STOP AF First: Cryoballoon Catheter Ablation in an Antiarrhythmic Drug Naive Paroxysmal Atrial Fibrillation
Phase: NA
Conditions: Atrial Fibrillation, Atrial Fibrillation New Onset
Sponsor: Medtronic Cardiac Ablation Solutions

 
 
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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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 
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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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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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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 
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 

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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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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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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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Medtronic Confidential 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

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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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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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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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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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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. 

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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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056-F275, Clinical Investigation Plan Template, Version 2.0 
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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.