-Up." 
Europace 9 (6): 335-379. 
Cosio, FG, E Aliot, GL Botto, and et. al. . 2008. "Delayed rhythm control of atrial fibrillation may be a 
cause of failure to prevent recurrences: reasons for change to active antiarrhymic treatment at 
the time of the first detected episode." Europace 10: 21-7. 
De Vos, CB, R Pisters, R Nieuwlaat, and et. al. . 2010. "Progression from paroxysmal to persistent atrial 
fibrillation clinical correlates and prognosis." J Am Coll Cardiol 55: 725-31. 
Go, A, E Hylek, K Phillips, and et. al. 2001. "Prevalence of Diagnosed Atrial Fibrillation in Adults: National 
Implications for Rhythm Management and Stroke Prevention: the Anticoagulation and Risk 
Factors in Atrial Fibrillation (ATRIA) Study." JAMA 285 (18): 2370-2375. 
Hommel, G. 1988. "A stagewise rejective multiple test procedure based on a modified Bonferroni test." 
Biometricka 75: 383-386. 
Jais, P, MD O'Neill, Y Takahashi, and et. al. . 2006. "Stepwise Catheter Ablation of Chronic Atrial 
Fibrillation: Importance of Discrete Anatomic Sites for Termination." J Cardiovasc Electrophysiol 
17 (Suppl. 3): S28-S36. 
Jalife, J, and K Kaur. 2015. "Atrial remodeling, fibrosis, and atrial fibrillation." Trends Cardiovasc Med 25: 
475-84. 
January, CT, and et. al. . 2014. "2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial 
Fibrillation." JACC 64 (21): e1-76. 
January, CT, LS Wann, JS Alpert, ME Field, H Calkins, KT Murray, JC Cleveland Jr., et al. 2014. "2014 
AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive 
Summary." Journal of the American College of Cardiology.  
Knight, BP, PG Novak, R Sangrigoli, and et. al. 2016. "Second generation cryoballoon: results from the 
multicenter STOP AF Post Approval Study 12-month clinical outcomes following pulmonary vein 
isolation using the Arctic Front Adfance." Cardiostim (abstract).  
Kuck, KH, J Brugada, A Furnkranz, A Metzner, F Ouyang, KR Julian Chun, A Elvan, et al. 2016. 
"Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation." N Engl J Med 374: 
2235-45. 
Lafuente-Lafuente, C, L Valembois, JF Bergmann, and J Belmin. 2015. "Antiarrhythmics for maintaining 
sinus rhythm after cardioversion of atrial fibrillation." Cochrane Database of Systematic Reviews.  


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Lafuente-Lafuente, C, S Mouly, MA Longas-Tejero, and et. al. 2006. "Antiarrhythmic drugs for maintaining 
sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled 
trials." Arch Intern Med 166: 719-28. 
Morillo, CA, A Verma, SJ Connolly, and et. al. 2014. "Radiofrequency ablation vs. antiarrhythmic drugs as 
first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): A randomized trial." JAMA 311 (7): 
692-700. 
Nattel, S, E Guasch, I Savelieva, and et. al. 2014. "Early management of atrial fibrillation to prevent 
cardiovascular complications." Eur heart J 35: 1448-56. 
Nielsen, JC, A Johannessen, P Raatikainen, G Hindricks, H Walfridsson, O Kongstad, S Pehrson, et al. 
2012. "Radiofrequency Ablation as Initial Therapy in Paroxysmal Atrial Fibrillation." New England 
Journal of Medicine, October 25: 1587-96. 
Oral, H, BP Knight, H Tada, and et. al. . 2002. "Pulmonary vein isolation for paroxysmal and persistent 
atrial fibrillation." Circulation 105: 1077-81. 
Packer, D, R Kowal, K Wheelan , J Irwin, J Champagne, P Guerra, M Dubuc, et al. 2013. "CryoBalloon 
ablation: first results of North America STOP AF pivotal trial." J Am Coll Cardiol 61 (16): 1713-
1723. 
Raviele, et. al. . 2012. "Venice Chart International consensus document on atrial fibrillation: 2011 
Update." J Cardiovasc Electrophysiol 23: 890-923. 
Romero, J, C Gianni, L Di Biase, and A Natale. 2015. "Catheter ablation for long-standing persistent atrial 
fibrillation: On-treatment analysis of the randomized controlled MANTRA-PAF trial." Int J Cardiol J 
11: 87-93. 
Shaw, JW, JA Johnson, and SJ Coons. 2004. "U.S. Valuation of the EQ-5D Heatlh States: Development 
and Testing of the D1 Valuation Model." Medical Care.  
Shulka, A, and AB Curtis. 2014. "Avoiding permanent atrial fibrillation: treatment approaches to prevent 
disease progression." Vasc Health Risk Manag 10: 1-12. 
Spertus, J, P Dorian, R Bubien, S Lewis, D Godejohn, MR Reynolds, DR Lakkireddy, AP Wimmer, A 
Bhandari, and C Burk. 2011. "Development and validation of the Atrial Fibrillation Effect on 
Quality-of-Life (AFEQT) Questionnaire in patients with atrial fibrillation." Circ Arrhythm 
Electrophysiol, Feb 4: 15-25. 
Tanner, H, K Makowski, L Roten , and et. al. 2011. "Catheter ablation of atrial fibrillation as first-line 
therapy- a single-center experience." Europace 13: 646-53. 
Walters, TE, A Nisbet, GM Morris, and et. al. 2016. "Progression of atrial remodeling in patients with high-
burden atrial fibrillation: Implications for early ablative intervention." Heart Rhythm 13: 331-9. 
Wazni, OM, NF Marrouche, DO Martin, A Verma, M Bhargava, W Saliba, D Bash, et al. 2005. 
"Radiofrequency Ablation vs. Antiarrhythmic Drugs as First-Line Treatment of Symptomatic Atrial 
Fibrillation." JAMA, June 1: 2634-40. 
Wijesurendra, RS, and B Casadei. 2015. "Atrial fibrillation: effects beyond the atrium?" Cardiovasc Res 
105: 238-47. 
Wolf, P, R Abbott, and W Kannel. 1991. "Atrial fibrillation as an independent risk factor for stroke: the 
Framingham Study." Stroke 22 (8): 983-988. 






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Additional articles Medtronic was aware of or that were published after the searches were conducted 
were included. 
 
 


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Appendix B: DRAFT DATA COLLECTION ELEMENTS (CASE REPORT FORMS) 
Draft Case Report Forms for the STOP AF First study will be provided under separate cover.  Final CRFs 
will be provided to study centers via the electronic data management system after the center has fulfilled 
all requirements for database access. 
 
 


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Appendix C: INFORMED CONSENT FORM TEMPLATE 
The Informed Consent Form Template will be distributed under separate cover. 
 
 


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Appendix D: PARTICIPATING INVESTIGATOR AND INSTITUTIONS 
A list of participating Investigators and institutions will be distributed under separate cover. 
 
 


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Appendix E: IRB LIST 
A final IRB list will be distributed under separate cover. 
 
 


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Appendix F: FORESEEABLE ADVERSE EVENTS 
The information provided in this section pertains to foreseeable adverse events that may be observed in 
study subjects and may collectively assist in identifying those events for a given device or therapy that 
are unexpected in nature.  The foreseeable adverse events information consists of two parts: a listing of 
potential adverse events associated with cryoablation therapy/procedure and adverse event rates 
reported in published literature for same therapy/procedure (see Appendix A).  An evaluation of 
potentially anticipated events and reported events in literature may be used in combination with device 
labeling/IFU, current event reporting information, and other published data to assess for an unexpected 
occurrence. 
The cryoablation procedure involves surgery, therefore, standard adverse events associated with a 
surgical procedure may be experienced (e.g. anesthesia complications, injury, infections, bleeding, 
exacerbation of pre-existing conditions, healing complications, etc.). The focus of this section is to 
specifically address in more detail, those events that are foreseeable due to the use, performance, and/or 
presence of the Arctic Front Advance™ CryoAblation Catheter under investigation. 
Additional potential risks associated with the Arctic Front Advance™ CryoAblation Catheter, as well as risk 
minimization are discussed within section 12. 
Treatment required for procedure and/or cryoablation system related adverse events that are 
experienced may include medication or other surgical and medical remedies. The adverse events 
associated with the use of the Arctic Front Advance™ CryoAblation Catheter include but are not limited to 
those in Table 14 and Table 15. 
Table 14 pertains to the foreseeable/anticipated adverse events that may be observed in the study and 
may assist in identifying those adverse events that are unexpected in nature. 
Table 14: Foreseeable Adverse Events 
Anemia 
Feeling cold 
Pseudoaneurysm 
Anxiety 
Fever 
Pulmonary edema 
Arrhythmia 
Gastrointestinal 
discomfort 
Pulmonary embolism 
Arteriovenous fistula 
Gastroparesis 
Pulmonary 
hemorrhage 
Atrial fibrillation 
Headache 
Pulmonary 
hypertension 
Atrial flutter 
Heart block 
Pulmonary infarction 
Atrio-esophageal fistula  
Heart failure 
Pulmonary 
infiltration 
Back pain 
Hematemesis 
Pulmonary vein 


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stenosis 
Bleeding 
Hematoma 
Renal impairment 
Blurred vision 
Hemoptysis 
Respiratory arrest or 
pulmonary arrest 
Bronchial fistula 
Hemothorax 
Right bundle branch 
block 
Bronchitis 
Hiccups 
Shivering 
Bruising 
Hypertension 
Shortness of breath 
Cardiac arrest or 
cardiopulmonary arrest 
Hypotension 
Sore throat 
Cardiac perforation or 
cardiac vein perforation 
or perforation of 
surrounding tissue 
Hypoxia 
ST segment 
elevation 
Cardiac tamponade 
Injury to pulmonary vein 
e.g. pulmonary vein 
dissection, pulmonary 
vein hematoma  
Stroke or 
cerebrovascular 
accident 
Cerebral embolism 
Lightheadedness 
Syncope 
Chest discomfort or pain 
or pressure 
Lung injury 
Tachycardia 
Coronary artery spasm 
Myocardial infarction 
Thrombosis or 
thrombus 
Cough 
Nausea 
Transient ischemic 
attack 
Death 
Nerve injury e.g. phrenic 
nerve injury 
Urinary infection 
Diarrhea 
Neurological impairment 
Vascular access site 
complication 








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Appendix G: PRE-CLINICAL TESTING 
A summary of results from pre-clinical testing with the Arctic Front Advance™ Cardiac CryoAblation 
Catheter is provided in the Report of Prior Investigations Summary. 
 

Prot_004.pdf: 
 
 
Clinical Investigation Plan Title 
STOP AF First 
Clinical Investigation Plan Identifier 
MDT16012AFS001 
Study Product 
Arctic Front Advance™ Cardiac CryoAblation Catheter 
Application Number 
IDE #G1160219 
ClinicalTrials.gov Identifier 
NCT03118518 
Sponsor 
Medtronic 
8200 Coral Sea St NE 
Mounds View, MN  55112 
Document Title 
STOP AF First Clinical Investigation Plan 
Document Version (Date) 
4.0 (10-APR-2017) 
 


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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title STOP AF First 
Clinical Investigation Plan Identifier MDT16012AFS001 
Study Product Name Arctic Front AdvanceTM  Cardiac CryoAblation 
Catheter 
Sponsor/Local Sponsor United States of America 
Medtronic, Inc. 
8200 Coral Sea St NE 
Mounds View, MN U.S.A. 55112 
 
Europe 
Medtronic, Bakken Research Center B.V. 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
Document Version Version 4.0, 10APR2017 
Lead Principal Investigator Oussama Wazni, MD 
Cleveland Clinic 
9500 Euclid Ave, 
Cleveland, OH 44195 
Coordinating Investigators Gopi Dandmudi, MD 
Indiana University Krannert Institute of Cardiology 
1801 N. Senate Blvd, Suite 4000 
Indianapolis, IN  46202 
 
Steve Nissen, MD 
Cleveland Clinic 
9500 Euclid Avenue 
Cleveland, OH  44195 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Medtronic.  
Any distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly 
prohibited.  Persons to whom the information is disclosed must know that it is confidential and that it 
may not be further disclosed by them. 
 
 




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2.0 
Section 10, Selection of Subjects- Modified the 
first Inclusion Criteria per FDA feedback “A 
diagnosis of symptomatic paroxysmal AF with 
the following documentation: (1) physician’s 
note indicating recurrent self- terminating AF or 
paroxysmal AF; and (2) any ECG documented 
AF within 6 months prior to enrollment. “  
Exclusion criteria- changed 3 months and 6 
months to 90 days and 180 days for clarity.   
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
2.0 
Section 11.1, Study Procedures, Schedule of 
Events- Added randomization, treatment arm, 
reablation/crossover ablation requirements, 
pregnancy screen, chest x-ray for phrenic nerve 
injury, MRI or CT scan for suspected PV 
stenosis, health care utilization data collection.  
Changed QOL screening from SF-12 to EQ-5D.  
Changed Holter to “continuous ambulatory ECG 
monitoring.” 
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
2.0 
Section 11.2, Study Procedures, Medications- 
Added control arm medication requirements and 
more detailed anticoagulation requirements.   
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
2.0 
Section 11.3, Study Procedures, Subject 
Consent- Updated to add EU and for ISO 14155 
compliance. 
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
2.0 
Section 11.4, Study Procedures, Randomization 
and Treatment Assignment- Modified from single 
arm study to randomized study. 
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
2.0 
Section 11.5, Study Procedures, Description of 
All Study Procedures and Visits- Updated per 
Section 11.1, Schedule of Events, added 
antiarrhythmic drug arm requirements, modified 
anticoagulation and TEE requirements, updated 
phrenic nerve injury screening requirements, 
added assessment of whether neurological 
evaluation is required at hospital discharge, 
changed six week phone/office visit to one 
month office visit and added additional 
requirements to the visit, changed Holter 
requirement to a general term “24 hour 
continuous monitoring,” describe the 24 hour 
continuous monitoring and patient activated ECG 
data collection.      
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 


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Section 11.10, Subject Withdrawal or 
Discontinuation- Updated reasons for withdrawal 
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
2.0 
Section 12, Risks and Benefits- Added risks per 
FDA feedback  
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
2.0 
Section 13, Adverse Event Assessments- Added 
antiarrhythmic drug related category and ISO 
14155 requirements.   
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
2.0 
Section 15, Statistical Design and Methods- 
Updated based on modified objectives and 
endpoints.   
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
2.0 
Section 16, Ethics- Updated to include Europe 
and ISO 14155 regulations.   
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
2.0 
Section 17, Study Administration- Updated to 
include Europe and ISO 14155 regulations.   
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
3.0 
Changed “Objective Performance Criteria” to 
“Performance Goal” in Section 2, Glossary, and 
Sections 15.2.4 and 15.2.6 in the Statistical 
Design and Methods section.   
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
3.0 
Updated the following sections to change the 30 
day AAD optimization period to a 90 day AAD 
optimization period:  3.0, Synopsis, 6.0, Figure 
1, Study Design Table, 11.1, Schedule of Events, 
and 5.1.4.1, Primary Efficacy Endpoint, 11.5.8, 
Scheduled Follow-up Visits, 15.1.2, Endpoint 
Definition 
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
3.0 
Added the following statement to the medication 
sections:  The 2014 AHA/ACC/HRS Guideline for 
the Management of Patients with Atrial 
Fibrillation should be consulted for AAD 
prescriptions.  (Sections 11.2, 11.5.2, and 
11.5.5) 
Kirsten Rasmussen, Clinical 
Research Specialist 
Chris Anderson, Sr. Statistician 
4.0 
Edited two exclusion criteria:  1) changed the 
BMI value from >35 to >40; 2) added “severe” 
prior to obstructive sleep apnea. 
Mindy Hoey, Prin. Clinical Research 
Specialist 
Chris Anderson, Sr. Statistician 


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Table of Contents  
 
1. 
Version History ........................................................................................................... 2 
Table of Contents ................................................................................................................. 5 
Listing of Tables ................................................................................................................. 10 
Listing of Figures ............................................................................................................... 11 
Listing of Appendices ......................................................................................................... 11 
Sponsor Contact information .............................................................................................. 12 
Contract Research Organizations ....................................................................................... 13 
Steering Committee ............................................................................................................ 13 
2. 
Glossary ..................................................................................................................... 14 
3. 
Synopsis .................................................................................................................... 17 
4. 
Introduction .............................................................................................................. 23 
4.1. 
Background ................................................................................................................. 23 
4.2. 
Purpose ........................................................................................................................ 24 
5. 
Objectives and Endpoints ......................................................................................... 25 
5.1. 
Objectives ................................................................................................................... 25 
5.1.1. 
Primary Objective(s) ........................................................................................................... 25 
5.1.1.1. 
Primary Efficacy Objective ............................................................................................. 25 
5.1.1.2. 
Primary Safety Objective ................................................................................................ 25 
5.1.2. 
Secondary Objectives ......................................................................................................... 25 
 
 
5.1.4. 
Primary Endpoint ................................................................................................................. 26 
5.1.4.1. 
Primary Efficacy Endpoint .............................................................................................. 26 
5.1.4.2. 
Primary Safety Endpoint ................................................................................................. 27 
5.1.5. 
Secondary Endpoints .......................................................................................................... 28 
 
 
 
6. 
Study Design ............................................................................................................. 30 
6.1. 
Duration ....................................................................................................................... 31 
6.2. 
Rationale ..................................................................................................................... 31 
6.3. 
Minimization of Bias.................................................................................................. 32 
7. 
Product Description .................................................................................................. 33 
7.1. 
General......................................................................................................................... 33 
7.2. 
Arctic Front Advance™ Cardiac CryoAblation Catheters ................................... 35 
7.3. 
Freezor ® MAX Cardiac CryoAblation Catheters ................................................. 35 


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7.4. 
FlexCath Advance™ Steerable Sheath .................................................................. 36 
7.5. 
Achieve™ or Achieve Advance™ Mapping Catheter ........................................... 36 
7.6. 
CryoCath CryoAblation Console ............................................................................. 37 
7.7. 
Coaxial Umbilical Cable ............................................................................................ 38 
7.8. 
Electrical Umbilical Cable ........................................................................................ 38 
7.9. 
Manual Retraction Kit ............................................................................................... 38 
7.10. 
Additional Study Devices ......................................................................................... 39 
7.11. 
Product Training Requirements ............................................................................. 39 
7.12. 
Packaging .................................................................................................................... 39 
7.13. 
Investigational Device Storage, Handling and Traceability ............................. 39 
8. 
Investigator/Investigator Center Selection ................................................................ 41 
9. 
Center Activation ....................................................................................................... 42 
10. 
Selection of Subjects .................................................................................................. 43 
10.1. 
Study Population ....................................................................................................... 43 
10.2. 
Subject Enrollment .................................................................................................... 43 
10.3. 
Inclusion Criteria ....................................................................................................... 44 
10.4. 
Exclusion Criteria ....................................................................................................... 44 
11. 
Study Procedures ....................................................................................................... 46 
11.1. 
Schedule of Events .................................................................................................... 46 
11.2. 
Medications ................................................................................................................. 47 
11.3. 
Subject Consent ......................................................................................................... 48 
11.4. 
Randomization and Treatment Assignment ........................................................ 50 
11.5. 
Description of All Study Procedures and Visits ................................................... 50 
11.5.1. 
Enrollment & Baseline ..................................................................................................... 50 
11.5.2. 
Control Arm- AAD Initiation ........................................................................................... 51 
11.5.3. 
Treatment Arm- Cryoablation Procedure ..................................................................... 52 
11.5.3.1. 
Esophageal Visualization and Temperature Monitoring ......................................... 52 
11.5.3.2. 
Pre-procedure Anticoagulation .................................................................................. 52 
11.5.3.3. 
Intra-procedure Anticoagulation ............................................................................... 52 
11.5.3.4. 
Post-procedure Anticoagulation................................................................................. 52 
11.5.3.5. 
Diaphragm Movement ................................................................................................. 53 
11.5.3.6. 
Balloon Pulmonary Vein (PV) Cryoablation .............................................................. 53 
11.5.3.7. 
Other Ablations During Index Procedure ................................................................. 54 
11.5.3.8. 
Cardioversion ................................................................................................................ 54 
11.5.3.9. 
Procedure Documentation .......................................................................................... 54 
11.5.4. 
Hospital Discharge .......................................................................................................... 55 
11.5.5. 
Medication Compliance ................................................................................................... 55 
11.5.6. 
Subsequent Ablation Procedures .................................................................................. 56 
11.5.7. 
Cardioversions.................................................................................................................. 56 
11.5.8. 
Scheduled Follow-up Visits ............................................................................................ 56 


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11.5.8.1. 
One Month Office Visit ................................................................................................ 57 
11.5.8.2. 
Three Month Office Visit ............................................................................................. 58 
11.5.8.3. 
Six Month Office Visit .................................................................................................. 58 
11.5.8.4. 
Twelve month Office Visit .......................................................................................... 59 
11.5.9. 
Unscheduled Office Visits ............................................................................................... 60 
11.5.10. 
Re-Ablation/Crossover Ablation ................................................................................. 60 
11.5.11. 
12 lead Electrocardiograms ........................................................................................ 60 
11.5.12. 
Ambulatory Monitoring ............................................................................................... 61 
11.5.13. 
Study Exit ...................................................................................................................... 61 
11.6. 
Assessment of Efficacy ............................................................................................. 61 
11.7. 
Assessment of Safety................................................................................................ 61 
11.8. 
Recording Data .......................................................................................................... 61 
11.9. 
Deviation Handling .................................................................................................... 62 
11.10. 
Subject Withdrawal or Discontinuation ............................................................ 63 
12. 
Risks and Benefits ..................................................................................................... 65 
12.1. 
Potential Risks ........................................................................................................... 65 
12.2. 
Risk Minimization ...................................................................................................... 68 
12.3. 
Potential Benefits ...................................................................................................... 68 
12.4. 
Risk-Benefit Rationale.............................................................................................. 68 
13. 
Adverse Event Assessments....................................................................................... 69 
13.1. 
Definitions/Classifications ...................................................................................... 69 
13.2. 
Reporting of Adverse Events ................................................................................... 72 
13.2.1. 
Device Deficiencies.......................................................................................................... 72 
13.2.2. 
Adverse Event Reporting Requirements ...................................................................... 73 
13.3. 
Adverse Event Classification ................................................................................... 76 
13.3.1. 
Subject Death .................................................................................................................. 77 
13.3.1.1. 
Death Data Collection ................................................................................................. 77 
13.3.1.2. 
Death Classification and Reporting ........................................................................... 78 
13.3.2. 
Product Complaints ......................................................................................................... 78 
14. 
Data Review Committees .......................................................................................... 80 
15. 
Statistical Design and Methods ................................................................................. 81 
15.1. 
Primary Efficacy Objective ...................................................................................... 82 
15.1.1. 
Hypothesis ........................................................................................................................ 82 
15.1.2. 
Endpoint Definition .......................................................................................................... 82 
15.1.3. 
Performance Requirements ........................................................................................... 83 
15.1.4. 
Rationale for performance criteria ................................................................................ 83 
15.1.5. 
Analysis Methods ............................................................................................................. 83 
15.1.6. 
Sample Size ...................................................................................................................... 84 
15.1.7. 
Determination of Patients/Data for Analysis ............................................................... 84 
15.2. 
Primary Safety Objective ......................................................................................... 85 


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15.2.1. 
Hypothesis ........................................................................................................................ 85 
15.2.2. 
Endpoint Definition .......................................................................................................... 85 
15.2.3. 
Performance requirements ............................................................................................ 85 
15.2.4. 
Rationale for Performance Criteria ............................................................................... 85 
15.2.5. 
Analysis Methods ............................................................................................................. 86 
15.2.6. 
Sample Size ...................................................................................................................... 86 
15.2.7. 
Determination of Patients/Data for Analysis ............................................................... 87 
15.3. 
Secondary Objectives ............................................................................................... 88 
15.3.1. 
Atrial Fibrillation Effect on Quality-of-Life (AFEQT).................................................... 88 
15.3.1.1. 
Hypothesis .................................................................................................................... 88 
15.3.1.2. 
Endpoint Definition ...................................................................................................... 89 
15.3.1.3. 
Analysis Methods ......................................................................................................... 89 
15.3.1.4. 
Performance Criteria ................................................................................................... 89 
15.3.1.5. 
Rationale for Performance Criteria ............................................................................ 89 
15.3.1.6. 
Determination of Subjects/Data for Analysis ........................................................... 89 
15.3.1.7. 
Additional analyses ...................................................................................................... 89 
15.3.2. 
EQ-5D Questionnaire ...................................................................................................... 90 
15.3.2.1. 
Hypothesis .................................................................................................................... 90 
15.3.2.2. 
Endpoint Definition ...................................................................................................... 90 
15.3.2.3. 
Analysis Methods ......................................................................................................... 90 
15.3.2.4. 
Performance criteria .................................................................................................... 90 
15.3.2.5. 
Rationale for Performance Criteria ............................................................................ 90 
15.3.2.6. 
Determination of Subjects/Data for Analysis ........................................................... 90 
15.3.3. 
Cardiovascular hospitalizations, ED and unscheduled office visits .......................... 91 
15.3.3.1. 
Hypothesis .................................................................................................................... 91 
15.3.3.2. 
Endpoint Definition ...................................................................................................... 91 
15.3.3.3. 
Analysis Methods ......................................................................................................... 91 
15.3.3.4. 
Performance Requirements ........................................................................................ 91 
15.3.3.5. 
Rationale for Performance Requirements ................................................................ 91 
15.3.3.6. 
Determination of Subjects/Data for Analysis ........................................................... 92 
15.3.4. 
Cardioversions.................................................................................................................. 92 
15.3.4.1. 
Hypothesis .................................................................................................................... 92 
15.3.4.2. 
Endpoint Definition ...................................................................................................... 92 
15.3.4.3. 
Analysis Methods ......................................................................................................... 92 
15.3.4.4. 
Performance Requirements ........................................................................................ 92 
15.3.4.5. 
Rationale for Performance Criteria ............................................................................ 93 
15.3.4.6. 
Determination of Subjects/Data for Analysis ........................................................... 93 
 
 
 
 
 
 
 
 
 
 
 


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16. 
Ethics ........................................................................................................................ 98 
16.1. 
Statement(s) of Compliance ................................................................................... 98 
17. 
Study Administration ............................................................................................... 100 
17.1. 
Role of the Sponsor Representatives .................................................................. 100 
17.2. 
Monitoring ................................................................................................................. 100 
17.3. 
Data Management ................................................................................................... 100 
17.4. 
Direct Access to Source Data/Documents ......................................................... 101 
17.5. 
Confidentiality .......................................................................................................... 101 
17.6. 
CIP Amendments ..................................................................................................... 101 
17.7. 
Record Retention and Reports ............................................................................. 101 
17.7.1. 
Investigator Records ..................................................................................................... 102 
17.7.2. 
Investigator Reports ..................................................................................................... 102 
17.7.3. 
Sponsor Records ............................................................................................................ 105 
17.7.4. 
Sponsor Reports ............................................................................................................ 106 
17.8. 
Publication and Use of Information .................................................................... 110 
17.8.1. 
Management of Primary, Secondary and Ancillary Publications............................. 111 
17.8.2. 
Criteria for Determining Authorship............................................................................ 111 
17.8.3. 
Transparency ................................................................................................................. 112 
17.9. 
Suspension or Early Termination ......................................................................... 112 
17.9.1. 
Planned Study Closure .................................................................................................. 112 
17.9.2. 
Early Termination or Suspension ................................................................................ 112 
17.9.3. 
Study-wide termination or suspension ....................................................................... 112 
17.9.4. 
Site termination or suspension .................................................................................... 113 
17.9.5. 
Procedures for Termination or Suspension ............................................................... 113 
17.9.5.1. 
Medtronic-initiated and regulatory authority-initiated ......................................... 113 


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17.9.5.2. 
Investigator-initiated ................................................................................................. 113 
17.9.5.3. 
IRB/EC-initiated.......................................................................................................... 114 
18. 
References ............................................................................................................... 115 
19. 
Appendices .............................................................................................................. 117 
 
Listing of Tables 
Table 1: Study sponsor and monitoring contact information................................................................. 12 
Table 2: CRO information .................................................................................................................. 13 
Table 3: Steering Committee contact information ................................................................................ 13 
Table 4: Device Information .............................................................................................................. 33 
Table 5: Visit Schedule and Data Collection Requirements Summary .................................................... 46 
Table 6: Follow-up Visit Windows ....................................................................................................... 57 
Table 7: Adverse Event and Device Deficiency Reporting Requirements................................................ 73 
Table 8: Adverse Event Classification Responsibilities .......................................................................... 77 
Table 9: Investigator reports applicable for all geographies per Medtronic Requirements ..................... 103 
Table 10: Additional Investigator reports applicable to the United States ............................................ 104 
Table 11: Investigator reports applicable to Europe........................................................................... 105 
Table 12: Sponsor Reports for the United States ............................................................................... 107 
Table 13: Sponsor reports for Europe ............................................................................................... 109 
Table 14: Foreseeable Adverse Events ............................................................................................. 123 
Table 15: Arctic Front and Arctic Front Advance™ Complications Reported in Literate for Paroxysmal and 
Persistent AF Patients ...................................................................................................................... 125 
 
 
 


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Listing of Figures 
Figure 1:  Study Design ..................................................................................................................... 30 
Figure 2: Arctic Front AdvanceTM Cardiac Cryoablation Catheter ........................................................... 35 
Figure 3: FlexCath AdvanceTM Steerable Sheath with Cryoablation Catheter .......................................... 36 
Figure 4: Achieve™ Mapping Catheter ................................................................................................ 37 
Figure 5: CryoCath CryoAblation Console ............................................................................................ 37 
Figure 6: Coaxial Umbilical Cable ....................................................................................................... 38 
Figure 7: Electrical Umbilical Cable ..................................................................................................... 38 
Figure 8: Manual Retraction Kit .......................................................................................................... 39 
 
Listing of Appendices 
Appendix A: CRYOBALLOON SAFETY DATA LITERATURE SEARCH...................................................... 117 
Appendix B: DRAFT DATA COLLECTION ELEMENTS (CASE REPORT FORMS) ...................................... 119 
Appendix C: INFORMED CONSENT FORM TEMPLATE ........................................................................ 120 
Appendix D: PARTICIPATING INVESTIGATOR AND INSTITUTIONS .................................................... 121 
Appendix E: IRB LIST ...................................................................................................................... 122 
Appendix F: FORESEEABLE ADVERSE EVENTS .................................................................................. 123 
Appendix G: PRE-CLINICAL TESTING ............................................................................................... 128 
 
 
 












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3. Synopsis 
 
Title 
STOP AF First 
Clinical Study Type 
Pivotal (US)/ Post-market interventional (Europe) 
Product Name 
Arctic Front AdvanceTM Cardiac CryoAblation Catheter 
Sponsor  
United States of America 
Medtronic, Inc. 
8200 Coral Sea St NE  
Mounds View, MN U.S.A. 55112 
Local Sponsor 
Europe 
Medtronic, Bakken Research Center B.V. 
Endeplosdomein 5 
6229 GW Maastricht 
The Netherlands 
Indication Under 
Investigation  
Current indication in the US:  The Arctic Front Advance™ Cardiac 
CryoAblation Catheter is indicated for the treatment of drug refractory 
recurrent symptomatic paroxysmal atrial fibrillation. 
Indication under investigation for the US:  The Arctic Front Advance™ 
Cardiac CryoAblation Catheter is indicated for the treatment of recurrent 
symptomatic paroxysmal atrial fibrillation. 
The indication under investigation is within the approved indication in 
Europe. 
Investigation Purpose 
The purpose of the study is to provide data demonstrating the safety 
and effectiveness of the Arctic Front Advance™ Cardiac CryoAblation 
Catheter for the treatment of recurrent symptomatic paroxysmal AF, 
without the requirement that the subjects be drug refractory.  
Product Status 
The Arctic Front Advance™ Cardiac CryoAblation Catheter is market 
released and will become investigational when used as indicated in the 
study in the US.  The catheter is market released and will be used within 
the approved indications in Europe, therefore is not considered 
investigational for the intended patient population in Europe.   
Primary Objective 
Primary Efficacy Objective: 
Demonstrate the superiority of cryoballoon ablation as compared to 
antiarrhythmic drug (AAD) therapy in terms of the rate of freedom from 
AF/AT/AFL in a non-drug refractory paroxysmal AF population. 


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Primary Safety Objective: 
Demonstrate an acceptable safety profile of the cryoballoon ablation 
procedure as a first line therapy in a non-drug refractory paroxysmal AF 
population. 
Secondary Objectives 
Secondary Objectives are as follows: 
1. Assess changes in quality of life (QoL) between baseline and 12 
months in the cryoballoon ablation arm.     
2. Compare health care utilization (HCU) between the treatment 
and control arms.   
 
 
 
 
 
  
 
 
 
 
 
 
 
  
Primary Endpoint 
Primary Efficacy Endpoint: 
The primary endpoint is treatment success at 12 months after AAD 
initiation (control arm) or after the pulmonary vein isolation ablation 
procedure utilizing the Arctic Front Advance™ Cardiac CryoAblation 
Catheter (treatment arm).  A treatment success is the opposite of a 
treatment failure. 
Treatment failure is defined as any of the following components: 
a) Acute procedural failure (treatment arm only) 
b) Documented AF/AT/AFL on ambulatory monitoring/12-lead ECG 
after the 90 day post-ablation blanking period (treatment 
arm)/AAD optimization period (control arm) 
o 
Minimum of 30 seconds on ambulatory monitoring or 10 
seconds on 12-lead ECG. 
o 
Note: Documented occurrence and treatment of typical 
right-sided cavotricuspid isthmus dependent atrial flutter 
is not considered a failure if confirmed by entrainment 
maneuvers during EP testing. 
c) Any subsequent AF surgery or ablation in the left atrium.   
d) Any subsequent cardioversion after the 90 day post-ablation 
blanking period (treatment arm)/AAD optimization period 
(control arm). 
 


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e) Class I or III antiarrhythmic drug (or sotalol) use after the 90 
day blanking period (treatment arm only). 
The AAD optimization period is defined as the first 90 days after AAD 
initiation (control arm).  The post-ablation blanking period is defined as 
the first 90 days after the index ablation procedure (treatment arm).  
Recurrences of atrial arrhythmias during the AAD optimization/blanking 
periods will not be counted in the determination of the first clinical 
failure for the primary endpoint.   
Within the AAD optimization period/post-ablation blanking period, 
recurrent arrhythmias can be managed with medications or 
cardioversions.  Reablation will be considered a primary endpoint failure 
at all times, including during the 90 day post-ablation blanking period. 
Acute procedural failure (treatment arm only) is defined as: 
a) Inability to isolate all accessible targeted pulmonary veins 
(assessed for entrance block and, where assessable, exit block) 
during the index ablation procedure. 
b) Left atrial non-PVI ablations including but not limited to, ablation 
of linear lesions  
c) Use of a non-study device in the left atrium. 
 
Primary Safety Endpoint: 
The following adverse events will be counted towards the primary safety 
endpoint:  
• 
Transient Ischemic Attack (TIA)within 7 days 
• 
Cerebrovascular accident within 7 days 
• 
Major bleeding that requires transfusion or results in a 20% or 
greater fall in hematocrit (HCT) within 7 days 
• 
Development of a significant pericardial effusion within 30 days.   
A significant pericardial effusion is one that results in 
hemodynamic compromise, requires elective or urgent 
pericardiocentesis, or results in a 1-cm or more pericardial 
effusion as documented by echocardiography.  
• 
Symptomatic PV stenosis within 12 months; accompanied by 
one of the following: 50%-75% reduction in diameter of the 
pulmonary vein, with symptoms not explained by other 
conditions; OR >75% reduction in diameter of the pulmonary 
vein  
• 
MI within 7 days 
• 
PNI unresolved at 12 months 
• 
AE fistula within 12 months 
• 
Major vascular complication that requires intervention, prolongs 


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the hospital stay, or requires hospital admission (within 7 days).   
Secondary Endpoints 
1. The difference in composite scores from the AFEQT 
questionnaire taken at baseline and 12 month visits, and the 
difference in composite scores for the EQ-5D questionnaire 
taken at baseline and 12-month visits.  
2. 12-month rates of cardiovascular HCU events, and 12-month 
rates of cardioversion (either electrical or pharmacological).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
Study Design 
Prospective, interventional, multi-center, randomized, controlled, 
unblinded clinical study. 
The study will be conducted at up to 30 sites in the US and up to 10 in 
Europe. 
Study Duration 
All randomized study subjects will be followed from the time of consent 
through 12 months post-index cryoballoon ablation procedure 
(treatment arm), or AAD initiation (control arm). 
Subjects will be exited from the study at the conclusion of the 12 month 
follow-up visit.  The expected total study duration is approximately 30 
months, representing 18 months of enrollment and 12 months of subject 
follow-up.  


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Sample Size 
210 enrolled subjects in the US and Europe. 
Inclusion/Exclusion 
Criteria 
The following is a list of inclusion/exclusion criteria: 
Inclusion criteria 
• 
A diagnosis of symptomatic paroxysmal AF with the following 
documentation: (1) physician’s note indicating recurrent self- 
terminating AF or paroxysmal AF; and (2) any ECG documented 
AF within 6 months prior to enrollment.  
• 
Age 18-80 
Exclusion criteria 
• 
History of AF treatment with class I or III antiarrhythmic drug, 
including sotalol, with the intention to prevent an AF recurrence.  
However, patients pretreated with above AAD for less than 7 
days with the intention to convert an AF episode are allowed. 
• 
Prior persistent AF (cardioversion after 48 hr or continuous AF 
that is sustained  >7 days) 
• 
Left atrial diameter greater than 5.0 cm 
• 
Prior left atrial ablation or left atrial surgical procedure 
• 
Presence or likely implant of a permanent pacemaker, 
biventricular pacemaker, loop recorder, or any type of 
implantable cardiac defibrillator (with or without biventricular 
pacing function) 
• 
Body mass index (BMI) >40 kg/m2 
• 
Presence of any pulmonary vein stents 
• 
Known presence of any pre-existing pulmonary vein stenosis 
• 
Pre-existing hemidiaphragmatic paralysis 
• 
Presence of any cardiac valve prosthesis 
• 
Moderate or severe mitral valve regurgitation or stenosis  
• 
Any cardiac surgery, myocardial infarction, PCI / PTCA or 
coronary artery stenting which occurred during the 90 day 
interval preceding the date the subject signed the Informed 
Consent Form 
• 
Unstable angina 
• 
NYHA class III or IV congestive heart failure and/or known left 
ventricular ejection fraction (LVEF) less than 45%  
• 
Diagnosis of primary pulmonary hypertension 
• 
Rheumatic heart disease 
• 
Thrombocytosis, thrombocytopenia 
• 
Contraindication to anticoagulation therapy 
• 
Active systemic infection 


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• 
Hypertrophic cardiomyopathy 
• 
Cryoglobulinemia 
• 
Known reversible causes of AF, including but not limited to 
uncontrolled hyperthyroidism, severe obstructive sleep apnea, 
and acute alcohol toxicity. 
• 
Any cerebral ischemic event (strokes or TIAs) which occurred 
during the 180 day interval preceding the date the subject 
signed the Informed Consent Form, or any known unresolved 
complications from previous stroke/TIA 
• 
Existing thrombus 
• 
Pregnancy 
• 
Patient with life expectancy that makes it unlikely 12 months of 
follow-up will be completed.   
• 
Current or anticipated participation in any other clinical trial of a 
drug, device or biologic during the duration of this study not 
pre-approved by Medtronic 
• 
Patients with contraindications to a Holter monitor 
• 
Unwilling or unable to comply fully with study procedures and 
follow-up 
Study Procedures and 
Assessments 
Subjects in the treatment arm will undergo a pulmonary vein isolation 
(PVI) ablation procedure with the Arctic Front Advance™ Cardiac 
CryoAblation Catheter.   
Subjects in the control arm will be treated with an antiarrhythmic drug 
as prescribed by the study investigator.   
Subjects will have follow-up visits at 1, 3, 6, and 12 months post-AAD 
initiation or ablation.  Subjects will be exited at the conclusion of the 12 
month visit.   
Safety Assessments 
Adverse event data collection will begin once subjects sign the Informed 
Consent Form and will continue through study exit.  For the purposes of 
the study, the following Adverse Events will be collected: 
• 
All procedure related AEs 
• 
All cryoablation system related AEs 
• 
All AAD related AEs 
• 
All cardiovascular related AEs 
• 
All Serious Adverse Events (SAEs), regardless of relatedness 


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4. Introduction  
4.1. 
Background  
Atrial Fibrillation (AF) is a common and disabling cardiac arrhythmia with a heterogeneous clinical 
presentation.  The fundamental pathophysiology consists of atrial wavelets propagating in different 
directions, causing disorganized atrial depolarization without effective atrial contraction, with concomitant 
rapid and irregular ventricular contractions.  AF can be clinically stratified based on whether episodes are 
self-terminating (paroxysmal) or persistent.  Paroxysmal AF (PAF) is defined as recurrent AF (≥ 2 
episodes) that terminates spontaneously within 7 days.  Persistent AF is defined as continuous AF that is 
sustained for greater than 7 days (Calkins, et. al. 2012). 
AF is the most common of the sustained arrhythmias affecting millions of people worldwide. In the US, 
AF affects between 2.7 million and 6.1 million adults (January, et al. 2014), and that number is expected 
to double over the next 25 years (Go, et al. 2001).  Prolonged AF may lead to electrical, mechanical, and 
structural changes to the left atrium, which may then progress to tachycardia-induced cardiomyopathy, 
heart failure and persistent AF.  The prognosis is related to the underlying cause of the disease, with 
idiopathic causes having the best prognosis and ischemic cardiomyopathy having a poor prognosis.  The 
mortality rate in patients with AF is twice that of patients without AF and the risk of AF-related stroke is 
5-fold compared to the risk in patients without AF (Wolf, Abbott and Kannel 1991). 
In the US, approved treatment options for newly diagnosed symptomatic paroxysmal AF are limited to 
pharmaceutical therapy because the labeling of cardiac ablation catheters is for “drug refractory” 
patients.  Patients must be refractory or intolerant to at least 1 class I or III antiarrhythmic drug (AAD) 
before ablation may be attempted.  Pharmacological therapy for AF (paroxysmal and persistent) has 
limited antiarrhythmic efficacy, with recurrence of AF reported at 44% to 67% within one year, based on 
a systematic review of 45 randomized controlled clinical trials (Lafuente-Lafuente, et al. 2006).  
Treatment with AADs may also result in an increased risk for adverse events. Results of an AFFIRM sub 
study showed that adverse events resulting in discontinuation of the treatment were common for AADs, 
occurring in 11.1% to 28.1% of patients, depending on the AAD used (AFFIRM First Antiarrhythmic Drug 
Substudy Investi. 2003).  The RAAFT-2 study found that AAD’s had a success rate of 42% at one year in 
61 previously treatment-naive paroxysmal AF patients; meanwhile, the 2014 AHA/ACC/HRS guideline for 
the management of patients with AF stated that “much like other antiarrhythmic drugs, with the 
exception of amiodarone, the rates of maintaining sinus rhythm at 1 year for sotalol are 30 -50%” 
(January et. al. 2014) (Morillo, et al. 2014). 
Atrial fibrillation is known to cause electrical remodeling of the atria as well as structural changes that 
promote perpetuation and progression of symptoms (Wijesurendra and Casadei 2015) (Shulka and Curtis 
2014) (Jalife and Kaur 2015).  Untreated PAF can give rise to persistent or permanent forms of the 
disease (De Vos, et al. 2010), which may be more resistant to contemporary AF treatments (Oral, et al. 
2002) (Romero, et al. 2015).  As such, early and effective intervention is key for normalizing sinus rhythm 
(SR) and preventing further remodeling and disease progression (Nattel, et al. 2014) (Cosio, et al. 2008).  
AAD treatments have little to no effect on remodeling (Nattel, et al. 2014) and although may restore SR 
in the short-term, have high long-term relapse rates (45-90%) (Cosio, et al. 2008) making this treatment 
largely ineffective at preventing progression of AF.  By contrast, early evidence seems to indicate that 
catheter ablation may reverse indicators of structural remodeling associated with AF (Walters, et al. 
2016) (Wu, et al. 2016).  Furthermore, catheter ablation, particularly using the Arctic Front Advance™ 
Cardiac CryoAblation Catheter, hereafter also referred to as the cryoballoon, has a much higher efficacy 
rate and may be even more effective when provided earlier after AF onset (Arena, et al. 2016) (Tanner, 
et al. 2011). 


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Catheter ablation treatment strategies for AF have evolved over time and currently include pulmonary 
vein isolation (PVI) as a cornerstone of ablation therapy in all types of AF (paroxysmal and persistent) 
(Raviele 2012) (Jais, et al. 2006).  AF arises primarily from the left side of the heart in (or near) the 
atrium, particularly where the pulmonary veins (PVs) join the atrium.  The fundamental basis for the AF 
ablation procedure is the creation of myocardial lesions that block the propagation of AF wave fronts from 
the triggering source.  The muscular sleeves within the PVs have been established as a critical source of 
AF triggers (Caulkins and et. al. 2007). 
The safety profile of cryoballoon ablation is also well established. The STOP AF trial (Packer, et al. 2013) 
was a prospective, multicenter, randomized, controlled investigation device exemption (IDE) study 
designed to compare outcomes of cryoballoon and antiarrhythmic drug therapies in patients with PAF.  
Six point one percent (6.1%) of cryoballoon subjects experienced a procedure-related event or major 
adverse event versus 8.5% of AAD subjects.  An analysis of 149 cryoballoon studies with 11,242 patients 
(see Appendix A for literature search methodology) showed similar complication rates to STOP AF. 
The STOP AF Post Approval Study was designed to provide long-term safety and effectiveness of the 
Arctic Front and Arctic Front Advance™ Cardiac Cryoablation Catheter System, including the Freezor® 
MAX Cardiac cryoablation catheter according to the Product Labeling.  Inexperienced users were selected 
as study Investigators in order to understand complication rates in a real world setting.  There were 402 
subjects enrolled.  The study is currently in the follow-up phase, with all enrolled subjects having been 
followed for one year post-ablation procedure.  Major procedure related events occurred in 20/341 
patients (5.9% of patients and 5.7% of procedures).  No device or procedure related deaths were 
reported (Knight, et al. 2016). 
4.2. 
Purpose 
The purpose of the STOP AF First study is to provide data demonstrating the safety and effectiveness of 
the Arctic Front AdvanceTM Cardiac CryoAblation Catheter for the treatment of recurrent symptomatic 
paroxysmal AF, without the requirement that subjects be drug refractory.  The current indication is the 
US is as follows: The Arctic Front Advance™ Cardiac CryoAblation Catheter is indicated for the treatment 
of drug refractory recurrent symptomatic paroxysmal atrial fibrillation.  The proposed indication in the US 
is as follows: The Arctic Front Advance™ Cardiac CryoAblation Catheter is indicated for the treatment of 
recurrent symptomatic paroxysmal atrial fibrillation. The proposed indication is within the approved 
indications for use in Europe. 
 
 


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5. Objectives and Endpoints 
5.1. 
Objectives 
 
Primary Objective(s) 
5.1.1.
5.1.1.1. Primary Efficacy Objective 
Demonstrate the superiority of cryoballoon ablation as compared to AAD therapy in terms of the rate of 
freedom from AF/AT/AFL in a non-drug refractory paroxysmal AF population. 
5.1.1.2. Primary Safety Objective 
Demonstrate an acceptable safety profile of the cryoballoon ablation procedure as a first line therapy in a 
non-drug refractory paroxysmal AF population. 
 
Secondary Objectives 
5.1.2.
Secondary Objectives are as follows: 
1. Assess changes in quality of life between baseline and 12 months in the cryoballoon ablation 
arm.   
2. Compare health care utilization between the treatment and control arms.   
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 


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Primary Endpoint 
5.1.4.
5.1.4.1. 
Primary Efficacy Endpoint 
The primary endpoint is treatment success at 12 months after AAD initiation (control arm) or after the 
pulmonary vein isolation ablation procedure utilizing the Arctic Front Advance™ Cardiac CryoAblation 
Catheter (treatment arm).  A treatment success is the opposite of a treatment failure. 
Treatment failure is defined as any of the following components: 
a) Acute procedural failure (treatment arm only) 
b) Documented AF/AT/AFL on ambulatory monitoring/12-lead ECG after the 90 day post-ablation 
blanking period (treatment arm)/AAD optimization period (control arm).   
o 
Minimum of 30 seconds on ambulatory monitoring or 10 seconds on 12-lead ECG. 
o 
Note: Documented occurrence and treatment of typical right-sided cavotricuspid isthmus 
dependent atrial flutter is not considered a failure if confirmed by entrainment 
maneuvers during EP testing. 
c) Any subsequent AF surgery or ablation in the left atrium. 
d) Any subsequent cardioversion after the 90 day post-ablation blanking period (treatment 
arm)/AAD optimization period (control arm). 
e) Class I or III antiarrhythmic drug (or sotalol) use after the 90 day blanking period (treatment arm 
only). 
The AAD optimization period is defined as the first 90 days after AAD initiation (control arm).  The post-
ablation blanking period is defined as the first 90 days after the index ablation procedure (treatment 
arm).  Recurrences of atrial arrhythmias during the AAD optimization/blanking periods will not be counted 
in the determination of the first clinical failure for the primary endpoint.   
Within the AAD optimization period/post-ablation blanking period, recurrent arrhythmias can be managed 
with medications or cardioversions.  Reablation will be considered a primary endpoint failure at all times, 
including during the 90 day post-ablation blanking period. 
Acute procedural failure (treatment arm only) is defined as: 
a) Inability to isolate all accessible targeted pulmonary veins (assessed for entrance block and, 
where assessable, exit block) during the index ablation procedure. 
b) Left atrial non-PVI ablations including but not limited to, ablation of linear lesions  
c) Use of a non-study device in the left atrium. 
 
 


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5.1.4.2. 
Primary Safety Endpoint 
The following adverse events will be counted towards the primary safety endpoint:  
• 
TIA within 7 days 
• 
Cerebrovascular accident within 7 days 
• 
Major bleeding that requires transfusion or results in a 20% or greater fall in hematocrit (HCT) 
within 7 days 
• 
Development of a significant pericardial effusion within 30 days.   A significant pericardial 
effusion is one that results in hemodynamic compromise, requires elective or urgent 
pericardiocentesis, or results in a 1-cm or more pericardial effusion as documented by 
echocardiography.  
• 
Symptomatic PV stenosis within 12 months; accompanied by one of the following: 50%-75% 
reduction in diameter of the pulmonary vein, with symptoms not explained by other conditions; 
OR >75% reduction in diameter of the pulmonary vein  
• 
MI within 7 days 
• 
PNI unresolved at 12 months 
• 
Atrial-esophageal fistula within 12 months 
• 
Major vascular complication that requires intervention, prolongs the hospital stay, or requires 
hospital admission (within 7 days).   
 
 


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Secondary Endpoints 
5.1.5.
1. The difference in composite scores from the AFEQT questionnaire taken at baseline and 12 
month visits, and the difference in composite scores for the EQ-5D questionnaire taken at 
baseline and 12-month visits.  
• 
The AFEQT and EQ-5D questionnaires will be utilized for this objective.  The AFEQT 
questionnaire is an atrial fibrillation specific health-related quality of life questionnaire to 
assess the impact of AF on a subject’s life.  The overall score ranges from 0–100, where 0 
corresponds to complete disability and 100 correspond to no disability.  The EQ-5D 
questionnaire is a standardized instrument for measuring generic health status.  The EQ-5D 
has two sections.  The first section is a descriptive section where the subject checks a box by 
the most appropriate statement.  The second section is a visual analog scale. 
2. 12-month rates of cardiovascular health care utilization (HCU) events, and 12-month rates of 
cardioversion (either electrical or pharmacological). 
• 
The number of cardiovascular-related hospitalizations, emergency department visits, and 
unscheduled visits will be reported and compared between the treatment and control arms.   
• 
The number of electrical and pharmacological cardioversions experienced by subjects will be 
reported and compared between the treatment and control arms.    
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.1. 
Duration 
All randomized study subjects will be followed from the time of consent through 12 months post-index 
cryoballoon ablation procedure (treatment arm), or AAD initiation (control arm). 
Subjects will be exited from the study at the conclusion of the 12 month follow-up visit.  The expected 
total study duration is approximately 30 months, representing 18 months of enrollment and 12 months of 
subject follow-up.  Subjects will not be replaced with newly enrolled subjects upon early study exit. The 
objectives will be analyzed for a Premarket Approval Supplement (PMA-S) after all randomized subjects 
complete 12 months of follow-up after the index cryoballoon ablation procedure (treatment arm), or AAD 
initiation (control arm). 
6.2. 
Rationale 
The study has primary objectives designed to evaluate the safety and effectiveness of the Arctic Front 
Advance™ Cardiac CryoAblation Catheter for treatment of recurrent symptomatic paroxysmal AF.  In the 
US, there are no ablation catheters approved to treat patients with paroxysmal AF unless they have 
demonstrated intolerance or refractoriness to anti-arrhythmic drug therapy.  The study will provide 
patients with more options for treatment and the possibility of improving their health and quality of life 
and a decrease in stroke risk.  If successful, the STOP AF First study will demonstrate meaningful 
therapeutic benefit in this population.  This evaluation will support an indication expansion for the 
treatment of recurrent symptomatic paroxysmal AF.  The study will be considered successful if it meets 
the primary objectives, contingent upon FDA review and approval. 
The study will compare cryoablation to AAD therapy, the current standard of care for subjects 
experiencing atrial fibrillation for the first time.   
Cryoablation efficacy will be demonstrated by showing that subjects in the cryoablation arm will 
experience a higher rate of efficacy success than the AAD arm (treatment success described in Section 
5.1.4.1).  The STOP AF Pivotal trial showed an efficacy success rate of 69.9%.  Several trials were 
completed comparing radiofrequency ablation to AADs in the same non-drug refractory patient population 
(Nielsen, et al. 2012) (Morillo, et al. 2014) (Wazni, et al. 2005).  The RAAFT-2 study monitored for 
recurrent arrhythmia in a manner similar to the requirements of this protocol; they required regular and 
symptomatic transtelephonic monitor transmissions (Morillo, et al. 2014).  In RAAFT-2, approximately 
45% of subjects in the AAD arm experienced recurrent atrial fibrillation by one year.  The superiority 
analysis in this study is designed to show that subjects in the cryoablation treatment arm will experience 
less AF recurrence than subjects in the AAD arm, assuming similar recurrence rates to those in the STOP 
AF Pivotal trial and RAAFT-2.   
Cryoablation safety will be demonstrated by showing that the rate of a pre-specified list of known 
potential complications is consistent with previous trials and current literature (Packer, et al. 2013). 
 
 


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6.3. 
Minimization of Bias 
Selection of subjects, treatment of subjects, and evaluation of study data are potential sources of bias.  
Methods incorporated in the study design to minimize potential bias include (but are not limited to): 
• 
Subjects will undergo screening to confirm eligibility for enrollment with defined 
inclusion/exclusion criteria prior to enrollment. 
• 
Subject demographics will be collected at baseline in order to later assess possible characteristics 
that may influence endpoints. 
• 
All centers and geographies will use the same version of the clinical investigation plan and case 
report forms. 
• 
All investigational center personnel and Medtronic personnel will be trained on their respective 
aspects of the study using standardized training materials. 
• 
All investigational center personnel will be trained on and required to follow the CIP. 
• 
An independent Clinical Events Committee (CEC) will be utilized regularly to review and 
adjudicate reported adverse events and deaths.   
• 
An independent core lab will be utilized to review and adjudicate all ECG recordings from study 
required 12-lead ECGs and ambulatory monitoring. 
• 
A statistical analysis plan (SAP) will be developed prior to analyzing data.  The plan will document 
all pre-specified analyses and analysis methods. 
• 
Monitoring will be conducted to review adherence to the CIP and perform source data verification 
per the Monitoring Plan. 
• 
A maximum of 31 treated subjects will be allowed at a single investigational center to ensure an 
even distribution of total subjects across centers. 
• 
All study investigators in all geographies will be required to comply with 21CFR Part 54, Financial 
Disclosure by Clinical Investigators. 
In summary, potential sources of bias that may be encountered in this clinical study have been 
considered and minimized by thorough, careful study design. 
 
 






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7.2. 
Arctic Front Advance™ Cardiac CryoAblation Catheters 
In the US, the Arctic Front Advance™ Cardiac CryoAblation Catheters (23mm and 28mm) are FDA 
approved and indicated for the treatment of drug refractory recurrent symptomatic paroxysmal atrial 
fibrillation. 
The investigational indication in the US is for the treatment of recurrent symptomatic paroxysmal atrial 
fibrillation without the requirement that the AF be drug refractory. 
In Europe, the Arctic Front AdvanceTM Cardiac CryoAblation Catheters (23mm and 28mm) are CE marked 
and indicated for the treatment of patients with atrial fibrillation.  The catheter is not considered 
investigational for the intended patient population in Europe, as it is being used within the approved 
indication. 
The catheters are sterile, single use, minimally invasive intravascular balloon catheters specifically 
designed for tissue cryoablation.  The Arctic Front Advance™ Cardiac CryoAblation Catheter is used 
together with the CryoConsole and related devices.  Arctic Front Advance™ Cardiac CryoAblation 
Catheters are percutaneously advanced to the heart chamber from the femoral access via a transseptal 
sheath in the vasculature.  Once the catheter reaches the left atrium, the balloon is inflated and the 
cooling segment creates circumferential lesions at the antrum of the targeted pulmonary veins. 
Figure 2: Arctic Front AdvanceTM Cardiac Cryoablation Catheter 
 
7.3. 
Freezor ® MAX Cardiac CryoAblation Catheters 
In the US and Europe, the Freezor® MAX Cardiac CryoAblation Catheter is market released and approved 
for use in the study intended patient population, therefore, is not considered investigational.   
Approved indication in the US: The Freezor® MAX Cardiac CryoAblation Catheter is used as an adjunctive 
device in the endocardial treatment of paroxysmal atrial fibrillation in conjunction with the Arctic Front 
Advance™ Cardiac CryoAblation Catheter. 


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Approved indication in Europe: The Freezor® MAX Cardiac CryoAblation Catheter is intended for use in 
the treatment of cardiac arrhythmias. 
The Freezor® MAX Cardiac CryoAblation Catheter is a flexible, steerable catheter used to ablate cardiac 
tissue.  It is used together with the CryoConsole and related components.  The tip of the Freezor® MAX 
Cryocatheter reaches cryoablation temperatures when refrigerant is injected from the CryoConsole to the 
tip of the catheter.  The catheter tip has an integrated thermocouple for temperature reading capability.  
The catheter is introduced into the vasculature by traditional minimally invasive techniques. 
7.4. 
FlexCath Advance™ Steerable Sheath 
The FlexCath AdvanceTM Steerable Sheath is a percutaneous introducer fitted with a hemostasis valve to 
allow for introduction, withdrawal and swapping of catheters and wires while providing a barrier 
preventing air ingress into the valve and minimizing blood loss.  A side-port with stopcock is integrated 
into the hemostasis valve to allow continuous drip infusion, injection through the center lumen, flushing, 
aspiration, blood sampling and pressure monitoring.  The FlexCath AdvanceTM Steerable Sheath is 
intended to allow sheath deflection to facilitate catheter positioning.  It is supplied sterile and packaged 
together with a dilator. 
 
Figure 3: FlexCath AdvanceTM Steerable Sheath with Cryoablation Catheter 
 
7.5. 
Achieve™ or Achieve Advance™ Mapping Catheter 
The AchieveTM and Achieve AdvanceTM Mapping Catheters are intra-cardiac electrophysiology diagnostic 
catheters indicated for multiple electrode electrophysiological mapping of the cardiac structures of the 
heart, i.e., recording or stimulation only.  The AchieveTM and Achieve Advance Mapping Catheters are 
designed to obtain electrograms in the atrial regions of the heart. 


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Figure 4: Achieve™ Mapping Catheter 
 
7.6. 
CryoCath CryoAblation Console 
The CryoConsole houses the electronics and compatible software for controlling and recording the 
ablation procedure, stores and controls delivery of liquid refrigerant under high pressure through the co-
axial umbilical to the catheter, recovers the expanded refrigerant vapor from the catheter under vacuum, 
and disposes of the refrigerant through the hospital scavenging system. 
The hardware controls the safety monitoring system while the software provides the user interface 
patient information, procedure temperature, time set point in automatic mode and procedure data 
information. 
Figure 5: CryoCath CryoAblation Console 
 


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7.7. 
Coaxial Umbilical Cable 
The Sterile Coaxial Umbilical delivers the Nitrous Oxide (N2O) gas from the console to the catheter and 
transports refrigerant vapors from the catheter to the console, which is then vented into the hospital 
scavenging system. 
Figure 6: Coaxial Umbilical Cable 
 
7.8. 
Electrical Umbilical Cable 
The Sterile Electrical Umbilical is an electrical extension cable that transports: 
• 
Temperature feedback from the catheter to the console 
• 
Leak detection signals from the catheter to the console 
• 
Blood sensor signals from the catheter to the console 
• 
Pressure sensor form the catheter to the console 
 
Figure 7: Electrical Umbilical Cable 
 
 
 
7.9. 
Manual Retraction Kit 
The manual retraction kit contains one large syringe, one 3-way stopcock and a coaxial-to-luer adaptor.  
The kit is used during the rewrap procedure of the Arctic Front Advance™ Cardiac CryoAblation Catheter 
if the physician cannot retract the catheter using the normal catheter retraction cycle. 


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Figure 8: Manual Retraction Kit 
 
7.10. Additional Study Devices 
Medtronic may incorporate additional components, software, and devices into this clinical study as they 
receive appropriate license or regulatory approval and are released commercially by Medtronic in the 
region where they will be used providing that the scientific soundness of the study is not adversely 
affected as evaluated by Medtronic. 
7.11. Product Training Requirements 
Physicians performing the cryoablation procedure must have been trained in the handling of Arctic Front 
Advance™ Cardiac CryoAblation Catheter and CryoCath Cardiac CryoAblation System.  They must be 
qualified by Medtronic AF Solutions Training and Education (US ONLY), and must have performed at least 
20 ablation procedures with Arctic Front or Arctic Front Advance™ and associated products. 
7.12. Packaging 
In the US and Europe, the Arctic Front Advance™ Cardiac CryoAblation Catheters will not be labeled as 
investigational.  These devices will be considered investigational upon opening per the CIP (US only). 
Commercially available products will be used for the study. 
7.13. Investigational Device Storage, Handling and Traceability 
The Arctic Front Advance™ Cardiac CryoAblation Catheters used in this study are commercially available 
in the US and Europe; they will not be labeled as investigational and will not be provided to the 
investigational centers. 
The Arctic Front Advance™ Cardiac CryoAblation Catheter will be considered investigational in the US 
when opened with the intent to use in this study.  The catheter is market-released and will be used 
within the approved indication in Europe, therefore, will be considered non-investigational in Europe. 
In the US, device tracking information will be entered into the study database for any catheter that is 
considered investigational in this study.  The device tracking information must be maintained and 
updated when the investigational catheter is disposed of or returned to Medtronic. 


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NOTE: this is a deviation to Section 18.1 of the ISO standard because device accountability for the Arctic 
Front Advance™ Cardiac CryoAblation Catheters will not be performed in Europe and only upon package 
opening with the intent of using the catheter for a study subject in the US. 
 
 


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8. Investigator/Investigator Center Selection 
All clinical Investigators managing the subject’s arrhythmia must be qualified practitioners and 
experienced in the diagnosis and treatment of subjects with atrial arrhythmias. Investigators performing 
the cryoablation procedure must have been trained in the handling of Arctic Front Advance™ Cardiac 
CryoAblation Catheters. 
 
The role of the Principal Investigator is to implement and manage the day-to-day conduct of the clinical 
investigation as well as ensure data integrity and the rights, safety and well-being of the subjects 
involved in the clinical investigation. 
 
The minimum required criteria for a Principal Investigator and proposed investigational center are listed 
below: 
• 
Investigator/site is qualified by training, education, and relevant experience appropriate to the 
use of the product and associated procedures.   
• 
Investigator/site expects to have adequate time and resources to conduct the study throughout 
the duration of the study. 
• 
Investigator/site has access to an adequate number of eligible subjects.  
• 
Ability to comply with applicable Institutional Review Board (IRB)/Ethics Committee (EC) and 
regulatory requirements. 
• 
Investigator is not debarred, disqualified, or working under sanctions in applicable regions. 
 
Center personnel training will be completed prior to participation in this clinical study. 
 
 


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9. Center Activation 
During the activation process (prior to subject enrollment), Medtronic will train center personnel on the 
CIP, relevant standards and regulations, informed consent, and on data collection and reporting tools. If 
new members join the study center team, they will receive training on the applicable clinical study 
requirements relevant to their role before contributing to the clinical study. 
 
Prior to performing study related activities, all local regulatory requirements shall be fulfilled, including, 
but not limited to the following: 
 
• 
IRB/MEC approval (and membership roster/voting list) of the current version of the CIP, Patient 
Informed Consent Form, subject facing materials, Report of Prior Investigation, Investigator 
Brochure as required by local laws and other materials, as necessary. 
• 
Regulatory authority approval or notification (as required per local law) 
• 
Fully executed Clinical Trial Agreement (CTA) and Investigator Statement where applicable 
• 
Financial Disclosure of Investigators 
• 
Curriculum Vitae (CV) of Investigators and key members of the investigation center team (as 
required by local law) (in Europe, CVs are required for the Principal Investigator and all center 
members who have been delegated tasks) 
• 
Documentation of delegated tasks 
• 
Documentation of study training 
 
Documentation of delegated tasks must be completed prior to any person other than the Principal 
Investigator performing study activities. 
 
Additional requirements imposed by the IRB/MEC and regulatory authority shall be followed. 
 
In addition, all participating center staff must be trained on the current version of the CIP and must be 
delegated by the Principal Investigator to perform study related activities. 
 
Medtronic will provide each study center with documentation of study center/Investigator readiness in the 
form of a center readiness letter; this letter must be received prior to subject enrollment. Additional 
center personnel included after the initial activation will be notified when all requirements have been 
completed. 
 
 


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10. Selection of Subjects 
10.1. Study Population 
The study population includes adult patients with recurrent symptomatic paroxysmal atrial fibrillation.  
The AF classifications that will be used for this study are defined in the 2012 HRS/EHRA/ECAS Expert 
Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation. (Calkins, et. al. 2012) 
Paroxysmal AF is defined as recurrent AF (≥2 episodes) that terminates spontaneously within 7 days.  
Episodes of AF ≤ 48 hours’ duration that are terminated with electrical or pharmacologic cardioversion 
will be classified as paroxysmal AF episodes. 
Patients in persistent AF are excluded from the study.  Persistent AF is defined as continuous AF that is 
sustained beyond 7 days.  Episodes of AF in which a decision is made to electrically or pharmacologically 
cardiovert the patient after ≥ 48 hours of AF, but prior to 7 days, will also be classified as persistent AF 
episodes. 
10.2. Subject Enrollment 
Patients will be screened to ensure they meet all of the inclusion criteria and none of the exclusion 
criteria prior to study enrollment. Institutional Review Board (IRB)/Ethics Committee (EC) and Medtronic 
approval of this CIP and the Informed Consent Form (ICF) must be obtained prior to enrolling subjects in 
the study.  Subjects are considered enrolled in the study upon signing and dating the ICF. Subjects must 
provide informed consent (IC) before any study related procedures occur. 


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10.3. Inclusion Criteria 
• 
A diagnosis of symptomatic paroxysmal AF with the following documentation: (1) physician’s note 
indicating recurrent self- terminating AF or paroxysmal AF; and (2) any ECG documented AF 
within 6 months prior to enrollment.  
• 
Age 18-80 
10.4. Exclusion Criteria 
• 
History of AF treatment with class I or III antiarrhythmic drug, including sotalol, with the 
intention to prevent an AF recurrence.  However, patients pretreated with above AAD for less 
than 7 days with the intention to convert an AF episode are allowed. 
• 
Prior persistent AF (cardioversion after 48 hours or continuous AF that is sustained  >7 days) 
• 
Left atrial diameter greater than 5.0 cm 
• 
Prior left atrial ablation or left atrial surgical procedure 
• 
Presence or likely implant of a permanent pacemaker, biventricular pacemaker, loop recorder, or 
any type of implantable cardiac defibrillator (with or without biventricular pacing function) 
• 
Body mass index (BMI) >40 kg/m2 
• 
Presence of any pulmonary vein stents 
• 
Known presence of any pre-existing pulmonary vein stenosis 
• 
Pre-existing hemidiaphragmatic paralysis 
• 
Presence of any cardiac valve prosthesis 
• 
Moderate or severe mitral valve regurgitation or stenosis  
• 
Any cardiac surgery, myocardial infarction, PCI / PTCA or coronary artery stenting which occurred 
during the 90 day interval preceding the date the subject signed the Informed Consent Form 
• 
Unstable angina 
• 
NYHA class III or IV congestive heart failure and/or known left ventricular ejection fraction 
(LVEF) less than 45%  
• 
Diagnosis of primary pulmonary hypertension 
• 
Rheumatic heart disease 
• 
Thrombocytosis, thrombocytopenia 
• 
Contraindication to anticoagulation therapy 
• 
Active systemic infection 
• 
Hypertrophic cardiomyopathy 
• 
Cryoglobulinemia 
• 
Known reversible causes of AF, including but not limited to uncontrolled hyperthyroidism, severe 
obstructive sleep apnea, and acute alcohol toxicity. 
• 
Any cerebral ischemic event (strokes or TIAs) which occurred during the 180 day interval 
preceding the date the subject signed the Informed Consent Form, or any known unresolved 
complications from previous stroke/TIA 
• 
Existing thrombus 
• 
Pregnancy 
• 
Patient with life expectancy that makes it unlikely 12 months of follow-up will be completed. 


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• 
Current or anticipated participation in any other clinical trial of a drug, device or biologic during 
the duration of this study not pre-approved by Medtronic 
• 
Patients with contraindications to a Holter monitor 
• 
Unwilling or unable to comply fully with study procedures and follow-up 
 
 


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11. Study Procedures  
Prior to performing study related procedures, all sites must have IRB/EC approval as well as 
documentation from Medtronic of center readiness. 
11.1. Schedule of Events 
The visit schedule and data collection requirements are summarized in Table 5. 
Table 5: Visit Schedule and Data Collection Requirements Summary 
 
Baseline 
Procedure 
Hospital 
Discharge 
1M 
3M  
6 & 12 M 
Unscheduled 
Reablation/ 
Crossover Ablation 
Treatment 
Arm Only 
Informed Consent 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
Pregnancy Screening1 
X 
 
 
 
 
 
 
 
Review Medications 
X 
 
X 
X 
X 
X 
X 
X 
Review of AF Symptoms 
X 
 
 
X 
X 
X 
X 
X 
Collect Health Care Utilization 
Information  
 
 
 
X 
X 
X 
X 
X 
12 Lead ECG 
X 
 
X 
X 
X 
X 
X 
 
EQ-5D & AFEQT 
X 
 
 
 
 
X 
 
X 
Trans-thoracic Echocardiogram 
(TTE)2 
X 
 
 
 
 
 
 
 
Trans-esophageal 
Echocardiogram (TEE)3 
 
X 
 
 
 
 
 
X 
                                               
 
1 Required only for female subjects of childbearing potential. 
2 Only required if data not available from within prior 6 months from consent date. 
3 TEE must be performed in all subjects who present to the ablation procedure in atrial fibrillation lasting more than 48 hours in 
duration (or of an unknown duration).  However, the TEE is not required if the subject has adequate systemic anticoagulation that 
has been maintained for at least 3 weeks prior to presenting to the ablation procedure in AF.  TEE must be performed if subjects 
have a CHA2DS2-VASc ≥2 and present to the procedure with a sub-therapeutic INR  (<2.0) or if the subject has had a significant 
interruption of NOACs. A significant interruption of NOACs is defined as any missed dose within 21 days prior to the ablation 
procedure.  


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Baseline 
Procedure 
Hospital 
Discharge 
1M 
3M  
6 & 12 M 
Unscheduled 
Reablation/ 
Crossover Ablation 
Treatment 
Arm Only 
Ablation Procedure Data 
 
X 
 
 
 
 
 
X 
24 hour continuous ambulatory 
ECG monitoring 
 
 
 
 
 
X 
 
 
Patient Activated Ambulatory 
ECG Monitoring4 
 
 
 
 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Device Deficiencies 
As they occur 
Study Deviations 
As they occur 
Chest X-ray  
(treatment arm only) 
If phrenic nerve injury is detected during the procedure, 
the subject will be evaluated with inspiration/expiration 
chest x-ray at PHD and all follow-up visits until resolved. 
MRI or CT Scan  
(treatment arm only) 
Required only for subjects with suspected PV stenosis.   
11.2. Medications 
Information regarding drugs prescribed to treat atrial arrhythmias will be collected, including the purpose 
for their use/reason for modification, and start and stop dates. Information regarding anticoagulation 
mediations will be collected, including start and stop dates. 
Control Arm (AAD):  Subjects must initiate a Class I or III AAD within 30 days of randomization.  It is 
recommended that AADs be initiated as soon as possible after randomization, with a target of within 14 
days.  The investigator should choose the appropriate AAD per his or her standard of care; however, 
amiodarone should only be used if other AADs were not tolerated or failed.  The 2014 AHA/ACC/HRS 
Guideline for the Management of Patients with AF should be consulted for AAD prescriptions.  
Modifications to AADs (type or dosage increase) may be made for up to 90 days after AAD initiation.  This 
is referred to as the AAD optimization period.  Dosing of AADs can be individually tailored until the end of 
the AAD optimization period. After the optimization period, further AAD therapy optimization or change 
should be avoided or at least allowed only up to physicians’ discretion to guarantee the safety of the 
patients.  The possible concomitant use of beta blockers can still be optimized after the optimization 
period. 
                                               
 
4 Subjects shall submit ECG transmissions weekly and whenever symptoms occur after the AAD optimization/post-ablation blanking 
periods through 12 month follow-up.   


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Treatment Arm (Cryoablation):  Subjects may be prescribed Class I or III AADs for up to 80 days 
post-ablation procedure at the discretion of the Investigator.  Subjects must stop taking all Class I or III 
AADs before day 81 post-ablation.  Use of amiodarone is not permitted. 
Anticoagulation requirements for all subjects: 
Anticoagulation pre-procedure should be determined based upon the subjects CHA2DS2-VASc score.   
a. Oral anticoagulants are required if the subject has had a prior stroke or TIA, or if the subject 
has a CHA2DS2-VASc score ≥2.  When anticoagulation is required, subjects must take it for 
at least 21 days prior to an ablation procedure.   
b. Oral anticoagulants are not required for subjects with nonvalvular AF and a CHA2DS2-VASc 
score of 0 or 1. 
Note:  TEE must be performed within one day prior to the cryoablation procedure if subjects have a 
CHA2DS2- VASc ≥2 and present to the procedure with a sub-therapeutic INR (<2.0) or if the subject has 
had a significant interruption of NOACs.  A significant interruption of NOACs is defined as any missed 
dose within 21 days prior to the ablation procedure. 
11.3. Subject Consent 
Patient informed consent (IC) is defined as a legally effective documented confirmation of a subject’s (or 
their legally authorized representative, US ONLY) voluntary agreement to participate in a particular 
clinical study after information has been given to the subject on all aspects of the clinical study that are 
relevant to the subject’s decision to participate. This process includes obtaining an Informed Consent 
Form (ICF) and an Authorization to Use and Disclose Personal Health Information that has been approved 
by the study center’s IRB/EC and signed and dated by the subject (or their legally authorized 
representative, US ONLY). A subject may only consent after information has been given to the subject on 
all aspects of the clinical investigation that are relevant to the subject’s decision to participate. Informed 
consent may be given by their legally authorized representative (US ONLY) only if a subject is unable to 
make the decision to participate in a clinical investigation. In such cases, the subject shall also be 
informed about the clinical investigation within his/her ability to understand. 
 
Prior to enrolling subjects, the ICF must have been approved by each center’s IRB/EC. Each site must 
also use an Authorization to Use and Disclose Personal Health Information/Research Authorization/other 
privacy language as required by law. The ICF must be controlled (i.e. versioned and dated) to ensure it is 
clear which version(s) were approved by the IRB/EC. Any modifications to the sample ICF must be 
reviewed and approved by Medtronic and the IRB/EC reviewing the application prior to enrolling subjects.  
 
The Investigator must notify the subject (US ONLY: or their legally-authorized representative) of any 
significant new findings about the study that become available during the course of the study which are 
pertinent to the safety and well-being of the subject. This could impact a subject’s willingness to 
participate in the study. If relevant, approval may be requested from subjects to confirm their continued 
participation. 
 
Prior to initiation of any study-specific procedures, documented IC must be obtained from the subject (or 
their legally authorized representative, US ONLY). Likewise, privacy or health information protection 
regulation may require subjects to sign additional forms to authorize centers to submit subject 
information to the study sponsor. The IC process must be conducted by the principal Investigator or an 
authorized designee, and the ICF and the Authorization to Use and Disclose Personal Health 


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Information/Research Authorization/other privacy language as required by law must be given to the 
subject (or their legally authorized representative, US ONLY) in a language he/she is able to read and 
understand. The process of IC must be conducted without using coercion, undue or improper influence 
on, or inducement of the subject to participate by the Investigator or other center personnel. The 
informed consent process shall not waive or appear to waive the subject’s legal rights. The language 
used shall be as non-technical as possible and must be understandable to the subject and the impartial 
witness, where applicable. 
 
The subject must have ample time and opportunity to read and understand the ICF to inquire about 
details of the study, and to decide whether or not to participate in the clinical study. All questions about 
the study should be answered to the satisfaction of the subject. When the subject decides to participate 
in the clinical study, the ICF and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law must be signed and 
personally dated by the subject (or their legally authorized representative, except in Europe) and either 
the Investigator or the Investigator’s authorized designee, as required by local law. If applicable, witness 
shall also sign and personally date the consent form to attest that the information in the ICF was 
accurately explained and clearly understood by the subject, and that IC was freely given. 
 
In Europe, include a personally dated signature by the Principal Investigator or authorized designee 
responsible for conducting the informed consent process. The Principal Investigator or designee must 
conduct the informed consent discussion. 
 
A copy of the ICF and the Authorization to Use and Disclose Personal Health Information/Research 
Authorization/other privacy language as required by law, signed and dated as required by law, must be 
provided to the subject. 
 
If consent is obtained the same day the subject begins participating in study-related procedures, it must 
be documented in the subject’s case history that consent was obtained prior to participation in any study 
related procedures. It is best practice for the IC process to be documented in the subject’s case history, 
regardless of circumstance. In the event the subject cannot read and/or write, a witnessed (impartial 
third party) ICF will be allowed, provided detailed documentation of the process is recorded in the 
subject’s case history and the witness signs and dates the ICF to attest that the information was 
accurately explained and that informed consent was freely given. In Europe, when a subject cannot read 
and/or write, an independent witness shall be present throughout the process, the written ICF and any 
other information shall be read aloud and explained to the prospective subject. The subject should “make 
his mark” (sign or otherwise physically mark the document so as to indicate consent) on the ICF as well. 
The ICF should document the method used for communication with the prospective subject and the 
specific means by which the prospective subject communicated agreement to participate in the study. 
 
The original of the signed ICF and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law must be filed in the 
hospital/clinical chart and/or with the subject’s study documents. The ICF and the Authorization to Use 
and Disclose Personal Health Information/Research Authorization/other privacy language as required by 
law should also be available for monitoring and auditing. Any Medtronic Field personnel who support the 
study procedure must be able to review the subject’s signed and dated ICF and verify its completeness 
prior to proceeding with the procedure. In the event the Medtronic Field personnel identify an ICF as 
being incomplete, the study procedure will not be allowed to occur until the consent of the subject can be 
adequately and appropriately obtained. 


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11.4. Randomization and Treatment Assignment 
Enrolled subjects are eligible for randomization after all inclusion and none of the exclusion criteria are 
met and after the baseline QoL questionnaires are completed.  Subjects will be randomized in a 1:1 
fashion to undergo a cryoablation procedure (treatment arm) or receive AAD therapy (control arm).   
See Section 11.5.2 for control arm procedures and Section 11.5.3 for treatment arm procedures. 
Subjects will be randomized using an electronic randomization system.  The randomization schedule will 
be stratified by study site to ensure that within each study site randomization is approximately 1:1.   
Subjects will be analyzed according to a modified intention-to-treat protocol: subjects who withdraw their 
informed consent prior to the index cryoablation procedure or initiation of AAD therapy will be excluded 
from the analysis of the primary safety and efficacy endpoints. Otherwise, the standard intention-to-treat 
protocol is applied: subjects who receive either therapy, regardless of what it actually is, will be analyzed 
according to their randomization status. This allows for the protection of the benefits of randomization, 
while avoiding the problem of attrition and adverse events occurring in the time between randomization 
and the initiation of treatment, which, due to the practicality of scheduling can be up to 30 days. All 
randomized subjects should be encouraged to comply with the study procedures until study closure. 
11.5. Description of All Study Procedures and Visits 
 
Enrollment & Baseline  
11.5.1.
The patient is considered a subject enrolled in the study upon completion of the IC process.  The date 
the subject signed the ICF and HIPAA/data protection authorization/or other privacy language where 
required by law must be documented in the subject’s medical records. 
All baseline assessments must be performed prior to treatment (cryoablation procedure or initiation of 
AADs). The following evaluations will be performed after the subject signs the ICF, unless previously 
performed as part of routine clinical evaluations within the specified windows: 
Within 6 months prior to the date the subject signed the Informed Consent Form: 
• 
Trans-thoracic echocardiogram (TTE) for the collection of left atrial size, left ventricular ejection 
fraction, and mitral valve impairment.  A repeat TTE procedure for the purpose of this study is 
not required if a TTE was performed within 6 months of the date the subject signed the Informed 
Consent Form and all data are available. 
After the date the subject signed the Informed Consent Form, but prior to cryoablation procedure or AAD 
treatment: 
Note: The time between randomization and the procedure/AAD initiation must not exceed 30 days.  It is 
recommended that AAD initiation occur within 14 days of randomization.  It is recommended that the 
cryoablation procedure occur within 21 days of randomization.  


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• 
Assessment of all factors specified for evaluation under Inclusion Criteria and Exclusion 
Criteria (Section 10.3 and 10.4), including TTE (required prior to randomization). 
• 
EQ-5D and AFEQT Questionnaires (required prior to randomization) 
• 
Randomization 
• 
Demographics 
• 
Medical history 
• 
Physical examination 
• 
CHA2DS2-VASc  Score 
• 
Pregnancy screen (required only for female subjects of childbearing potential) 
o 
For this study, a woman of childbearing potential is defined as a premenopausal female 
capable of becoming pregnant (not sterilized or post-menopausal). 
• 
Review of AF symptoms 
• 
12 lead ECG 
• 
Review of medications to treat atrial arrhythmias and anticoagulation medications  
• 
Transesophageal Echocardiogram (TEE) (treatment arm only) 
o 
TEE must be performed in all subjects who present to the ablation procedure in atrial 
fibrillation lasting more than 48 hours in duration (or of an unknown duration).  However, 
the TEE is not required if the subject has adequate systemic anticoagulation that has 
been maintained for at least 3 weeks prior to presenting to the ablation procedure in AF. 
o 
TEE must be performed if subjects have a CHA2DS2- VASc ≥2 and present to the 
procedure with a sub-therapeutic INR (<2.0) or if the subject has had a significant 
interruption of NOACs.  A significant interruption of NOACs is defined as any missed dose 
within 21 days prior to the ablation procedure. 
o 
Performance of a TEE in subjects who are in sinus rhythm at the time of ablation or 
eligible subjects that have been in AF for 48 hours or less prior to AF ablation may be 
considered but is not mandatory. 
o 
The subject will not proceed with the study ablation procedure and will be exited from 
the study if a cardiac thrombus is visualized.  
o 
TEE, when required, must be performed within 1 day of the ablation procedure (on the 
day of or within the day prior to). 
 
Control Arm- AAD Initiation 
11.5.2.
Subjects must initiate a Class I or III AAD within 30 days of randomization.  It is recommended that AADs 
be initiated as soon as possible after randomization, with a target of within 14 days.  The investigator 
should choose the appropriate AAD per his or her standard of care; however, amiodarone should only be 
used if other AADs were not tolerated or failed.  The 2014 AHA/ACC/HRS Guideline for the Management 
of Patients with AF should be consulted for AAD prescriptions.  Modifications to AADs (type or dosage 
increase) may be made for up to 90 days after AAD initiation.  This is referred to as the AAD optimization 
period.  Dosing of AADs can be individually tailored until the end of the AAD optimization period. After the 
optimization period, further AAD therapy optimization or change should be avoided or at least allowed 
only up to physicians’ discretion to guarantee the safety of the patients.  The possible concomitant use of 
beta blockers can still be optimized after the optimization period.  Reason for AAD modification must be 
documented.   


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Crossovers from AAD therapy to cryoablation will be allowed only if the subject in the control group is 
deemed a treatment failure.  Crossovers must be pre-approved by the Medtronic Clinical Study Manager.  
Approval will be granted after verification that the subject is an efficacy failure.   
Treatment failure is defined in section 5.1.4.1. 
 
Treatment Arm- Cryoablation Procedure  
11.5.3.
Within 30 days of randomization, perform the pulmonary vein isolation procedure using the Arctic Front 
Advance™ Cardiac CryoAblation Catheter.  
If needed, a Freezor® MAX Cardiac CryoAblation Catheter may also be utilized for gap ablation to 
complete electrical isolation of the pulmonary veins and creation of ablation lines between the inferior 
vena cava and the tricuspid valve.  The Investigator is to perform the procedure according to the 
procedural steps in this CIP and the Instructions for Use for the catheters.  Appropriate sedation and 
venous access should be attained at the Investigator’s standard practice according to their institution’s 
pre-established procedures/guidelines at the time of the procedure.   
The use of any non-study device in the left atrium is not permitted. 
Only the Medtronic FlexCath sheath family should be used with the Arctic Front Advance™ Cardiac 
CryoAblation Catheter.  The use of other sheaths may damage the device.  The Investigator may choose 
compatible guidewires and mapping catheters at his or her discretion. 
11.5.3.1. Esophageal Visualization and Temperature Monitoring 
Ensure an esophageal temperature monitor is used for each cryoablation application.  The cryoapplication 
must be ceased if the temperature reaches ≤ 15°C. 
11.5.3.2. Pre-procedure Anticoagulation 
Current recommendations for anticoagulation are found in the 2012 HRS/EHRA/ECAS Expert Consensus 
Statement on Catheter and Surgical Ablation of Atrial Fibrillation (Calkins, et. al. 2012).   Anticoagulation 
pre-procedure should be determined based upon the subjects CHA2DS2-VASc score. Oral anticoagulants 
are required if the subject has had a prior stroke or TIA, or if the subject has a CHA2DS2-VASc score ≥2.  
When anticoagulation is required, subjects must take it for at least 21 days prior to an ablation 
procedure.  Oral anticoagulants are not required for subjects with nonvalvular AF and a CHA2DS2-VASc 
score of 0 or 1. 
11.5.3.3. Intra-procedure Anticoagulation 
Heparin should be administered prior to or immediately following transseptal puncture during AF ablation 
procedures and adjusted to achieve and maintain an ACT of 300-400 during the procedure, with ACT 
recommended to be checked at 30 minutes intervals.  Administration of protamine following ablation to 
reverse heparin should be considered. 
11.5.3.4. Post-procedure Anticoagulation 
Systemic oral anticoagulation should be initiated on the day of the procedure and is recommended for at 
least two months following an AF ablation procedure.  Decisions regarding the continuation of systemic 


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anticoagulation agents more than two months following ablation should be based on the patient’s risk 
factors for stroke as estimated by the CHA2DS2-VASc score and not on the presence or type of AF. 
Discontinuation of systemic anticoagulation therapy post ablation is not recommended in patients who 
are at high risk of stroke as estimated by the CHA2DS2-VASc score. 
11.5.3.5. Diaphragm Movement  
a. Prior to the first cryoablation application, the Investigator will make a fluoroscopic recording 
of inspiratory and expiratory movement of the diaphragm. 
b. Continuous phrenic nerve pacing with abdominal palpitation must be performed for all right 
pulmonary vein cryoapplications and should be considered for all cryoapplications.  
Additional methods of phrenic nerve monitoring are encouraged, such as diaphragmatic 
compound motor action potential (CMAP). 
c. After the last cryoablation application, the Investigator will make a fluoroscopic recording of 
inspiratory and expiratory movement of the diaphragm. 
11.5.3.6. Balloon Pulmonary Vein (PV) Cryoablation 
a. Every effort consistent with subject welfare will be made to treat all PVs or their anomalous 
equivalents. 
b. The catheter will be advanced into the left atrium over the mapping catheter or guidewire 
and inflated.  Once inflated, the catheter will be tracked over the Achieve™ catheter and 
positioned at the entrance of the PV. 
c. Assess the positioning, contact and occlusion of the PV by the catheter’s balloon by 
injection of contrast material, ultrasound imaging, or other technique.  Reposition as 
needed. 
d. Each pulmonary vein must be assessed for entrance block and, where assessable, exit block 
to demonstrate electrical isolation. 
e. It is recommended that the Investigator use cryoapplications of three (3) minutes each.  
Once PV isolation has been achieved, one (1) additional application of three (3) minutes at 
the same PV should be performed; however, it is up to the operator’s discretion to assess 
application time and necessity of the additional freeze given factors such as time to 
isolation of prior application(s), temperature of prior application(s), risk of collateral 
damage, etc. 
f. 
Upon the Investigator’s assessment of procedure completion, isoproterenol and/or 
adenosine may be used to assess pulmonary vein isolation. 


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11.5.3.7. Other Ablations During Index Procedure 
a. Ablation of the cavotricuspid isthmus is required in subjects with a history of typical atrial 
flutter or inducible cavotricuspid isthmus depend atrial flutter.  Complete an assessment for 
bi-directional block if this procedure is performed.  Any commercially released catheter 
deemed appropriate for the procedure may be used. 
 
b. The following are not allowed: 
o 
Left atrial non-PVI ablations including but not limited to, ablation of linear lesions, 
complex fractionated electrograms or non-PV triggers 
o 
Ablation using any non-study device in the left atrium 
11.5.3.8. Cardioversion 
a. Electrical or pharmacological cardioversion to sinus rhythm must be attempted following the 
PVI portion of the procedure if sinus rhythm wasn’t restored.  Cardioversion may be 
performed prior to PVI if needed. 
11.5.3.9. Procedure Documentation  
During the procedure the investigator will document the following:  
• 
Catheters used (i.e. Arctic Front Advance™, Freezor® MAX and Achieve™ Mapping Catheter, 
etc.) 
• 
Minimum temperature for each cryoapplication 
• 
Duration of each cryoapplication 
• 
Vein location for each cryoapplication (e.g. right superior PV) 
• 
Use of phrenic nerve pacing or other phrenic nerve monitoring technique for each 
cryoapplication, specifically those cryoapplications surrounding the RS and RI PVs 
• 
Demonstrated electrical block and, if real-time signals are available, time to isolation 
• 
Adjunctive catheters, mapping or visualization devices, sedation type, procedure information, 
esophageal temperature, ACT, cardioversion use and fluoroscopy time will be collected. 
 
 


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Hospital Discharge 
11.5.4.
At or shortly before hospital discharge, the following will be performed and collected: 
a. Adverse event assessment 
b. In the case of suspected PV stenosis, Magnetic Resonance Imaging (MRI) or 
Computerized Tomography Scanning (CT scan) is required. 
c. Review medications 
d. 12 lead ECG 
e. Chest X-ray:  For any subject whose post-procedural fluoroscopy demonstrated 
study-related PNI, a follow-up chest X-ray, including inspiration and expiration films, 
will be performed  
f. 
Review study requirements with the subject to help ensure compliance with follow-
up procedures 
g. Evaluate the subject’s neurological status per institutional standard of care to 
determine if a formal neurological consultation should be performed for stroke 
assessment.  Report any adverse events that result from the neurologic evaluation 
and consultation, if applicable.   
 
Medication Compliance 
11.5.5.
Information regarding medications prescribed for anticoagulation or to treat atrial arrhythmias will be 
collected through study exit.  The following information will be collected for medications to treat atrial 
arrhythmias:  medication name, purpose for use, start and stop dates, dose, dosage changes (and 
reasons for changes), and route of administration.  Data collection for anticoagulation medication will be 
limited to medication name and start and stop dates.   
Control Arm (AAD):   
Subjects must initiate a Class I or III AAD within 30 days of randomization.  It is recommended that AADs 
be initiated as soon as possible after randomization, with a target of within 14 days.  The investigator 
should choose the appropriate AAD per his or her standard of care; however, amiodarone should only be 
used if other AADs were not tolerated or failed.  The 2014 AHA/ACC/HRS Guideline for the Management 
of Patients with AF should be consulted for AAD prescriptions.  Modifications to AADs (type or dosage 
increase) may be made for up to 90 days after AAD initiation.  This is referred to as the AAD optimization 
period.  Dosing of AADs can be individually tailored until the end of the AAD optimization period. After the 
optimization period, further AAD therapy optimization or change should be avoided or at least allowed 
only up to physicians’ discretion to guarantee the safety of the patients.  The possible concomitant use of 
beta blockers can still be optimized after the optimization period. 
Cryoablation (Treatment Arm): 
Per physician discretion, class I or III antiarrhythmic, including sotalol, medication use is permitted for up 
to 80 days following the ablation procedure.  Use of amiodarone is not permitted.  Prescriptions for these 
drugs must not allow a quantity that will last longer than 80 days post-procedure.  It is recommended 
that site personnel contact subjects on day 80 post-ablation procedure to ensure they have stopped 
taking class I or III antiarrhythmic drugs.  Class I or III antiarrhythmic drug use after the 90 day blanking 
period will be considered a primary endpoint failure. 


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Systemic oral anticoagulation should be initiated on the day of the procedure and is recommended for at 
least two months following an AF ablation procedure.  Decisions regarding the continuation of systemic 
anticoagulation agents more than two months following ablation should be based on the patient’s risk 
factors for stroke as estimated by the CHA2DS2-VASc score and not on the presence or type of AF.  
Discontinuation of systemic anticoagulation therapy post ablation is not recommended in patients who 
are at high risk of stroke as estimated by the CHA2DS2-VASc score. 
 
All Subjects: 
All other medications (those that are not specified above) are permitted in the study, with the exception 
of investigational drugs that may confound the study results.  Beta-blockers may be prescribed per 
standard of care.   
 
Subsequent Ablation Procedures 
11.5.6.
Any subsequent ablation in the left atrium or AF surgery will be counted as an endpoint failure.  There is 
no 90 day blanking period for repeat ablation.  Subsequent ablations and AF surgeries will be 
documented on an eCRF. 
Subsequent ablations in the right atrium are allowed (e.g. typical atrial flutter ablation). 
 
Cardioversions 
11.5.7.
Electrically and pharmacologically cardioverting the subject to sinus rhythm is allowed in the 90 day post-
procedure blanking period (treatment arm)/AAD optimization period (control arm) at the discretion of the 
Investigator.  Electrically or pharmacologically cardioverting the subject to sinus rhythm after the 
blanking period/AAD optimization period will be counted as an efficacy endpoint failure.   
 
Scheduled Follow-up Visits 
11.5.8.
After the index cryoablation procedure (treatment arm) or AAD initiation (control arm) is reported in the 
study database, the database will calculate the target dates and windows for each visit to the site. Should 
a subject miss a visit or the visit fall outside the pre-specified window, a study deviation must be reported 
and the original follow-up schedule maintained for subsequent visits.  
Data analyses include follow-up visits, regardless of whether the visit occurs within the window.  
Therefore, a late visit is preferred over a missed visit but must be accompanied by a deviation. Follow-up 
visit windows are listed in Table 6 and are based on days post-index procedure or AAD initiation. 
 
 




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11.5.8.2. Three Month Office Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
Health care utilization assessment- collect information about hospitalizations or emergency 
department visits experienced by the subject since the last visit 
• 
12 lead ECG 
• 
Provide the subject with patient-activated ambulatory monitoring equipment; provide instructions 
for and weekly and symptomatic transmissions. 
• 
Chest X-ray 
o 
For any subject whose post-procedural fluoroscopy demonstrated study-related PNI, a 
follow-up chest X-ray, including inspiration and expiration films, will be performed if the 
PNI was unresolved at the one month visit 
• 
In the case of suspected PV stenosis, Magnetic Resonance Imaging (MRI) or Computerized 
Tomography Scanning (CT scan) is required.  It is not required at this visit if it was already 
completed at an earlier visit and PV stenosis was confirmed.   
11.5.8.3. Six Month Office Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
Health care utilization assessment- collect information about hospitalizations or emergency 
department visits experienced by the subject since the last visit 
• 
12 lead ECG 
• 
24h continuous ECG monitoring with ambulatory monitoring equipment  
• 
EQ-5D and AFEQT Questionnaires 
• 
Review the patient-activated ambulatory monitoring instructions with the subject.   
• 
Chest X-ray, including inspiration and expiration films, is required for subjects whose PNI was 
unresolved at the 3 month visit 
• 
In the case of suspected PV stenosis, Magnetic Resonance Imaging (MRI) or Computerized 
Tomography Scanning (CT scan) is required.  It is not required at this visit if it was already 
completed at an earlier visit and PV stenosis was confirmed.   
 
 


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11.5.8.4. Twelve month Office Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
Health care utilization assessment- collect information about hospitalizations or emergency 
department visits experienced by the subject since the last visit 
• 
12 lead ECG 
• 
24h continuous ECG monitoring with ambulatory monitoring equipment.  The subject will be 
instructed to apply the continuous monitoring patches and complete the 24 hours of continuous 
monitoring within 7 days prior to the 12 month visit.   It is recommended that the study 
personnel call the subject to remind them of this requirement.  If the subject is not able to apply 
the device prior to the visit, it may be applied by study personnel at the 12 month visit.   
• 
EQ-5D and AFEQT Questionnaires 
• 
Collect the ambulatory monitoring equipment and return to Medtronic (or designee).  If the 
subject did not perform the continuous monitoring prior to the 12 month visit, apply the device to 
the subject to complete 24 hour continuous monitoring.  Give the subject instructions on how to 
return the equipment.   
• 
Chest X-ray, including inspiration and expiration films, is required for subjects whose PNI was 
unresolved at the 6 month visit 
• 
In the case of suspected PV stenosis, Magnetic Resonance Imaging (MRI) or Computerized 
Tomography Scanning (CT scan) is required.  It is not required at this visit if it was already 
completed at an earlier visit and PV stenosis was confirmed.   
• 
Inform the subject they have completed the study 
 
 


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Unscheduled Office Visits 
11.5.9.
An unscheduled visit is defined as any unplanned cardiovascular-related office visit at the study site that 
is performed by personnel participating in the study and occurs between CIP required visits.  Submit to 
the core lab any 12 lead ECG or continuous monitoring completed in conjunction with an unscheduled 
office visit.  The following information is required to be collected at unscheduled follow-up visits: 
• 
Review medications 
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
Health care utilization assessment- collect information about hospitalizations or emergency 
department visits experienced by the subject since the last visit 
• 
12 lead ECG 
 Re-Ablation/Crossover Ablation 
11.5.10.
• 
Obtain approval from Medtronic for crossover ablations (not required for treatment arm 
reablation) 
• 
Perform the following assessments prior to the cryoablation: 
o 
Review medications 
o 
Adverse event assessment 
o 
Review symptoms suggestive of recurrent AF/AT/AFL 
o 
EQ-5D and AFEQT Questionnaires 
o 
Health care utilization assessment- collect information about hospitalizations or 
emergency department visits experienced by the subject since the last visit 
• 
Procedure Data: 
o 
Catheters used (i.e. Arctic Front Advance™, Freezor® MAX and Achieve™ Mapping 
Catheter, etc.) 
o 
Minimum temperature for each cryoapplication 
o 
Duration of each cryoapplication 
o 
Vein location for each cryoapplication (e.g. right superior PV) 
o 
Use of phrenic nerve pacing or other phrenic nerve monitoring technique for each 
cryoapplication, specifically those cryoapplications surrounding the RS and RI PVs 
o 
Demonstrated electrical block and, if real-time signals are available, time to isolation 
o 
Adjunctive catheters, mapping or visualization devices, sedation type, procedure 
information, esophageal temperature, ACT, cardioversion use and fluoroscopy time will 
be collected 
o 
Pulmonary vein isolation stats from previous ablation (re-ablations only) 
 12 lead Electrocardiograms 
11.5.11.
All study required 12 lead ECGs will be sent to the core lab.  The core lab will be responsible for 
adjudication of atrial arrhythmias for the primary objective of the study.  The core lab will send the 
results of all ECG analyses to the Investigators for appropriate follow-up, if necessary, and assessment 
for adverse event reporting.  Copies of additional source documents may be requested. 


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 Ambulatory Monitoring 
11.5.12.
Market- released ambulatory monitoring equipment will be distributed by a core lab to centers after 
activation has occurred.  Subjects will be provided with a small patient-activated electronic ambulatory 
monitoring device after the AAD optimization (control arm) or post-ablation blanking period (treatment 
arm) ends.  This device will serve two functions: 
• 
24 hour continuous monitoring:  This is traditionally done using a Holter monitor.  The 
investigative site personnel will apply the device patches for the subject during the subject’s 6 
month visit and train the subject how to apply the device.  The subject will be asked to apply the 
continuous monitoring patches themselves prior to the 12 month study visit.  Additionally, 
subjects may be asked to perform 24 hour continuous monitoring on their own if they miss a 
scheduled study visit.   
• 
Patient-activated mode:  Subjects will be asked to transmit ECG data weekly and whenever they 
experience AF symptoms.  This mode does not require adhesive patches; the subject simply 
holds the device to his or her chest for a short period of time.   
In both modes, the data automatically transmits to the core lab via a secured cell phone connection.     
The core lab will manage maintenance, calibration and tracking of the ambulatory monitoring equipment. 
The core lab will be responsible for adjudication of rhythm documentation for the primary efficacy 
objective of the study.  The core lab will send the results of all ambulatory monitoring analyses to the 
Investigators for appropriate follow-up, if necessary, and assessment for adverse event reporting. 
Subjects will return the ambulatory monitoring equipment at the 12 month follow-up visit. 
 Study Exit 
11.5.13.
Subjects will be exited from the study upon completion of the 12 month follow-up visit.  For information 
about subject withdrawal and discontinuation, see section 11.10. 
11.6. Assessment of Efficacy 
The primary efficacy objective is based on the data collected as discussed in section 5.1.1 and 5.1.4. 
11.7. Assessment of Safety 
The secondary safety objective is based on the Adverse Event data collected.  Further information on the 
collection and assessment of safety data is discussed in section 13. 
11.8. Recording Data 
The study will collect data using an electronic data management system for clinical studies. Centers will 
enter data onto eCRFs within the database.  The core lab will also enter data onto CRFs within a separate 
electronic database. 
Procedures in the CIP require source documentation. Source documentation will be maintained at the 
study center.  Source documents, which may include worksheets, subject medical records, and 
console files, must be created and maintained by the investigational center team.  The data reported 
on the eCRFs shall be derived from source documents and be consistent with these source 


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documents, and any discrepancies shall be explained in writing.  The eCRF may be considered source 
for the following data collection elements: 
• 
Time of isolation of the cryoablation catheter 
• 
Esophageal temperature 
• 
Investigator assessment of adverse event or death relatedness and severity 
• 
Date center became aware of the adverse event, device deficiency or death 
• 
Reason for study deviation 
• 
Database generated patient reference ID 
When copies or print-outs of the source documents are made, center personnel must sign and date 
any copies or printouts of original source documents with a statement that this is complete and true 
reproduction of the original source document.  The sponsor or a regulatory authority may audit or 
inspect the study center to evaluate the conduct of the study.  
The clinical Investigator(s)/institution(s) shall allow study related monitoring, audits, IRB/EC review 
and regulatory inspection by providing direct access to source data/documents.  Further detail on 
data management is provided in Section 17.3. 
11.9. Deviation Handling 
A study deviation is defined as an event within the study that did not occur according to requirements 
specific to the CIP or CTA. Every attempt must be made to avoid study deviations.  Prior approval by 
Medtronic is expected in situations where the Investigator anticipates, contemplates, or makes a 
conscious decision to deviate. In countries following ISO 14155:2011, prior approval for study deviations 
will be reported to local authorities and ethics boards per local requirements.  If the deviation affects 
subject’s rights, safety and well-being, or the scientific integrity of the study, prior approval from ethics 
board and/or competent authority (CA) is also required, depending on local legislations. Prior approval is 
not required when a deviation is necessary to protect the safety, rights, or well-being of a subject in an 
emergency or in unforeseen situations beyond the Investigator’s control (e.g. subject failure to attend 
scheduled follow-up visits, inadvertent loss of date due to computer malfunction, inability to perform 
required procedures due to subject illness). Subjects’ failure to submit ambulatory monitoring 
transmissions per the CIP do not require a deviation to be reported.  Ambulatory monitoring transmission 
compliance will be tracked by Medtronic personnel and the Core Lab.   
For medically justifiable conditions which preempt a subject’s ability to complete a study required 
procedure, it may be permitted to report only one deviation which will apply to all visits going forward.  
This may also apply for other unforeseen situations (e.g. the subject permanently refuses to complete a 
study required procedure and the data will not contribute to the primary endpoint analysis.). However, 
prior approval from Medtronic is required for such situations. 
All study deviations must be reported to Medtronic regardless of whether they are medically justifiable, 
pre-approved by Medtronic, an inadvertent occurrence, or taken to protect the subject in an emergency.  
The description of the deviation and justification must be documented and submitted to Medtronic via 
eCRF completion.   
 
In the event the deviation involves a failure to obtain a signed Informed Consent Form, or is made to 
protect the life or physical well-being of a subject in an emergency, the deviation must be reported to the 
IRB/EC as well as Medtronic within five (5) working days.  Reporting of all other study deviations should 


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comply with IRB/EC policies and/or local laws and must be reported to Medtronic as soon as possible 
upon the site becoming aware of the deviation.  Refer to  
Table 9 for reporting requirements. 
Medtronic is responsible for reviewing deviations, assessing their significance, and identifying any 
necessary corrective and/or preventive actions (e.g. amend the CIP, conduct additional training, and 
terminate the investigation).  Repetitive or serious Investigator compliance issues may result in initiation 
of a corrective action plan with the Investigator and center, and in some cases, may necessitate 
suspending a center’s ability to enroll until the problem is resolved, or ultimately terminating the 
Investigator’s participation in the study. Medtronic will provide center-specific reports to Investigators 
summarizing information on deviations that occurred at the investigational center on a periodic basis.  
11.10. 
 Subject Withdrawal or Discontinuation  
A subject can withdraw from the study at any time.  If the subject wishes to exit from the study (i.e. the 
subject revokes consent), the center is required to document the reason for exit on an eCRF.  In addition, 
centers shall follow the regulations set forth by their IRB/EC. 
Prior to exiting a subject from the study, it is recommended to follow the subject until all ongoing device 
and/or procedure related adverse events are resolved or unresolved with no further actions planned.  An 
unscheduled office visit should be attempted if the subject exits the study outside of a scheduled follow-
up visit. 
Following exit, subjects will continue to receive standard medical care.  Upon exiting from the study, no 
further study data will be collected or study visits will occur for the subject.  All data available through the 
time of the subject’s exit will be used for analysis. 
Reasons for subject withdrawal or discontinuation include: 
• 
Subject is lost to follow-up 
• 
Subject did not meet inclusion/exclusion criteria after the date the subject signed the Informed 
Consent Form and prior to randomization.  
• 
The subject was randomized to the treatment arm, but no cryoballoon ablation procedure was 
attempted 
• 
The subject was randomized to the control arm, but no AAD was initiated 
• 
Subject chooses to withdraw (e.g., Informed Consent Form 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 or regulatory authority decides the study will be closed or a particular center will be 
closed 
 
 


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The following information is required to be collected at early study exit: 
• 
Reason for exit must be documented on the eCRF and in the subject’s medical record 
• 
An unscheduled office visit should be attempted if the subject exits the study outside of a 
scheduled follow-up visit 
In the case that the subject is determined to be lost to follow-up, details of a minimum of two attempts 
and the method of attempt (e.g., one letter and one phone record or two letters) to contact the subject 
must be recorded.  In addition, follow the regulations set forth by the governing IRB/EC. 
 
 


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12. Risks and Benefits 
12.1. Potential Risks 
Medtronic follows rigorous Quality Assurance and Control procedures throughout the life of a product, 
from the business analysis phase through development, market release, and post-market surveillance. 
The residual risks associated with the Arctic Front Advance™ Cardiac CryoAblation Catheter have been 
found to be acceptable and have been mitigated to the fullest extent possible. The potential benefits 
related to the use of the Arctic Front Advance™ Cardiac CryoAblation Catheter have been determined to 
outweigh any potential risks.  The device has never been recalled. 
There are potential risks and side effects associated with ablation procedures.  The Investigator shall 
describe risks in further detail when asked by the subject.  The risks must be continuously monitored, 
assessed and documented by the Investigator.  The risks associated with the cryoablation procedure are 
listed below.   
• 
Anemia-deficiency of red blood cells or of hemoglobin in the blood resulting in weariness. 
• 
Anxiety-a feeling of worry, nervousness, or unease. 
• 
Back pain- pain felt in the lower or upper back. 
• 
Bleeding e.g. bleeding into the retroperitoneal space. 
• 
Bronchitis, cough, pneumonia-inflammation of the lungs can be caused by a virus or bacteria. 
• 
Cardiac tamponade-pressure on the heart as a result of fluid collecting in the sac surrounding the 
heart. 
• 
Cardiopulmonary arrest-cessation of blood circulation and/or respiration due to dysfunction of the 
heart and/or lungs. 
• 
Chest discomfort/pain/pressure-includes a range of feeling from sharp stabbing to dull ache in 
the chest. 
• 
Cold feeling-having a low or inadequate temperature. 
• 
Complications associated with contrast agents-adverse effects of contrast agents used during the 
procedure (e.g. allergic reaction or radio contrast nephropathy). 
• 
Complications associated with medications commonly utilized during the procedure-known risks 
of medications commonly used during the procedure (e.g. narcotics, anxiolytics, other pain 
medications, anti-vasospasm agents). 
• 
Complications at catheter insertion site in the groin: 
o 
AV fistula-an abnormal connection between an artery and a vein (i.e., cause by needle 
insertion through the femoral artery and vein). 
o 
Hematoma/Bruising-a collection of blood in the tissue surrounding the catheter insertion 
site. 
o 
Infection-localized redness, heat swelling and pain at the catheter insertion site. 
o 
Pain-discomfort at the catheter insertion site that can range from mild to severe. 


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o 
Pseudoaneurysm-a collection of blood in the tissue surrounding the catheter insertion site 
due to ongoing leaking of blood from a blood vessel. 
o 
Significant bleeding-blood loss from the catheter insertion site requiring surgery or 
transfusion of 2 or more units of packed red blood cells (PRBCs). 
• 
Coronary artery spasm, vasospasm-constriction of a blood vessel. 
• 
Death-a complication or deterioration of health ultimately leading to a patient’s death. 
• 
Dissection of a blood vessel-a tear within the wall of a blood vessel. 
• 
Dizziness, lightheadedness-feeling faint, woozy, weak or unsteady. 
• 
Embolism-formation and dislodgement of a blood clot (thrombus) or dislodgement of 
cholesterol/plaque within the blood vessel, which travels downstream into small vessels, blocking 
blood flow and causing temporary or permanent damage to organs distal to blockage.  Emboli 
are known to cause myocardial infarction, transient ischemic attack, stroke/cardiovascular 
accident, blurred vision, visual changes, paralysis, paresis, or kidney damage, peripheral ischemia 
and may ultimately lead to incapacitation or death.  Symptomatic and non-symptomatic. 
• 
Endocarditis –inflammation of the inner surface of the heart. 
• 
Esophageal injury –damage to your swallowing tube, atrio-esophageal fistula - abnormal 
passageway between the heart and esophagus, hematemesis (vomiting blood). 
• 
Fatigue- extreme tiredness. 
• 
Fever- abnormally high body temperature. 
• 
Gastroparesis- delayed gastric emptying. 
• 
Headache- pain in the head. 
• 
Heartblock requiring permanent pacemaker implantation 
• 
Heart rhythm disturbances-disruption of normal heart rate or rhythm (e.g. atrial flutter, 
tachycardia, bradycardia). 
• 
Hemothorax –collection of blood around the lungs. 
• 
Hiccups- involuntary spasm of the diaphragm and respiratory organs. 
• 
Hypertension-high blood pressure. 
• 
Hypotension-low blood pressure. 
• 
Injury to lung- (e.g. bronchial lesion, hemoptysis, constriction, pulmonary hemorrhage, bronchia 
fistula). 
• 
Mild skin discomfort or irritation-redness sensitivity of the skin cause during or after the 
procedures (e.g. electrodes used with the ECG and Holter recorder might cause mild skin 
discomfort or irritation or some skin discomfort following electrode removal or tape removal). 
• 
Nausea-a sensation of unease and discomfort in the upper stomach with an urge to vomit. 
• 
Perforation of a blood vessel or cardiac tissue-unintended puncture through the wall of a blood 
vessel or cardiac tissue. 
• 
Pericardial effusion- fluid collecting in the sac that surrounds the heart. 


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• 
Pericarditis –inflammation of the sac that surrounds the heart. 
• 
Phrenic nerve injury –damage to the nerve that controls breathing. 
• 
Pleural effusion –collection of extra fluid around the lungs. 
• 
Pulmonary edema- excess fluid in the lungs. 
• 
Pulmonary hypertension- high blood pressure that affects the arteries in the lungs and the right 
side of the heart. 
• 
Pulmonary vein hematoma- trauma to the pulmonary vein. 
• 
Pulmonary vein stenosis –blockage in the blood vessels takes blood from the lungs to the heart. 
• 
Pneumothorax – collapsed lung. 
• 
Renal dysfunction-kidneys fail to adequately filter waste products from the blood. 
• 
Right sided heart failure- right side of the heart is not pumping blood to the lung normally. 
• 
Shivering- body shaking. 
• 
Shortness of breath- difficulty breathing. 
• 
Small ischemic cerebral (brain) lesions not accompanied by clinically apparent symptoms have 
been found on brain imaging performed after an AF ablation procedure.  So far, the relationship 
between these lesions and an increased incidence of stroke or transient ischemic attack (a mini 
stroke) has not been established.  However, whether these lesions will result in long term 
cognitive decline (e.g. loss of memory and trouble thinking) is unclear. 
• 
ST elevation- the ST segment of an ECG is abnormally high above the baseline. 
• 
Sore throat- pain in the throat. 
• 
Urinary infection- an infection in the urinary system. 
• 
Vascular complications requiring surgery-damage to an artery (e.g. femoral) or vein requiring 
surgical repair. 
• 
Vasovagal reaction- reflex of the involuntary nervous system that causes the heart to slow down 
and blood pressure drops. 
• 
Vomiting-forceful expulsion of stomach contents through the mouth and/or nose. 
The risks of participating in this clinical study are the same as the cryoablation procedure risks, and also 
include: 
• 
Risks/discomforts associated with sedation/anesthesia: 
o 
Hoarseness. 
o 
Myalgia (pain in the muscles). 
o 
Numbness and tingling of the fingers. 
o 
Diarrhea. 
o 
Dry mouth. 
o 
Sleepiness. 


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• 
Radiation exposure due to potential for additional CT/MRI scan or Chest X-rays. 
• 
Patches and adhesive used with the ambulatory monitoring equipment may cause skin discomfort 
or irritation, or some skin discomfort following patch removal. 
12.2. 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 CIP. 
• 
Requiring that investigators be actively involved in the procedure and follow-up of the subjects 
who undergo a study procedure. 
• 
Providing guidelines for subject selection and evaluation. 
• 
Requiring that subjects be followed at regular intervals following the ablation procedure to 
monitor for recurrence of atrial arrhythmias and to assess for adverse events. 
12.3. Potential Benefits 
The Arctic Front AdvanceTM Cardiac CryoAblation Catheter may reduce or eliminate atrial fibrillation in 
subjects who have not yet failed an AAD; however, some subjects may not receive this benefit.  The 
information gained from the study could result in improved management of atrial fibrillation.  It is 
possible that subjects will experience no benefit from participating in the study. 
12.4. Risk-Benefit Rationale 
The cohort of subjects for inclusion in the study is symptomatic as a result of their atrial fibrillation, but 
has not yet tried AAD therapy.  Cryoablation therapy offers the opportunity to reduce the episodes of 
atrial fibrillation without the subject having to take AADs or experience the side effects of AAD therapy. 
In the US, there are no ablation catheters approved to treat subjects with paroxysmal atrial fibrillation 
who have not yet attempted AAD therapy.  If successful, this study could demonstrate meaningful 
therapeutic benefit in this patient population and provide patients with additional treatment options 
earlier in disease progression. 
 
 








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13.2. Reporting of Adverse Events 
For the purposes of this study, the following Adverse Events will be collected starting at the time the 
subject signs the Informed Consent Form through the duration of the subject’s participation in the study: 
• 
All procedure related AEs 
• 
All cryoablation system related AEs  
• 
All AAD related AEs 
• 
All cardiovascular related AEs 
• 
All Serious Adverse Events (SAEs), regardless of relatedness 
Reporting of these events to Medtronic will occur on an Adverse Event (AE) Form, including a description 
of AE, date of onset of AE, date of awareness of site, treatment, resolution, assessment of both the 
seriousness and the relatedness to the investigational device.  
Each AE must be recorded on a separate AE Form. Exceptions include: 
• 
Documented pre-existing conditions are not considered AEs unless the nature or severity of the 
condition has worsened.  Additionally, arrhythmia episodes that are not new or worsening 
conditions and for which no action is taken are not reportable as AEs. 
• 
Unavoidable Adverse Events, listed in section 13.1 need not be reported unless the adverse event 
worsens or is present outside the stated timeframe post-procedure. 
• 
Cardioversions (DC or Drug) for recurrent symptomatic atrial fibrillation and other atrial 
arrhythmias are not considered serious adverse events. 
For any changes in status of a previously reported adverse event (i.e. change in actions taken, change in 
outcome, change in relatedness), an update to the original AE must be provided.  All adverse events 
must be followed until the adverse event has been resolved, is unresolved with no further actions 
planned, the subject exits the study or until study closure, whichever occurs first. 
In the event that a subject is exited from the study prior to study closure, all efforts should be made to 
continue following the subject until all unresolved procedure or cryoablation system related adverse 
events, as classified by the investigator, are resolved or they are unresolved with no further actions 
planned. 
At the time of study exit, all adverse events with an outcome of “Unresolved, further actions or treatment 
planned” must be reviewed and an update to the original AE must be reported.  At a minimum, if there 
are no changes to the description, relatedness, test and procedures or actions taken, the outcome must 
be updated to reflect “Unresolved at time of study closure.” 
Subject deaths are also required to be reported. Refer to section 13.3.1 for Subject Death collection and 
reporting requirements. 
 
Device Deficiencies 
13.2.1.
Device deficiency (DD) information will be collected throughout the study and reported to Medtronic. 
Note that device deficiencies that result in an adverse device effect (ADE) to the subject should be 
captured as an Adverse Event only. 












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• 
Date of death 
• 
Detailed description of death 
• 
Cause of death  
• 
Relatedness to device and/or procedure 
• 
Death summary/hospital records (if available and allowed by state/local law) 
• 
Autopsy report (if available and allowed by state/local law) 
• 
Death certificate (if available and/or allowed by state/local law) 
13.3.1.2. Death Classification and Reporting 
Sufficient information will be required in order to properly classify the subject’s death.  The Investigator 
shall classify each subject death per the following definitions: 
• 
Cardiac Death: A death directly related to the electrical or mechanical dysfunction of the heart. 
• 
Sudden Cardiac Death (SCD): Natural death due to cardiac causes, indicated by abrupt loss of 
consciousness within one hour of the onset of acute symptoms; preexisting heart disease may 
have been known to be present, but the time and mode of death are unexpected. If time of 
onset cannot be determined, SCD will alternatively be defined as any unexpected cardiac death 
occurring out of the hospital or in the emergency room as dead on arrival. 
• 
Non-sudden Cardiac Death: All cardiac deaths that are not classified as sudden deaths, including 
all cardiac deaths of hospitalized subjects on inotropic support. 
• 
Non-cardiac Death: A death not classified as a cardiac death. 
• 
Unknown Classification: Unknown death classification is intended for use only when there is 
insufficient or inadequate information to classify the death. 
The CEC will review deaths and provide a final adjudication of the primary cause of death and cardiac 
classification. 
Regulatory reporting of subject deaths will be completed according to local regulatory requirements. 
 
Product Complaints 
13.3.2.
For devices that are market-released, product complaint reporting is applicable.  This includes when an 
AE is related to a market-released device during the study.  The reporting of product complaints is not 
part of the clinical study and should be done in addition to the Adverse Event reporting requirements.  
Refer to local regulations for reporting requirements. 
Product Complaint: Any written, electronic or oral communication that alleges deficiencies related to the 
identity, quality, durability, reliability, safety, effectiveness or performance of a medical device that has 
been placed on the market. 
It is the responsibility of the investigator to report all product complaint(s) associated with a medical 
device distributed by Medtronic, regardless whether they are related to intended use, misuse or abuse of 
the product.  Reporting must be done immediately and via the regular channels for market-released 
products. 
Medtronic will notify the regulatory authorities (e.g. FDA) as applicable for the following incidents 
immediately upon learning of them: 


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• 
Any malfunction or deterioration in the characteristics and/or performance of a device, as well as 
any inadequacy in the labeling or instructions for use which led or might have led to the death or 
serious deterioration in the state of health of a patient, user, or other person. 
• 
Any technical or medical reason resulting in withdrawal of a device from the market by the 
manufacturer. 
• 
A serious deterioration in the state of heath includes: 
o 
Life-threatening illness or injury 
o 
Permanent impairment of a body function or permanent damage to a body structure 
o 
A condition necessitating medical or surgical intervention to prevent permanent 
impairment of a body function or permanent damage to a body structure 
The investigator and Medtronic must abide by the reporting requirements shown in Table 7. 
 
 


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


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15. Statistical Design and Methods 
Medtronic employees will perform all statistical analyses. 
Additionally, a separate Statistical Analysis Plan (SAP) will be developed to further describe statistical 
methods, pre-specified data handling rules (including how missing data will be handled), and pre-
specified analyses, including subgroup analyses, that will be included in study reports (e.g. PMA report, 
final study report).  Any deviation from the pre-specified statistical analyses will be noted in the study 
report.  
The SAP will include a comprehensive description of the statistical methods and analyses to be included 
in reports that include analysis of endpoints.  Any change to the data analysis methods described in the 
CIP will require an amendment to the CIP only if it changes a principal feature of the CIP.  Any other 
change to the data analysis methods described in the CIP, and the justification for making the change, 
will be described in the clinical study report. 
Additional exploratory analyses of the data may be conducted as deemed appropriate. 
All objectives will be analyzed once all treated subjects complete the 12 month follow-up visit, or have 
exited the study.  A final report will be completed after all subjects complete the final follow-up visit, or 
have exited the study. No interim analyses are planned. 
The primary analysis will be conducted using a modified intent-to-treat protocol; all subjects for whom 
either AAD or cryoballoon ablation therapy is initiated will be analyzed according to their randomization 
status. Subjects who withdraw consent between randomization and initiation of therapy will be excluded 
from the primary efficacy analysis. 
 
 


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15.1. Primary Efficacy Objective 
Demonstrate the superiority of cryoballoon ablation as compared to AAD therapy in terms of the rate of 
freedom from AF/AT/AFL in a non-drug refractory paroxysmal AF population. 
 
Hypothesis 
15.1.1.
The hypothesis test used in assessment of the primary efficacy objective is that the proportion of subjects 
with treatment success at 12 months is greater in subjects randomized to cryoballoon ablation compared 
to subjects randomized to AAD therapy. 
The following hypothesis will be tested in a two-sided test with α = 0.05: 
H0: πcryo = πAAD 
Ha: πcryo ≠πAAD  
Where πcryo and πAAD  are the proportion of treatment successes at 12 months in the modified intention-
to-treat cohorts of the cryoballoon ablation and AAD groups, respectively. 
 
Endpoint Definition 
15.1.2.
A treatment success is the opposite of a treatment failure. 
A subject is considered a treatment failure if he/she experiences any of the following: 
 
• 
Acute procedural failure (defined in section 5.1.4.1; treatment arm only) 
• 
Documented AF/AT/AFL on ambulatory monitoring/12-lead ECG after the 90 day post-ablation 
blanking period (treatment arm)/AAD optimization period (control arm). 
o 
Minimum of 30 seconds on ambulatory monitoring or 10 seconds on 12-lead ECG. 
o 
Note: Documented occurrence and treatment of typical right-sided cavotricuspid isthmus 
dependent atrial flutter is not considered a failure if confirmed by entrainment 
maneuvers during EP testing. 
• 
Any subsequent AF surgery or ablation in the left atrium.   
• 
Any subsequent cardioversion after the 90 day post-ablation blanking period (treatment 
arm)/AAD optimization period (control arm). 
• 
Class I or III antiarrhythmic drug (or sotalol) use after the 90 day blanking period (treatment arm 
only). 
The AAD optimization period is defined as the first 90 days after AAD initiation (control arm).  The 
blanking period is defined as the first 90 days after the index ablation procedure (treatment arm).  
Recurrences of atrial arrhythmias during the AAD optimization/blanking periods will not be counted in the 
determination of the first clinical failure for the primary endpoint.  Within the 90 day AAD optimization 
period and 90 day post-ablation blanking period, recurrent arrhythmias can be managed with medications 
or cardioversions.   


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Performance Requirements 
15.1.3.
If a two-sided log-rank test shows the difference in 12-month success rates to be less than the pre-
specified alpha of 0.05, the null hypothesis (that cryoballoon ablation has similar 12-month efficacy rates 
compared to AAD therapy) will be rejected in favor of the alternative hypothesis (that 12-month success 
rates for subjects treated with cryoballoon ablation is greater than for those treated with AAD’s), 
demonstrating the superiority of the cryoballoon ablation procedure for this endpoint. 
 
Rationale for performance criteria 
15.1.4.
The performance requirement for this objective involves showing superior treatment efficacy rates 
through 12 months in a randomized study against the current standard of care, in a population of 
paroxysmal AF patients. The randomized nature of the study will provide the highest level of evidence 
that, in the event a statistically significant result is attained, that the treatment is indeed responsible for 
the difference in 12-month success. 
 
Analysis Methods 
15.1.5.
The probability of a subject achieving success at 12 months (365 days) will be estimated using Kaplan-
Meier survival analysis.  The standard error will be approximated using Greenwood's formula. A two-sided 
95% log-log confidence interval for the probability will be constructed. A two-sided log rank test with α = 
0.05 will be used to assess whether the failure rate differs between treatment groups. 
Day 0 is defined as either the day of the index cryoablation procedure or the day in which AAD drug 
therapy is initiated.  For subjects with treatment failure, the survival date will be set to the date of the 
treatment failure.  For subjects without treatment failure through 12 months,  those subjects will be 
censored at the last study contact date recorded on a CRF, which may include the last study visit, the exit 
date, or death date.  If a subject without a treatment failure is lost to follow-up, the censoring date will 
be set to the last recorded study visit date.  If treatment failure occurs on the day of index treatment, 
survival time will be set to 0.5 days. 
If an occurrence of documented AF/AT/AFL resulted from rhythm monitoring that was initiated at the 12-
month visit, then the date of occurrence used in the Kaplan-Meier analysis will be the minimum of 365 
days from the cryoballoon ablation procedure/date of AAD initiation or the actual date of occurrence.  
This allows counting of all AF/AT/ AFL events found at the 12-month follow-up, even if the follow-up 
occurred after 365 days post-ablation. 
The survival curves from 0 to 12 months will be presented for both treatment arms. 
 
 


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Sample Size 
15.1.6.
Sample size assumptions are: 
• 
Two-sided Fisher’s exact test 
• 
Alpha=0.05 
• 
AAD 12-month success rate = 45% 
• 
Cryoballoon ablation group 12-month success rate  = 69.9% 
• 
Power>90% 
• 
Attrition from enrollment to 1 year = 10% 
The above assumptions require 87 subjects per arm with data, or 174 total subjects.  Adding in 10% 
attrition brings the overall enrollment sample size to 194 for this objective. Note that a log-rank test will 
be used for the primary efficacy analysis, but the more conservative Fisher’s exact test was used for 
sample size estimation. 
 
Determination of Patients/Data for Analysis 
15.1.7.
A modified intention-to-treat protocol will be utilized for the primary efficacy analysis: all subjects for 
whom either AAD or cryoballoon ablation therapy is initiated will be analyzed according to their 
randomization status. Subjects who withdraw consent between randomization and initiation of therapy 
will be excluded from the primary efficacy analysis. 
 
 


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15.2. Primary Safety Objective 
Demonstrate an acceptable safety profile of the cryoballoon ablation procedure as a first line therapy in a 
non-drug refractory paroxysmal AF population. 
 
Hypothesis 
15.2.1.
The following hypothesis will be tested in a one-sided test with α = 0.025: 
H0: Ps ≥ 12% 
Ha: Ps < 12%, 
where Ps is the probability of a safety event in subjects from the cryoballoon arm. 
 
Endpoint Definition 
15.2.2.
A primary safety event is defined as a serious procedure-related or cryoablation system-related adverse 
event that includes any of the following: 
• 
TIA within 7 days 
• 
Cerebrovascular accident within 7 days 
• 
Major bleeding that requires transfusion or results in a 20% or greater fall in hematocrit (HCT) 
within 7 days 
• 
Development of a significant pericardial effusion within 30 days.   A significant pericardial 
effusion is one that results in hemodynamic compromise, requires elective or urgent 
pericardiocentesis, or results in a 1-cm or more pericardial effusion as documented by 
echocardiography.  
• 
Symptomatic PV stenosis within 12 months; accompanied by one of the following: 50%-75% 
reduction in diameter of the pulmonary vein, with symptoms not explained by other conditions; 
OR >75% reduction in diameter of the pulmonary vein  
• 
MI within 7 days 
• 
PNI unresolved at 12 months 
• 
AE fistula within 12 months 
• 
Major vascular complication that requires intervention, prolongs the hospital stay, or requires 
hospital admission (within 7 days).   
 
Performance requirements 
15.2.3.
If the upper bound of the two-sided 95% confidence interval of the safety event rate in cryoballoon arm 
subjects is <12%, this objective will be considered met.  
 
Rationale for Performance Criteria 
15.2.4.
The safety endpoint definition and performance goal (PG) of 12% for safety events were based on 
previous and current Medtronic cryoballoon ablation catheter studies, as well as based on feedback from 
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A primary safety event rate of 3.1% was observed in the STOP AF trial. The 2016 Annual Report for the 
STOP AF PAS study reports a 12 month safety event rate of 2.3%. For this study, the safety event 
definition has been expanded according to FDA guidance, and certain events (e.g., symptomatic PV 
stenosis from 50 – 75%, cardiac perforation/tamponade from 8 – 30 days after the procedure) not 
included in the two previous studies will be included. Based on the STOP AF trial and STOP AF PAS 
adverse event data and the expanded safety event definition, it is estimated that the current study will 
have a safety rate of 4.0%.  
The STOP AF pivotal study and STOP AF Post-Approval Study (STOP AF PAS) both set PG requirements of 
14.8%.  With an estimated 4% safety rate, a PG of 12% provides stricter criteria than used in prior 
cryoballoon studies, in order to account for differences in the study populations.  
Additionally, the STOP AF Pivotal trial reported that 8.5% of subject’s experienced a Major Atrial 
Fibrillation Events (MAFEs) in the AAD arm (Packer et al., 2013). A large systematic review also reported 
that withdrawals from AADs due to adverse events averaged 16.2% for Class I AADs and 11.4% for Class 
III AAD’s (Lafuente-Lafuente, Valembois, et al. 2015). Therefore the performance criteria established in 
this study is appropriate for demonstrating an acceptable risk-benefit in this drug-naïve PAF population. 
 
Analysis Methods 
15.2.5.
The probability of a safety event within 12 months will be estimated using Kaplan-Meier survival analysis. 
Greenwood’s formula will be used to approximate the standard error of the survival curve, and a two-
sided log-log confidence interval at 12 months will be reported. 
Day 0 is defined as the day of the index cryoablation procedure.  For subjects with a safety event, the 
survival date will be set to the date of the safety event. For subjects without a safety event, censoring 
will occur at the last study contact date with a corresponding CRF (i.e., the last study visit, exit date or 
death). If a subject without a safety event is lost to follow-up they will be censored on the date of the 
last study visit. 
Any subsequent ablations a subject may have after day 0 will not reset their survival time; the date of the 
index procedure will remain as day 0 for purposes of the primary safety analysis. Safety events related to 
repeat ablation procedures occurring up to 365 days after the index cryoablation date will be considered 
as having met criteria for the primary safety endpoint, and will be counted as failures for this analysis. 
 
Sample Size 
15.2.6.
Sample size assumptions are: 
• 
One-sample, one-sided exact binomial test 
• 
Alpha = 0.025 
• 
Cryoballoon ablation 12-month safety rate = 4% 
• 
PG = 12% 
• 
Attrition from enrollment to 1 year = 10%  
Under these conditions, 210 enrolled subjects are required at 1:1 randomization and 10% attrition in 
order to expect 94 randomized and analyzable subjects at 12-month follow-up in the cryoballoon ablation 
arm, which affords 80% power for a one-sided binomial test with α = 0.025. 


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Determination of Patients/Data for Analysis 
15.2.7.
All subjects randomized to the cryoablation arm and have the Arctic Front Advance Cardiac CryoAblation 
Catheter inserted into vasculature will be included.   
Subjects randomized to the AAD arm who receive a cryoablation procedure during follow-up will not be 
included in the primary safety analysis; however, safety events occurring in these subjects will be 
reported into the study database and summarized. 
 
 


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15.3. Secondary Objectives 
Two secondary objectives will be evaluated to gain additional information about the performance of the 
Arctic Front Advance Cardiac CryoAblation catheter, with four hypotheses to be tested. 
 
Secondary Objective #1: 
Assess changes in quality of life between baseline and 12 months in the cryoballoon ablation arm.  There 
are two hypotheses tested in the objective, with separate hypothesis tests for (1) the difference in 
composite scores from the AFEQT questionnaire taken at baseline and 12 month visits, and (2) for the 
difference in composite scores for the EQ-5D questionnaire taken at baseline and 12-month visits. 
 
Secondary Objective #2: 
Compare health care utilization between the treatment and control arms. There are two hypotheses 
tested in the objective, with separate hypothesis tests for: (1) the rate of total health care utilization 
events (cardiovascular-related hospitalizations, emergency room visits, or unscheduled office visits) over 
12 months, and (2) the rate of cardioversions (electrical or pharmacological) over 12 months.  
Testing for these objectives will be performed if the primary objectives are met. A Hochberg multiple 
testing procedure will be utilized to maintain an overall type I error rate of 0.05 for the four hypotheses 
being tested among the two secondary objectives.  
The Hochberg procedure is a stepwise procedure and will be implemented as follows:  
The four hypotheses will be defined as H(1), H(2), H(3), and H(4). For each of the hypotheses, p-values 
will be calculated and sorted p(1) < p(2) < p(3) < p(4). The decision rule to accept or reject each 
hypothesis will follow the step-up algorithm, where α=0.05:  
Step 1: If p(4) ≥ α, accept H(4) and go to Step 2, otherwise reject all hypotheses and stop  
Step 2: If p(3) ≥ α/2, accept H(3) and go to Step 3, otherwise reject H(3), H(2) and H(1) and stop  
Step 3: if p(2) ≥ a/3, accept H(2) and go to Step 4, otherwise reject H(2) and H(1) and stop 
Step 4: If  p(1) < a/4, reject H(1); otherwise accept H(1)  
 
Atrial Fibrillation Effect on Quality-of-Life (AFEQT) 
15.3.1.
15.3.1.1. Hypothesis 
The following hypothesis will be tested in a two-sided test: 
 
Ho: AFEQTmonth12 = AFEQTbaseline 
Ha: AFEQTmonth12 ≠ AFEQTbaseline, 
Where  AFEQTbaseline is the score from the AFEQT assessed at the baseline visit, and AFEQTmonth12 is the 
composite score from the AFEQT assessment from the 12-month follow-up. 


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15.3.1.2. Endpoint Definition 
The AFEQT questionnaire will be utilized for this objective.  The questionnaire is an atrial fibrillation 
specific health-related quality of life questionnaire to assess the impact of AF on a subject’s life.  The 
overall score ranges from 0 – 100, with 0 corresponding to complete disability and 100 corresponding to 
no disability.  The absolute difference between each subject’s baseline and 12 month scores is the 
endpoint of interest. 
15.3.1.3. Analysis Methods 
The difference in mean AFEQT scores will be assessed utilizing a paired t-test.   
15.3.1.4. Performance Criteria 
If the p-value from the two-sample t-test procedure is less than the alpha level determined by the 
Hochberg procedure described above, the objective will be considered met. 
15.3.1.5. Rationale for Performance Criteria 
If this analysis shows that scores from the AFEQT, a validated instrument for measuring quality of life in 
subjects with atrial fibrillation (Spertus, et al. 2011), are significantly higher 12 months after the procedure 
compared to before the procedure, it will show a documented association between the cryoballoon 
ablation procedure and QoL improvement in a non-drug refractory paroxysmal AF population. . While this 
hypothesis test will not be between randomized groups, in the context of a secondary objective that will 
only be tested if efficacy has been established, such results would provide evidence of a QoL 
improvement in cryoballoon ablation-treated patients. 
15.3.1.6.  Determination of Subjects/Data for Analysis 
All subjects randomized to the cryoballoon ablation group who have completed both baseline and 12-
month questionnaires will be included and analyzed. 
 
Comparison to the AAD arm is not planned as it is expected that a large percentage of AAD arm subjects 
will have a cryoballoon procedure during the 12 months of follow-up.  Having a cryoballoon procedure 
prior to 12 months will bias the AAD arm’s 12-month QOL results. 
15.3.1.7.  Additional analyses 
The AFEQT questionnaire has three subscale scores, Daily Activities Subscale, Treatment Concern, and 
Treatment satisfaction.  Each subscale ranges from 0 – 100, where 0 corresponds to low quality-of-life 
and 100 corresponds to high quality of life. 
 
Change in AFEQT subscale score is defined as 12-month AFEQT subscale score minus baseline AFEQT 
subscale score.  A two-sided 95% confidence interval will be calculated based on the t-distribution. 


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 EQ-5D Questionnaire 
15.3.2.
15.3.2.1. Hypothesis 
The following hypothesis will be tested in a two-sided test: 
 
Ho: EQ-5Dmonth12 = EQ-5DAAD 
Ha: EQ-5Dmonth12 ≠ EQ-5DAAD 
Where EQ-5Dmonth12 is the mean composite EQ5D score from subjects assessed at the 12 month visit, and 
EQ-5Dbaseline is the mean composite EQ-5D score for at baseline. 
15.3.2.2. Endpoint Definition 
The Euroqol EQ-5D questionnaire (which consists of a 5-question survey and a visual analog scale 
indicating the subject’s overall health) will be utilized for this objective. Composite scores will be indexed 
against a US reference population. (Shaw, Johnson and Coons 2004)   
15.3.2.3. Analysis Methods 
Change in EQ-5D composite score is defined as 12-month EQ-5D score minus baseline EQ-5D score.  
Differences in mean EQ-5D scores between visits will be assessed utilizing a paired t-test. A two-sided 
95% confidence interval will be calculated based on the t-distribution. 
15.3.2.4. Performance criteria 
If the p-value from the paired t-test is less than the alpha level determined by the Hochberg procedure 
described above, the objective will be considered met. 
15.3.2.5. Rationale for Performance Criteria 
If this analysis shows that EQ-5D scores are significantly higher after 12-months follow-up compared to 
baseline in cryoballoon-treated subjects, it will provide evidence of an association between cryoballoon 
ablation and a general QoL increase (as measured by a validated instrument) that may or may not be 
causal. While this hypothesis test will not be between randomized groups, in the context of a secondary 
objective that will only be tested if efficacy has been established, the evidence provided is stronger than 
if it were just performed in an isolated pre-post comparison. 
15.3.2.6. Determination of Subjects/Data for Analysis 
All cryoballoon ablation arm subjects who have completed both baseline and 12-month questionnaires 
will be included and analyzed. 
 
Comparison to the AAD arm is not planned as it is expected that a large percentage of AAD arm subjects 
will have a cryoballoon procedure during the 12 months of follow-up.  Having a cryoballoon procedure 
prior to 12 months will bias the AAD arm’s 12-month QoL results. 


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Cardiovascular hospitalizations, ED and unscheduled office visits 
15.3.3.
15.3.3.1. Hypothesis 
The following hypothesis will be tested. 
 
H0: θcryo = θAAD 
 
Ha: θcryo ≠ θAAD, 
where θcryo and θAAD are the 12-month rates of cardiovascular HCU events in the cryoballoon ablation and 
AAD arms, respectively. 
15.3.3.2. Endpoint Definition 
Healthcare utilization (HCU) events for this objective are defined as cardiovascular-related 
hospitalizations, cardiovascular-related emergency department visits, or cardiovascular-related 
unscheduled office visits occurring within 12 months after the index ablation (cryo arm) or the initiation 
of therapy (AAD arm).  Events occurring >365 days after initiation of treatment but before the 12-month 
visit will be included.  
15.3.3.3. Analysis Methods 
The probability of a subject achieving freedom from HCU events (defined above) at 12 months will be 
estimated using Kaplan-Meier survival analysis.  The standard error will be approximated using 
Greenwood's formula. A two-sided 95% log-log confidence interval for the probability at 12 months will 
be constructed. A two-sided log rank test will be used to assess whether the HCU event rate differs 
between treatment groups. 
Day 0 is defined as day of the index cryoablation procedure or the day in which drug therapy is initiated.  
For subjects with treatment failure, the survival date will be set to the date of the first HCU event.  For 
subjects without any HCU events through 12 months,  those subjects will be censored at the last study 
contact date recorded on a CRF which may include the last study visit, the exit date or the date of death.  
If a subject without any HCU events is lost to follow-up, the censoring date will be set to the last known 
study visit date.  For HCU events occurring on the day of index treatment, survival time will be set to 0.5 
days. 
The survival curve from 0 to 12 months will be presented for both treatment arms. HCU events will also 
be summarized by type and treatment group. 
15.3.3.4. Performance Requirements 
If the p-value from two-sided log-rank test is less than the alpha level determined by the Hochberg 
procedure described above, the objective will be considered met. 
15.3.3.5. Rationale for Performance Requirements 
If the test specified above indicates a statistically significant increase in the time to the first HCU event 
between cryoballoon ablation and AAD-treated subjects, this is sufficient evidence to say that the 
treatment has a lower rate of healthcare utilization within a year of treatment initiation, due to the 
randomized and intention-to-treat nature of the comparison.  


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15.3.3.6. Determination of Subjects/Data for Analysis 
The modified intent-to-treat cohort will be utilized.  All subjects who initiate either AAD therapy or 
cryoballoon ablation will be analyzed according to the group to which they were randomized. 
 
Cardioversions 
15.3.4.
15.3.4.1. Hypothesis 
The following hypothesis will be tested with a two-sided test.  
 
H0: γcryo = γAAD 
 
Ha: γcryo ≠ γAAD, 
where γcryo and γAAD are the 12-month rates of cardioversion (either electrical or pharmacological) in the 
cryoballoon ablation and AAD arms, respectively. 
15.3.4.2. Endpoint Definition 
A cardioversion event is defined as an electrical or pharmacological cardioversion post index ablation 
discharge for the treatment arm, and post AAD initiation for the AAD arm 
15.3.4.3. Analysis Methods  
The probability of a subject achieving freedom from cardioversion (defined above) at 12 months (365 
days) will be estimated using Kaplan-Meier survival analysis.  The standard error will be approximated 
using Greenwood's formula. A two-sided 95% log-log confidence interval for the probability at 12 months 
will be constructed. A two-sided log rank test, with significance level determined by the Hochberg 
procedure described above, will be used to assess whether the cardioversion rate differs between 
treatment groups. 
Day 0 is defined as the day of the index cryoablation procedure or the day in which drug therapy is 
initiated.  For subjects with at least one cardioversion, the survival date will be set to the date of the first 
cardioversion.  For subjects without any cardioversions through 12 months, those subjects will be 
censored at the last study contact date recorded on a CRF which may include the last study visit, the exit 
date, or the date of death.  If a subject without any cardioversions is lost to follow-up, the censoring date 
will be set to the last known study visit date.  For cardioversions occurring on the day of index treatment, 
survival time will be set to 0.5 days. 
The survival curve from 0 to 12 months will be presented for both treatment arms. Counts of all 
cardioversions administered over 12 months will also be summarized. 
15.3.4.4. Performance Requirements  
If the p-value from two-sided log-rank test is less than the alpha level determined by the Hochberg 
procedure described above, the objective will be considered met. 


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15.3.4.5. Rationale for Performance Criteria 
If the test specified above indicates a statistically significant increase in the time to the first cardioversion 
between cryoballoon ablation and AAD-treated subjects, this is sufficient evidence to say that the 
treatment has a lower rate of cardioversions within a year of treatment initiation, due to the randomized 
and intention-to-treat nature of the comparison. 
15.3.4.6. Determination of Subjects/Data for Analysis 
The modified intent-to-treat cohort will be utilized.  All subjects who initiate either AAD therapy or 
cryoballoon ablation will be analyzed according to the group to which they were randomized in the 
assessment of this objective. 
 
 


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15.4. Ancillary Objectives 
Ancillary objectives been defined to provide additional information about the performance of the Arctic 
Front Advance Cardiac CryoAblation Catheter. No hypotheses are defined for regulatory or labeling 
purposes. 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 


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16. Ethics 
16.1. Statement(s) of Compliance  
The study will be conducted in compliance with international ethical and scientific quality standards, 
known as good clinical practice (GCP). GCP includes review and approval by an independent Institutional 
Review Board (IRB)/ Ethics Committee (EC) before initiating a study, continuing review of an ongoing 
study by an IRB/EC, and obtaining and documenting the freely given informed consent of a subject 
before initiating the study.  
 
The study was designed to reflect the GCP principles outlined in ISO 14155:2011 and other international 
clinical requirements outlined below. These include the protection of the rights, safety and well-being of 
human subjects, controls to ensure the scientific conduct and credibility of the clinical investigation and 
the definition of responsibilities of the sponsor and Investigators. In accordance with ISO standard, the 
sponsor shall avoid improper influence on, or inducement of, the subject, monitor, any Investigator(s) or 
other parties participating in or contributing to the clinical investigation. All Investigators shall avoid 
improper influence on or inducement of the subject, sponsor, monitor, other Investigator(s) or other 
parties participating in or contributing to the clinical investigation. The ISO standard also informed study 
design in the areas of device deficiency reporting and risk evaluation, with the exception (to Section 6.4 
of the ISO standard) that only those Adverse Events (AEs) which are cardiovascular related, serious 
(regardless of relatedness), AAD related, cryoablation system related and/or procedure related will be 
collected. This ensures any AEs which could potentially be relevant will be collected. There is a second 
exemption (to Section 18.1 of the ISO standard) that device accountability will not be performed in 
Europe and only upon package opening in the US.  
 
The study will be conducted according to the CIP, federal, national and local laws, regulations, standards, 
and requirements of the countries/geographies where the study is being conducted. In Europe, the study 
will also be conducted in accordance with the Declaration of Helsinki 2013. For all geographies, the 
principles of the Declaration of Helsinki have been implemented through the patient informed consent 
(IC) process, IRB/EC approval, study training, clinical trial registration, preclinical testing, risk-benefit 
assessment and publication policy. 
 
Ultimately, all centers in all geographies will follow and comply with: 
 
• 
Principles of Declaration of Helsinki (including privacy and data protection laws), or the laws and 
regulations of each participating country, whichever affords greater protection for the study 
subjects 
• 
21 CFR Part 11 (Electronic Records, Electronic Signatures) 
• 
21 CFR Part 54 (Financial Disclosure by Clinical Investigators) 
• 
The procedures described with in this CIP 
• 
Local Ethics Board requirements 
 
All participating geographies will make study data available to the regulatory body such as FDA or 
competent authority if the regulatory body deems an onsite inspection necessary. The regulatory body 
will be able to inspect records at clinical centers around the world to resolve any uncertainties about 
whether the study was conducted in accordance with good clinical practice. 
 


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In addition to the regulatory requirements outlined above, the study will be conducted in compliance with 
relevant local laws. These include but are not limited to: 
 
• 
In the United States, US FDA 21 CFR Parts 
o 
50: Protection of Human subjects,  
o 
56: Institutional Review Boards  
o 
812: Investigational Device Exemptions 
• 
In Europe, Declaration of Helsinki 2013, the Competent Authority requirements, the Medical 
Device Directive (MDD) 93/42/EEC and ISO 14155:2011 with the exceptions stated earlier in this 
Section 
 
The study will be publicly registered prior to first enrollment in accordance with the 2007 Food and Drug 
Administration Amendments Act (FDAAA) and Declaration of Helsinki on http://clinicaltrials.gov (PL 110 
85, Section 810(a)). 
 
Approval of the Clinical Investigation Plan (CIP) is required from the following groups prior to any study 
procedures at a study center: 
 
• 
US Food and Drug Administration (FDA) or regulatory authority 
• 
Medtronic 
• 
Principal Investigators (where required by local law) 
• 
An independent IRB/EC 
 
Similarly, approval of subsequent revisions to the CIP is required at each study center from the above 
mentioned groups prior to implementation of the revised CIP at that center. 
 
Medtronic maintains appropriate clinical study liability insurance coverage as required under applicable 
laws and regulations and will comply with applicable local law and custom concerning specific insurance 
coverage.  If required, a clinical insurance statement/certificate will be provided to the IRB/EC. 
The study is conducted in multiple countries, therefore reimbursement and indemnification will be 
addressed on a country specific basis in the study documents and center Clinical Trial Agreements. 
 
 


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17. Study Administration 
17.1. Role of the Sponsor Representatives 
Sponsor representatives may provide support as required for the study under supervision of the Principal 
Investigator, including: 
• 
Provide study training relevant and pertinent to the involvement of personnel conducting study 
activities and investigator responsibilities 
• 
Technical support at the ablation procedure under the supervision of a study investigator, but no 
data entry, shall be performed by Medtronic personnel or their representatives at sites 
• 
Monitoring and auditing activities  
17.2. Monitoring  
It is the responsibility of Medtronic to ensure proper monitoring of this clinical study.  Trained Medtronic 
personnel or delegates appointed by Medtronic may perform study monitoring at the study center in order 
to ensure that the study is conducted in accordance with the CIP, the Clinical Trial Agreement, and 
applicable regulatory and local requirements.  Medtronic, or delegates, must therefore be allowed direct 
access to the subjects’ case histories (clinic and hospital records, and other source data/documentation) 
upon request as per the IC Form, Research Authorization (where applicable) and Clinical Trial Agreement.  
The Principal Investigator should also be available during monitoring visits. 
Frequency of monitoring visits will occur based on subject enrollment, duration of the study, study 
compliance, number of adverse events, number of deviations, findings from previous monitoring visits and 
any suspected inconsistency in data that requires investigation.  Regulatory documents (e.g., IRB/EC 
approval letters, etc.) may be reviewed at each study center.  Monitoring for the study may include, but 
are not limited to, site initiation visits, interim monitoring visits, and closeout visits, and will be done in 
accordance with the study-specific monitoring plan.  The extent of source data verification will be 
specified in the study-specific monitoring plan. 
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 and for unreported adverse events.  Monitors facilitate site regulatory and study compliance by 
identifying findings of non-compliance and communicating those findings along with recommendations for 
preventative/corrective actions to site personnel.  Findings and non-compliance will also be communicated 
to study personnel via a monitoring follow-up letter.  Monitors may work with study personnel to 
determine appropriate corrective action recommendations and to identify trends within the study or at a 
particular center. 
17.3. Data Management 
Data will be collected via an electronic data management system for clinical studies. 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.  
The Investigator must approve the completed CRFs and the Investigator, or authorized designee, must 
complete CRFs and make CRF corrections. 


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Data collected by ambulatory monitoring and 12-lead ECGs will be managed and over-read by a core lab.  
Final classification of recurrent AF/AT/AFL will be stored in the study database. 
Study management reports may be generated to monitor data quality and study progress.  At the end of 
the study, the data will be frozen and will be retained indefinitely by Medtronic. 
All records and other information about subjects participating in this study will be treated as confidential. 
Data will be transferred and processed by Medtronic or a third party designated by Medtronic in a key 
coded form, unless it’s impossible to make it anonymous, for instance, where the subject’s name cannot 
be removed from the data carrier, such as fluoroscopy images.  In the case that de-identifying is 
impossible or involves a disproportionate effort, files containing personal data of subjects shall only be 
made accessible to authorized persons (secured role-based access). 
17.4. Direct Access to Source Data/Documents  
The sponsor or a regulatory authority may audit or inspect the study site to evaluate the conduct of the 
study.  The clinical investigator(s)/institution(s) shall allow study related monitoring, audits, IRB review 
and regulatory inspection by providing direct access to source data/documents.  If direct access is not 
feasible, certified copies shall be provided to the sponsor or regulatory authority. 
17.5. Confidentiality 
All records and other information about subjects participating in this study will be treated as confidential. 
See sections 17.3 and 17.4 for further information. 
17.6. CIP Amendments 
Approval of subsequent revisions to the CIP is required at each study center from the following groups 
prior to implementation of the revised CIP at the center: 
• 
Medtronic 
• 
Principal Investigators (where required by local law) 
• 
Geography-specific regulatory authorities (if regulatory approval is required) 
• 
An independent EC or IRB 
If a CIP amendment occurs, center personnel will need to be re-trained as necessary, and will need to 
submit any changes to their IRB/EC as required by the committee.  CIP amendments will also be reported 
to and approved by the FDA. 
17.7. Record Retention and Reports 
Medtronic records and reports will be maintained in a password-protected document management 
system, and paper documents (where applicable) will be stored in stored in secured file cabinets at 
Medtronic during the course of this study. 
After closure of the study Medtronic will archive records and reports indefinitely. 


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Investigator Records 
17.7.1.
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 the date on which the investigation is terminated. 
• 
All correspondence between the IRB/EC, 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 
• 
Reports of Adverse Events 
• 
Signed and dated CRFs 
• 
Blank case report forms (Europe only) 
• 
Subject screening logs (if used) and subject identification logs (Europe only) 
• 
Randomization list 
• 
List of investigation centers 
• 
All approved versions of the CIP, ICF, and Investigator’s Brochure/Report of Prior Investigation 
Summary 
• 
Signed and dated Clinical Trial Agreement and Investigator Statement 
• 
Financial Disclosure of Investigators 
• 
Current curriculum vitae (signed and dated in Europe) of all participating Investigators and key 
members of investigation center team (Europe only) 
• 
Documentation of delegated tasks 
• 
IRB/EC approval documentation including written information that the investigator or other 
study staff, when member of the IRB/EC, did not participate in the approval process. 
Approval documentation must include the IRB/EC composition, in Europe and where required 
by local law. 
• 
Regulatory authority notification, correspondence and approval, where required by local law. 
• 
Study training records for center staff 
• 
Insurance certificates (where required by the IRB/EC) 
• 
Any other records that FDA or regulatory authorities 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 
• 
Final Clinical Study Report, including the statistical analysis 
 
Investigator Reports 
17.7.2.
The Investigator is responsible for the preparation (review and signature) and submission to the sponsor 
of all case report forms, adverse events, device deficiencies, deaths, and any deviations from the clinical 








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• 
All approved versions of the Clinical Investigation Plan and study related reports, 
Investigator’s Brochure/Report of Prior Investigation Summary 
• 
All case report forms and supporting documentation submitted by investigator, samples of 
Informed Consent Forms, and other information provided to the subjects 
• 
Copies of all IRB/EC approval letters and relevant IRB/EC correspondence and 
IRB/EC voting list/roster/letter of assurance 
• 
Names of the institutions in which the clinical investigation will be conducted 
• 
Regulatory authorities correspondence, notification and approval, as required by national 
legislation 
• 
Insurance certificates 
• 
Randomization List 
• 
Names/contact addresses of monitors 
• 
Monitoring visit reports and follow-up letters 
• 
Forms for reporting any adverse events and adverse device effects 
• 
Statistical analyses and underlying supporting data. 
• 
Final report of the clinical investigation 
• 
Study training records for center personnel and Medtronic personnel involved in the study 
• 
Any other records that local regulatory agencies require to be maintained 
 
Sponsor Reports 
17.7.4.
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/EC, regulatory agency or FDA, provide accurate, complete and current information about 
any aspect of the investigation. Safety data reporting requirements are listed in the adverse event 
section. 
 
 










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The publication committee’s role is to: 
• 
Manage elements addressed in the publication plan,  
• 
Develop the final publication plan under separate cover,  
• 
Execute the publication plan,  
• 
Oversee the publication of primary, secondary 
 study results,  
• 
Review and prioritize publication proposals,  
• 
Provide input on publication content,  
• 
Determine authorship,  
• 
Ensure the International Committee of Medical Journal Editors (ICMJE) quality and rules guidance 
is used, and  
• 
Determine procedure for documentation of decisions related to the generation of publications. 
In addition, the committee will apply and reinforce the authorship guidelines set forth in the publication 
plan.  Membership in the publication committee does not guarantee authorship.  The committee will meet 
at as needed. 
 
Management of Primary, Secondary and Ancillary Publications 
17.8.1.
The publication committee reviews, prioritizes, and manages all publications including primary, secondary 
and ancillary publications.  Primary and secondary publications are those that address analyses of any or 
all primary objectives or secondary objectives, respectively, as specified in the clinical investigation plan. 
An ancillary publication is any publication that does not address the study objectives identified in the 
clinical investigation plan.  They include publications proposed and developed by other Medtronic 
departments or entities, clinicians participating in this clinical study, and clinicians not participating in this 
clinical study.  The committee will work with Medtronic to ensure that requests do not present conflicts 
with other proposals, are not duplicative, and to determine which ancillary publication proposals, if any, 
will be supported. 
The committee may decide that no publications, including abstracts, will be published prior to the end of 
the study or with individual center data.  Requests for publications on study objectives utilizing subset 
data (e.g., regional) will be evaluated for scientific validity and the ability of Medtronic to provide 
resources. 
 
Criteria for Determining Authorship 
17.8.2.
Publications will adhere to authorship criteria defined by the International Committee of Medical Journal 
Editors (ICMJE, Uniform requirements for manuscripts submitted to biomedical journals, www.icmje.org).  
Individual authorship criteria defined by the target journal or conference will be followed when it differs 
from ICMJE criteria. 
Decisions regarding authorship and contributor-ship will be made by the committee. The selected authors 
will be responsible for drafting the publication.  All selected authors must fulfill the authorship conditions 
stated above to be listed as authors, and all contributors who fulfill the conditions must be listed as 
authors. 
All investigators not listed as co-authors will be acknowledged as the “STOP AF First Study Investigators” 
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and affiliation.  Any other contributors will be acknowledged by name with their specific contribution 
indicated. 
 
Transparency 
17.8.3.
Transparency of study results will be maintained by the following means: 
• 
A final report, describing the results of all objectives and analysis, will be distributed to all 
investigators and IRBs 
• 
Registering and posting the study results on ClinicalTrials.gov based on the posting rules 
stipulated 
• 
Submitting for publication the primary study results after the study ends 
• 
Disclosing conflicts of interest (e.g., financial) of the co-authors of publications according to the 
policies set forth by the corresponding journals and conferences 
• 
Making an individual center’s study data accessible to the corresponding investigator after the 
completion of the study, if requested 
17.9. Suspension or Early Termination 
 
Planned Study Closure 
17.9.1.
Study closure is a process initiated by distribution of a 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 CIP 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.  Ongoing IRB/EC oversight is required until the overall study closure process is complete. Refer to 
sections 11.5.13 and 11.10 for additional information regarding study exit procedures. 
 
Early Termination or Suspension 
17.9.2.
Early termination is the closure of a clinical study that occurs prior to meeting defined endpoints. This is 
possible for the whole study or a single site.  Study suspension is a temporary postponement of study 
activities related to enrollment.  This is possible for the whole study or a single site. 
 
Study-wide termination or suspension 
17.9.3.
Possible reasons for considering study suspension or termination of the study include but are not limited 
to: 
• 
Decision by Medtronic or regulatory body (where the study is operating under regulatory body 
authority) 
• 
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 
• 
Enrollment is slower than anticipated 


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Site termination or suspension  
17.9.4.
Possible reasons for clinical investigator or site termination or suspension include but are not limited to: 
• 
Failure to obtain initial IRB approval or annual renewal of the study 
• 
Persistent non-compliance to the clinical investigation  
• 
Lack of enrollment 
• 
Noncompliance to regulations and the terms of the CTA (e.g. failure to submit data in a timely 
manner, failure to follow-up on data queries and monitoring findings in a timely manner)  
• 
IRB/EC suspension of the site 
• 
Fraud or fraudulent misconduct is discovered (as defined by local law and regulations)  
• 
Investigator request (e.g., no longer able to support the study) 
 
Procedures for Termination or Suspension 
17.9.5.
17.9.5.1. Medtronic-initiated and regulatory authority-initiated 
• 
Medtronic will promptly inform the clinical investigators of the termination or suspension and the 
reasons and inform the regulatory authority where required 
• 
In the case of study termination or suspension for reasons other than a temporary IRB/EC 
approval lapse, the investigator will promptly inform the IRB/EC and the institution (where 
required per regulatory requirements) 
• 
In the case of study termination, the investigator must inform the subjects (or legally authorized 
designees or guardians, US ONLY), and may inform the personal physician of the subjects to 
ensure appropriate care and follow-up is provided 
• 
In the case of a study suspension, subject enrollment must stop until the suspension is lifted by 
Medtronic 
• 
In the case of study suspension, enrolled subjects should continue to be followed out of 
consideration of their safety, rights and welfare 
17.9.5.2. Investigator-initiated 
• 
The Investigator will 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/EC and regulatory authority (where required per 
regulatory requirements) 
• 
The Investigator will promptly inform the subjects, and may inform personal physician of the 
subjects to ensure appropriate care and follow-up is provided 
• 
In the case of study suspension, enrolled subjects should continue to be followed out of 
consideration of their safety, rights and welfare 


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17.9.5.3. IRB/EC-initiated 
• 
The Investigator will inform Medtronic and provide a detailed written explanation of the 
termination or suspension within 5 business days 
• 
Subject enrollment must stop until the suspension is lifted 
• 
Subjects already enrolled should continue to be followed in accordance with 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 (or legally authorized designees or guardians, 
except in Europe),  and may inform the personal physician of the subjects, with the rationale for 
the study termination or suspension 
• 
The Investigator will inform local regulatory authority, where required per regulatory 
requirements 
 
 


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18. References 
AFFIRM First Antiarrhythmic Drug Substudy Investi. "Maintenance of sinus rhythm in patients with atrial 
fibrillation: an AFFIRM substudy of the first antiarrhythmic drug." J Am Coll Cardiol 42 (2003): 
20-9. 
Arena, G, C Tondo, G Cattafi, and et. al. "Cryoballoon ablation as treatment of recent paroxysmal atrial 
fibrillation. Data from a large cohort of patients followed in a real world multicenter experience." 
Heart Rhythm 13 (2016): S375-76. 
Calkins, et. al. "HRS/EHRA/ECAS expert Consensus Statement on catether and surgical ablation of AF; 
recommendations for patient selection, procedural techniques and follow-up, definitions, 
endpoints, and research trial design. A report of the HRS task force..." Heart Rhythm 9, no. 4 
(2012): 632-696.e20. 
Caulkins, H, and et. al. . "HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical 
Ablation of Atrial Fibrillation: Recommendations for Personnel, Policy, Procedures and Follow-Up." 
Europace 9, no. 6 (2007): 335-379. 
Cosio, FG, E Aliot, GL Botto, and et. al. . "Delayed rhythm control of atrial fibrillation may be a cause of 
failure to prevent recurrences: reasons for change to active antiarrhymic treatment at the time of 
the first detected episode." Europace 10 (2008): 21-7. 
De Vos, CB, R Pisters, R Nieuwlaat, and et. al. . "Progression from paroxysmal to persistent atrial 
fibrillation clinical correlates and prognosis." J Am Coll Cardiol 55 (2010): 725-31. 
Go, A, E Hylek, K Phillips, and et. al. "Prevalence of Diagnosed Atrial Fibrillation in Adults: National 
Implications for Rhythm Management and Stroke Prevention: the Anticoagulation and Risk 
Factors in Atrial Fibrillation (ATRIA) Study." JAMA 285, no. 18 (2001): 2370-2375. 
Hommel, G. "A stagewise rejective multiple test procedure based on a modified Bonferroni test." 
Biometricka 75 (1988): 383-386. 
Jais, P, MD O'Neill, Y Takahashi, and et. al. . "Stepwise Catheter Ablation of Chronic Atrial Fibrillation: 
Importance of Discrete Anatomic Sites for Termination." J Cardiovasc Electrophysiol 17, no. 
Suppl. 3 (2006): S28-S36. 
Jalife, J, and K Kaur. "Atrial remodeling, fibrosis, and atrial fibrillation." Trends Cardiovasc Med 25 (2015): 
475-84. 
January, CT, and et. al. . "2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial 
Fibrillation." JACC 64, no. 21 (2014): e1-76. 
January, CT, et al. "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: 
Executive Summary." Journal of the American College of Cardiology, 2014. 
Knight, BP, PG Novak, R Sangrigoli, and et. al. "Second generation cryoballoon: results from the 
multicenter STOP AF Post Approval Study 12-month clinical outcomes following pulmonary vein 
isolation using the Arctic Front Adfance." Cardiostim (abstract). 2016. 
Kuck, KH, et al. "Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation." N Engl J Med 
374 (2016): 2235-45. 
Lafuente-Lafuente, C, L Valembois, JF Bergmann, and J Belmin. "Antiarrhythmics for maintaining sinus 
rhythm after cardioversion of atrial fibrillation." Cochrane Database of Systematic Reviews, 2015. 


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Lafuente-Lafuente, C, S Mouly, MA Longas-Tejero, and et. al. "Antiarrhythmic drugs for maintaining sinus 
rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled 
trials." Arch Intern Med 166 (2006): 719-28. 
Morillo, CA, A Verma, SJ Connolly, and et. al. "Radiofrequency ablation vs. antiarrhythmic drugs as first-
line treatment of paroxysmal atrial fibrillation (RAAFT-2): A randomized trial." JAMA 311, no. 7 
(2014): 692-700. 
Nattel, S, E Guasch, I Savelieva, and et. al. "Early management of atrial fibrillation to prevent 
cardiovascular complications." Eur heart J 35 (2014): 1448-56. 
Nielsen, JC, et al. "Radiofrequency Ablation as Initial Therapy in Paroxysmal Atrial Fibrillation." New 
England Journal of Medicine, October 25, 2012: 1587-96. 
Oral, H, BP Knight, H Tada, and et. al. . "Pulmonary vein isolation for paroxysmal and persistent atrial 
fibrillation." Circulation 105 (2002): 1077-81. 
Packer, D, et al. "CryoBalloon ablation: first results of North America STOP AF pivotal trial." J Am Coll 
Cardiol 61, no. 16 (2013): 1713-1723. 
Raviele, et. al. . "Venice Chart International consensus document on atrial fibrillation: 2011 Update." J 
Cardiovasc Electrophysiol 23 (2012): 890-923. 
Romero, J, C Gianni, L Di Biase, and A Natale. "Catheter ablation for long-standing persistent atrial 
fibrillation: On-treatment analysis of the randomized controlled MANTRA-PAF trial." Int J Cardiol J 
11 (2015): 87-93. 
Shaw, JW, JA Johnson, and SJ Coons. "U.S. Valuation of the EQ-5D Heatlh States: Development and 
Testing of the D1 Valuation Model." Medical Care, 2004. 
Shulka, A, and AB Curtis. "Avoiding permanent atrial fibrillation: treatment approaches to prevent disease 
progression." Vasc Health Risk Manag 10 (2014): 1-12. 
Spertus, J, et al. "Development and validation of the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) 
Questionnaire in patients with atrial fibrillation." Circ Arrhythm Electrophysiol, Feb 4, 2011: 15-
25. 
Tanner, H, K Makowski, L Roten , and et. al. "Catheter ablation of atrial fibrillation as first-line therapy- a 
single-center experience." Europace 13 (2011): 646-53. 
Walters, TE, A Nisbet, GM Morris, and et. al. "Progression of atrial remodeling in patients with high-
burden atrial fibrillation: Implications for early ablative intervention." Heart Rhythm 13 (2016): 
331-9. 
Wazni, OM, et al. "Radiofrequency Ablation vs. Antiarrhythmic Drugs as First-Line Treatment of 
Symptomatic Atrial Fibrillation." JAMA, June 1, 2005: 2634-40. 
Wijesurendra, RS, and B Casadei. "Atrial fibrillation: effects beyond the atrium?" Cardiovasc Res 105 
(2015): 238-47. 
Wolf, P, R Abbott, and W Kannel. "Atrial fibrillation as an independent risk factor for stroke: the 
Framingham Study." Stroke 22, no. 8 (1991): 983-988. 
Wu, J-H, H-K Li, DM Couri, and et. al. "Reversal of pulmonary vein remodeling after catheter ablation of 
atrial fibrillation." J Geriatr Cardiol 13 (2016): 163-8. 
 






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Appendix B: DRAFT DATA COLLECTION ELEMENTS (CASE REPORT FORMS) 
Draft Case Report Forms for the STOP AF First study will be provided under separate cover.  Final CRFs 
will be provided to study centers via the electronic data management system after the center has fulfilled 
all requirements for database access. 
 
 


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Appendix C: INFORMED CONSENT FORM TEMPLATE 
The Informed Consent Form Template will be distributed under separate cover. 
 
 


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Appendix D: PARTICIPATING INVESTIGATOR AND INSTITUTIONS 
A final list of participating Investigators and institutions has not been finalized prior to development of the 
Clinical Investigation Plan and will be distributed under separate cover. 
 
 


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Appendix E: IRB LIST 
A final IRB list has not been finalized prior to development of the Clinical Investigation Plan and will be 
distributed under separate cover. 
 
 


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Appendix F: FORESEEABLE ADVERSE EVENTS 
The information provided in this section pertains to foreseeable adverse events that may be observed in 
study subjects and may collectively assist in identifying those events for a given device or therapy that 
are unexpected in nature.  The foreseeable adverse events information consists of two parts: a listing of 
potential adverse events associated with cryoablation therapy/procedure and adverse event rates 
reported in published literature for same therapy/procedure (see Appendix A).  An evaluation of 
potentially anticipated events and reported events in literature may be used in combination with device 
labeling/IFU, current event reporting information, and other published data to assess for an unexpected 
occurrence. 
The cryoablation procedure involves surgery, therefore, standard adverse events associated with a 
surgical procedure may be experienced (e.g. anesthesia complications, injury, infections, bleeding, 
exacerbation of pre-existing conditions, healing complications, etc.). The focus of this section is to 
specifically address in more detail, those events that are foreseeable due to the use, performance, and/or 
presence of the Arctic Front Advance™ CryoAblation Catheter under investigation. 
Additional potential risks associated with the Arctic Front Advance™ CryoAblation Catheter, as well as risk 
minimization are discussed within section 12. 
Treatment required for procedure and/or cryoablation system related adverse events that are 
experienced may include medication or other surgical and medical remedies. The adverse events 
associated with the use of the Arctic Front Advance™ CryoAblation Catheter include but are not limited to 
those in Table 14 and Table 15. 
Table 14 pertains to the foreseeable/anticipated adverse events that may be observed in the study and 
may assist in identifying those adverse events that are unexpected in nature. 
Table 14: Foreseeable Adverse Events 
Anemia 
Feeling cold 
Pseudoaneurysm 
Anxiety 
Fever 
Pulmonary edema 
Arrhythmia 
Gastrointestinal 
discomfort 
Pulmonary embolism 
Arteriovenous fistula 
Gastroparesis 
Pulmonary 
hemorrhage 
Atrial fibrillation 
Headache 
Pulmonary 
hypertension 
Atrial flutter 
Heart block 
Pulmonary infarction 
Atrio-esophageal fistula  
Heart failure 
Pulmonary 
infiltration 
Back pain 
Hematemesis 
Pulmonary vein 


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stenosis 
Bleeding 
Hematoma 
Renal impairment 
Blurred vision 
Hemoptysis 
Respiratory arrest or 
pulmonary arrest 
Bronchial fistula 
Hemothorax 
Right bundle branch 
block 
Bronchitis 
Hiccups 
Shivering 
Bruising 
Hypertension 
Shortness of breath 
Cardiac arrest or 
cardiopulmonary arrest 
Hypotension 
Sore throat 
Cardiac perforation or 
cardiac vein perforation 
or perforation of 
surrounding tissue 
Hypoxia 
ST segment 
elevation 
Cardiac tamponade 
Injury to pulmonary vein 
e.g. pulmonary vein 
dissection, pulmonary 
vein hematoma  
Stroke or 
cerebrovascular 
accident 
Cerebral embolism 
Lightheadedness 
Syncope 
Chest discomfort or pain 
or pressure 
Lung injury 
Tachycardia 
Coronary artery spasm 
Myocardial infarction 
Thrombosis or 
thrombus 
Cough 
Nausea 
Transient ischemic 
attack 
Death 
Nerve injury e.g. phrenic 
nerve injury 
Urinary infection 
Diarrhea 
Neurological impairment 
Vascular access site 
complication 








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Appendix G: PRE-CLINICAL TESTING 
A summary of results from pre-clinical testing with the Arctic Front Advance™ Cardiac CryoAblation 
Catheter is provided in the Report of Prior Investigations Summary. 
 

SAP_007.pdf: 
 
 
Clinical Investigation Plan Title 
STOP AF First 
Clinical Investigation Plan Identifier 
MDT16012AFS001 
Study Product 
Arctic Front Advance™ Cardiac CryoAblation Catheter 
Application Number 
IDE #G1160219 
ClinicalTrials.gov Identifier 
NCT03118518 
Sponsor 
Medtronic 
8200 Coral Sea St NE 
Mounds View, MN  55112 
Document Title 
STOP AF First Statistical Analysis Plan 
Document Version (Date) 
2.0 (09-MAY-2018) 
 


STOP AF First Statistical Analysis Plan 
 
 
 
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Statistical Analysis Plan 
Clinical Investigation Plan Title STOP AF First 
Clinical Investigation Plan Identifier
MDT16012AFS001 
Sponsor/Local Sponsor
United States of America 
Medtronic, Inc. 
8200 Coral Sea St NE 
Mounds View, MN U.S.A. 55112 
 
Europe 
Medtronic, Bakken Research Center B.V. 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
Document Version
2.0 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Medtronic. Any 
distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly 
prohibited. Persons to whom the information is disclosed must know that it is confidential and that it may 
not be further disclosed by them. 
 
 
 


 
 
Clinical Investigation Plan Title 
STOP AF First 
Clinical Investigation Plan Identifier 
MDT16012AFS001 
Study Product 
Arctic Front Advance™ Cardiac CryoAblation Catheter 
Application Number 
IDE #G1160219 
ClinicalTrials.gov Identifier 
NCT03118518 
Sponsor 
Medtronic 
8200 Coral Sea St NE 
Mounds View, MN  55112 
Document Title 
STOP AF First Statistical Analysis Plan 
Document Version (Date) 
2.0 (09-MAY-2018) 
 


STOP AF First Statistical Analysis Plan 
 
 
 
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  056-F286, Statistical Analysis Plan Template, 
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Table of Contents 
1.  Version History ....................................................................................... 3 
2.  List of Abbreviations and Definitions of Terms ....................................... 3 
3.  Introduction ............................................................................................ 4 
4.  Investigation Plan .................................................................................. 4 
5.  Study Objectives ..................................................................................... 6 
5.1. 
Primary Efficacy Objective: ............................................................................................. 6 
5.2. 
Primary Safety Objective: ............................................................................................... 6 
5.3. 
Secondary Objectives ..................................................................................................... 6 
 
 
6.  Statistical Methods ................................................................................. 7 
6.1. 
Study Subjects ............................................................................................................... 7 
6.2. 
General Methodology and Evaluation of Objectives ........................................................... 8 
6.3. 
Center Pooling ............................................................................................................. 22 
6.4. 
Handling of Missing, Unused, and Spurious Data and Dropouts ........................................ 23 
6.5. 
Adjustments for Multiple Comparisons ........................................................................... 25 
6.6. 
Interim Analyses .......................................................................................................... 25 
6.7. 
Subgroup Analyses ....................................................................................................... 26 
6.8. 
Changes to Planned Analysis ......................................................................................... 26 
7.  Determination of Sample Size .............................................................. 28 
7.1. 
Sample Size Determination for Primary Efficacy Objective ................................................ 28 
7.2. 
Sample Size Determination for Primary Safety Objective .................................................. 29 
8.  Validation Requirements ...................................................................... 31 
9.  References ............................................................................................ 32 
 
 
 
 
 
 




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3. 
Introduction 
The purpose of the Statistical Analysis Plan (SAP) for the STOP AF First trial is to provide pre-analysis 
documentation and rationale for the statistical procedures that will be employed in the planned analyses 
that are performed throughout this study.  Specifically, this plan outlines methods used in the study’s 
final report, as well as the primary study results publication. It does not limit the analysis that will be 
completed, as further analysis beyond what is specified in this document is likely.    
This SAP was developed based on version 6.0 of the STOP AF First Clinical Investigation Protocol 
(referred to as the CIP in this SAP), dated 16-JAN-2018. Topics included in this document which are not 
included in the CIP are handling of missing data (section 6.4), subgroup analyses (section 6.7), and 
validation requirements (section 8). 
 
4. 
Investigation Plan 
The purpose of the STOP AF First study is to provide data demonstrating the safety and effectiveness of 
the Arctic Front AdvanceTM Cardiac CryoAblation Catheter for the treatment of recurrent symptomatic 
paroxysmal Atrial Fibrillation (AF), without the requirement that subjects be drug refractory.  The current 
indication is the US is as follows: The Arctic Front Advance™ Cardiac CryoAblation Catheter is indicated 
for the treatment of drug refractory recurrent symptomatic paroxysmal atrial fibrillation.  The proposed 
indication in the US is: The Arctic Front Advance™ Cardiac CryoAblation Catheter is indicated for the 
treatment of recurrent symptomatic paroxysmal atrial fibrillation. The proposed indication is already 
within the approved indications for use in Europe. 
Medtronic, Inc. is sponsoring the STOP AF First study; a prospective, interventional, multi-center, 
randomized, controlled, unblinded clinical study. The study will compare cryoablation to Anti-Arrhythmic 
Drug (AAD) therapy, the current standard of care for subjects experiencing first-time repeat occurrences 
of paroxysmal AF.  Up to 30 sites in the US, and up to 10 in Europe will participate in the trial.  Two 
hundred and ten (210) subjects will be randomized.  Subjects will be randomized 1:1 to either AAD 
therapy (control arm) or cryoablation (treatment arm).  Subjects will be followed at 1 month, 3 months, 6 
months, and 12 months following either cryoablation or AAD initiation.  Subjects will be exited from the 
study at the 12-month follow-up visit.   Guidance for procedures completed at study visits are provided in 
the CIP including evaluations at baseline, cryoablation procedure, and scheduled follow up visits. No 
interim analyses are planned.  
 
 


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Figure 1:  Study Design 
 
 
 
 






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having been performed if a cryoballoon catheter was inserted into a subject’s vasculature. This analytical 
cohort does not include AAD arm subjects who cross over into the cryoablation group, and does not 
include subjects who withdraw consent or are withdrawn by an investigator prior to their first day at risk 
for events. This set will be used in the analysis of the primary safety objective, 
 
. 
6.2. General Methodology and Evaluation of Objectives 
 
6.2.1. 
Overview 
The analysis described in this SAP will be conducted by Medtronic statisticians. Prior to evaluation of the 
study’s primary objectives, a descriptive analysis will be performed: demographic and other key baseline 
characteristics will be summarized by randomization group for the mITT dataset.  Additional exploratory 
analyses of the data may be conducted as deemed appropriate. 
 
6.2.2. 
Primary Efficacy Objective 
Demonstrate the superiority of cryoballoon ablation as compared to AAD therapy in terms of the rate of 
freedom from AF/AT/AFL in a non-drug refractory paroxysmal AF population. 
6.2.2.1. 
Hypothesis 
The hypothesis test used in assessment of the primary efficacy objective is that the proportion of subjects 
with treatment success at 12 months is greater in subjects using cryoballoon ablation compared to 
subjects using AAD therapy. 
The following hypothesis will be tested in a two-sided test with α = 0.05: 
H0: πcryo = πAAD 
Ha: πcryo ≠πAAD  
Where πcryo and πAAD  are the proportion of treatment successes at 12 months in the modified intention-to-
treat cohorts of the cryoballoon ablation and AAD groups, respectively. 
6.2.2.2. 
Endpoint Definition 
A treatment success is the opposite of a treatment failure. 
A subject is considered a treatment failure if he/she experiences any of the following: 


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 
Acute procedural failure (treatment arm only), which is any of these: 
o 
Inability to isolate all accessible targeted pulmonary veins (assessed for entrance block 
and, where assessable, exit block) during the index ablation procedure, OR 
o 
Left atrial non-PVI ablations including but not limited to, ablation of linear lesions, OR 
o 
Use of a non-study device in the left atrium. 
 
Documented AF/AT/AFL on ambulatory monitoring/12-lead ECG after the 90-day post-ablation 
blanking period (treatment arm). 
o 
Minimum of 30 seconds on ambulatory monitoring or 10 seconds on 12-lead ECG. 
o 
Note: Documented occurrence and treatment of typical right-sided cavotricuspid isthmus 
dependent atrial flutter is not considered a failure if confirmed by entrainment 
maneuvers during EP testing. 
 
Any subsequent AF surgery or ablation in the left atrium.   
 
Any subsequent cardioversion after the 90-day post-ablation blanking period. 
 
Class I or III antiarrhythmic drug (or sotalol) use after the 90-day blanking period (treatment arm 
only). 
The blanking period is defined as the first 90 days after the index ablation procedure (treatment arm) or 
AAD initiation (control arm).  Recurrences of atrial arrhythmias during the blanking period will not be 
counted in the determination of the first clinical failure for the primary endpoint.  Within the 90-day 
blanking period, recurrent arrhythmias can be managed with medications or cardioversions.   
6.2.2.3. 
Performance Requirements 
This hypothesis test is for superiority of the cryoablation procedure over AAD’s as a treatment for 
AF/AFL/AT in a drug-naïve population. If a two-sided log-rank test shows the difference in 12-month 
success rates to be less than the pre-specified alpha of 0.05, the null hypothesis (that cryoballoon 
ablation has similar 12-month efficacy rates compared to AAD therapy) will be rejected in favor of the 
alternative hypothesis (that 12-month success rates for subjects treated with cryoballoon ablation is 
greater than for those treated with AAD’s). 
6.2.2.4. 
Analysis Methods 
The probability of a subject achieving success at 12 months (365 days) will be estimated using Kaplan-
Meier survival analysis.  The standard error will be approximated using Greenwood's formula. A two-sided 
95% log-log confidence interval for the probability will be constructed. A log rank test with α = 0.05 will 
be used to assess whether the failure rate differs between treatment groups. 
Day 0 is defined as either the day of the index cryoablation procedure or the day in which AAD drug 
therapy is initiated.  For subjects with treatment failure, the survival date will be set to the date of the 
treatment failure.  For subjects without treatment failure through 12 months, those subjects will be 
censored at the last study contact date recorded on a CRF, which may include the last study visit, the exit 
date, or death date.  If a subject without a treatment failure is lost to follow-up, the censoring date will 
be set to the last recorded study visit date.  If treatment failure occurs on the day of index treatment, 
survival time will be set to 0.5 days. 
If an occurrence of documented AF/AT/AFL resulted from rhythm monitoring that was initiated at the 12-
month visit, then the date of occurrence used in the Kaplan-Meier analysis will be the minimum of 365 


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days from the cryoballoon ablation procedure/date of AAD initiation, or the actual date of occurrence.  
This allows counting of all AF/AT/ AFL events found at the 12-month follow-up, even if the follow-up 
occurred after 365 days post-ablation but still within the visit window. Events found at 12-month visits 
outside of the window will be censored at the previous follow-up and described in deviation listings.  
The survival curves from 0 to 12 months will be presented for both treatment arms.  
6.2.2.5. 
Determination of Subjects for Analysis 
The mITT cohort will be used for this analysis. 
6.2.3. 
Primary Safety Objective 
Demonstrate an acceptable safety profile of the cryoballoon ablation procedure as a first line therapy in a 
non-drug refractory paroxysmal AF population. 
6.2.3.1. 
Hypothesis 
The following hypothesis will be tested in a one-sided test with α = 0.025: 
H0: Ps ≥ 12% 
Ha: Ps < 12%, 
where Ps is the probability of a safety event in subjects from the cryoablation arm. 
6.2.3.2. 
Endpoint Definition 
A primary safety event is defined as a serious procedure-related or cryoablation system-related adverse 
event that includes any of the following: 


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 
TIA within 7 days 
 
Cerebrovascular accident within 7 days 
 
Major bleeding that requires transfusion or results in a 20% or greater fall in hematocrit (HCT) 
within 7 days 
 
Development of a significant pericardial effusion within 30 days.   A significant pericardial 
effusion is one that results in hemodynamic compromise, requires elective or urgent 
pericardiocentesis, or results in a 1-cm or more pericardial effusion as documented by 
echocardiography.  
 
Symptomatic PV stenosis within 12 months; accompanied by one of the following: 50%-70% 
reduction in area of the pulmonary vein, with symptoms not explained by other conditions; OR 
>70% reduction in area of the pulmonary vein  
 
MI within 7 days 
 
PNI unresolved at 12 months 
 
AE fistula within 12 months 
 
Major vascular complication that requires intervention, prolongs the hospital stay, or requires 
hospital admission (within 7 days).   
6.2.3.3. 
Performance Requirements 
If the upper bound of the two-sided 95% confidence interval of the safety event rate in cryoablation arm 
subjects is <12%, this objective will be considered met.  
6.2.3.4. 
Analysis Methods 
The probability of a safety event within 12 months will be estimated using Kaplan-Meier survival analysis. 
Greenwood’s formula will be used to approximate the standard error of the survival curve, and a two-
sided log-log confidence interval at 12 months will be reported. 
Day 0 is defined as the day of the index cryoablation procedure.  For subjects with a safety event, the 
survival date will be set to the date of the safety event. For subjects without a safety event, censoring 
will occur at the last study contact date with a corresponding CRF (i.e., the last study visit, exit date or 
death). If a subject without a safety event is lost to follow-up they will be censored on the date of the 
last study visit. 
Any subsequent ablations a subject may have after day 0 will not reset their survival time; the date of the 
index procedure will remain as day 0 for purposes of the primary safety analysis. Safety events related to 
repeat ablation procedures occurring up to 365 days after the index cryoablation date will be considered 
as having met criteria for the primary safety endpoint, and will be counted as failures for this analysis. 
Safety events only observed at 12-month follow-up visits that occur 365 - 395 days after the index 
ablation (i.e. are in the visit window) will also count as safety failures at one year. Like with the primary 
efficacy objective, safety events found at 12-month visits outside of the window (>395 days from index 
ablation) will not be counted in this endpoint, but will be described in AE listings. 
 


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6.2.3.5. 
Determination of Subjects for Analysis  
The primary safety objective will be assessed in the CTR cohort. 
 
6.2.3.6. 
Additional Safety Analysis Specifications 
Subjects randomized to the AAD arm who receive a cryoablation procedure during follow-up will not be 
included in the primary safety analysis (as they are not included in the CTR dataset). However, events 
corresponding to the primary safety endpoint (treatment success, treatment safety, QoL and HCU) 
occurring in this cohort of subjects will be reported and summarized as well. Kaplan-Meier methods will 
be used to estimate event rates and corresponding confidence intervals, with day 0 being set to the date 
of the crossover ablation. Standard error will be approximated with Greenwood’s formula, and a two-
sided log-log confidence interval will be presented. No hypothesis testing is planned for analysis of 
crossover ablation subjects, and there is no planned comparison of this cohort to the CTR cohort. 
Depending on the number of repeat ablations observed over the course of the study, a similar set of 
analyses may also be performed on the subset of subjects having a second ablation, with day 0 being set 
to the date of the repeat ablation. If 10 or fewer repeat ablations are observed, associated characteristics 
and outcomes of repeat ablation will be described through listings. 
 
6.2.4. 
Secondary Objective 1: Quality of Life 
Assess changes in quality of life between baseline and 12 months in the cryoballoon ablation arm.   
There are two hypotheses tested in the objective, with separate hypothesis tests for (1) the difference in 
composite scores from the AFEQT questionnaire taken at baseline and 12 month visits, and (2) for the 
difference in composite scores for the EQ-5D questionnaire taken at baseline and 12-month visits. 
Hypothesis tests for this objective and secondary objective 2 will have type I error controlled using the 
Hochberg procedure, which is described in section 6.5. Testing for secondary objectives will only be 
performed if the primary objectives are met.  
Comparison to the AAD arm is not planned as it is expected that a large percentage of AAD arm subjects 
will have a cryoballoon procedure during the 12 months of follow-up. An intention-to-treat comparison 
between the treatment and control arms would be biased toward the null hypothesis of no difference in 
such circumstances. 
6.2.4.1. 
AFEQT 
6.2.4.1.1. Hypothesis 
The following hypothesis will be tested in a two-sided test: 
 
Ho: AFEQTmonth12 = AFEQTbaseline 
Ha: AFEQTmonth12 ≠ AFEQTbaseline, 
Where  AFEQTbaseline is the score from the AFEQT assessed at the baseline visit, and AFEQTmonth12 is the 
composite score from the AFEQT assessment from the 12-month follow-up. 


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6.2.4.1.2. Endpoint Definition 
The AFEQT questionnaire will be utilized for this objective.  The questionnaire is an atrial fibrillation 
specific health-related quality of life questionnaire to assess the impact of AF on a subject’s life.  The 
overall score ranges from 0 – 100, with 0 corresponding to complete disability and 100 corresponding to 
no disability.  The absolute difference between each subject’s baseline and 12 month scores is the 
endpoint of interest. 
6.2.4.1.3. Analysis Methods 
A paired t-test will be used to assess the difference in mean AFEQT scores between baseline and 12 
month measurements. If the p-value from this test is less than the alpha level determined by the 
Hochberg procedure (described in section 0), the objective will be considered met. This analysis requires 
subjects to have assessments at both the baseline and annual follow-up visit. It will be performed in 
subjects from the CTR cohort who have paired data. 
In addition to the composite score, which is of primary interest for this objective, the AFEQT 
questionnaire has three subscale scores: the Daily Activities Subscale, Treatment Concern, and Treatment 
satisfaction.  Each subscale ranges from 0 – 100, where 0 corresponds to low quality-of-life and 100 
corresponds to high quality of life. Change in AFEQT subscale score is defined as 12-month AFEQT 
subscale score minus baseline AFEQT subscale score.  A two-sided 95% confidence interval will be 
calculated for each change in subscale score based on the t-distribution. 
6.2.4.1.4. Determination of Subjects for Analysis 
This analysis will be performed in the CTR cohort, but subjects who do not have paired AFEQT 
assessment data will be excluded. 
6.2.4.2. 
EQ-5D 
 
6.2.4.2.1 Hypothesis 
The following hypothesis will be tested in a two-sided test: 
 
Ho: EQ-5Dmonth12 = EQ-5DAAD 
Ha: EQ-5Dmonth12 ≠ EQ-5DAAD 
Where EQ-5Dmonth12 is the mean composite EQ5D score from subjects assessed at the 12 month visit, and 
EQ-5Dbaseline is the mean composite EQ-5D score for at baseline. 
6.2.4.2.2. Endpoint Definition 
The Euroqol EQ-5D questionnaire (which consists of a 5-question survey and a visual analog scale 
indicating the subject’s overall health) will be utilized for this objective. Composite scores will be indexed 
against a US reference population (Shaw, Johnson and Coons 2004). We provide SAS code that may be 
used as a starting point for calculating the composite EQ-5D score in appendix 10.1. 
6.2.4.2.3. Analysis Methods 
Change in EQ-5D composite score is defined as 12-month EQ-5D score minus baseline EQ-5D score.  
Differences in mean EQ-5D scores between visits will be assessed utilizing a paired t-test. A two-sided 
95% confidence interval will be calculated based on the t-distribution. If the p-value from the paired t-


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test is less than the alpha level determined by the Hochberg procedure (described in section 6.5), the 
objective will be considered met. This analysis requires subjects to have assessments at both the baseline 
and annual follow-up visit. 
6.2.4.2.4. Determination of Subjects for Analysis 
This analysis will take place in the CTR dataset, but will be limited to subjects with paired EQ-5D 
assessments.  
6.2.5. 
Secondary Objective 2: Healthcare Utilization 
Compare health care utilization between the treatment and control arms. There are two hypotheses 
tested in the objective, with separate hypothesis tests for: (1) the rate of total health care utilization 
events (cardiovascular-related hospitalizations, emergency room visits, or unscheduled office visits) over 
12 months, and (2) the rate of cardioversions (electrical or pharmacological) over 12 months.  Hypothesis 
tests for this objective and secondary objective 1 will have type I error controlled using the Hochberg 
procedure, which is described in section 6.5. Testing for secondary objectives will only be performed if 
the primary objectives are met.  
6.2.5.1. 
Cardiovascular hospitalizations, ED and unscheduled office visits 
 
6.2.5.1.1. Hypothesis 
The following hypothesis will be tested. 
 
H0: θcryo = θAAD 
 
Ha: θcryo ≠ θAAD, 
where θcryo and θAAD are the 12-month rates of cardiovascular HCU events in the cryoballoon ablation and 
AAD arms, respectively. 
6.2.5.1.2. Endpoint Definition 
Healthcare utilization (HCU) events for this objective are defined as cardiovascular-related 
hospitalizations, cardiovascular-related emergency department visits, or cardiovascular-related 
unscheduled office visits occurring within 12 months after the index ablation (cryo arm) or the initiation 
of therapy (AAD arm).  Events occurring >365 days after initiation of treatment but before the 12-month 
visit (if within its window) will be included.  
6.2.5.1.3. Analysis Methods 
The probability of a subject achieving freedom from HCU events (defined above) at 12 months will be 
estimated using Kaplan-Meier survival analysis.  The standard error will be approximated using 
Greenwood's formula. A two-sided 95% log-log confidence interval for the probability at 12 months will 
be constructed. A two-sided log rank test will be used to assess whether the HCU event rate differs 
between treatment groups. If the p-value from this log-rank test is less than the alpha level determined 
by the Hochberg procedure (described in section 6.5), the objective will be considered met. 


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Day 0 is defined as day of the index cryoablation procedure or the day in which drug therapy is initiated.  
For subjects with treatment failure, the survival date will be set to the date of the first HCU event.  For 
subjects without any HCU events through 12 months, those subjects will be censored at the last study 
contact date recorded on a CRF which may include the last study visit, the exit date or the date of death.  
If a subject without any HCU events is lost to follow-up, the censoring date will be set to the last known 
study visit date.  For HCU events occurring on the day of index treatment, survival time will be set to 0.5 
days.  
The survival curve from 0 to 12 months will be presented for both treatment arms. HCU events will also 
be summarized by type and treatment group.  
6.2.5.1.4. Determination of Subjects for Analysis 
This analysis will be performed in the mITT dataset. 
6.2.5.2. 
Cardioversions 
 
6.2.5.2.1. Hypothesis 
The following hypothesis will be tested with a two-sided test.  
 
H0: γcryo = γAAD 
 
Ha: γcryo ≠ γAAD, 
where γcryo and γAAD are the 12-month rates of cardioversion (either electrical or pharmacological) in the 
cryoballoon ablation and AAD arms, respectively. 
 
6.2.5.2.2. Endpoint Definition 
A cardioversion event is defined as an electrical or pharmacological cardioversion post index ablation 
discharge for the treatment arm, and post AAD initiation for the AAD arm. 
 
6.2.5.2.3. Analysis Methods 
The probability of a subject achieving freedom from cardioversion (defined above) at 12 months (365 
days) will be estimated using Kaplan-Meier survival analysis.  The standard error will be approximated 
using Greenwood's formula. A two-sided 95% log-log confidence interval for the probability at 12 months 
will be constructed. A two-sided log rank test will be used to assess whether the cardioversion rate differs 
between treatment groups. If the p-value from the log-rank test is less than the alpha level determined 
by the Hochberg procedure (described in section 6.5), the objective will be considered met. 
Day 0 is defined as the day of the index cryoablation procedure or the day in which drug therapy is 
initiated.  For subjects with at least one cardioversion, the survival date will be set to the date of the first 
cardioversion.  For subjects without any cardioversions through 12 months, those subjects will be 
censored at the last study contact date recorded on a CRF which may include the last study visit, the exit 














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6.3. Center Pooling 
The STOP AF First study is expected to be conducted at up to 10 sites in Europe and 30 sites in the US, 
with a total of 210 subjects randomized across all study centers. Per the CIP, each site will enroll 
between 0 and 31 subjects. The protocol also specifies that no more than 50% of the total enrollment 
will come from outside of the US. 
Data from all sites will be combined without regard to center location for the analysis of the study’s 
primary, secondary 
 endpoints. However, it will be assessed whether site-to-site and 
geographical heterogeneity exists in the rate of pre-specified primary endpoints using a fixed-effects 
meta-analytic approach. This analysis will investigate two things. First, whether sites exhibit significant 
heterogeneity in event rates, and second, whether geography (a binary variable representing whether a 
site is located in the US or Europe) moderates any statistically significant heterogeneity that is observed. 
Models will be fit separately for each primary outcome; in the analysis of each, any center having ≤5 
subjects with complete data will be combined into ‘US_Small’ and ‘EU_Small’ analysis groups. If a 
Cochran’s Q-test1 for heterogeneity shows p<0.05, it will be taken as evidence of significant 
heterogeneity between sites. Evidence of between-site heterogeneity will not necessarily preclude pooling 
data; rather, it will prompt further investigation into the sources of the apparent differences in event 
rates between sites2. At a minimum, findings of analyses on heterogeneity between study sites and 
between all US and all European sites will be shown in the final report in a table by endpoint. 
 
 
 
1 Cochran, WG. “The Comparison of Percentages in Matched Samples”. Biometrika, 1950: 37 (3-4), 256-
266. 
 
2 Borenstein, M., Hedges, L. V., Higgins, J. P. T. and Rothstein, H. R. 2009. Introduction to meta-
analysis, Chichester, UK: Wiley. 
 


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6.4. Handling of Missing, Unused, and Spurious Data and 
Dropouts 
6.4.1. 
Tipping Point Analysis 
It is expected that 10% of the subjects enrolled in this trial will exit the 
study before their 12-month visit. Two general strategies will be used to 
mitigate the impact of missing data in this study. First, most objectives will 
be analyzed using Kaplan-Meier survival analysis methods, which allow data 
from subjects lost to follow-up to still be utilized up until their last date of 
contact. Second, to test the sensitivity of the primary efficacy and safety 
analyses to the range of values possible, but unobserved in subjects exiting 
prior to 12 months, a tipping point analysis will be performed on the full 
analysis set.  
 
Primary objective data will be sorted by ascending event times, as shown in the fictional example dataset 
below from an efficacy analysis where p < 0.05: 
 
 
Treatment 
Time 
Event 
 
Cryoablation 
0.5 
1 
 
 
… 
 
AAD 
 
363 
1 
 
Cryoablation 
364 
0 
 
Cryoablation 
365 
1 
 
AAD 
 
371 
1 
 
 
… 
 
Cryoablation 
378 
0 
 
Cryoablation 
379 
0 
 
AAD 
 
380 
0 
 
In this example, ‘Treatment’ is the group to which the subject was randomized, ‘Time’ is the number of 
days from treatment initiation (either the index ablation or AADs) to the 12-month follow-up, end of 
study, or endpoint event, and ‘Event’ takes a value of 0 to indicate censoring or a value of 1 to indicate 
that the endpoint was met. Then starting from the first time < 0, the following algorithm is followed:  
 
1) If a failure is observed, skip steps 2 and 3; 
2) If the observation is censored: 
o 
 set the time = 365 if the observation was from an AAD subject 
o 
set time = time + 1 and event = 1 if the observation was from a cryoablation 
subject.  


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3) Apply the log-rank test specified in section 6.2.2.4 to find the new two-sided p-value 
4) If P is still < 0.05 and a larger event time < 365 exists, repeat the process with that 
observation; otherwise stop. 
 
Essentially, this process goes through the hypothetical exercise of sequentially assuming unobserved 
control arm subjects are successes, and unobserved treatment arm subjects are failures the day after 
being lost to follow-up until the log-rank test supports a different conclusion (in this case, when p 
>=0.05). This first subject for which p <0.05 is no longer true is the point at which the analysis ‘tips’. 
Larger numbers of treatment failures and control successes needed to change the conclusion indicate 
findings that are more robust to informative censoring. If the primary efficacy analysis as specified in 
section 6.2.2.4 shows p ≥0.05, the tipping point analysis will be modified to quantify how many 
treatment arm successes and control arm failures would be necessary to reach a different conclusion for 
the hypothesis test.  
The primary safety endpoint is only measured in the cryoablation arm. As such, the algorithm to find the 
tipping point of the primary safety algorithm is slightly different. Like with the efficacy tipping point 
analysis, data will be sorted by ascending event times, and subjects who are censored prior to 365 days 
are assigned an event time equal to (date of last contact –index ablation date). Then, for each 
observation: 
1) If a failure is observed, skip steps 2 and 3; 
2) If the observation is censored, set time = time + 1 and event = 1.  
3) Apply the log-rank test specified in section 6.2.3.4 to find the new two-sided p-value and 
95% log-log confidence interval. 
4) If P is still < 0.05 and a larger event time < 365 exists, repeat the process with that 
observation; otherwise stop. 
The first observation where the confidence interval includes 12.0% is the tipping point for the primary 
safety analysis. This analysis will be performed in the CTR dataset. For either primary endpoint, if fewer 
than 5 subjects have missing data, a worst-case analysis will be done instead of a tipping point analysis.  
 
 
 


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6.5. Adjustments for Multiple Comparisons 
A Hochberg multiple testing procedure will be utilized to maintain an overall type I error rate of 0.05 for 
the four hypotheses being tested among the two secondary objectives. Testing for these objectives will 
be performed if the primary objectives are met. 
 
The Hochberg procedure is a stepwise procedure and will be implemented as follows. The four 
hypotheses are abbreviated as H(1), H(2), H(3), and H(4). For each of these, p-values will be calculated 
and sorted p(1) < p(2) < p(3) < p(4). The decision rule to accept or reject each hypothesis will follow 
the step-up algorithm, where α=0.05:  
 
Step 1: If p(4) ≥ α, accept H(4) and go to Step 2, otherwise reject all hypotheses and stop  
Step 2: If p(3) ≥ α/2, accept H(3) and go to Step 3, otherwise reject H(3), H(2) and H(1) and stop  
Step 3: if p(2) ≥ α /3, accept H(2) and go to Step 4, otherwise reject H(2) and H(1) and stop  
Step 4: If p(1) < α /4, reject H(1); otherwise accept H(1) 
 
In practice, this adjustment may be done simultaneously on a dataset from the four p-values produced, 
 
 
 
 
 
6.6. Interim Analyses  
No interim analyses are planned.  
 
 


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6.7. Subgroup Analyses 
 
A limited number of additional analyses will be performed to evaluate evidence for a differential effect of 
cryoablation vs. AAD therapy on the primary and secondary endpoints within subgroups of subjects.  
At the time of this SAP, current FDA guidance3 recommends additional evaluation of primary objectives 
within the following demographic subgroups: 
‐ 
Age (calculated as [year of randomization date – year of birth]) 
‐ 
Gender (captured as male or female by the CRF, with a third level for no response) 
‐ 
Race (White, Black or African American, Asian, American Indian or Alaskan Native, Native 
Hawaiian or Other Pacific Islander, Other, Not Stated) 
‐ 
Ethnicity (Hispanic or Latino, or not) 
Subgroup analyses will be performed separately for each of the demographic variables listed above, using 
Kaplan-Meier survival methods. Handling of censoring, visit windows, etc. will be consistent with what is 
described in the corresponding general methods above in section 6.2 for each objective. 
 
 
 
 
 
 
 
Demographic strata with <5 events will be combined with other strata if the resulting combination is still 
deemed analytically meaningful, or may be ignored due to the sparseness of information. Age will be 
calculated as [year of randomization date – year of birth] as the case report form does not collect the 
exact date of birth for a subject.  For subgroup analysis, age will be divided into quartiles.  If the overall 
log-rank test of equality over strata is significant for strata with more than two levels, Tukey’s range test 
will be used to adjust type I error for the comparison between multiple subgroups. Subgroup analyses 
will be performed in the same datasets in which the corresponding primary objectives are analyzed. 
 
 
6.8. Changes to Planned Analysis  
Additional details on analysis methods have been added to this SAP, but only 
 minor changes to the 
statistical methods defined in the STOP AF First CIP version 4 are noted. First, the definition of the PV 
stenosis component of this study’s primary safety endpoint has been altered according to FDA study 
design considerations. The criteria of 70% PV area reduction stated in this document reflects this update, 
whereas the CIP version 4 shows the original definition of 75% reduction. Second, the sample size 
calculation for the primary efficacy analysis incorrectly states that Fisher’s exact test was used in the 
 
3 
https://www.fda.gov/downloads/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstoth
eFDCAct/FDASIA/UCM365544.pdf 
 
https://www.fda.gov/downloads/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstoth
eFDCAct/FDASIA/UCM365544.pdf 


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calculation. In actuality, a Pearson’s chi-squared test was used, as stated in section 7.1 of this SAP, which 
led to the stated analytic sample size of 174. The significance of this edit is negligible, since in both cases 
the planned endpoint analysis involves using Kaplan-Meier methods, and the sample size for the study is 
driven by the primary safety endpoint. 
 
 
 Analytical deviations from procedures this SAP may be addressed by 
the release of newer SAP versions (if feasible), or will be described in the final report and/or main 
manuscript, along with the rationale for the deviation. 
 
 
 


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7. 
Determination of Sample Size 
Sample size for STOP AF First was determined by finding the minimum number of subjects enrolled which 
provides adequate power under the assumptions to both the hypothesis test for the primary efficacy 
objective, as well as the hypothesis test for the primary safety objective. Calculations are provided 
separately for each primary endpoint. 
7.1. Sample Size Determination for Primary Efficacy Objective 
Sample size was estimated using Proc Power in SAS v9.4. The calculation was done to find the number of 
analyzed subjects necessary to provide a two-sided Pearson’s chi-square test with α = 0.05 and 90% 
power to detect a difference between two binomial proportions, one of which was 69.9%, and the other 
45.9%, under a 1:1 randomization ratio. The two groups’ rates represent the cryoablation and AAD arm 
12-month success rates, respectively. The assumed cryoablation arm success rate was what was 
observed in the STOP AF pivotal trial. The AAD arm success rate estimate, 28 of 61 successes at one 
year, was observed under similar circumstances in the RAAFT-2 trial (Morillo, et al.). 
 
 
 
   
 
 
 
    
 
 
 
      
 
      
 
      
 
 
Computed N Total 
Actual Power N Total
0.901
174
 
 
This shows an analytical sample size of 174 subjects is required. However, it was assumed that 10% 
attrition would occur between enrollment and the 12-month follow-up. Therefore, the necessary 
enrollment calculated to yield a 90.1% probability of detecting the presumed treatment success 
difference is 194 subjects. 
The sample size estimate attained based on using a chi-square test is conservative compared to the 
actual number of subjects required using the Kaplan-Meier methods described in 6.2.2, since in the latter 
case, attrition is partial: data is included for all subjects up until they exit the study, so only subjects who 
exit prior to day 0 (index ablation or AAD initiation) will provide no information to the analysis. 
 
 


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7.2. Sample Size Determination for Primary Safety Objective 
Sample size was estimated using Proc Power in SAS 9.4.  The parameters of the calculation were for a 
one-sided exact binomial test with α = 0.025 and 80% power, with a true safety event rate of 4.0% and 
a performance goal of 12%. The same conditions for attrition (10% from enrollment to 12 months) and 
randomization ratio (1:1) were assumed in this calculation as they were for the primary efficacy endpoint.  
The event rate of 4% was derived by applying the definition of the primary safety endpoint 
retrospectively to subjects from the STOP AF pivotal study; when this was performed, event rates of 
5/163 (3.1%) or 7/163 (4.3%) were observed, depending on how asymptomatic phrenic nerve injuries 
were counted. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Computed Power 
Lower Crit
Val
Upper Crit
Val
Actual Alpha Power
5
.
0.0246
0.825
Under the above conditions, 80% power is achieved with 94 cryoablation arm subjects analyzed.  
Assuming 10% attrition, then 105 enrolled subjects are needed, requiring 210 subjects to be enrolled and 
randomized 1:1.  
The required sample size of 210 is the smallest number that results in adequate power for both the 
primary efficacy and safety analyses under the specified conditions, and will be used as the enrollment 
target for the study.  Figures 2 and 3 (below) show the sensitivity of the STOP AF First power calculations 
to deviations from the event rate assumptions used above, for the efficacy and safety endpoints, 
respectively. 


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8. 
Validation Requirements 
Verification of analyses of both the primary efficacy objective and the primary safety objective will be 
completed with level I validation (independent programming).  Secondary 
 objectives will be 
validated with a minimum of level II validation.  Analyses that are not related to primary objectives 
 
 will be validated at a minimum of level II validation if being presented externally in an 
abstract or publication. 
 
 
 


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9. 
References  
Borenstein, M., Hedges, L. V., Higgins, J. P. T. and Rothstein, H. R. 2009. Introduction to meta-
analysis, 107- 125, Chichester, UK: Wiley. 
Cochran, WG. “The Comparison of Percentages in Matched Samples”. Biometrika, 1950: 37 (3-4), 256-
266. 
Hochberg, Y. “A Sharper Bonferroni Procedure for Multiple Significance Testing,” Biometrika, 1988: 75, 
800–803. 
Shaw, JW, JA Johnson, and SJ Coons. "U.S. Valuation of the EQ-5D Heatlh States: Development and 
Testing of the D1 Valuation Model." Medical Care, 2004. 
Spertus, J, et al. "Development and validation of the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) 
Questionnaire in patients with atrial fibrillation." Circ Arrhythm Electrophysiol, Feb 4, 2011: 15-
25. 
U.S. Food and Drug Administration. “FDA Report: Collection, Analysis and Availability of Demographic 
Subgroup Data for FDA-Approved Medical Products.” FDA Web Site. 
https://www.fda.gov/downloads/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstoth
eFDCAct/FDASIA/UCM365544.pdf. Published August 2013. Accessed April 28, 2017.  
U.S. Food and Drug Administration. “Evaluation of Sex-Specific Data in Medical Device Clinical Studies”. 
FDA Web Site. 
https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM
283707.pdf. Published August 22, 2014. Accessed May 11, 2017. 
 
 
 




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Prot_006.pdf: 
 
 
Clinical Investigation Plan Title 
STOP AF First 
Clinical Investigation Plan Identifier 
MDT16012AFS001 
Study Product 
Arctic Front Advance™ Cardiac CryoAblation Catheter 
Application Number 
IDE #G1160219 
ClinicalTrials.gov Identifier 
NCT03118518 
Sponsor 
Medtronic 
8200 Coral Sea St NE 
Mounds View, MN  55112 
Document Title 
STOP AF First Clinical Investigation Plan 
Document Version (Date) 
6.0 (16-JAN-2018) 
 


056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 1 of 130 
 
 
Version 6.0  
STOP AF First 
Page 1 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
 
 
Clinical Investigation Plan 
Clinical Investigation Plan/Study Title STOP AF First 
Clinical Investigation Plan Identifier MDT16012AFS001 
Study Product Name Arctic Front AdvanceTM  Cardiac CryoAblation 
Catheter 
Sponsor/Local Sponsor United States of America 
Medtronic, Inc. 
8200 Coral Sea St NE 
Mounds View, MN U.S.A. 55112 
 
Europe 
Medtronic, Bakken Research Center B.V. 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
Document Version Version 6.0, 16JAN2018 
Lead Principal Investigator Oussama Wazni, MD 
Cleveland Clinic 
9500 Euclid Ave, 
Cleveland, OH 44195 
Coordinating Investigators Gopi Dandmudi, MD 
Indiana University Krannert Institute of Cardiology 
1801 N. Senate Blvd, Suite 4000 
Indianapolis, IN  46202 
 
Steve Nissen, MD 
Cleveland Clinic 
9500 Euclid Avenue 
Cleveland, OH  44195 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Medtronic.  
Any distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly 
prohibited.  Persons to whom the information is disclosed must know that it is confidential and that it 
may not be further disclosed by them. 
 
 














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4. 
Introduction .............................................................................................................. 24 
 
Background ....................................................................................................................... 24 
 
3XUSRVH ........................................................................................................................ 26 
5. 
Objectives and Endpoints ......................................................................................... 27 
 
Objectives .......................................................................................................................... 27 
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6. 
Study Design ............................................................................................................. 32 
 
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Product Description .................................................................................................. 35 
 
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Data Review Committees .......................................................................................... 81 
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Statistical Design and Methods ................................................................................. 82 
 
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18. 
References ............................................................................................................... 116 
19. 
Appendices .............................................................................................................. 118 
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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 13 of 130 
 
 
Version 6.0  
STOP AF First 
Page 13 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
Table 7: Adverse Event and Device Deficiency Reporting Requirements................................................ 74 
Table 8: Adverse Event Classification Responsibilities .......................................................................... 78 
Table 9: Investigator reports applicable for all geographies per Medtronic Requirements ..................... 104 
Table 10: Additional Investigator reports applicable to the United States ............................................ 105 
Table 11: Investigator reports applicable to Europe........................................................................... 106 
Table 12: Sponsor Reports for the United States ............................................................................... 108 
Table 13: Sponsor reports for Europe ............................................................................................... 110 
Table 14: Foreseeable Adverse Events ............................................................................................. 125 
Table 15: Arctic Front and Arctic Front Advance™ Complications Reported in Literate for Paroxysmal and 
Persistent AF Patients ...................................................................................................................... 127 
 
Listing of Figures 
Figure 1:  Study Design ..................................................................................................................... 32 
Figure 2: Arctic Front AdvanceTM Cardiac Cryoablation Catheter ........................................................... 37 
Figure 3: FlexCath AdvanceTM Steerable Sheath with Cryoablation Catheter .......................................... 38 
Figure 4: Achieve™ Mapping Catheter ................................................................................................ 39 
Figure 5: CryoCath CryoAblation Console ............................................................................................ 39 
Figure 6: Coaxial Umbilical Cable ....................................................................................................... 40 
Figure 7: Electrical Umbilical Cable ..................................................................................................... 40 
Figure 8: Manual Retraction Kit .......................................................................................................... 41 
 
Listing of Appendices 
Appendix A: CRYOBALLOON SAFETY DATA LITERATURE SEARCH...................................................... 118 
Appendix B: DRAFT DATA COLLECTION ELEMENTS (CASE REPORT FORMS) ...................................... 121 
Appendix C: INFORMED CONSENT FORM TEMPLATE ........................................................................ 122 
Appendix D: PARTICIPATING INVESTIGATOR AND INSTITUTIONS .................................................... 123 
Appendix E: IRB LIST ...................................................................................................................... 124 
Appendix F: FORESEEABLE ADVERSE EVENTS .................................................................................. 125 
Appendix G: PRE-CLINICAL TESTING ............................................................................................... 130 
 
 
 












056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 19 of 130 
 
 
Version 6.0  
STOP AF First 
Page 19 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
3. Synopsis 
Title 
STOP AF First 
Clinical Study Type 
Pivotal (US)/ Post-market interventional (Europe) 
Product Name 
Arctic Front AdvanceTM Cardiac CryoAblation Catheter 
Sponsor  
United States of America 
Medtronic, Inc. 
8200 Coral Sea St NE  
Mounds View, MN U.S.A. 55112 
Local Sponsor 
Europe 
Medtronic, Bakken Research Center B.V. 
Endeplosdomein 5 
6229 GW Maastricht 
The Netherlands 
Indication Under 
Investigation  
Current indication in the US:  The Arctic Front Advance™ Cardiac 
CryoAblation Catheter is indicated for the treatment of drug refractory 
recurrent symptomatic paroxysmal atrial fibrillation. 
Indication under investigation for the US:  The Arctic Front Advance™ 
Cardiac CryoAblation Catheter is indicated for the treatment of recurrent 
symptomatic paroxysmal atrial fibrillation. 
The indication under investigation is within the approved indication in 
Europe. 
Investigation Purpose 
The purpose of the study is to provide data demonstrating the safety 
and effectiveness of the Arctic Front Advance™ Cardiac CryoAblation 
Catheter for the treatment of recurrent symptomatic paroxysmal AF, 
without the requirement that the subjects be drug refractory.  
Product Status 
The Arctic Front Advance™ Cardiac CryoAblation Catheter is market 
released and will become investigational when used as indicated in the 
study in the US.  The catheter is market released and will be used within 
the approved indications in Europe, therefore is not considered 
investigational for the intended patient population in Europe.   
Primary Objective 
Primary Efficacy Objective: 
Demonstrate the superiority of cryoballoon ablation as compared to 
antiarrhythmic drug (AAD) therapy in terms of the rate of freedom from 
AF/AT/AFL in a non-drug refractory paroxysmal AF population. 
 


056-F275, Clinical Investigation Plan Template, Version 2.0 
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Version 6.0  
STOP AF First 
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16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
Primary Safety Objective: 
Demonstrate an acceptable safety profile of the cryoballoon ablation 
procedure as a first line therapy in a non-drug refractory paroxysmal AF 
population. 
Secondary Objectives 
Secondary Objectives are as follows: 
1. Assess changes in quality of life (QoL) between baseline and 12 
months in the cryoballoon ablation arm.     
2. Compare health care utilization (HCU) between the treatment 
and control arms.   
 
 
 
 
 
  
 
 
 
 
 
 
 
  
Primary Endpoint 
Primary Efficacy Endpoint: 
The primary endpoint is treatment success at 12 months after AAD 
initiation (control arm) or after the pulmonary vein isolation ablation 
procedure utilizing the Arctic Front Advance™ Cardiac CryoAblation 
Catheter (treatment arm).  A treatment success is the opposite of a 
treatment failure. 
Treatment failure is defined as any of the following components: 
• Acute procedural failure (treatment arm only) 
• Documented AF/AT/AFL on ambulatory monitoring/12-lead 
ECG after the 90 day post-ablation blanking period 
(treatment arm)/AAD optimization period (control arm) 
o 
Minimum of 30 seconds on ambulatory monitoring or 10 
seconds on 12-lead ECG. 
o 
Note: Documented occurrence and treatment of typical 
right-sided cavotricuspid isthmus dependent atrial flutter 
is not considered a failure if confirmed by entrainment 
maneuvers during EP testing. 
• Any subsequent AF surgery or ablation in the left atrium.   
• Any subsequent cardioversion after the 90 day post-ablation 
blanking period (treatment arm)/AAD optimization period 
(control arm). 
• Class I or III antiarrhythmic drug (or sotalol) use after the 90 
day blanking period (treatment arm only). 
The AAD optimization period is defined as the first 90 days after AAD 
initiation (control arm).  The post-ablation blanking period is defined as 
the first 90 days after the index ablation procedure (treatment arm).  


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STOP AF First 
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16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
Recurrences of atrial arrhythmias during the AAD optimization/blanking 
periods will not be counted in the determination of the first clinical 
failure for the primary endpoint.   
Within the AAD optimization period/post-ablation blanking period, 
recurrent arrhythmias can be managed with medications or 
cardioversions.  Reablation will be considered a primary endpoint failure 
at all times, including during the 90 day post-ablation blanking period. 
Acute procedural failure (treatment arm only) is defined as: 
a) Inability to isolate all accessible targeted pulmonary veins 
(assessed for entrance block and, where assessable, exit block) 
during the index ablation procedure. 
b) Left atrial non-PVI ablations including but not limited to, ablation 
of linear lesions  
c) Use of a non-study device in the left atrium. 
 
Primary Safety Endpoint: 
The following adverse events will be counted towards the primary safety 
endpoint:  
• 
Transient Ischemic Attack (TIA)within 7 days 
• 
Cerebrovascular accident within 7 days 
• 
Major bleeding that requires transfusion or results in a 20% or 
greater fall in hematocrit (HCT) within 7 days 
• 
Development of a significant pericardial effusion within 30 days.   
A significant pericardial effusion is one that results in 
hemodynamic compromise, requires elective or urgent 
pericardiocentesis, or results in a 1-cm or more pericardial 
effusion as documented by echocardiography.  
• 
Symptomatic PV stenosis within 12 months; accompanied by 
one of the following: 50%-70% reduction in diameter of the 
pulmonary vein, with symptoms not explained by other 
conditions; OR >70% reduction in diameter of the pulmonary 
vein  
• 
MI within 7 days 
• 
PNI unresolved at 12 months 
• 
AE fistula within 12 months 
• 
Major vascular complication that requires intervention, prolongs 
the hospital stay, or requires hospital admission (within 7 days).   
Secondary Endpoints 
1. The difference in composite scores from the AFEQT 
questionnaire taken at baseline and 12 month visits, and the 
difference in composite scores for the EQ-5D questionnaire 
taken at baseline and 12-month visits.  
2. 12-month rates of cardiovascular HCU events, and 12-month 
rates of cardioversion (either electrical or pharmacological).  
 
 
 
 
 


056-F275, Clinical Investigation Plan Template, Version 2.0 
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Version 6.0  
STOP AF First 
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16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Study Design 
Prospective, interventional, multi-center, randomized, controlled, 
unblinded clinical study. 
The study will be conducted at up to 30 sites in the US and up to 10 in 
Europe. 
Study Duration 
All randomized study subjects will be followed from the time of consent 
through 12 months post-index cryoballoon ablation procedure 
(treatment arm), or AAD initiation (control arm). 
Subjects will be exited from the study at the conclusion of the 12 month 
follow-up visit.  The expected total study duration is approximately 30 
months, representing 18 months of enrollment and 12 months of subject 
follow-up.  
Sample Size 
In the US and Europe, up to 250 subjects will be enrolled. 210 subjects 
will be randomized. 
Inclusion/Exclusion 
Criteria 
The following is a list of inclusion/exclusion criteria: 
Inclusion criteria 
• 
A diagnosis of symptomatic paroxysmal AF with the following 
documentation: (1) physician’s note indicating recurrent self- 
terminating AF or paroxysmal AF; and (2) any ECG documented 
AF within 6 months prior to enrollment.  
• 
Age 18-80 


056-F275, Clinical Investigation Plan Template, Version 2.0 
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STOP AF First 
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16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
Exclusion criteria 
• 
History of AF treatment with class I or III antiarrhythmic drug, 
including sotalol, with the intention to prevent an AF recurrence.  
However, patients pretreated with above AAD for less than 7 
days with the intention to convert an AF episode are allowed.  
• 
Prior persistent AF (continuous AF that is sustained  >7 days) 
• 
Left atrial diameter greater than 5.0 cm 
• 
Prior left atrial ablation or left atrial surgical procedure 
• 
Presence or likely implant of a permanent pacemaker, 
biventricular pacemaker, loop recorder, or any type of 
implantable cardiac defibrillator (with or without biventricular 
pacing function) 
• Presence of any pulmonary vein stents 
• 
Known presence of any pre-existing pulmonary vein stenosis 
• 
Pre-existing hemidiaphragmatic paralysis 
• 
Presence of any cardiac valve prosthesis 
• 
Moderate or severe mitral valve regurgitation or stenosis  
• 
Any cardiac surgery, myocardial infarction, PCI / PTCA or 
coronary artery stenting which occurred during the 90 day 
interval preceding the date the subject signed the Informed 
Consent Form 
• 
Unstable angina 
• 
NYHA class III or IV congestive heart failure and/or known left 
ventricular ejection fraction (LVEF) less than 45%  
• 
Diagnosis of primary pulmonary hypertension 
• 
Rheumatic heart disease 
• 
Thrombocytosis, thrombocytopenia 
• 
Contraindication to anticoagulation therapy 
• 
Active systemic infection 
• 
Hypertrophic cardiomyopathy 
• 
Cryoglobulinemia 
• 
Known reversible causes of AF, including but not limited to 
uncontrolled hyperthyroidism, severe obstructive sleep apnea, 
and acute alcohol toxicity. 
• 
Any cerebral ischemic event (strokes or TIAs) which occurred 
during the 180 day interval preceding the date the subject 
signed the Informed Consent Form, or any known unresolved 
complications from previous stroke/TIA 
• 
Existing thrombus 
• 
Pregnancy 
• 
Patient with life expectancy that makes it unlikely 12 months of 
follow-up will be completed.   
• 
Current or anticipated participation in any other clinical trial of a 
drug, device or biologic during the duration of this study not 
pre-approved by Medtronic 
• 
Patients with contraindications to a Holter monitor 
• 
Unwilling or unable to comply fully with study procedures and 
follow-up 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
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Version 6.0  
STOP AF First 
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16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
before ablation may be attempted.  Pharmacological therapy for AF (paroxysmal and persistent) has 
limited antiarrhythmic efficacy, with recurrence of AF reported at 44% to 67% within one year, based on 
a systematic review of 45 randomized controlled clinical trials (Lafuente-Lafuente, Mouly, et al. 2006).  
Treatment with AADs may also result in an increased risk for adverse events. Results of an AFFIRM sub 
study showed that adverse events resulting in discontinuation of the treatment were common for AADs, 
occurring in 11.1% to 28.1% of patients, depending on the AAD used (AFFIRM First Antiarrhythmic Drug 
Substudy Investi. 2003).  The RAAFT-2 study found that AAD’s had a success rate of 42% at one year in 
61 previously treatment-naive paroxysmal AF patients; meanwhile, the 2014 AHA/ACC/HRS guideline for 
the management of patients with AF stated that “much like other antiarrhythmic drugs, with the 
exception of amiodarone, the rates of maintaining sinus rhythm at 1 year for sotalol are 30 -50%” 
(January et. al. 2014) (Morillo, et al. 2014). 
Atrial fibrillation is known to cause electrical remodeling of the atria as well as structural changes that 
promote perpetuation and progression of symptoms (Wijesurendra and Casadei 2015) (Shulka and Curtis 
2014) (Jalife and Kaur 2015).  Untreated PAF can give rise to persistent or permanent forms of the 
disease (De Vos, et al. 2010), which may be more resistant to contemporary AF treatments (Oral, et al. 
2002) (Romero, et al. 2015).  As such, early and effective intervention is key for normalizing sinus rhythm 
(SR) and preventing further remodeling and disease progression (Nattel, et al. 2014) (Cosio, et al. 2008).  
AAD treatments have little to no effect on remodeling (Nattel, et al. 2014) and although may restore SR 
in the short-term, have high long-term relapse rates (45-90%) (Cosio, et al. 2008) making this treatment 
largely ineffective at preventing progression of AF.  By contrast, early evidence seems to indicate that 
catheter ablation may reverse indicators of structural remodeling associated with AF (Walters, et al. 
2016) (Wu, et al. 2016).  Furthermore, catheter ablation, particularly using the Arctic Front Advance™ 
Cardiac CryoAblation Catheter, hereafter also referred to as the cryoballoon, has a much higher efficacy 
rate and may be even more effective when provided earlier after AF onset (Arena, et al. 2016) (Tanner, 
et al. 2011). 
Catheter ablation treatment strategies for AF have evolved over time and currently include pulmonary 
vein isolation (PVI) as a cornerstone of ablation therapy in all types of AF (paroxysmal and persistent) 
(Raviele 2012) (Jais, et al. 2006).  AF arises primarily from the left side of the heart in (or near) the 
atrium, particularly where the pulmonary veins (PVs) join the atrium.  The fundamental basis for the AF 
ablation procedure is the creation of myocardial lesions that block the propagation of AF wave fronts from 
the triggering source.  The muscular sleeves within the PVs have been established as a critical source of 
AF triggers (Caulkins and et. al. 2007). 
The safety profile of cryoballoon ablation is also well established. The STOP AF trial (Packer, et al. 2013) 
was a prospective, multicenter, randomized, controlled investigation device exemption (IDE) study 
designed to compare outcomes of cryoballoon and antiarrhythmic drug therapies in patients with PAF.  
Six point one percent (6.1%) of cryoballoon subjects experienced a procedure-related event or major 
adverse event versus 8.5% of AAD subjects.  An analysis of 149 cryoballoon studies with 11,242 patients 
(see Appendix A for literature search methodology) showed similar complication rates to STOP AF. 
The STOP AF Post Approval Study was designed to provide long-term safety and effectiveness of the 
Arctic Front and Arctic Front Advance™ Cardiac Cryoablation Catheter System, including the Freezor® 
MAX Cardiac cryoablation catheter according to the Product Labeling.  Inexperienced users were selected 
as study Investigators in order to understand complication rates in a real world setting.  There were 402 
subjects enrolled.  The study is currently in the follow-up phase, with all enrolled subjects having been 
followed for one year post-ablation procedure.  Major procedure related events occurred in 20/341 
patients (5.9% of patients and 5.7% of procedures).  No device or procedure related deaths were 
reported (Knight, et al. 2016). 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 29 of 130 
 
 
Version 6.0  
STOP AF First 
Page 29 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
5.1.4.2. 
Primary Safety Endpoint 
The following adverse events will be counted towards the primary safety endpoint:  
• 
TIA within 7 days 
• 
Cerebrovascular accident within 7 days 
• 
Major bleeding that requires transfusion or results in a 20% or greater fall in hematocrit (HCT) 
within 7 days 
• 
Development of a significant pericardial effusion within 30 days.   A significant pericardial 
effusion is one that results in hemodynamic compromise, requires elective or urgent 
pericardiocentesis, or results in a 1-cm or more pericardial effusion as documented by 
echocardiography.  
• 
Symptomatic PV stenosis within 12 months; accompanied by one of the following: 50%-70% 
reduction in diameter of the pulmonary vein, with symptoms not explained by other conditions; 
OR >70% reduction in diameter of the pulmonary vein  
• 
MI within 7 days 
• 
PNI unresolved at 12 months 
• 
Atrial-esophageal fistula within 12 months 
• 
Major vascular complication that requires intervention, prolongs the hospital stay, or requires 
hospital admission (within 7 days).   
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 31 of 130 
 
 
Version 6.0  
STOP AF First 
Page 31 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


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16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
NOTE: this is a deviation to Section 9.8 of the ISO standard because device accountability for the Arctic 
Front Advance™ Cardiac CryoAblation Catheters will not be performed in Europe and only upon package 
opening with the intent of using the catheter for a study subject in the US. 
 
 


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Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
8. Investigator/Investigator Center Selection 
All clinical Investigators managing the subject’s arrhythmia must be qualified practitioners and 
experienced in the diagnosis and treatment of subjects with atrial arrhythmias. Investigators performing 
the cryoablation procedure must have been trained in the handling of Arctic Front Advance™ Cardiac 
CryoAblation Catheters. 
 
The role of the Principal Investigator is to implement and manage the day-to-day conduct of the clinical 
investigation as well as ensure data integrity and the rights, safety and well-being of the subjects 
involved in the clinical investigation. 
 
The minimum required criteria for a Principal Investigator and proposed investigational center are listed 
below: 
• 
Investigator/site is qualified by training, education, and relevant experience appropriate to the 
use of the product and associated procedures.   
• 
Investigator/site expects to have adequate time and resources to conduct the study throughout 
the duration of the study. 
• 
Investigator/site has access to an adequate number of eligible subjects.  
• 
Ability to comply with applicable Institutional Review Board (IRB)/Ethics Committee (EC) and 
regulatory requirements. 
• 
Investigator is not debarred, disqualified, or working under sanctions in applicable regions. 
 
Center personnel training will be completed prior to participation in this clinical study. 
 
 


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Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
9. Center Activation 
During the activation process (prior to subject enrollment), Medtronic will train center personnel on the 
CIP, relevant standards and regulations, informed consent, and on data collection and reporting tools. If 
new members join the study center team, they will receive training on the applicable clinical study 
requirements relevant to their role before contributing to the clinical study. 
 
Prior to performing study related activities, all local regulatory requirements shall be fulfilled, including, 
but not limited to the following: 
 
• 
IRB/MEC approval (and membership roster/voting list) of the current version of the CIP, Patient 
Informed Consent Form, subject facing materials, Report of Prior Investigation, Investigator 
Brochure as required by local laws and other materials, as necessary. 
• 
Regulatory authority approval or notification (as required per local law) 
• 
Fully executed Clinical Trial Agreement (CTA) and Investigator Statement where applicable 
• 
Financial Disclosure of Investigators 
• 
Curriculum Vitae (CV) of Investigators and key members of the investigation center team (as 
required by local law) (in Europe, CVs are required for the Principal Investigator and all center 
members who have been delegated tasks) 
• 
Documentation of delegated tasks 
• 
Documentation of study training 
 
Documentation of delegated tasks must be completed prior to any person other than the Principal 
Investigator performing study activities. 
 
Additional requirements imposed by the IRB/MEC and regulatory authority shall be followed. 
 
In addition, all participating center staff must be trained on the current version of the CIP and must be 
delegated by the Principal Investigator to perform study related activities. 
 
Medtronic will provide each study center with documentation of study center/Investigator readiness in the 
form of a center readiness letter; this letter must be received prior to subject enrollment. Additional 
center personnel included after the initial activation will be notified when all requirements have been 
completed. 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
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16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
• Diagnosis of primary pulmonary hypertension 
• Rheumatic heart disease 
• Thrombocytosis, thrombocytopenia 
• Contraindication to anticoagulation therapy 
• Active systemic infection 
• Hypertrophic cardiomyopathy 
• Cryoglobulinemia 
• Known reversible causes of AF, including but not limited to uncontrolled hyperthyroidism, 
severe obstructive sleep apnea, and acute alcohol toxicity. 
• Any cerebral ischemic event (strokes or TIAs) which occurred during the 180 day interval 
preceding the date the subject signed the Informed Consent Form, or any known unresolved 
complications from previous stroke/TIA 
• Existing thrombus 
• Pregnancy 
• Patient with life expectancy that makes it unlikely 12 months of follow-up will be completed. 
• Current or anticipated participation in any other clinical trial of a drug, device or biologic during 
the duration of this study not pre-approved by Medtronic 
• Patients with contraindications to a Holter monitor 
• Unwilling or unable to comply fully with study procedures and follow-up 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 50 of 130 
 
 
Version 6.0  
STOP AF First 
Page 50 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
participate in the study. If relevant, approval may be requested from subjects to confirm their continued 
participation. 
 
Prior to initiation of any study-specific procedures, documented IC must be obtained from the subject (or 
their legally authorized representative, US ONLY). Likewise, privacy or health information protection 
regulation may require subjects to sign additional forms to authorize centers to submit subject 
information to the study sponsor. The IC process must be conducted by the principal Investigator or an 
authorized designee, and the ICF and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law must be given to the 
subject (or their legally authorized representative, US ONLY) in a language he/she is able to read and 
understand. The process of IC must be conducted without using coercion, undue or improper influence 
on, or inducement of the subject to participate by the Investigator or other center personnel. The 
informed consent process shall not waive or appear to waive the subject’s legal rights. The language 
used shall be as non-technical as possible and must be understandable to the subject and the impartial 
witness, where applicable. 
 
The subject must have ample time and opportunity to read and understand the ICF to inquire about 
details of the study, and to decide whether or not to participate in the clinical study. All questions about 
the study should be answered to the satisfaction of the subject. When the subject decides to participate 
in the clinical study, the ICF and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law must be signed and 
personally dated by the subject (or their legally authorized representative, except in Europe) and either 
the Investigator or the Investigator’s authorized designee, as required by local law. If applicable, witness 
shall also sign and personally date the consent form to attest that the information in the ICF was 
accurately explained and clearly understood by the subject, and that IC was freely given. 
 
In Europe, include a personally dated signature by the Principal Investigator or authorized designee 
responsible for conducting the informed consent process. The Principal Investigator or designee must 
conduct the informed consent discussion. 
 
A copy of the ICF and the Authorization to Use and Disclose Personal Health Information/Research 
Authorization/other privacy language as required by law, signed and dated as required by law, must be 
provided to the subject. 
 
If consent is obtained the same day the subject begins participating in study-related procedures, it must 
be documented in the subject’s case history that consent was obtained prior to participation in any study 
related procedures. It is best practice for the IC process to be documented in the subject’s case history, 
regardless of circumstance. In the event the subject cannot read and/or write, a witnessed (impartial 
third party) ICF will be allowed, provided detailed documentation of the process is recorded in the 
subject’s case history and the witness signs and dates the ICF to attest that the information was 
accurately explained and that informed consent was freely given. In Europe, when a subject cannot read 
and/or write, an independent witness shall be present throughout the process, the written ICF and any 
other information shall be read aloud and explained to the prospective subject. The subject should “make 
his mark” (sign or otherwise physically mark the document so as to indicate consent) on the ICF as well. 
The ICF should document the method used for communication with the prospective subject and the 
specific means by which the prospective subject communicated agreement to participate in the study. 
 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
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Version 6.0  
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Page 54 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
11.5.3.4. Post-procedure Anticoagulation 
Systemic oral anticoagulation should be initiated on the day of the procedure and is recommended for at 
least two months following an AF ablation procedure.  Decisions regarding the continuation of systemic 
anticoagulation agents more than two months following ablation should be based on the patient’s risk 
factors for stroke as estimated by the CHA2DS2-VASc score and not on the presence or type of AF. 
Discontinuation of systemic anticoagulation therapy post ablation is not recommended in patients who 
are at high risk of stroke as estimated by the CHA2DS2-VASc score. 
11.5.3.5. Diaphragm Movement  
a. Prior to the first cryoablation application, the Investigator will make a fluoroscopic recording 
of inspiratory and expiratory movement of the diaphragm. 
b. Continuous phrenic nerve pacing with abdominal palpitation must be performed for all right 
pulmonary vein cryoapplications and should be considered for all cryoapplications.  
Additional methods of phrenic nerve monitoring are encouraged, such as diaphragmatic 
compound motor action potential (CMAP). 
c. After the last cryoablation application, the Investigator will make a fluoroscopic recording of 
inspiratory and expiratory movement of the diaphragm. 
11.5.3.6. Balloon Pulmonary Vein (PV) Cryoablation 
a. Every effort consistent with subject welfare will be made to treat all PVs or their anomalous 
equivalents. 
b. The catheter will be advanced into the left atrium over the mapping catheter or guidewire 
and inflated.  Once inflated, the catheter will be tracked over the Achieve™ catheter and 
positioned at the entrance of the PV. 
c. Assess the positioning, contact and occlusion of the PV by the catheter’s balloon by 
injection of contrast material, ultrasound imaging, or other technique.  Reposition as 
needed. 
d. Each pulmonary vein must be assessed for entrance block and, where assessable, exit block 
to demonstrate electrical isolation. 
e. It is recommended that the Investigator use cryoapplications of three (3) minutes each.  
Once PV isolation has been achieved, one (1) additional application of three (3) minutes at 
the same PV should be performed; however, it is up to the operator’s discretion to assess 
application time and necessity of the additional freeze given factors such as time to 
isolation of prior application(s), temperature of prior application(s), risk of collateral 
damage, etc. 
f. 
Upon the Investigator’s assessment of procedure completion, isoproterenol and/or 
adenosine may be used to assess pulmonary vein isolation. 


056-F275, Clinical Investigation Plan Template, Version 2.0 
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Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
11.5.3.7. Other Ablations During Index Procedure 
a. Ablation of the cavotricuspid isthmus is required in subjects with a history of typical atrial 
flutter or inducible cavotricuspid isthmus depend atrial flutter.  Complete an assessment for 
bi-directional block if this procedure is performed.  Any commercially released catheter 
deemed appropriate for the procedure may be used. 
 
b. The following are not allowed: 
• Left atrial non-PVI ablations including but not limited to, ablation of linear lesions, complex 
fractionated electrograms or non-PV triggers 
• Ablation using any non-study device in the left atrium 
11.5.3.8. Cardioversion 
a. Electrical or pharmacological cardioversion to sinus rhythm must be attempted following the 
PVI portion of the procedure if sinus rhythm wasn’t restored.  Cardioversion may be 
performed prior to PVI if needed. 
11.5.3.9. Procedure Documentation  
During the procedure the investigator will document the following:  
• Catheters used (i.e. Arctic Front Advance™, Freezor® MAX and Achieve™ Mapping Catheter, 
etc.) 
• Minimum temperature for each cryoapplication 
• Duration of each cryoapplication 
• Vein location for each cryoapplication (e.g. right superior PV) 
• Use of phrenic nerve pacing or other phrenic nerve monitoring technique for each 
cryoapplication, specifically those cryoapplications surrounding the RS and RI PVs 
• Demonstrated electrical block and, if real-time signals are available, time to isolation 
• Adjunctive catheters, mapping or visualization devices, sedation type, procedure information, 
esophageal temperature, ACT, cardioversion use and fluoroscopy time will be collected. 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 59 of 130 
 
 
Version 6.0  
STOP AF First 
Page 59 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
11.5.8.2. Three Month Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
Health care utilization assessment- collect information about hospitalizations or emergency 
department visits experienced by the subject since the last visit 
• 
12 lead ECG 
• 
Provide the subject with patient-activated ambulatory monitoring equipment; provide instructions 
for and weekly and symptomatic transmissions. 
• 
Chest X-ray 
o 
For any subject whose post-procedural fluoroscopy demonstrated study-related PNI, a 
follow-up chest X-ray, including inspiration and expiration films, will be performed if the 
PNI was unresolved at the one month visit 
• 
In the case of suspected PV stenosis, Magnetic Resonance Imaging (MRI) or Computerized 
Tomography Scanning (CT scan) is required.  It is not required at this visit if it was already 
completed at an earlier visit and PV stenosis was confirmed.   
11.5.8.3. Six Month Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
Health care utilization assessment- collect information about hospitalizations or emergency 
department visits experienced by the subject since the last visit 
• 
12 lead ECG 
• 
24h continuous ECG monitoring with ambulatory monitoring equipment  
• 
EQ-5D and AFEQT Questionnaires 
• 
Review the patient-activated ambulatory monitoring instructions with the subject.   
• 
Chest X-ray, including inspiration and expiration films, is required for subjects whose PNI was 
unresolved at the 3 month visit 
• 
In the case of suspected PV stenosis, Magnetic Resonance Imaging (MRI) or Computerized 
Tomography Scanning (CT scan) is required.  It is not required at this visit if it was already 
completed at an earlier visit and PV stenosis was confirmed.   
 
 


056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 60 of 130 
 
 
Version 6.0  
STOP AF First 
Page 60 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
11.5.8.4. Twelve month Office Visit 
• 
Review medications  
• 
Adverse event assessment 
• 
Review symptoms suggestive of recurrent AF/AT/AFL 
• 
Health care utilization assessment- collect information about hospitalizations or emergency 
department visits experienced by the subject since the last visit 
• 
12 lead ECG 
• 
24h continuous ECG monitoring with ambulatory monitoring equipment.  The subject will be 
instructed to apply the continuous monitoring patches and complete the 24 hours of continuous 
monitoring within 7 days prior to the 12 month visit.   It is recommended that the study 
personnel call the subject to remind them of this requirement.  If the subject is not able to apply 
the device prior to the visit, it may be applied by study personnel at the 12 month visit.   
• 
EQ-5D and AFEQT Questionnaires 
• 
Collect the ambulatory monitoring equipment and return to Medtronic (or designee).  If the 
subject did not perform the continuous monitoring prior to the 12 month visit, apply the device to 
the subject to complete 24 hour continuous monitoring.  Give the subject instructions on how to 
return the equipment.   
• 
Chest X-ray, including inspiration and expiration films, is required for subjects whose PNI was 
unresolved at the 6 month visit 
• 
In the case of suspected PV stenosis, Magnetic Resonance Imaging (MRI) or Computerized 
Tomography Scanning (CT scan) is required.  It is not required at this visit if it was already 
completed at an earlier visit and PV stenosis was confirmed.   
• 
Inform the subject they have completed the study 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 66 of 130 
 
 
Version 6.0  
STOP AF First 
Page 66 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
o 
Pain-discomfort at the catheter insertion site that can range from mild to severe. 
o 
Pseudoaneurysm-a collection of blood in the tissue surrounding the catheter insertion site 
due to ongoing leaking of blood from a blood vessel. 
o 
Significant bleeding-blood loss from the catheter insertion site requiring surgery or 
transfusion of 2 or more units of packed red blood cells (PRBCs). 
• 
Coronary artery spasm, vasospasm-constriction of a blood vessel. 
• 
Death-a complication or deterioration of health ultimately leading to a patient’s death. 
• 
Dissection of a blood vessel-a tear within the wall of a blood vessel. 
• 
Dizziness, lightheadedness-feeling faint, woozy, weak or unsteady. 
• 
Embolism-formation and dislodgement of a blood clot (thrombus) or dislodgement of 
cholesterol/plaque within the blood vessel, which travels downstream into small vessels, blocking 
blood flow and causing temporary or permanent damage to organs distal to blockage.  Emboli 
are known to cause myocardial infarction, transient ischemic attack, stroke/cardiovascular 
accident, blurred vision, visual changes, paralysis, paresis, or kidney damage, peripheral ischemia 
and may ultimately lead to incapacitation or death.  Symptomatic and non-symptomatic. 
• 
Endocarditis –inflammation of the inner surface of the heart. 
• 
Esophageal injury –damage to your swallowing tube, atrio-esophageal fistula - abnormal 
passageway between the heart and esophagus, hematemesis (vomiting blood). 
• 
Fatigue- extreme tiredness. 
• 
Fever- abnormally high body temperature. 
• 
Gastroparesis- delayed gastric emptying. 
• 
Headache- pain in the head. 
• 
Heartblock requiring permanent pacemaker implantation 
• 
Heart rhythm disturbances-disruption of normal heart rate or rhythm (e.g. atrial flutter, 
tachycardia, bradycardia). 
• 
Hemothorax –collection of blood around the lungs. 
• 
Hiccups- involuntary spasm of the diaphragm and respiratory organs. 
• 
Hypertension-high blood pressure. 
• 
Hypotension-low blood pressure. 
• 
Infection (e.g. sepsis) 
• 
Injury to lung- (e.g. bronchial lesion, hemoptysis, constriction, pulmonary hemorrhage, bronchia 
fistula). 
• 
Mild skin discomfort or irritation-redness sensitivity of the skin cause during or after the 
procedures (e.g. electrodes used with the ECG and Holter recorder might cause mild skin 
discomfort or irritation or some skin discomfort following electrode removal or tape removal). 
• 
Nausea-a sensation of unease and discomfort in the upper stomach with an urge to vomit. 


056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 67 of 130 
 
 
Version 6.0  
STOP AF First 
Page 67 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
• 
Perforation of a blood vessel or cardiac tissue-unintended puncture through the wall of a blood 
vessel or cardiac tissue. 
• 
Pericardial effusion- fluid collecting in the sac that surrounds the heart. 
• 
Pericarditis –inflammation of the sac that surrounds the heart. 
• 
Phrenic nerve injury –damage to the nerve that controls breathing. 
• 
Pleural effusion –collection of extra fluid around the lungs. 
• 
Pneumothorax – collapsed lung.Pulmonary edema- excess fluid in the lungs. 
• 
Pulmonary hypertension- high blood pressure that affects the arteries in the lungs and the right 
side of the heart.Pulmonary vein hematoma- trauma to the pulmonary vein. 
• 
Pulmonary vein stenosis –blockage in the blood vessels takes blood from the lungs to the heart. 
• 
Renal dysfunction-kidneys fail to adequately filter waste products from the blood. 
• 
Right sided heart failure- right side of the heart is not pumping blood to the lung normally. 
• 
Shivering- body shaking. 
• 
Shortness of breath- difficulty breathing. 
• 
Small ischemic cerebral (brain) lesions not accompanied by clinically apparent symptoms have 
been found on brain imaging performed after an AF ablation procedure.  So far, the relationship 
between these lesions and an increased incidence of stroke or transient ischemic attack (a mini 
stroke) has not been established.  However, whether these lesions will result in long term 
cognitive decline (e.g. loss of memory and trouble thinking) is unclear. 
• 
ST elevation- the ST segment of an ECG is abnormally high above the baseline. 
• 
Sore throat- pain in the throat. 
• 
Urinary infection- an infection in the urinary system. 
• 
Vascular complications requiring surgery-damage to an artery (e.g. femoral) or vein requiring 
surgical repair. 
• 
Vasovagal reaction- reflex of the involuntary nervous system that causes the heart to slow down 
and blood pressure drops. 
• 
Vomiting-forceful expulsion of stomach contents through the mouth and/or nose. 
The risks of participating in this clinical study are the same as the cryoablation procedure risks, and also 
include: 
• 
Risks/discomforts associated with sedation/anesthesia: 
o 
Hoarseness. 
o 
Myalgia (pain in the muscles). 
o 
Numbness and tingling of the fingers. 
o 
Diarrhea. 
o 
Dry mouth. 
o 
Sleepiness. 


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Page 79 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
13.3.1.2. Death Classification and Reporting 
Sufficient information will be required in order to properly classify the subject’s death.  The Investigator 
shall classify each subject death per the following definitions: 
• 
Cardiac Death: A death directly related to the electrical or mechanical dysfunction of the heart. 
• 
Sudden Cardiac Death (SCD): Natural death due to cardiac causes, indicated by abrupt loss of 
consciousness within one hour of the onset of acute symptoms; preexisting heart disease may 
have been known to be present, but the time and mode of death are unexpected. If time of 
onset cannot be determined, SCD will alternatively be defined as any unexpected cardiac death 
occurring out of the hospital or in the emergency room as dead on arrival. 
• 
Non-sudden Cardiac Death: All cardiac deaths that are not classified as sudden deaths, including 
all cardiac deaths of hospitalized subjects on inotropic support. 
• 
Non-cardiac Death: A death not classified as a cardiac death. 
• 
Unknown Classification: Unknown death classification is intended for use only when there is 
insufficient or inadequate information to classify the death. 
The CEC will review deaths and provide a final adjudication of the primary cause of death and cardiac 
classification. 
Regulatory reporting of subject deaths will be completed according to local regulatory requirements. 
 
 


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16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
14. Data Review Committees  
At regular intervals, an independent Clinical Events Committee (CEC) will review and adjudicate all 
reported adverse events and deaths for subjects participating in the study. 
The CEC will consist of a minimum of three (3) non-Medtronic employed physicians that are not 
participating Investigators for the study, including a CEC chairperson. 
Medtronic personnel may facilitate and participate in a CEC meeting but will be non-voting members. 
For adverse events and deaths reviewed by the CEC, Medtronic will provide the CEC with the 
Investigator’s description and classification.  The CEC is responsible for reviewing the Investigator’s 
assessment and supportive documentation (when available), reviewing applicable definitions, and 
determining final classifications for all adjudication parameters.  Additionally, the CEC will provide an 
adjudication of the death classification for all reported deaths including primary cause of death and 
cardiac classification. 
If the CEC disagrees with the Investigator’s classification of the event, the rationale will be provided to 
the Investigator. If the Investigator agrees with the CEC’s adjudication, the eCRF documenting the event 
will be updated accordingly. 
If the Investigator does not agree with the CEC’s adjudication classification, both determinations will be 
provided within the final report; however, the CEC’s adjudication will be used for data analysis.  The 
disagreement will also be included in reporting to IRB and regulatory authorities, if required. 
 
 


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16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
15. Statistical Design and Methods 
Medtronic employees will perform all statistical analyses. 
Additionally, a separate Statistical Analysis Plan (SAP) will be developed to further describe statistical 
methods, pre-specified data handling rules (including how missing data will be handled), and pre-
specified analyses, including subgroup analyses, that will be included in study reports (e.g. PMA report, 
final study report).  Any deviation from the pre-specified statistical analyses will be noted in the study 
report.  
The SAP will include a comprehensive description of the statistical methods and analyses to be included 
in reports that include analysis of endpoints.  Any change to the data analysis methods described in the 
CIP will require an amendment to the CIP only if it changes a principal feature of the CIP.  Any other 
change to the data analysis methods described in the CIP, and the justification for making the change, 
will be described in the clinical study report. 
Additional exploratory analyses of the data may be conducted as deemed appropriate. 
All objectives will be analyzed once all treated subjects complete the 12 month follow-up visit, or have 
exited the study.  A final report will be completed after all subjects complete the final follow-up visit, or 
have exited the study. No interim analyses are planned. 
The primary analysis will be conducted using a modified intent-to-treat protocol; all subjects for whom 
either AAD or cryoballoon ablation therapy is initiated will be analyzed according to their randomization 
status. Subjects who withdraw consent between randomization and initiation of therapy will be excluded 
from the primary efficacy analysis. 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 90 of 130 
 
 
Version 6.0  
STOP AF First 
Page 90 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
15.3.1.2. Endpoint Definition 
The AFEQT questionnaire will be utilized for this objective.  The questionnaire is an atrial fibrillation 
specific health-related quality of life questionnaire to assess the impact of AF on a subject’s life.  The 
overall score ranges from 0 – 100, with 0 corresponding to complete disability and 100 corresponding to 
no disability.  The absolute difference between each subject’s baseline and 12 month scores is the 
endpoint of interest. 
15.3.1.3. Analysis Methods 
The difference in mean AFEQT scores will be assessed utilizing a paired t-test.   
15.3.1.4. Performance Criteria 
If the p-value from the two-sample t-test procedure is less than the alpha level determined by the 
Hochberg procedure described above, the objective will be considered met. 
15.3.1.5. Rationale for Performance Criteria 
If this analysis shows that scores from the AFEQT, a validated instrument for measuring quality of life in 
subjects with atrial fibrillation (Spertus, et al. 2011), are significantly higher 12 months after the 
procedure compared to before the procedure, it will show a documented association between the 
cryoballoon ablation procedure and QoL improvement in a non-drug refractory paroxysmal AF population. 
. While this hypothesis test will not be between randomized groups, in the context of a secondary 
objective that will only be tested if efficacy has been established, such results would provide evidence of 
a QoL improvement in cryoballoon ablation-treated patients. 
15.3.1.6.  Determination of Subjects/Data for Analysis 
All subjects randomized to the cryoballoon ablation group who have completed both baseline and 12-
month questionnaires will be included and analyzed. 
 
Comparison to the AAD arm is not planned as it is expected that a large percentage of AAD arm subjects 
will have a cryoballoon procedure during the 12 months of follow-up.  Having a cryoballoon procedure 
prior to 12 months will bias the AAD arm’s 12-month QOL results. 
15.3.1.7.  Additional analyses 
The AFEQT questionnaire has three subscale scores, Daily Activities Subscale, Treatment Concern, and 
Treatment satisfaction.  Each subscale ranges from 0 – 100, where 0 corresponds to low quality-of-life 
and 100 corresponds to high quality of life. 
 
Change in AFEQT subscale score is defined as 12-month AFEQT subscale score minus baseline AFEQT 
subscale score.  A two-sided 95% confidence interval will be calculated based on the t-distribution. 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 94 of 130 
 
 
Version 6.0  
STOP AF First 
Page 94 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
15.3.4.5. Rationale for Performance Criteria 
If the test specified above indicates a statistically significant increase in the time to the first cardioversion 
between cryoballoon ablation and AAD-treated subjects, this is sufficient evidence to say that the 
treatment has a lower rate of cardioversions within a year of treatment initiation, due to the randomized 
and intention-to-treat nature of the comparison. 
15.3.4.6. Determination of Subjects/Data for Analysis 
The modified intent-to-treat cohort will be utilized.  All subjects who initiate either AAD therapy or 
cryoballoon ablation will be analyzed according to the group to which they were randomized in the 
assessment of this objective. 
 
 


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056-F275, Clinical Investigation Plan Template, Version 2.0 
Page 100 of 130 
 
 
Version 6.0  
STOP AF First 
Page 100 of 130 
16JAN2018 
Clinical Investigational Plan 
 
Medtronic Confidential 
 
 
In addition to the regulatory requirements outlined above, the study will be conducted in compliance with 
relevant local laws. These include but are not limited to: 
 
• 
In the United States, US FDA 21 CFR Parts 
o 
50: Protection of Human subjects,  
o 
56: Institutional Review Boards  
o 
812: Investigational Device Exemptions 
• 
In Europe, Declaration of Helsinki 2013, the Competent Authority requirements, the Medical 
Device Directive (MDD) 93/42/EEC and ISO 14155:2011 with the exceptions stated earlier in this 
Section 
 
The study will be publicly registered prior to first enrollment in accordance with the 2007 Food and Drug 
Administration Amendments Act (FDAAA) and Declaration of Helsinki on http://clinicaltrials.gov (PL 110 
85, Section 810(a)). 
 
Approval of the Clinical Investigation Plan (CIP) is required from the following groups prior to any study 
procedures at a study center: 
 
• 
US Food and Drug Administration (FDA) or regulatory authority 
• 
Medtronic 
• 
Principal Investigators (where required by local law) 
• 
An independent IRB/EC 
 
Similarly, approval of subsequent revisions to the CIP is required at each study center from the above 
mentioned groups prior to implementation of the revised CIP at that center. 
 
Medtronic maintains appropriate clinical study liability insurance coverage as required under applicable 
laws and regulations and will comply with applicable local law and custom concerning specific insurance 
coverage.  If required, a clinical insurance statement/certificate will be provided to the IRB/EC. 
The study is conducted in multiple countries, therefore reimbursement and indemnification will be 
addressed on a country specific basis in the study documents and center Clinical Trial Agreements. 
 
 


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• 
The Investigator will promptly inform the subjects (or legally authorized designees or guardians, 
except in Europe),  and may inform the personal physician of the subjects, with the rationale for 
the study termination or suspension 
• 
The Investigator will inform local regulatory authority, where required per regulatory 
requirements 
 
 


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18. References 
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atrial fibrillation: an AFFIRM substudy of the first antiarrhythmic drug." J Am Coll Cardiol 42: 20-
9. 
Arena, G, C Tondo, G Cattafi, and et. al. 2016. "Cryoballoon ablation as treatment of recent paroxysmal 
atrial fibrillation. Data from a large cohort of patients followed in a real world multicenter 
experience." Heart Rhythm 13: S375-76. 
Calkins, et. al. 2017. "2017 HRS/EHRA/ECAS expert Consensus Statement on catether and surgical 
ablation of AF." Heart Rhythm 14 (10): 275-444. 
Caulkins, H, and et. al. . 2007. "HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical 
Ablation of Atrial Fibrillation: Recommendations for Personnel, Policy, Procedures and Follow-Up." 
Europace 9 (6): 335-379. 
Cosio, FG, E Aliot, GL Botto, and et. al. . 2008. "Delayed rhythm control of atrial fibrillation may be a 
cause of failure to prevent recurrences: reasons for change to active antiarrhymic treatment at 
the time of the first detected episode." Europace 10: 21-7. 
De Vos, CB, R Pisters, R Nieuwlaat, and et. al. . 2010. "Progression from paroxysmal to persistent atrial 
fibrillation clinical correlates and prognosis." J Am Coll Cardiol 55: 725-31. 
Go, A, E Hylek, K Phillips, and et. al. 2001. "Prevalence of Diagnosed Atrial Fibrillation in Adults: National 
Implications for Rhythm Management and Stroke Prevention: the Anticoagulation and Risk 
Factors in Atrial Fibrillation (ATRIA) Study." JAMA 285 (18): 2370-2375. 
Hommel, G. 1988. "A stagewise rejective multiple test procedure based on a modified Bonferroni test." 
Biometricka 75: 383-386. 
Jais, P, MD O'Neill, Y Takahashi, and et. al. . 2006. "Stepwise Catheter Ablation of Chronic Atrial 
Fibrillation: Importance of Discrete Anatomic Sites for Termination." J Cardiovasc Electrophysiol 
17 (Suppl. 3): S28-S36. 
Jalife, J, and K Kaur. 2015. "Atrial remodeling, fibrosis, and atrial fibrillation." Trends Cardiovasc Med 25: 
475-84. 
January, CT, and et. al. . 2014. "2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial 
Fibrillation." JACC 64 (21): e1-76. 
January, CT, LS Wann, JS Alpert, ME Field, H Calkins, KT Murray, JC Cleveland Jr., et al. 2014. "2014 
AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive 
Summary." Journal of the American College of Cardiology.  
Knight, BP, PG Novak, R Sangrigoli, and et. al. 2016. "Second generation cryoballoon: results from the 
multicenter STOP AF Post Approval Study 12-month clinical outcomes following pulmonary vein 
isolation using the Arctic Front Adfance." Cardiostim (abstract).  
Kuck, KH, J Brugada, A Furnkranz, A Metzner, F Ouyang, KR Julian Chun, A Elvan, et al. 2016. 
"Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation." N Engl J Med 374: 
2235-45. 
Lafuente-Lafuente, C, L Valembois, JF Bergmann, and J Belmin. 2015. "Antiarrhythmics for maintaining 
sinus rhythm after cardioversion of atrial fibrillation." Cochrane Database of Systematic Reviews.  


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Lafuente-Lafuente, C, S Mouly, MA Longas-Tejero, and et. al. 2006. "Antiarrhythmic drugs for maintaining 
sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled 
trials." Arch Intern Med 166: 719-28. 
Morillo, CA, A Verma, SJ Connolly, and et. al. 2014. "Radiofrequency ablation vs. antiarrhythmic drugs as 
first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): A randomized trial." JAMA 311 (7): 
692-700. 
Nattel, S, E Guasch, I Savelieva, and et. al. 2014. "Early management of atrial fibrillation to prevent 
cardiovascular complications." Eur heart J 35: 1448-56. 
Nielsen, JC, A Johannessen, P Raatikainen, G Hindricks, H Walfridsson, O Kongstad, S Pehrson, et al. 
2012. "Radiofrequency Ablation as Initial Therapy in Paroxysmal Atrial Fibrillation." New England 
Journal of Medicine, October 25: 1587-96. 
Oral, H, BP Knight, H Tada, and et. al. . 2002. "Pulmonary vein isolation for paroxysmal and persistent 
atrial fibrillation." Circulation 105: 1077-81. 
Packer, D, R Kowal, K Wheelan , J Irwin, J Champagne, P Guerra, M Dubuc, et al. 2013. "CryoBalloon 
ablation: first results of North America STOP AF pivotal trial." J Am Coll Cardiol 61 (16): 1713-
1723. 
Raviele, et. al. . 2012. "Venice Chart International consensus document on atrial fibrillation: 2011 
Update." J Cardiovasc Electrophysiol 23: 890-923. 
Romero, J, C Gianni, L Di Biase, and A Natale. 2015. "Catheter ablation for long-standing persistent atrial 
fibrillation: On-treatment analysis of the randomized controlled MANTRA-PAF trial." Int J Cardiol J 
11: 87-93. 
Shaw, JW, JA Johnson, and SJ Coons. 2004. "U.S. Valuation of the EQ-5D Heatlh States: Development 
and Testing of the D1 Valuation Model." Medical Care.  
Shulka, A, and AB Curtis. 2014. "Avoiding permanent atrial fibrillation: treatment approaches to prevent 
disease progression." Vasc Health Risk Manag 10: 1-12. 
Spertus, J, P Dorian, R Bubien, S Lewis, D Godejohn, MR Reynolds, DR Lakkireddy, AP Wimmer, A 
Bhandari, and C Burk. 2011. "Development and validation of the Atrial Fibrillation Effect on 
Quality-of-Life (AFEQT) Questionnaire in patients with atrial fibrillation." Circ Arrhythm 
Electrophysiol, Feb 4: 15-25. 
Tanner, H, K Makowski, L Roten , and et. al. 2011. "Catheter ablation of atrial fibrillation as first-line 
therapy- a single-center experience." Europace 13: 646-53. 
Walters, TE, A Nisbet, GM Morris, and et. al. 2016. "Progression of atrial remodeling in patients with high-
burden atrial fibrillation: Implications for early ablative intervention." Heart Rhythm 13: 331-9. 
Wazni, OM, NF Marrouche, DO Martin, A Verma, M Bhargava, W Saliba, D Bash, et al. 2005. 
"Radiofrequency Ablation vs. Antiarrhythmic Drugs as First-Line Treatment of Symptomatic Atrial 
Fibrillation." JAMA, June 1: 2634-40. 
Wijesurendra, RS, and B Casadei. 2015. "Atrial fibrillation: effects beyond the atrium?" Cardiovasc Res 
105: 238-47. 
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Framingham Study." Stroke 22 (8): 983-988. 






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Additional articles Medtronic was aware of or that were published after the searches were conducted 
were included. 
 
 


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Appendix B: DRAFT DATA COLLECTION ELEMENTS (CASE REPORT FORMS) 
Draft Case Report Forms for the STOP AF First study will be provided under separate cover.  Final CRFs 
will be provided to study centers via the electronic data management system after the center has fulfilled 
all requirements for database access. 
 
 


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Appendix C: INFORMED CONSENT FORM TEMPLATE 
The Informed Consent Form Template will be distributed under separate cover. 
 
 


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Appendix D: PARTICIPATING INVESTIGATOR AND INSTITUTIONS 
A list of participating Investigators and institutions will be distributed under separate cover. 
 
 


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Appendix E: IRB LIST 
A final IRB list will be distributed under separate cover. 
 
 


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Appendix F: FORESEEABLE ADVERSE EVENTS 
The information provided in this section pertains to foreseeable adverse events that may be observed in 
study subjects and may collectively assist in identifying those events for a given device or therapy that 
are unexpected in nature.  The foreseeable adverse events information consists of two parts: a listing of 
potential adverse events associated with cryoablation therapy/procedure and adverse event rates 
reported in published literature for same therapy/procedure (see Appendix A).  An evaluation of 
potentially anticipated events and reported events in literature may be used in combination with device 
labeling/IFU, current event reporting information, and other published data to assess for an unexpected 
occurrence. 
The cryoablation procedure involves surgery, therefore, standard adverse events associated with a 
surgical procedure may be experienced (e.g. anesthesia complications, injury, infections, bleeding, 
exacerbation of pre-existing conditions, healing complications, etc.). The focus of this section is to 
specifically address in more detail, those events that are foreseeable due to the use, performance, and/or 
presence of the Arctic Front Advance™ CryoAblation Catheter under investigation. 
Additional potential risks associated with the Arctic Front Advance™ CryoAblation Catheter, as well as risk 
minimization are discussed within section 12. 
Treatment required for procedure and/or cryoablation system related adverse events that are 
experienced may include medication or other surgical and medical remedies. The adverse events 
associated with the use of the Arctic Front Advance™ CryoAblation Catheter include but are not limited to 
those in Table 14 and Table 15. 
Table 14 pertains to the foreseeable/anticipated adverse events that may be observed in the study and 
may assist in identifying those adverse events that are unexpected in nature. 
Table 14: Foreseeable Adverse Events 
Anemia 
Feeling cold 
Pseudoaneurysm 
Anxiety 
Fever 
Pulmonary edema 
Arrhythmia 
Gastrointestinal 
discomfort 
Pulmonary embolism 
Arteriovenous fistula 
Gastroparesis 
Pulmonary 
hemorrhage 
Atrial fibrillation 
Headache 
Pulmonary 
hypertension 
Atrial flutter 
Heart block 
Pulmonary infarction 
Atrio-esophageal fistula  
Heart failure 
Pulmonary 
infiltration 
Back pain 
Hematemesis 
Pulmonary vein 


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stenosis 
Bleeding 
Hematoma 
Renal impairment 
Blurred vision 
Hemoptysis 
Respiratory arrest or 
pulmonary arrest 
Bronchial fistula 
Hemothorax 
Right bundle branch 
block 
Bronchitis 
Hiccups 
Shivering 
Bruising 
Hypertension 
Shortness of breath 
Cardiac arrest or 
cardiopulmonary arrest 
Hypotension 
Sore throat 
Cardiac perforation or 
cardiac vein perforation 
or perforation of 
surrounding tissue 
Hypoxia 
ST segment 
elevation 
Cardiac tamponade 
Injury to pulmonary vein 
e.g. pulmonary vein 
dissection, pulmonary 
vein hematoma  
Stroke or 
cerebrovascular 
accident 
Cerebral embolism 
Lightheadedness 
Syncope 
Chest discomfort or pain 
or pressure 
Lung injury 
Tachycardia 
Coronary artery spasm 
Myocardial infarction 
Thrombosis or 
thrombus 
Cough 
Nausea 
Transient ischemic 
attack 
Death 
Nerve injury e.g. phrenic 
nerve injury 
Urinary infection 
Diarrhea 
Neurological impairment 
Vascular access site 
complication 








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Appendix G: PRE-CLINICAL TESTING 
A summary of results from pre-clinical testing with the Arctic Front Advance™ Cardiac CryoAblation 
Catheter is provided in the Report of Prior Investigations Summary.