POLARx Cardiac Cryoablation System Post Market Clinical Follow-up Study
Conditions: Atrial Fibrillation
Sponsor: Boston Scientific Corporation

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POLARx Cardiac Cryoablation system 
Post Market Clinical Follow-up study 
POLAR ICE 
PY003 
 
 
CLINICAL INVESTIGATION PLAN 
 
 
 
 
 
NCT04250714 
 
Sponsored By 
Boston Scientific Corporation  
4100 Hamline Ave. N. 
St. Paul, MN 55112 
 
and 
 
Boston Scientific International S.A. 
Le Val Saint-Quentin,  
2 rue René Caudron,  
78960 Voisins le Bretonneux, France 
 
 
 
 
 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation. The protocol should be 
held confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
 
 
 
 
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Contact Information 
Role 
Contact  
Clinical Contact 
Clinical Trial Managers, Protocol Authors 
 
Nele Cielen 
Clinical  Trial Manager 
 
 
 
 
 
 
 
 
Giovanni Raciti 
Sr. Clinical Trial Manager 
 
 
 
 
 
 
 
Steering 
Committee 
members 
Dr. Ante Anic 
 
 
 
 
Dr. Claire Martin 
 
 
 
 
 
 
Pr. Pascal Defaye 
 
 
 
 
Prof. Roland Tilz 
 
 
 
Dr. Armin Luik 
 
 
 
 
Dr. Sing-Chien Yap 
 
 
 
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Original Release: 13 February 2020 
Current Version: 07 MAY 2020 
 
 
 
Revision 
Version 
Protocol 
Date 
Template 
number 
and 
version 
Protocol Section 
Modified 
Summary of Changes 
 
Justification for Modification 
A 
13 
February 
2020 
C 
N/A 
Initial Release 
N/A 
B 
07 May 
2020 
C 
Multiple 
Initial Release to the sites (Administrative updates prior to 
release to sites) 
N/A 
 
 
 
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2. Protocol Synopsis 
POLARx Cardiac Cryoablation system 
Post Market Clinical Follow-up study 
POLAR ICE 
Study 
Objective(s) 
Primary Objective: This is a Post Market Clinical Follow-up (PMCF) 
study designed to establish the continued safety and effectiveness profile 
of the Boston Scientific Cardiac Cryoablation System after receiving CE 
mark.  
Secondary Objective: The study will provide information on real-world 
usage of the Boston Scientific Cardiac Cryoablation System when used to 
perform pulmonary vein isolation (PVI) for the ablation treatment of atrial 
fibrillation (AF), according to the current and future guidelines and system 
indications for use. This may include but not limited to: repeated ablations 
to treat AF, concomitant or delayed adjunctive ablation strategies with 
other products and use of different diagnostic products to validate the 
results such as 3D mapping systems. 
Collected information and analyses will include, but not limited to, the 
following: 
• Arrhythmia characterisation at the time of enrollment: time since 
first AF diagnosis, number and duration of reported episodes, prior 
electrical cardioversions (if any);  
• History of prior ablations and repeated ablations during follow-up 
period;  
• Use of anti-arrhythmic drugs (AAD); 
• Methods used for verification of procedure success (pulmonary 
vein isolation): entrance/exit block, adenosine (if used), use of 
three-dimensional (3D) mapping. 
Indication(s) 
for Use  
Subjects enrolled in the POLAR ICE study will be clinically indicated for 
an ablation procedure for the treatment of atrial fibrillation according to 
current and future guidelines and system indications for use.  
Device/System  The Boston Scientific Cardiac Cryoablation System (“Cryoablation 
System”) consists of the following devices and components: 
• POLARx™ Cryoablation Catheter (“Cryoablation Catheter”); 
• POLARMAP™ Catheter (“Cryo Mapping Catheter”); 
• POLARSHEATH™ Steerable Sheath (“Cryo Steerable Sheath”);  
• SMARTFREEZE™ Console (“Console”); 
• Related Accessories. 
Control Device  This study has no control device(s) 
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POLARx Cardiac Cryoablation system 
Post Market Clinical Follow-up study 
POLAR ICE 
Study Design 
Prospective, non-randomized, multicenter (international), single arm 
study.  
All subjects signing the consent, undergoing the index procedure and 
treated with the study devices will be followed up for one year.  
Planned 
Number of 
Subjects 
A minimum of 200 subjects (with the possibility to expand up to 
maximum 400 subjects) will be included in this study. A minimum of 
199 De Novo TREATMENT subjects (i.e. first treatment for AF in the 
left atrium) for paroxysmal atrial fibrillation (PAF) will be analyzed to 
establish the continued safety and effectiveness profile of the 
Cryoablation System and fulfill the PMCF requirements for the 
submitted labeling of the Cryoablation System. This number represents 
the minimum number for the primary endpoint statistical hypothesis 
testing. 
The entire study cohort will provide information on real-world usage of 
the Cryoablation System and will be analyzed for secondary objectives. 
These will include subgroup analysis in selected subjects of interest 
(including (but not limited to) De Novo ablation versus repeated 
ablations). These analyses will be non-powered but in case some of these 
subgroups will be poorly represented in the study, Boston Scientific may 
propose in the future to extend the sample size to up to 400 subjects. 
Planned 
Number of 
Sites / 
Countries 
Approximately 25 centers in Europe and Middle East will be included in 
the study. 
Primary Safety 
Endpoint 
Safety event free rate at 12 months post-index procedure.  
Primary safety events will consist of a composite of the following 
procedure-related and device-related adverse events.  
Acute primary safety endpoint events, events occurring up to 7 days post-
index procedure or hospital discharge, whichever is later, include:  
• 
Death 
• 
Myocardial infarction (MI) 
• 
Persistent gastroparesis/injury to vagus nerve 
• 
Transient ischemic attack (TIA) 
• 
Stroke/Cerebrovascular accident (CVA) 
• 
Thromboembolism/Air embolism* 
• 
Cardiac tamponade/perforation 
• 
Pneumothorax 
• 
Serious vascular access complications** 
• 
Pulmonary edema/heart failure 
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POLARx Cardiac Cryoablation system 
Post Market Clinical Follow-up study 
POLAR ICE 
• 
AV block not attributable to medication effect or 
vasovagal reaction. 
 
* Thromboembolic or /air embolic events collected in the study refer to any occlusion of 
blood vessel(s) that results in clinical symptoms  
** Defined as prolongation of hospitalization, requirement of surgical intervention or 
blood transfusion 
 
Chronic primary safety endpoint events, events occurring through 12 
months post-index procedure, include: 
• 
Atrial esophageal fistula 
• 
Pulmonary vein stenosis (≥ 70% reduction of diameter) 
• 
Symptomatic pericardial effusion  
• 
Persistent Phrenic nerve injury*** 
 
***A non-recovered phrenic nerve injury at 12 months post-index procedure will count 
as a chronic primary endpoint. The study will collect information on phrenic nerve palsy 
observed before the end of the index procedure and, in case it occurred, will track 
information for potential recovery during the study visits. 
Primary 
Effectiveness 
Endpoint 
Failure free rate at 12 months post-index procedure.  
 
Failure defined as: 
• 
Failure to achieve acute procedural success* in the index 
procedure;  
• 
More than one repeat procedure during the blanking period 
(within 90 days post-index procedure); 
• 
Documented atrial fibrillation, or new onset of atrial flutter 
or atrial tachycardia event (≥ 30 seconds in duration or 
from a 10 second 12-lead ECG) between days 91 and days 
365 post-index procedure **; 
• 
Any of the following interventions for atrial fibrillation, or 
new onset of atrial flutter or atrial tachycardia between 
days 91 and days 365 post-index procedure: 
• 
Repeat procedure; 
• 
Electrical and/or pharmacological cardioversion for 
AF/AFL/AT;  
• 
Prescribed a higher dose of any AAD*** 
documented at baseline or a new AAD*** not 
documented at baseline.  
 
* Acute procedural success is defined as isolation of the all pulmonary veins or 
anatomical equivalents achieved with the Cryoablation Catheter at the end of the index 
procedure and  as demonstrated at minimum by entrance block using the Cryo Mapping 
Catheter  (Other techniques of assessment are per investigator’s discretion).   
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POLARx Cardiac Cryoablation system 
Post Market Clinical Follow-up study 
POLAR ICE 
** Subjects will be monitored for recurrences of the arrhythmias by means of clinical 
visits, ECG and 24-hour Holter monitoring. Recurrences documented with other devices 
only (eg. ILR, PM, ICD, CRT) will not be counted as primary effectiveness endpoint 
events 
*** AADs for endpoint will consist of all Class I/III and any Class II/IV medications 
taken for control of AF/AT/AFL recurrence 
Secondary 
Effectiveness 
Endpoint 
Documentation and rate of acute procedural success, defined as pulmonary 
vein isolation achieved with the Cryoablation System. Electrical isolation 
of a PV is demonstrated at minimum by entrance block using the Cryo 
Mapping Catheter (Other techniques of assessment are per investigator’s 
discretion). 
Information on isolation method used per site standard of care will be 
collected with a minimum by entrance block in all PVs or anatomical 
equivalents. Additional data, if available, will be collected on Exit Block 
or Conduction Block verification using 3D mapping. 
Additional 
Endpoints 
Additional endpoints and analyses include, but are not limited to:  
• Procedure times: LA dwell time*, total ablation time, number of 
cryo applications per vein, time to thaw, total fluoroscopy time 
and total procedure time;  
• Time-To-Isolation per ablation application, if available; 
• Freedom from recurrence of individual types of atrial arrhythmias 
(AF, AFL, AT) between days 91 and days 365 post-index 
procedure; 
• Analysis of ablation techniques (i.e. segmental approach to left 
common trunk, additional linear ablations, etc.); 
• Analysis of different anaesthesia techniques (General anaesthesia 
with or without intubation versus sedation); 
• Freedom from recurrence in subjects with non-common 
anatomical configurations of PV (e.g. left common trunk); 
• Freedom from primary effectiveness failure evaluated in 
subgroups of subjects (termination of AAD versus continuation 
of AAD after blanking period); 
• For the subgroup of subjects undergoing 3D mapping with the 
Boston Scientific mapping Rhythmia system and performing a 
post-procedural map, map information will be collected to 
determine lesion locations; 
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POLARx Cardiac Cryoablation system 
Post Market Clinical Follow-up study 
POLAR ICE 
• For subjects that will undergo repeat ablation during the course 
of the clinical follow-up, anatomical location of ablations gaps 
will be assessed. 
* LA dwell time is defined as time from the Cryoablation Catheter introduced in the left 
atrium (LA) to the last time of Cryoablation Catheter exiting the LA. 
 
Additional ancillary analyses on specific subgroup of subjects, may be 
presented. 
These analyses will include but not limited to the following: 
• Age (<60 versus ≥ 60 years); 
• Gender (Male versus Female); 
• Monitoring (Subjects with data from continuous ECG recording 
systems (eg. ILR, PM, ICD, CRT) versus those without). 
Method of 
Assigning 
subjects to 
Treatment 
Any subject who signs the consent form will be considered enrolled in the 
study.  
Any subject that signs the consent form, has the study device inserted into 
the body and undergoes protocol specific treatment for the intended 
disease (cryoablation) will be assigned to the TREATMENT group. 
The 12 Month follow-up data from minimum 199 De Novo 
TREATMENT subjects with  paroxysmal atrial fibrillation will serve as 
PMCF data and an interim report will be generated once the follow-ups 
are completed.  
Follow-up 
Schedule 
Visits schedule: pre-discharge, 3 months (blanking period), 6 months and 
12 months.  
Study Duration Enrollment is expected to be completed in approximately 12 months; 
therefore, the total study duration is estimated to be approximately 24 
months. 
Participant 
Duration 
The study duration for each subject is expected to be approximately 12 
months. 
Inclusion 
Criteria 
1. Subjects indicated for the treatment of AF with the cryoablation 
system according to current and future Guidelines and system 
indications for use; 
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POLARx Cardiac Cryoablation system 
Post Market Clinical Follow-up study 
POLAR ICE 
2. Subjects who are willing and capable of providing informed 
consent;  
3. Subjects who are willing and capable of participating in all 
testing associated with this clinical study at an approved clinical 
investigational center; 
4. Subjects whose age is 18 years or above, or who are of legal age 
to give informed consent specific to state and national law. 
Exclusion 
Criteria 
1. Any known contraindication to an AF ablation or 
anticoagulation, including those listed in the instructions for 
use; 
2. Subjects with indication for treatment of AF that is not 
according to current and future Guidelines and system 
indications for use; 
3. Atrial fibrillation secondary to electrolyte imbalance, 
thyroid disease, or any other reversible or non-cardiac cause; 
4. Known or pre-existing severe Pulmonary Vein Stenosis; 
 
5. Evidence of myxoma, LA thrombus or intracardiac mural 
thrombus; 
6. Previous cardiac surgery (e.g. ventriculotomy or atriotomy, 
CABG, PTCA, stent procedure) within 90 days prior to 
enrollment; 
7. Implantable cardiac device procedures (e.g. PM, ICD, CRT) 
within 30 days prior to enrollment; 
8. Implanted Left Atrial Appendage Closure device prior to the 
index procedure; 
9. Interatrial baffle, closure device, patch, or patent foramen 
ovale (PFO) occluder; 
 
10. Subjects with severe valvular disease OR with a prosthetic – 
mechanical or biological - heart valve (not including valve 
repair and annular rings);   
 
11. Presence of any pulmonary vein stents; 
12. Active systemic infection; 
13. Vena cava embolic protection filter devices and/ or known 
femoral thrombus; 
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POLARx Cardiac Cryoablation system 
Post Market Clinical Follow-up study 
POLAR ICE 
14. Any previous history of cryoglobulinemia; 
15. History of blood clotting or bleeding disease; 
16. Any prior history of documented cerebral infarct, TIA or 
systemic embolism (excluding a post-operative deep vein 
thrombosis (DVT))  ≤ 180 days prior to enrollment; 
17. Subjects who are hemodynamically unstable; 
18. The subject is unable or not willing to complete follow-up 
visits and examination for the duration of the study; 
 
19. Life expectancy ≤ 1 year per investigator’s opinion; 
 
20. Women of childbearing potential who are, or plan to 
become, pregnant during the time of the study (method of 
assessment upon investigator’s discretion); 
 
21. Unrecovered/unresolved Adverse Events from any previous 
invasive Procedure; 
 
22. Subjects 
who 
are 
currently 
enrolled 
in 
another 
investigational study or registry that would directly interfere 
with the current study, except when the subject is 
participating in a mandatory governmental registry, or a 
purely observational registry with no associated treatments; 
each instance must be brought to the attention of the sponsor 
to determine eligibility. 
Primary 
Statistical 
Hypothesis and 
Statistical Test 
Methods 
 
Endpoint 
Hypothesis 
Analysis Method 
Primary Safety 
Endpoint 
The primary safety endpoint 
event-free rate at 12 months 
post-procedure >86% 
Kaplan-Meier rate with pointwise 
log-log confidence limit 
Primary 
Effectiveness 
Endpoint  
The 
primary 
effectiveness 
event-free rate at 12 months 
post-procedure >50% 
Kaplan-Meier rate with pointwise 
log-log confidence limit 
Sample Size 
Parameters 
 
 
 
 
 
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POLARx Cardiac Cryoablation system 
Post Market Clinical Follow-up study 
POLAR ICE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
3. Table of Contents 
1. 
TITLE PAGE  ................................................................................................................. 1 
2. 
PROTOCOL SYNOPSIS ................................................................................................... 4 
3. 
TABLE OF CONTENTS ................................................................................................. 11 
 Table of Figures ............................................................................................... 15 
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 Table of Tables ................................................................................................ 16 
4. 
INTRODUCTION ........................................................................................................... 17 
 Background ...................................................................................................... 17 
 Study Rationale ............................................................................................... 18 
5. 
DEVICE DESCRIPTION ................................................................................................ 18 
 Commercial Device ......................................................................................... 18 
 
Cryoablation Catheter (POLARx ™) ................................................. 19 
 
Cryo Mapping Catheter ...................................................................... 20 
 
Cryo Steerable Sheath ......................................................................... 21 
 
Console ............................................................................................... 22 
 
Diaphragm Movement Sensor ............................................................ 23 
 
Esophageal temperature monitoring ................................................... 24 
 
Other Cryoablation System Components ........................................... 25 
5.1.7.1. 
Inter Connection Box (ICB) ............................................... 25 
5.1.7.2. 
Console Foot Switch .......................................................... 25 
5.1.7.3. 
Console Scavenging Hose .................................................. 25 
5.1.7.4. 
Cryo Cable ......................................................................... 26 
5.1.7.5. 
Cryoablation Catheter Electrical Cable ............................. 26 
5.1.7.6. 
Cryo Mapping Catheter EP Electrical Cables .................... 26 
6. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................ 26 
 Study Objective ............................................................................................... 26 
 Study Endpoints .............................................................................................. 26 
 
Primary Safety Endpoint ..................................................................... 26 
 
Primary Effectiveness Endpoint ......................................................... 27 
 
Secondary Effectiveness Endpoint ..................................................... 28 
 
Additional analyses ............................................................................. 28 
7. 
STUDY DESIGN ........................................................................................................... 29 
 Scale and Duration .......................................................................................... 30 
 Treatment Assignment .................................................................................... 30 
 Justification for the Study Design .................................................................. 30 
8. 
SUBJECT SELECTION .................................................................................................. 31 
 Study Population and Eligibility .................................................................... 31 
 Inclusion Criteria ............................................................................................ 31 
 Exclusion Criteria ........................................................................................... 32 
9. 
SUBJECT ACCOUNTABILITY ....................................................................................... 34 
 Point of Enrollment ......................................................................................... 34 
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 Withdrawal ...................................................................................................... 34 
 Lost to Follow-Up ............................................................................................ 34 
 Subject Status and Classification ................................................................... 35 
 End-of-Study Definition.................................................................................. 36 
10. STUDY METHODS ....................................................................................................... 37 
 Data Collection ................................................................................................ 37 
 Study Candidate Screening ............................................................................ 40 
 Enrollment and Informed Consent................................................................ 40 
 Baseline Visit .................................................................................................... 40 
 Medications ......................................................................................... 41 
10.4.1.1. Anti-Arrhythmic Drugs ...................................................... 41 
10.4.1.2. Anticoagulation .................................................................. 41 
 Ablation Procedure (Day 0)............................................................................ 42 
 General Info ........................................................................................ 42 
10.5.1.1. Esophagus Management .................................................... 42 
10.5.1.2. Phrenic Nerve Activity Monitoring ................................... 42 
10.5.1.3. Pulmonary Vein Isolation .................................................. 42 
10.5.1.4. Cryoablation System Preparation ...................................... 43 
 Cryoablation protocol ......................................................................... 43 
10.5.2.1. Cryoablation-specific recommendations ........................... 44 
 Additional ablation(s) ......................................................................... 45 
 3D mapping ........................................................................................ 45 
 Data Collection ................................................................................... 45 
 Pre-Discharge (0-7days post index procedure) ............................................. 47 
 Day 7 Follow-up Contact (eg. Phone call – window of + 7 days) ................ 48 
 Month 3 Follow-up (91 ± 14 days) (in-clinic visit) ........................................ 48 
 Month 6 Follow-up (180 ± 30 days) (in-clinic visit) ...................................... 48 
 
Month 12 Follow-up (365 ± 30 days) (in-clinic visit) ..................... 49 
 
Additional Follow-up ........................................................................ 49 
 
Repeat (or additional) ablation procedure ..................................... 50 
 
Study Completion ............................................................................. 51 
 
Source Documents ............................................................................ 51 
11. STATISTICAL CONSIDERATIONS ................................................................................ 52 
 Endpoints ......................................................................................................... 52 
 Primary Safety Endpoint ..................................................................... 52 
11.1.1.1. Hypotheses ......................................................................... 52 
11.1.1.2. Sample Size ........................................................................ 53 
11.1.1.3. Statistical Methods ............................................................. 53 
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 Primary Effectiveness Endpoint ......................................................... 53 
11.1.2.1. Hypotheses ......................................................................... 54 
11.1.2.2. Sample Size ........................................................................ 54 
11.1.2.3. Statistical Methods ............................................................. 54 
 Data Analyses .................................................................................................. 55 
 Secondary Effectiveness Endpoint ..................................................... 55 
 Interim Analyses ................................................................................. 55 
 Subgroup Analyses ............................................................................. 55 
 Pooling Analysis ................................................................................. 55 
 Multivariable Analyses ....................................................................... 55 
 Additional Analyses ............................................................................ 56 
 Changes to Planned Analyses ............................................................. 57 
 General Statistical Methods ........................................................................... 57 
 Analysis Sets ....................................................................................... 57 
 Control of Systematic Error/Bias ........................................................ 57 
 Number of Subjects per Investigative Site ......................................... 57 
12. DATA MANAGEMENT ................................................................................................. 57 
 Data Collection, Processing, and Review ...................................................... 57 
 Data Retention ................................................................................................. 58 
 Technical Source Forms ................................................................................. 58 
13. DEVIATIONS ................................................................................................................ 58 
14. COMPLIANCE .............................................................................................................. 59 
 Statement of Compliance ................................................................................ 59 
 Investigator Responsibilities .......................................................................... 59 
 Delegation of Responsibility .............................................................. 61 
 Ethics Committee ............................................................................................ 61 
 Sponsor Responsibilities ................................................................................. 61 
 Role of Boston Scientific Representatives ......................................... 62 
 Insurance .......................................................................................................... 63 
15. MONITORING .............................................................................................................. 63 
16. POTENTIAL RISKS AND BENEFITS ............................................................................. 63 
 Instructions for Use ......................................................................................... 63 
 Risks associated with Participation in the Clinical Study ........................... 63 
 Risk Minimization Actions ............................................................................. 63 
 Anticipated Benefits ........................................................................................ 63 
 Risk to Benefit Rationale, if applicable ......................................................... 64 
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17. SAFETY REPORTING ................................................................................................... 64 
 Reportable Events by investigational site to Boston Scientific ................... 64 
 Definitions and Classification ......................................................................... 65 
 Relationship to Device(s) ................................................................................ 66 
 Investigator Reporting Requirements ........................................................... 68 
 Boston Scientific Device Deficiencies ............................................................. 70 
 Reporting to Regulatory Authorities  / ECs / Investigators ........................ 70 
 Subject Death Reporting ................................................................................ 70 
18. INFORMED CONSENT .................................................................................................. 71 
19. COMMITTEES ............................................................................................................. 73 
 Safety Monitoring Process .............................................................................. 73 
 Steering Committee ......................................................................................... 73 
20. SUSPENSION OR TERMINATION .................................................................................. 73 
22.1 Premature Termination of the Study ............................................................ 73 
22.1.1 
Criteria for Premature Termination of the Study ................................ 73 
22.2 Termination of Study Participation by the Investigator or Withdrawal of 
EC Approval .................................................................................................... 73 
22.3 Requirements for Documentation and Subject Follow-up .......................... 74 
22.4 Criteria for Suspending/Terminating a Study Site ...................................... 74 
21. PUBLICATION POLICY ................................................................................................ 74 
22. BIBLIOGRAPHY ........................................................................................................... 75 
23. ABBREVIATIONS AND DEFINITIONS ........................................................................... 76 
 Abbreviations ................................................................................................... 76 
 Definitions ........................................................................................................ 77 
 
 
 Table of Figures 
Figure 1: Cryoablation Catheter Distal Tip ....................................................................... 20 
Figure 2:  Cryoablation Catheter Handle ........................................................................... 20 
Figure 3:  Mapping Catheter Assembly ............................................................................. 21 
Figure 4:  Cryo Mapping Catheter with Electrode Arrangements ..................................... 21 
Figure 5:  Cryo Console ..................................................................................................... 23 
Figure 6:  Diaphragm Movement Sensor (DMS) Data Cryo Console Display Phrenic Nerve 
Pacing Signal & Alert ..................................................................................... 24 
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Figure 7:  Esophagus Temperature Monitoring Data Display Phrenic Nerve Pacing Signal 
& Alert ............................................................................................................ 25 
 
 Table of Tables 
Table 5.1-1: Cryoablation System Components and Accessories ..................................... 19 
Table 5.1-2: Cryoablation Catheter Specifications ............................................................ 20 
Table 5.1-3: Cryoablation Catheter Specifications ............................................................ 21 
Table 5.1-4: Cryo Steerable Sheath Specifications ............................................................ 22 
Table 6.2-1 Overview of objectives and endpoints ........................................................... 29 
Table 8.2-1: Inclusion Criteria ........................................................................................... 32 
Table 8.3-1: Exclusion Criteria .......................................................................................... 33 
Table 10.1-1: Data Collection Schedule ............................................................................ 38 
Table 10.14-1: Source Documentation Requirements ....................................................... 51 
Table 17.2-1: Safety Definitions ........................................................................................ 65 
Table 17.3-1: Criteria for Assessing Relationship of Study Device or Procedure to Adverse 
Event ............................................................................................................... 67 
Table 17.4-1: Investigator reporting Requirements ........................................................... 69 
Table 23.1-1: Abbreviations .............................................................................................. 76 
Table 23.2-1 Definitions .................................................................................................... 77 
 
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4. Introduction 
 Background 
Atrial fibrillation (AF) is the most commonly encountered sustained cardiac arrhythmia in 
clinical practice (1). In the United States, the incidence of atrial fibrillation is estimated to 
increase from an estimated 2.66 million people in 2010 to as many as 12 million people by 
2050 (2). It is also estimated that the number of patients with AF in 2030 in Europe will be 
14–17 million and the number of new cases of AF per year at 120,000–215,000 (3). In 
addition, the prevalence and incidence of AF are increasing over time due to the aging of 
the population and a substantial increase in the age-specific occurrence of AF (4,5,6).   
AF causes symptoms that impair quality of life, increases the risk of stroke fivefold, and 
increases mortality (7).  
There are multiple therapies in current use for the treatment of AF. Treatment options 
include medical management, pacing, cardioversion, implantable devices, surgery, and 
ablation therapy to eliminate the arrhythmia (8,9). 
Currently, the most recent guidelines form the European Society of Cardiology for the 
management of AF state that catheter ablation of AF (10) is effective in restoring and 
maintaining sinus rhythm in patients with symptomatic paroxysmal, persistent, and 
probably long-standing persistent AF, in general as second-line treatment after failure of or 
intolerance to antiarrhythmic drug therapy. In particular, it has been increasingly 
recognized that focal pulmonary vein (PV) triggers of AF can account for 80 to 95 percent 
of paroxysmal cases that are drug resistant.  As outlined in the 2017 Heart Rhythm Society 
(HRS) consensus document (11), electrical isolation of the pulmonary veins is now 
recognized as the cornerstone of AF ablation. At most centers where AF ablation is 
performed, a strategy of creating a series of point-by-point radiofrequency lesions that 
encircle the PVs is used.  
Although great progress has been made in improving the techniques and outcomes of AF 
catheter ablation, many challenges remain. Two of the current limitations of atrial 
fibrillation ablation include the use of catheters designed for pinpoint lesions to perform 
large-area ablations in a point-by-point fashion and the dexterity required to perform such 
a lesion set.   
A cryoballoon system for treatment of AF is comprised of components that deliver 
cryogenic refrigerant in a controlled fashion, from a reservoir located in a console through 
a conduit accessory and into a treatment catheter. The treatment catheter has a balloon at 
its distal end that is delivered to a target location within the patient’s heart. Once the balloon 
is positioned in the antrum of the target PV, refrigerant is delivered to the balloon to extract 
heat from tissue in contact with the balloon.  By navigating the balloon to the ostium of the 
PV and occluding blood flow, a PV may be isolated with a single 3 to 4‐minute application 
of cryo‐energy.  
The currently approved cryoablation technology (Arctic Front™/ Arctic Front Advance™ 
Cryoablation Balloon, Medtronic®) has completed two studies demonstrating effective 
therapy for PAF management with approximately 70% and 65% efficacy respectively 
(12,13). In addition to these efficacy and safety results, the simplicity of the procedure and 
the ability for average skilled interventionalists to match the results of elite RF operators 
provides cardiologists with the means to address the fast‐growing patient numbers. Balloon 
catheter cryoablation therapy to treat Paroxysmal Atrial Fibrillation (PAF) has gained 
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significant utilization worldwide, with an estimated 370,000 procedures performed to date 
(12). 
Catheter and sheath performance for cryoablation balloon procedures has not changed since 
inception, more than ten years ago. Knowing that electrophysiologists are familiar with 
treating AF with cryo‐therapy, the Boston Scientific Cardiac Cryoablation System was 
designed with a clinical user focus and set out to improve the user experience. This was 
accomplished by improving balloon stability and achieving continuous inflation and 
uniform balloon pressure during all phases of the cryoablation, improving sheath 
maneuverability and incorporating general safety/ workflow improvements over current 
technology. 
Extensive pre‐clinical and performance bench testing studies have been performed to date. 
A first-in-man clinical study was completed on 30 patients with one month follow-up in 
2018 and its data has been used to obtain CE-mark. Additionally, data of up to 405 subjects 
who will undergo treatment with the Boston Scientific Cryoablation System for de-novo 
PAF are objective of the IDE trial that will enroll patients in the United States, Canada and 
in Asia. This study seeks to obtain approval for the Boston Scientific Cryoablation System 
in North America. The present study will provide post market data at support of continued 
safety and effectiveness assessment for the Cryoablation System, when used under standard 
of care in Europe. 
 
 Study Rationale 
The goal of any novel design or therapeutic strategy for AF is to restore normal sinus 
rhythm and to reduce or eliminate the symptoms due to rapid atrial response.  
Boston Scientific developed a Cryoablation Balloon that can maintain constant and stable 
pressure during the entire procedure. A cryoablation balloon that has been designed to 
maintain constant pressure is likely to provide improved stability during all phases of the 
cryoablation, improving user experience and preserving the proven design validated by the 
Medtronic® Arctic Front Advance™ Catheter.  
This post market clinical follow-up study intends to establish the continued safety and 
effectiveness profile of the Boston Scientific Cryoablation System when used in real-world 
settings in the treatment of atrial fibrillation. This may include repeated ablations to treat 
atrial fibrillation, concomitant or delayed adjunctive ablation strategies with other products 
and use of different diagnostic products to validate the results such as 3D mapping systems. 
 
5.  Device Description  
 Commercial Device  
 
The Boston Scientific Cardiac Cryoablation System (henceforth “Cryoablation System”) is 
indicated for cryoablation and electrical mapping of the pulmonary veins for pulmonary 
vein isolation (PVI) in the ablation treatment of atrial fibrillation (AF) as per current and 
future guidelines and system instructions for use.  
The components and accessories of the Cryoablation system and their associated model 
numbers are listed in Table 5.1-1.     
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Table 5.1-1: Cryoablation System Components and Accessories 
Component 
Model Number 
POLARx™ Cryoablation Catheter (Cryoablation Catheter) 
 
2315 (Short tip and 
long tip) 
 
SMARTFREEZE™ Console (Console) 
2314 
POLARMAP™ Catheter (Cryo Mapping Catheter) 
2317 (20mm) 
 
POLARSHEATH™ Steerable Sheath (Cryo Steerable Sheath) 
2316 
Accessories  
Diaphragm Movement Sensor (DMS) 
2314 
Inter Connection Box (ICB) 
2314 
Cryo-Console Foot Switch 
2314 
Cryo-Cable 
2318 
Cryo-Catheter Extension Cable 
2319 
EP Electrical Cable 
2320 
 
 Cryoablation Catheter (POLARx ™) 
The Cryoablation Catheter is a component of the Boston Scientific Cardiac Cryoablation 
System (“Cryoablation System”) and is a single use, flexible, over-the-wire balloon 
catheter used to ablate cardiac tissue. The Cryoablation Catheter is used in conjunction with 
the Console to induce thermal injury and endocardial tissue necrosis when the balloon is in 
contact with cardiac tissue and reaches cryoablation temperatures created by a refrigerant 
injected from the Console into the balloon segment of the POLARx™. The Cryoablation 
catheter connects to the Console with a Cryo-Cable (for N2O delivery and removal) and an 
Extension Cable (for electrical connection via the Interconnection Box). The Cryoablation 
catheter is designed to be used with a Cryo Mapping Catheter circular mapping catheter 
deployed within the guidewire lumen during ablation procedures.  
 
During an electrophysiology (EP) ablation procedure, the Cryoablation catheter (including 
the Cryo Mapping Catheter) is inserted through the Cryo Steerable Sheath 
(POLARSHEATH™) into the venous system, directed into the left atrium (LA) and 
towards the ostium of the target pulmonary vein (PV). Once positioning that occludes the 
PV has been verified, refrigerant is delivered through the Cryo-Cable to the injection coil, 
which directs the flow of refrigerant toward the interior distal surface of the  balloon. This 
results in a cooled region at the balloon tissue interface, which adheres to the endocardial 
surface. The low temperature and pressure gradient allows the  balloon to thermally create 
transmural, circumferential tissue necrosis (lesions) and interrupt electrical conduction.  
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The Cryoablation Catheter is comprised of the following major components, distal to 
proximal:  
• Atraumatic tip  
• Double layer balloon system  
• Guide wire lumen  
• Internal balloon thermocouple  
• Injection coil and manifold for delivery of the refrigerant; liquid nitrous oxide 
(N2O)  
• Catheter shaft; to retrieve the expanded N2O gas  
• Catheter handle  
• Distal handle connections  
 
 
Figure 1: Cryoablation Catheter Distal Tip 
 
Figure 2:  Cryoablation Catheter Handle 
 
 
 
 
  
  
  
 
 
 
 
 
 
 Cryo Mapping Catheter 
The Cryo Mapping Catheter is a single-use, sterile, multi-electrode, diagnostic catheter 
designed to map cardiac signals during ablation procedures. The catheter is provided in a 
20mm diameter with 8 evenly spaced radiopaque electrodes. The proximal end of the 
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handle contains an electrical connection that integrates with EP lab recording systems.  
Once deployed through the central guidewire lumen of the Cryoablation Catheter and into 
the pulmonary vein (PV), a circular shape is established such that the electrodes contact the 
endocardial surface. This allows for recording and interrogation of electrical conduction 
between the LA and the pulmonary veins. The Cryo Mapping Catheter also allows for 
delivery of pacing stimuli used in the interpretation of PV isolation (PVI).   
 
Figure 3:  Mapping Catheter Assembly 
 
 
Figure 4:  Cryo Mapping Catheter with Electrode Arrangements 
 
 
 
Table 5.1-3: Cryoablation Catheter Specifications 
 
 
 
 
 
 
 
 Cryo Steerable Sheath 
The Cryo Steerable Sheath is a single use, disposable, steerable percutaneous introducer 
sheath designed for additional maneuverability of standard catheters that are advanced 
through the sheath and into cardiac chambers.  It is comprised of a composite structured 
single lumen shaft, an ergonomic handle to provide torque and active deflection, and a 
hemostasis valve to allow safe introduction, withdrawal, and swapping of catheters and 
wires while preventing air ingress and minimizing blood loss. A side-port is integrated to 
allow continuous drip infusion, injection through the center lumen, flushing, aspiration, 
blood sampling and pressure monitoring. 
 
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As a component of the Cryoablation System, the Cryo Steerable Sheath is intended to 
facilitate the placement of diagnostic and/or therapeutic intracardiac devices during 
percutaneous catheter ablation procedures. The device is indicated for left-sided cardiac 
procedures via a transseptal approach. 
 
 
Table 5.1-4: Cryo Steerable Sheath Specifications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Console 
The Console is a device that uses N2O provided from a refillable cylinder to safely 
pressurize (inflate) and cool the Cryoablation Catheter to cryogenic ablative temperatures. 
The Console houses the electrical components and software/firmware needed to perform 
cryoablation procedures. It controls the delivery, recovery, and disposal of N2O 
(cryoablation refrigerant) safely and efficiently. The Console user interface provides a 
means for initiating and ceasing refrigerant delivery. Once the command is received from 
the console, N2O is delivered as a chilled liquid to the Cryoablation Catheter for a 
programmable time duration.  The user interface also displays key information allowing 
the operator to focus attention on critical tasks and speed up the overall procedure. 
 
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Figure 5:  Cryo Console 
 
Integration between the Cryoablation Catheter and the Console includes monitoring 
catheter as well as console functionality, aided by a number of components such as: power 
cords, extension cables, inter connection box, foot switch, diaphragm movement sensor, 
esophageal temperature monitor, scavenging hose, wrench and nitrous oxide tanks.   
 
 Diaphragm Movement Sensor 
The Diaphragm Movement Sensor (DMS) is a patch device placed on the patient just 
below the costal cartilage on the right side and used to monitor a phrenic nerve pacing 
response. It is connected to the Inter Connection Box (ICB) sending data to be displayed 
on the user interface of the Console. By integrating the information into the Cryo Console, 
the user can be informed when the measured pacing response is lower than a pre-determined 
value set by the physician. 
 
Phrenic nerve monitoring is a known and essential component in determining safety during 
a cryoablation procedure. The current standard-of-care technique which is used to monitor 
for phrenic nerve palsy is to have the physician place his/her hand on the subject’s abdomen 
and assess the subject’s diaphragmatic movement during the period within the procedure 
that requires the physician’s full attention (when ablation is occurring). 
It has been reported with cryoablation balloon technology that the incidence of permanent 
phrenic nerve injury  occurs in up to 0.4% of the cases (10) of patients undergoing a 
cryoablation procedure. The physician subjectively decides when injury may be occurring 
based on the change in diaphragmatic movement during respiration. The physician 
suspends ablation if there is a significant reduction in diaphragmatic movement. This is a 
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manual and physician dependent technique where the incidence of occurrence is related to 
experience in the cryoablation procedure. 
 
An accelerometer in the DMS detects any reduction of diaphragmatic movement indicating 
phrenic nerve impact, thus helping to reduce procedure related adverse events and 
potentially improve procedural safety. The DMS is connected to the ICB of the Cryo-
Console and sends data to be displayed on the Cryo-Console’s user interface (see Figure 6 
below). 
 
 
Figure 6:  Diaphragm Movement Sensor (DMS) Data Cryo Console Display Phrenic 
Nerve Pacing Signal & Alert 
 
 
By integrating the information into the Console, the physician can be informed when the 
measured pacing response falls below a pre-set value. The pre-determined value is 
programmed by the physician. The value is displayed as a percentage; with the first physical 
excursion establishing the baseline at 100%. The measurement display changes from 
“Blue” to “Red” if the value falls below the physician’s programmed pre-set value (see 
Figure 6 above). 
 
The DMS is designed to be used as an adjunct accessory to continually evaluate diaphragm 
movement during ablation; as a reminder alert to augment the established clinical practice 
described above for phrenic nerve assessment. The DMS is not a substitute for physician 
standard practice of phrenic nerve assessment during a cryoablation; i.e. physician 
palpation of the diaphragm, or attentive medical practice.  
 
 Esophageal temperature monitoring 
Esophageal temperature monitoring is a frequently used technique, especially  when there 
is an anatomical concern related to the proximity of the esophagus to the inferior pulmonary 
veins and posterior wall of the Left Atrium (LA). The esophageal ulceration is generally 
reversible, with a reported incidence of 17% of patients (10). 
 
This feature integrates the detection of the esophageal temperature and provides a reminder 
alert to the physician if the esophageal temperature goes below a physician pre-set value. 
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The measured esophageal temperature turns the measurement display from “Blue” to “Red” 
if the temperature probe falls below a physician pre-set value. This feature potentially 
reduces adverse events such as esophageal ulcerations and fistulas. This is a optional safety 
alert system to the measurement systems used today although the alert is now displayed on 
the Console. 
 
 
Figure 7:  Esophagus Temperature Monitoring Data Display Phrenic Nerve Pacing 
Signal & Alert 
 
As noted below, the ICB is designed to receive information from other proprietary devices 
such as an esophageal temperature probe. When connected, the esophageal temperature 
probe provides monitoring and alert data to the console for display. Esophageal temperature 
probes are widely available in stand-alone measurement systems and used as such within 
the EP lab. The Cryterion Medical Esophageal Temperature Sensor Cable enables the 
connection of a commercially available 400 series temperature probe (for example, Truer 
Medical 400 Series General Purpose Probes and DeRoyal Temperature Monitoring, 
Product No. 81-020409) to be connected to the Console 
 Other Cryoablation System Components 
5.1.7.1. Inter Connection Box (ICB) 
The ICB interfaces the Cryoablation Catheter with the Console. It receives the Catheter 
monitoring signals, DMS data, as well as information from other proprietary devices such 
as an esophageal temperature probe, a tip pressure sensor and various other safety systems.  
The ICB then transmits this information to the Console for display and user analysis. 
5.1.7.2. Console Foot Switch 
The Console Foot Switch interfaces with the Console and allows the user to inflate the 
Cryoablation Catheter, start and stop flow of N2O (cryoablation) as well as deflate the 
Cryoablation Catheter at the conclusion of the ablation. 
5.1.7.3. Console Scavenging Hose 
The Console Scavenging Hose is a flexible N2O exhaust line that connects to the hospital 
gas scavenging system and allows removal of N2O gas. 
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5.1.7.4. Cryo Cable 
The Cryo Cable is a sterile, single-use cable that provides the connectivity between the 
Cryoablation Catheter to the Console to support the delivery of liquid refrigerant and the 
evacuation of remaining N2O gas.  
5.1.7.5. Cryoablation Catheter Electrical Cable 
The Cryoablation Catheter Electrical Cable is a sterile, single-use cable that provides the 
connectivity between the Cryoablation Catheter and the Console ICB.  
5.1.7.6. Cryo Mapping Catheter EP Electrical Cables 
The EP Electrical Cable is a sterile, single-use accessory for the Cryo Mapping Catheter 
and is designed to interface (connect) the Cryo Mapping Catheter with standard EP 
recording systems.  
 
6. Study Objectives and Endpoints 
 Study Objective 
This is a Post Market Clinical Follow-up (PMCF) study designed to establish the continued 
safety and effectiveness profile of the Cryoablation System after receiving CE mark.  
The study will also provide information on real-world usage of the Cryoablation System 
when used to perform pulmonary vein isolation (PVI) for the ablation treatment of atrial 
fibrillation (AF), according to the current and future guidelines and system indications for 
use. 
This may include (but not limited to) repeated ablations to treat AF, concomitant or delayed 
adjunctive ablation strategies with other products and use of different diagnostic products 
to validate the results such as 3D mapping systems. 
 
Collected information and analyses will include, but not limited to, the following: 
• Arrhythmia characterisation at the time of enrollment: time since first AF diagnosis, 
number and duration of reported episodes, prior electrical cardioversions (if any);  
• History of prior ablations and repeated ablations during follow-up period;  
• Use of anti-arrhythmic drugs (AAD); 
• Methods used for verification of procedure success (pulmonary vein isolation): 
entrance/exit block, adenosine (if used), use of three-dimensional (3D) mapping. 
 
 Study Endpoints 
 Primary Safety Endpoint 
The primary safety endpoint will be evaluated by the safety event free rate at 12 months 
post-index procedure.  
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Primary safety events will consist of a composite of the following procedure-related and 
device-related adverse events.  
Acute primary safety endpoint events, events occurring up to 7 days post-index procedure 
or hospital discharge, whichever is later, include:  
• 
Death 
• 
Myocardial infarction (MI) 
• 
Persistent gastroparesis/injury to vagus nerve 
• 
Transient ischemic attack (TIA) 
• 
Stroke/Cerebrovascular accident (CVA) 
• 
Thromboembolism/ Air embolism* 
• 
Cardiac tamponade/perforation 
• 
Pneumothorax 
• 
Serious vascular access complications** 
• 
Pulmonary edema/heart failure 
• 
AV block not attributable to medication effect or vasovagal reaction 
 
*Thromboembolic or air embolic events collected in the study refer to any occlusion of blood vessel(s) that 
results in clinical symptoms  
** Defined as prolongation of hospitalization, requirement of surgical intervention or blood transfusion 
 
 
Chronic primary safety endpoint events, events occurring through 12 months post-index 
procedure, include: 
• 
Atrial esophageal fistula 
• 
Pulmonary vein stenosis (≥ 70% reduction of diameter) 
• 
Symptomatic pericardial effusion  
• 
Persistent Phrenic nerve injury*** 
 
***A non-recovered phrenic nerve injury at 12 months post-index procedure will count as a chronic primary 
endpoint. The study will collect information on phrenic nerve palsy observed before the end of the index 
procedure and, in case it occurred, will track information for potential recovery during the study visits. 
 
 Primary Effectiveness Endpoint 
Failure free rate at 12 months post-index procedure.  
 
Failure defined as: 
• 
Failure to achieve acute procedural success* in the index procedure;  
• 
More than one repeat procedure during the blanking period (within 90 days 
post-index procedure); 
• 
Documented atrial fibrillation, or new onset of atrial flutter or atrial 
tachycardia event (≥ 30 seconds in duration or from a 10 second 12-lead 
ECG) between days 91 and days 365 post-index procedure**; 
• 
Any of the following interventions for atrial fibrillation, or new onset of 
atrial flutter or atrial tachycardia between days 91and days 365 post-index 
procedure: 
• 
Repeat procedure; 
• 
Electrical and/or pharmacological cardioversion for AF/AFL/AT; 
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• 
Prescribed a higher dose of any AAD*** documented at baseline or 
a new AAD*** not documented at baseline.  
 
*Acute procedural success is defined as isolation of the all pulmonary veins or anatomical equivalents 
achieved with the Cryoablation Catheter at the end of the index procedure and as demonstrated at minimum 
by entrance block using the Cryo Mapping Catheter (Other techniques of assessment are per investigator’s 
discretion).   
**Subjects will be monitored for recurrences of the arrhythmias by means of clinical visits, ECG and 24-hour 
Holter monitoring. Recurrences documented with other devices only (eg. ILR, PM, ICD, CRT) will not be 
counted as primary effectiveness endpoint events. 
***AADs for endpoint will consist of all Class I/III and any Class II/IV medications taken for control of 
AF/AFL/AT recurrence 
 Secondary Effectiveness Endpoint 
Documentation and rate of acute procedural success (definition see section 6.2.2.). 
Electrical isolation of a PV is demonstrated at minimum by entrance block using the Cryo 
Mapping Catheter (Other techniques of assessment are per investigator’s discretion). 
Information on isolation method used per site standard of care will be collected with a 
minimum by entrance block in all PVs or anatomical equivalents. Additional data, if 
available, will be collected on Exit Block or Conduction Block verification using 3D 
mapping. 
 Additional analyses 
Additional analyses include, but are not limited to:  
• Procedure times: LA dwell time*, total ablation time, number of cryo applications 
per vein, time to thaw, total fluoroscopy time and total procedure time;  
• Time-To- Isolation per ablation application, if available; 
• Freedom from recurrence of individual types of atrial arrhythmias (AF, AFL, AT) 
between days 91 and days 365 post-index procedure; 
• Analysis of ablation techniques (i.e. segmental approach to left common trunk, 
additional linear ablations, etc.); 
• Analysis of different anaesthesia techniques (General anaesthesia with or without 
intubation versus sedation) 
• Freedom from recurrence in subjects with non-common anatomical configurations 
of PV (e.g. left common trunk); 
• Freedom from primary effectiveness failure evaluated in subgroups of subjects 
(termination of AAD versus continuation of AAD after blanking period);  
• For the subgroup of subjects undergoing 3D mapping with the Boston Scientific 
mapping Rhythmia system and performing a post-procedural map, map 
information will be collected to determine lesion locations; 
• For subjects that will undergo repeat ablation during the course of the clinical 
follow-up, anatomical location of ablations gaps will be assessed. 
*LA dwell time is defined as time from the Cryoablation Catheter introduced in the left atrium (LA) to the 
last time of Cryoablation Catheter exiting the LA. 
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Table 6.2-1 Overview of objectives and endpoints 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
Establish the continued safety 
of the Cryoablation System 
Event free rate of a composite of 
procedure and device (acute (7 
days) and chronic (12 month 
follow-up)) study specific adverse 
events 
List of events were selected 
from those typically associated 
with catheter ablation of AF 
Establish the effectiveness of 
the Cryoablation System 
Failure- free rate at 12 months 
including failure to achieve success 
at index or repeat procedure in 
blanking 
period, 
documented 
AF/AT/AFL or interventions to 
treat 
these 
arrhythmias 
after 
blanking period, including repeated 
procedures 
cardioversion 
or 
prescription of new anti-arrhythmic 
drugs (or higher dose)  
Performance goal and expected 
rates calculated from pivotal 
studies on AF ablation 
Secondary 
Acute procedural success  
Success of procedure (PVI) 
Component of the primary 
effectiveness endpoint 
Safety endpoint analysis for 
subgroups (PVI only vs PVI+ 
additional techniques) 
Same as primary Safety endpoint 
definition, evaluated in specific 
sub-groups (non powered) 
Additional ablations after PVI 
with other devices are common 
in standard of care due to non-
PV triggers of AF in some 
subjects.  
Additional 
Procedure-related times 
LA dwell time, ablation time, 
number of cryo applications per 
vein, total fluoroscopy time, total 
procedure time, time to isolation (if 
available) 
To relate with published data on 
other AF ablation devices 
Single procedure success 
Rate 
of 
subjects 
free 
from 
AF/AT/AFL undergoing the index 
procedure ablation only 
To assess success rate in 
subjects who do not  undergo a 
repeated 
ablation 
during 
blanking period 
Approach 
to 
uncommon 
anatomies 
Analysis of ablation techniques (i.e. 
segmental) and freedom from 
recurrence in subjects with non-
common anatomical configurations 
of PV 
Over 10 years’ experience with 
the cryoballoon ablation made 
site able to treat subjects with 
peculiar 
anatomical 
PV 
configurations. This study wants 
to collect rate and outcome for 
this subgroup 
 
7. Study Design 
Prospective, non-randomized, multicenter (international), single arm study. 
All subjects signing the consent, undergoing the index procedure and treated with the study 
devices will be followed up for one year.  
 
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 Scale and Duration 
Approximately 25 sites in Europe and Middle East will be included in the study. 
A minimum of 200 subjects (with the possibility to expand up to a maximum of 400 
subjects) will be enrolled in the study. A minimum of 199 subjects with De Novo treatment 
(i.e. first treatment for AF in the left atrium) for paroxysmal atrial fibrillation (PAF) will 
be analyzed to establish the continued safety and effectiveness profile of the Cryoablation 
System and fulfill the PMCF requirements for the submitted labeling of the Cryoablation 
System. This number represents the minimum number for the primary endpoint statistical 
hypothesis testing.  
The entire study cohort will provide information on real-world usage of the Cryoablation 
System and will be analyzed for secondary objectives. These will include subgroup analysis 
in selected subjects of interest (including (but not limited to) De Novo ablation versus 
repeated ablations). These analyses will be non-powered but in case some of these 
subgroups will be poorly represented in the study, Boston Scientific may propose in the 
future to extend the sample size to up to 400 subjects. 
 
Each subject will be followed at specific time points after the index procedure:  pre-
discharge, at 3 months (blanking period), 6 months and 12 months post-index procedure. 
Therefore, the study duration for each subject is expected to be approximately 12 months. 
Subjects will be monitored for recurrences of the arrhythmias by means of clinical visits, 
ECG and 24-hour Holter monitoring. 
 
Study enrollment is expected to be completed in approximately 12 months. Therefore, the 
total study duration is estimated to be approximately 24 months. 
 
 Treatment Assignment 
Any subject who signs the consent form will be considered enrolled in the study. 
Any subject that signs the consent form, has the study device inserted into the body and 
undergoes the protocol specific treatment for the intended disease (cryoablation) will be 
assigned to the treatment group. 
Enrollment will progress until reaching a minimum of 200 subjects and a maximum of 400 
subjects. A minimum of 199 De Novo (ie. first treatment for AF in the left atrium) 
TREATMENT subjects with PAF is needed for the assessment of the primary endpoint 
statistical hypothesis testing (section 11.1).   
  
 Justification for the Study Design 
Boston Scientific believes that a prospective study on AF treatment with the Cryoablation 
System device powered for standard safety and effectiveness objective performance criteria 
is adequate for supporting post market requirements for the assessment of the continued 
safety and effectiveness of the device after market release in CE mark regions.  
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According to the most recent guidelines (11) catheter ablation has deemed effective in 
restoring and maintaining sinus rhythm in subjects with atrial fibrillation. The current study 
design ensures that the minimal number of subjects with De Novo PAF is reached to ensure 
testing of the statistical hypothesis and enroll a sufficient number of subjects to  allow 
analysis on real-world usage of the Cryoablation System. 
In the context of catheter ablation of AF, adjunctive ablation strategies to PV isolation are 
currently recommended by clinical guidelines (10) in different conditions including: Cavo-
Tricuspid Isthmus ablation, linear ablation lesions in the left atrium or focal ablation of 
reproducible triggers. These adjunctive strategies can be applied with commercial 
focal/linear catheters either during a PV isolation procedure or during a repeated procedure, 
according to site standard of care. 
Therefore, the heterogeneous scenarios that an electrophysiologist may encounter when 
approaching a subject with AF and candidate for catheter ablation could lead to different 
choices during the procedure.  
Accordingly, this study will collect data on instance that may include concomitant or 
delayed adjunctive ablation strategies with other products and use of different diagnostic 
products to validate the results such as 3D mapping systems. 
 
 
8. Subject Selection  
 Study Population and Eligibility  
Subjects enrolled in the POLAR ICE study will be clinically indicated for an ablation 
procedure for the treatment of atrial fibrillation according to current and future guidelines 
and system indications for use. Subjects have to meet the study inclusion/exclusion criteria 
as outlined below in section 8.2 and 8.3. The subjects selected for participation will be from 
the investigator’s general subject population. The investigator or its designee has the 
responsibility for screening all potential subjects and selecting those who meet study 
eligibility criteria. 
 
 Inclusion Criteria 
Subjects who meet all of the following criteria (see Table 8.2-1) may be given consideration 
for inclusion in this clinical study, provided no exclusion criterion (see Table 8.3-1) is met.  
 
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Table 8.2-1: Inclusion Criteria 
Inclusion 
Criteria 
1. Subjects indicated for the treatment of AF with the Cryoablation 
System according to current and future Guidelines and system 
indications for use; 
 
2. Subjects who are willing and capable of providing informed 
consent;  
3. Subjects who are willing and capable of participating in all 
testing associated with this clinical study at an approved clinical 
investigational center; 
4. Subjects whose age is 18 years or above, or who are of legal age 
to give informed consent specific to state and national law. 
 
 
 Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 8.3-1) cannot be included in 
this study or will be excluded from this clinical study. 
 
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Table 8.3-1: Exclusion Criteria 
Exclusion 
Criteria 
1. Any known contraindication to an AF ablation or anticoagulation, including 
those listed in the instructions for use; 
2. Subjects with indication for treatment of AF that is not according to current and 
future Guidelines and system indications for use; 
3. Atrial fibrillation secondary to electrolyte imbalance, thyroid disease, or any 
other reversible or non-cardiac cause; 
4. Known or pre-existing severe Pulmonary Vein Stenosis; 
 
5. Evidence of myxoma, LA thrombus or intracardiac mural thrombus; 
6. Previous cardiac surgery (e.g. ventriculotomy or atriotomy, CABG, PTCA, 
stent procedure) within 90 days prior to enrollment; 
7. Implantable cardiac device procedure (e.g. PM, ICD, CRT) within 30 days 
prior to enrollment; 
8. Implanted Left Atrial Appendage Closure device prior to the index 
procedure 
9. Interatrial baffle, closure device, patch, or patent foramen ovale (PFO) occluder; 
10. Subjects with severe valvular disease OR  with a prosthetic – mechanical or 
biological - heart valve (not including valve repair and annular rings); 
 
11. Presence of any pulmonary vein stents; 
12. Active systemic infection; 
13. Vena cava embolic protection filter devices and/ or known femoral 
thrombus; 
14. Any previous history of cryoglobulinemia; 
15. History of blood clotting or bleeding disease; 
16. Any prior history of documented cerebral infarct, TIA or systemic embolism 
(excluding a post-operative deep vein thrombosis (DVT)) ≤ 180 days prior to 
enrollment; 
17. Subjects who are hemodynamically unstable; 
18. The subject is unable or not willing to complete follow-up visits and 
examination for the duration of the study; 
 
19. Life expectancy ≤ 1 year per investigator’s opinion; 
 
20. Women of childbearing potential who are, or plan to become, pregnant during 
the time of the study (method of assessment upon investigator’s discretion); 
 
21. Unrecovered/unresolved Adverse Events from any previous invasive 
Procedure; 
 
22. Subjects who are currently enrolled in another investigational study or registry 
that would directly interfere with the current study, except when the subject is 
participating in a mandatory governmental registry, or a purely observational 
registry with no associated treatments; each instance must be brought to the 
attention of the sponsor to determine eligibility. 
 
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9. Subject Accountability 
 Point of Enrollment 
Investigators will select subjects who are appropriate for study inclusion as per eligibility 
criteria as specified under section 8.2 and 8.3. Subjects who have given written informed 
consent are considered enrolled in the study. All enrolled subjects will be counted against 
the enrollment ceiling of maximum 400 subjects. A total of 199 De Novo TREATMENT 
subjects with paroxysmal atrial fibrillation will serve for PMCF reporting purposes. No 
study-related activities, testing, procedures, etc. can take place until the Informed Consent 
Form (ICF) is signed and dated by the subject. Screening tests that are part of standard of 
care can be used to determine pre-eligibility. Data from exams performed prior to 
consent/enrollment (e.g. TTE) will be collected as medical history data after the subject is 
consented/enrolled in the study. It is the investigator’s site responsibility to assess eligibility 
criteria before obtaining the Informed Consent Form. 
 Withdrawal 
All subjects enrolled in the clinical study (including those withdrawn from the clinical 
study) shall be accounted for and documented. If a subject withdraws from the clinical 
study, the reason(s) shall be reported. Withdrawn subjects will not be replaced. 
 
Reasons for withdrawal include but are not limited to physician discretion, subject choice 
to withdraw consent, lost to follow-up, or death. While study withdrawal is discouraged, 
subjects may withdraw from the study at any time, with or without reason, and without 
prejudice to further treatment. All applicable case report forms up to the point of subject 
withdrawal and a “End of Study” form must be completed.   
Every effort should be made to obtain full information on any ongoing reportable adverse 
events up to the point of withdrawal. All open reportable adverse events should be closed 
or documented as chronic. Data collected up to the point of subject withdrawal may be 
used, unless any local regulations apply. Additional data may no longer be collected after 
the point at which a subject has been withdrawn from the study or withdraws his/her 
consent, for whatever reason. If such withdrawal is due to problems related to device safety 
or performance, the investigator shall ask for the subject’s permission to follow his/her 
status/condition.  
 
 Lost to Follow-Up 
A subject will be considered lost to follow-up if he/she fails to return to scheduled visits as 
per Data Collection Schedule (Table 10.1-1), and is unable to be contacted by the study site 
staff. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the subject to reschedule the missed visit and counsel 
the subject on the importance of maintaining the assigned visit schedule and 
ascertain if the subject wishes to and/or should continue in the study. 
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• Before a subject is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the subject (3 attempts, including telephone calls 
and/or a certified letter to the participant’s last known mailing address or local 
equivalent methods, where possible). These contact attempts must be documented 
in the subject’s medical record or study file and in the “End of Study” eCRFs.  
• Should the subject continue to be unreachable, he or she will be considered lost to 
follow-up from the study. 
 
 Subject Status and Classification 
Consent Ineligible (Screening Failures) 
A subject who has given written informed consent but is found not to meet eligibility 
criteria before undergoing the index procedure and before having the study device inserted 
in the body, will be classified as “Consent Ineligible”.  
Subjects determined to be Consent Ineligible count towards the enrollment ceiling but will 
not be used for analysis of the endpoints. The original signed and dated Informed Consent 
must be maintained in the center’s subject file. A subject identification number (ID) will 
be assigned in the EDC system.  
For consent ineligible subjects, at the minimum the following forms must be completed: 
• Enrollment eCRFs; 
• Adverse Event eCRFs for any reportable event (as defined in section 17) that 
occurs after signing the Informed Consent, up to the point of subject withdrawal; 
• Protocol Deviation eCRF, if applicable; 
• End of Study eCRF. 
 
 
Intent 
A subject who has given written informed consent, meets eligibility criteria, but does not 
have any study devices inserted into the body will be classified as “INTENT”. This includes 
subjects that had been prepared for the procedure (e.g. medication administered) and/or 
who had non-study devices inserted into the body. Subjects that are enrolled in the study 
but do not undergo ablation procedure within 90 days from consent signature date must not 
be reconsented and will be withdrawn from the study and classified as “INTENT”. These 
subjects won’t be allowed to be re-enrolled in the study. 
There are no follow-up requirements for Intent subjects. Intent subjects will count towards 
the enrollment ceiling but will not be used for analysis of the endpoints. The original signed 
Informed Consent must be maintained in the center’s subject file. A subject ID will be 
assigned in the EDC system.  
For intent subjects, at the minimum the following forms must be completed:  
• Enrollment and Baseline eCRFs; 
• Adverse Event eCRFs for any reportable event (as defined in section 17) that 
occurs after signing the Informed Consent, up to the point of subject withdrawal; 
• Protocol Deviation eCRF, if applicable; 
• End of Study eCRF. 
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Attempt 
A subject who has given written informed consent, and has any study device inserted into 
the body but does not receive any Cryoablation application will be classified as 
“ATTEMPT.” Attempts subjects will count towards the enrollment ceiling and will be used 
for analysis of the endpoints as per section 11.3.1. The original signed Informed Consent 
must be maintained in the center’s subject file. A subject ID will be assigned in the EDC 
system. These subjects won’t be allowed to be re-enrolled in the study. 
Attempt subjects will be followed up to 7 days after index procedure or until discharge, 
whichever is later, for safety purposes. All applicable case report forms in the EDC system 
will be completed. The original signed Informed Consent and any relevant documentation 
must be maintained in the center’s subject file.  
 
For attempt subjects, at the minimum the following forms must be completed:  
• Enrollment and Baseline eCRFs; 
• Index Procedure eCRFs; 
• Pre-Discharge eCRFs and Day 7 follow-up contact eCRF (if applicable); 
• Adverse Event eCRFs or Device Deficiency eCRF for any reportable event (as 
defined in section 17) that occurs after signing the Informed Consent, up to the point 
of subject withdrawal; 
• Protocol Deviation eCRF, if applicable; 
• End of study eCRF. 
 
Treatment 
Any subject who has given written informed consent and has the specified study device 
inserted into the body and received at least one Cryoablation application will be classified 
as “TREATMENT”. These subjects are followed in accordance with the Data Collection 
Schedule (Table 10.1-1) and included in all study analyses. A subject ID will be assigned 
in the EDC system. For TREATMENT subjects, all applicable case report forms per the 
protocol will be completed. Treatment subjects do count towards the enrollment ceiling and 
will be used for analyses of the endpoints. The original signed Informed Consent and any 
relevant documentation must be maintained in the center’s subject file. 
 
 End-of-Study Definition  
The clinical study is considered completed when subjects are no longer being examined or 
the last subject’s last study visit has occurred. The subject’s end of study is defined as 
completion of the last visit or procedure as shown in the Data Collection Schedule (Table 
10.1-1) in the study.  
 
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10. Study Methods 
  Data Collection 
Each Treatment subject will be followed at index procedure, at pre-discharge visit, at the 
month 3 follow-up, month 6 follow-up and month 12 follow-up. To reliably capture subject 
status at study end, the month 12 follow-up must be scheduled within 365 ± 30 days 
following the index procedure. The data collection schedule is shown in Data Collection 
Schedule (Table 10.1-1).
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Table 10.1-1: Data Collection Schedule 
Procedure / 
Assessment 
Enrollment 
Baseline 
Index 
Procedure 
(Day 0) 
Blanking period 
Effectiveness Evaluation period 
Repeat 
(additional) 
ablation 
procedure 
Pre-
Discharge 
(0-7 days post 
procedure) 
Day 7 
contact 4 
(day 7 + 7 
days) 
Month 3 
Follow-Up 
(91±14 days) 
Month 6 
Follow-Up 
(180±30 
days) 
Month 12 
Follow-Up 
(365±30 days) 
Additional 
Follow-up 
Informed consent 
process, including 
informed consent 
signature date 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
LVEF, LA diameter 
and LA volume 
X1 
 
 
 
 
 
 
 
 
Physical assessment 
X 
 
X 
 
X 
X 
X 
(X) 
 
LA assessment3 
imaging and 
thrombus assessment 
(X)2 
 
 
 
 
 
 
(X)2 
Procedural Data 
 
X 
 
 
 
 
 
 
X 
3D Mapping 
information 
 
(X) 
 
 
 
 
 
 
(X) 
12-Lead ECG 
X 
X 
X 
 
X 
X 
X 
(X) 
X 
Holter Monitor (24 
hours) 6 
 
 
 
 
(X) 
X 
X 
(X) 
 
Documentation of 
intervention for 
AF/AT/AFL (if any) 
 
 
X 
 
X 
X 
X 
(X) 
 
Medications 
X 
X 
X 
 
X 
X 
X 
(X) 
X 
Protocol Deviations 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Adverse Event 
Assessment 
X5 
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X: Required; (X): Optional, per site standard of care;  
1 Per investigator’s method. It is recommended to have the assessment within 180 days prior to enrollment;   
2  Assessment of left atrium anatomy, pulmonary veins anatomy and rule-out presence of thrombus is strongly recommended and to be performed according to site’s standard of care 
practice - Assessments can be performed using CT, MRI, pulmonary venogram, ICE, TEE or other;  
3 It is recommended to have the LA assessment performed within 180 days prior to enrollment; 
4 If subject is discharged prior to day 7 post-index procedure, a (telephone) contact at day 7 (+ 7 days) is  required to assess any post-discharge adverse events and complications;  
5 Adverse event assessment will be performed as from enrollment until study completion;  
6 A 24H Holter monitor is required at 6 and 12 months follow-up for all subjects.  
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 Study Candidate Screening 
Investigators are responsible for screening all subjects and selecting those subjects who are 
appropriate for study inclusion, as per eligibility criteria (see section 8). 
The subjects selected for participation should be from the investigator’s general subject 
population. The investigator is expected to follow standard of care testing to diagnose and 
screen subjects for inclusion in the study. 
Prior to have any study related activities performed, subjects must give written informed 
consent to the study, as per section 10.3 and section 18. 
 Enrollment and Informed Consent 
Subjects who provide written informed consent are considered enrolled in the study. As 
soon as informed consent is obtained, subject’s eligibility criteria can be determined. 
Therefore, the investigator or designee needs to implement the consent process to verify 
and document if the subject meets the eligibility criteria. Informed consent is required for 
all subjects prior to their participation in the study. No study-specific procedures can be 
conducted prior to consent.  
The subject should be given ample time to consider participation and ask questions if 
necessary. An approved informed consent form (ICF) shall be signed and dated by the 
subject or legally authorized representative. The original, signed document is to be kept 
with the subject’s file and a copy must be provided to the subject.  The index procedure 
must be performed within 90 days post ICF signature. In case the index procedure has not 
been performed within this time period, the subject will be classified as Intent (see section 
9.4). The intent subject cannot be considered for re-enrollment as re-enrollment is not 
allowed for any subjects in this study. The site will ensure that originally signed ICFs and 
documentation of the ICF signature process are filed in subjects’ files and that the subject’s 
participation into the study is documented per hospital process (e.g.in the medical file). 
Originally signed ICFs and the ICF process documentation will be made available for 
review at Monitoring Visits. 
For additional information regarding the informed consent process, refer to section 18. 
 
 Baseline Visit 
The following assessments must be performed during the baseline visit. These assessments 
shall be recorded on the respective eCRF. 
• Visit date; 
• Documentation of Informed Consent process, including Informed Consent Form 
signature date; 
• Eligibility criteria check; 
• Demographics – including age at time of consent, gender, race, ethnicity; 
• Medical history – including, but not limited to: 
o Underlying Cardiovascular disease (if any) and history of cardiac events; 
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o Arrhythmia history; 
o Non-cardiac comorbidities; 
o Prior surgical interventions and/or cardiac procedures; 
• LVEF, left atrial diameter, left atrial volume (if available), as per investigator's method. 
It is recommended to have the assessment within 180 days prior to enrollment 
• Physical Assessment – including height, weight, resting heart rate, systolic and diastolic 
blood pressure; 
• Rhythm at the time of the visit (via 12-lead ECG); 
• Current Anti-Arrhythmic Drugs and Anticoagulation medication regimen.  
 
The assessment of LA anatomy* and the screening for potential LA thrombi prior to the 
procedure is strongly recommended to be performed according to the site’s standard of care 
practice, however it is recommended to follow the indications from the HRS consensus 
statement for AF ablation (11).  
This includes: 
• Cardiac MRI, spiral CT scan, TEE, ICE or pulmonary venogram, to assess PV 
anatomy and PV dimension.  
• Cardiac examination (TEE or ICE preferred) to rule out presence of left atrial 
thrombus**. 
*It is recommended to perform the LA anatomy assessment within 180 days prior to enrollment 
 
** If a thrombus is observed prior to ablation, the subject no longer meets eligibility criteria and shall not 
have the ablation procedure performed: the subject will then be withdrawn from the study, classified as 
Consent Ineligible and no further follow-up is required.  
 
 Medications 
10.4.1.1. Anti-Arrhythmic Drugs 
Information on all Anti-arrhythmic drug (AAD) medications will be collected on the eCRF 
starting from baseline visit. During the entire course of the study, details on changes will 
be specified on the eCRF. Post-index procedure AADs are allowed per investigator’s 
discretion during the blanking period (90 days post-index procedure). According to HRS 
consensus guidelines (11), it is recommended to stop the administration of AAD for any 
atrial tachyarrhythmia after blanking period. If the investigator determines that the subject 
must be prescribed an increased dosage of AAD or a new AAD for treatment of any atrial 
tachyarrhythmia after the blanking period, the subject will be considered a Primary 
Effectiveness Failure. 
AADs for endpoint will consist of all Class I/III and any Class II/IV medications taken for 
control of AF/AFL/AT recurrence.   
10.4.1.2. Anticoagulation 
The use of anticoagulation up to the procedure (including up to transseptal puncture) is per 
standard of care of the investigator. Information on anticoagulation therapy, pre and post 
index procedure will be collected in the eCRF. 
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It is recommended that heparin is administered prior to or immediately following 
transseptal puncture during ablation procedure and adjusted to achieve and maintain an 
ACT of at least 300 seconds. The ACT levels should be checked at a 15-30 minutes interval 
during the duration of the procedure. 
 
 
 Ablation Procedure (Day 0)  
 General Info 
The study-related ablation procedure, from transseptal access in the left atrium until end of 
the ablation procedure must be performed by study-delegated investigators trained in 
electrophysiology (EP). Any procedure activity as of first skin puncture and prior to 
transseptal access can be performed by a physician who is not a study investigator under 
the supervision of the study investigator. Any reportable safety events that occur must be 
reported on the Adverse Event eCRF. The index ablation procedure must be performed 
within 90 days of a subject’s enrollment into the study. 
10.5.1.1. Esophagus Management 
Information on esophagus management, if any, will be collected in the eCRF (e.g. 
temperature monitoring, esophageal deviation). It is highly recommended to perform 
temperature monitoring. If temperature monitoring is performed, monitoring will be 
performed via the Smartfreeze Console using compatible commercially available products, 
if available.  
10.5.1.2. Phrenic Nerve Activity Monitoring 
During ablation, phrenic nerve activity monitoring will be performed according to the 
standard of care at the site. It is highly recommended to use the Diaphragm Movement 
Sensor. If the Diaphragm Movement Sensor (DMS) is used, data will be collected in the 
eCRF. If a reduction in phrenic response is detected, the operating physician will continue 
to closely monitor phrenic nerve activity and pacing capture, and will consider immediately 
interrupting cryoablation. In case of phrenic nerve injury at the procedure the subject status 
and potential resolution of the adverse event will be monitored during the course of the 
study. 
 
10.5.1.3. Pulmonary Vein Isolation  
The goal of the ablation procedure is electrical isolation of all pulmonary veins or 
anatomical equivalents. Electrical isolation of the veins must be demonstrated at minimum 
with evidence of entrance block in all of the pulmonary veins using the Cryo Mapping 
Catheter (Other techniques of assessment are per investigator’s discretion).  
If the subject is in AF prior to the ablation, it will be up to the investigator’s discretion 
whether to cardiovert or proceed with the procedure with the subject in AF.  
Electrocardiographic documentation of the subject’s rhythm prior to ablation will be 
collected. 
 
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10.5.1.4. Cryoablation System Preparation  
All devices should be prepared as described in the Instructions for use. 
The Console will create a record for each ablation attempted, including (but not limited to) 
Ablation Duration and Cryoballoon Temperature. Esophagus Temperature and DMS 
activity data will also be collected if esophageal probe and DMS are connected.  
In order to accurately capture information relevant to the study, the following information 
must be entered into the Console at each index procedure: 
Prior to Ablation: 
• 
On the subject information screen, enter the subject’s identification (subject ID is 
provided by the EDC system when enrolling the subject) and the operating 
physician’s name. 
• 
If the physician decides to use DMS it should be connected to the subject during 
right PV ablations (for data acquisition). The DMS is an adjunctive sensor designed 
to monitor a phrenic nerve pacing response. Standard of care methods for evaluating 
phrenic nerve function and determining when intervention is needed (e.g. palpation, 
ICE) should always be applied during right pulmonary vein ablations. The DMS is 
not intended as a substitute for such standard of care methods.     
• 
It is recommended to update the console timer preferences: 
• 
Cooling timer to: -40°C 
• 
Thaw timer to: 0°C 
In case the DMS is used, the steps reported in the instructions for use (IFU) will be 
followed.  
 
 Cryoablation protocol 
Preparation activities should be performed as follows: 
1. Assessment of presenting rhythm by 12-lead ECG 
2. Baseline the fluoroscopy exposure time (Time 0).  
3. Place additional diagnostic catheters, for example in the coronary sinus or for 
pacing the phrenic nerve, at the discretion of the physician. 
4. Per institutional protocol, complete transseptal access (single or double).  
5. Per the IFU, prepare the Cryo Steerable Sheath. Insert the Cryo Steerable Sheath 
over the guidewire and advance the sheath across the atrial septum. 
6. Per the IFU, prepare the Cryoablation Catheter and the Cryo Mapping Catheter. 
Insert the Cryo Mapping Catheter into the Cryoablation Catheter. Insert the 
Cryoablation Catheter into the Cryo Steerable sheath and advance it into the left 
atrium. 
7. Baseline the LA dwell time. 
 
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Following the step-wise approach for the ablation procedure is recommended: 
8. Navigating and positioning of the balloon 
a. Advance the Cryo Mapping Catheter and Cryoablation Catheter under 
fluoroscopic guidance to the proximity of the target PV 
b. Inflate the balloon while remaining outside of the target PV 
c. Occlude blood flow by advancing the balloon as necessary but remain 
outside of the tubular portion of the vein. Confirm and grade the occlusion 
(per physician’s assessment) 
d. Verify balloon position for complete PV occlusion. Verification may be 
performed with fluoroscopy and/or contrast injection or other technique (per 
investigator’s discretion). 
9. Cryo Ablation of all target PVs 
a. Perform cryo ablation as per IFU. A minimum ablation time of TTI + 120sec 
is highly recommended, where possible. If no PV potential is visible, a 
minimum ablation time of 180sec is highly recommended.  
b. During each ablation application: annotate the anatomical location of 
ablation, the time-to-isolation*  (as observed on the PolarMap EGMs and 
representing the time point when electrical activity disappears) and the 
ablation duration. 
* Time-to-isolation is required to be captured through the console, when available. 
c. Wait for the thawing phase to be completed prior to manipulating the 
Cryoablation Catheter.  
d. As needed, perform additional cryoablation in the same PV, adjusting the 
position of the Cryoablation Catheter, if necessary. 
10. Confirmation of isolation of the PV at minimum by entrance block using the Cryo 
Mapping Catheter (Other techniques of assessment are per investigator’s discretion) 
is required for all pulmonary veins or their anatomical equivalent. 
 
Note: If at any time during the ablation procedure the investigator is unable to continue the 
ablation with the designated study catheter (for the PV isolation), the investigator may 
complete the case with a device determined best for the subject. The case will represent an 
acute procedural failure (per protocol definition), regardless of achievement of PVI with 
other catheters. The point at which failure was determined as well as the rationale 
(including a device deficiency or adverse event, if any) must be documented in the EDC 
system. A protocol deviation will be documented in the EDC system.  
10.5.2.1. Cryoablation-specific recommendations 
 
Investigators may deliver one or more cryo applications per each pulmonary vein (or their 
anatomical equivalent) in order to achieve PVI.   
In order to preserve subject’s safety, it is recommended to adhere to the following 
indications: 
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• Terminate ablation if, in case of temperature monitoring, esophagus temperature 
falls below 20°C. Do not start a 2nd ablation until esophagus temperature returns at 
baseline levels. 
• Terminate ablation if an impairment of diaphragmatic movement is detected by the 
operating investigator during ablation. Do not start a 2nd ablation until phrenic 
nerve activity returns at baseline levels. 
• Do not apply more than 2 consecutive ablations in the same PV location*  
• Do not apply more than 4 total ablations in a single PV* 
 
* Ablations inferior to 60 seconds in duration are not considered in the total ablation 
count. Multiple ablations superior to these recommended numbers are reasonable in case 
of segmental ablations of large common trunk. 
 Additional ablation(s)  
Additional ablation outside PVI for AF treatment or treatment of other arrhythmias could 
be done. This includes non-PV foci that initiate AF (including locations in the LA, LAA, 
RA, or SVC), targeting complex fractionated electrograms or ganglionated plexi or 
performing left atrial mitral isthmus or roof lines. Data will be collected in the eCRF.  
The Cryoablation System cannot be used for the ablation of other arrhythmia(s)/additional 
line(s) or applications outside the PVs. For this purpose another commercially available 
catheter will be used. 
If the subject presents with AF after all ablations are complete, cardioversion should be 
performed and will be noted. Cardioversions during the Index procedure do not signify 
procedural failures and are not to be reported as adverse events. Induction of or spontaneous 
conversion to AF during the procedure will not be considered an adverse event.   
 3D mapping 
Three-dimensional (3D) mapping may be used during the procedure. If 3D mapping is 
performed, a commercially available device will be used, and the information should be 
collected on the eCRF including but not limited to: mapping catheter, 3D mapping system, 
mapping times.  
In case a post PVI map is collected, information on lesion and/or presence of conduction 
gaps should be collected for each PV. Potential gaps or poor lesion extension will be 
collected including localization information: vein and anatomical location.  
 
 
 Data Collection 
The following data related to the procedure will be collected: 
• Date of procedure 
• Identification of study devices for the following:  
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o Cryoablation Catheter  
o Cryo Mapping Catheter  
o Cryo Steerable Sheath  
o Console  
o Related accessories 
• Identification of non-study devices (if applicable):  
o Any additional sheaths/introducers used during the procedure including 
manufacturer, model and type 
o Any additional catheter(s) used during the procedure including 
manufacturer, model, and type (e.g. CS catheter) 
 
o Mapping system, if used (manufacturer, model and software version) and 
appropriate interface cables (manufacturer, model and type) 
• Presenting rhythm at the beginning of the procedure (by means of a 12-lead ECG) 
• Method of delivering sedation or anesthesia for the procedure 
• Method of transseptal access to left atrium: single or double  
• Method of evaluating phrenic nerve function and determining when intervention is 
needed 
 
Specific to the PVI ablation the following information will be collected (including, but not 
limited to): 
• Per each ablation application: 
o Acute Time-to-Isolation (if available) 
o Minimum balloon temperature 
o Time to thaw  
o Duration of each cryo application 
o DMS and Esophageal temperature, if available 
o Reason, if any, for premature interruption of the ablation  
o If ablation was followed by a verification of entrance block and if successful 
or not. 
 
• For each pulmonary vein or anatomical equivalent: 
o PV isolation success, at minimum by entrance block using the Cryo 
Mapping Catheter (Other techniques of assessment are per investigator’s 
discretion) documented through EGMs printed from recording system 
and/or in medical file 
• Any other ablation performed during the index procedure (before, during or after 
PVI)   
 
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At the end of the procedure, the following information will be collected:  
 
• Total procedure time, defined as time elapsed from time first access sheath insertion 
into the subject until the last catheter removed; 
• Total Fluoroscopy time measured from baseline fluoroscopy time (Time 0);  
• Total Cryoablation time (duration of all cryo applications); 
• Duration of LA dwell time, defined as time from the Cryoablation Catheter 
introduced in the LA (exiting the sheath) to the last time of Cryoablation Catheter 
exiting the LA; 
• Rhythm at end of case (documented by means of a post-ablation EGM/12-lead 
ECG); 
• Cardioversion(s) performed during the procedure, if any; 
• Assessment of reportable Adverse Events including resolution of ongoing events, 
if applicable/Device Deficiencies; 
• Assessment of phrenic nerve palsy (method per investigator’s discretion, eg. 
through fluoroscopy of diaphragm movement); 
• Protocol Deviations, if applicable. 
 
The  ablation data report  collected through the Console will be exported to external media, 
printed, signed by the investigator and stored as source data.  
 Pre-Discharge (0-7days post index procedure) 
The pre-discharge follow-up visit should be completed before the subject is discharged 
from the hospital. The visit should occur within seven days post-index procedure. If the 
subject is to remain in the hospital beyond seven days post-index procedure, then the pre-
discharge follow-up visit should be conducted before the eighth day. 
Data collection during the Pre-Discharge visit will be recorded on the respective eCRF. 
Data collection includes: 
• Date of visit; 
• Physical assessment including at minimum resting heart rate, weight, systolic and 
diastolic blood pressure; 
• Rhythm at time of visit (by means of a 12-lead ECG); 
• Documentation of intervention of AF, AFL, AT, if any; 
• New, discontinued or changes to current Anti-Arrhythmic Drugs and Anticoagulation 
medication regimen; 
 
• Protocol Deviations, if applicable; 
• Reportable Adverse Events, including resolution of ongoing events, if applicable. 
In cases of phrenic nerve palsy at the index procedure, the subject should be 
assessed to evaluate if the event resolved (method per investigator’s discretion). 
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 Day 7 Follow-up Contact (eg. Phone call – window of + 7 days) 
In case the subject is discharged prior to 7 days post-index procedure, a (telephone) contact 
at day 7 (+ 7days) is required to assess if any adverse events, complications etc. have 
occurred since hospital discharge.   
 
 Month 3 Follow-up (91 ± 14 days) (in-clinic visit) 
The Month 3 follow-up should be completed between 77 and 105 days post-index 
procedure.  
Due to the range for the visit completion and the endpoint requirement for medication, 
AAD medication changes made during the Month 3 Follow-up visit will be counted as 
being made within the blanking period. 
Data collection during the Month 3 follow-up visit will be recorded on the respective eCRF. 
Data collection includes: 
• Date of visit; 
• Physical assessment including at minimum resting heart rate, weight, systolic and 
diastolic blood pressure; 
• Rhythm at time of visit (by means of a 12-lead ECG); 
• Holter monitor (24 hours) (optional, per standard of care); 
• Documentation of intervention of AF, AFL, AT, if any; 
• New, discontinued or changes to current Anti-Arrhythmic Drugs and Anticoagulation 
medication regimen; 
• Protocol deviations, if any; 
• Reportable Adverse Events, including resolution of ongoing events, if applicable. 
In cases of a pre-existing and unresolved phrenic nerve palsy the subject should be 
assessed to evaluate if the event resolved (method per investigator’s discretion). 
 
 Month 6 Follow-up (180 ± 30 days) (in-clinic visit) 
The Month 6 follow-up should be completed between 150 and 210 days post-index 
procedure.  
Data collection during the Month 6 follow-up visit will be recorded on the respective eCRF. 
Data collection includes  
• Date of visit; 
• Physical assessment including at minimum resting heart rate, weight, systolic and 
diastolic blood pressure; 
• Rhythm at time of visit (by means of a 12-lead ECG); 
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• Holter monitor (24 hours) (required); 
• Documentation of intervention of AF, AFL, AT, if any; 
• New, discontinued or changes to current Anti-Arrhythmic Drugs and Anticoagulation 
medication regimen; 
• Protocol deviations, if any; 
• Reportable Adverse Events, including resolution of ongoing events, if applicable. 
In cases of a pre-existing and unresolved phrenic nerve palsy the subject should be 
assessed to evaluate if the event resolved (method per investigator’s discretion). 
 Month 12 Follow-up (365 ± 30 days) (in-clinic visit) 
The Month 12 follow-up should be completed between 335 and 395 days post-index 
procedure.  
Data collection during the Month 12 follow-up visit will be recorded on the respective 
eCRF. 
Data collection includes  
• Date of visit; 
• Physical assessment including at minimum resting heart rate, weight, systolic and 
diastolic blood pressure; 
• Rhythm at time of visit (by means of a 12-lead ECG); 
• Holter monitor (24 hours) (required); 
• Documentation of intervention of AF, AFL, AT, if any; 
• New, discontinued or changes to current Anti-Arrhythmic Drugs and Anticoagulation 
medication regimen; 
• Protocol deviations, if any; 
• Reportable Adverse Events, including resolution of ongoing events, if applicable.  
In cases of a pre-existing and unresolved phrenic nerve palsy the subject should be 
assessed to evaluate if the event resolved (method per investigator’s discretion). 
 
 Additional Follow-up 
An additional follow-up visit at the investigational site is any subject visit triggered by 
subject symptoms that is not already defined as one of the study visits. 
Data collection during the additional follow-up visit will be recorded on the respective 
eCRF. 
Data collection should include: 
• Date of visit; 
• Physical assessment including at minimum resting heart rate, weight, systolic and 
diastolic blood pressure; 
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• Rhythm at time of visit (by means of a 12-lead ECG); 
• Holter monitor (24 hours) (per standard of care); 
• Documentation of intervention of AF, AFL, AT, if any; 
• New, discontinued or changes to current Anti-Arrhythmic Drugs and Anticoagulation 
medication regimen; 
• Protocol deviations, if any; 
• Reportable Adverse Events, including resolution of ongoing events, if applicable.  
In cases of a pre-existing and unresolved phrenic nerve palsy the subject should be 
assessed to evaluate if the event resolved (method per investigator’s discretion). 
 
 
Repeat (or additional) ablation procedure  
It is known that during the first 90 days post-index procedure (blanking period), subjects 
can suffer from recurrences of atrial tachycardias (AF, AFL, AT). Within the blanking 
period, one repeat ablation procedure, using a commercially available ablation system, is 
allowed. More than one repeat ablation procedure during the blanking period, or a repeat 
ablation procedure performed after blanking period will count as a failure for the primary 
effectiveness endpoint. 
During the repeat ablation procedure, the anatomical location of potential ablation gaps in 
the pulmonary veins will be assessed.  
In case a repeat ablation procedure occurs during the 12 month follow-up period, the data 
of this procedure will be entered in the ‘Additional Procedure’ eCRF.  In case this ablation 
procedure is performed to treat a supraventricular arrhytmia, including AF, AFL or AT, 
following detailed information about this repeat ablation procedure will be collected: 
• Was the ablation procedure performed in the LA?; 
• For repeat ablation procedures performed in the LA: was this repeat ablation 
procedure performed to treat atrial fibrillation? If no, specify the arrhythmia type; 
• For ablations in the LA collect potential results of imaging (e.g. CT/MRI/ICE) 
performed per standard of care, including data to rule out thrombus prior to ablation 
or asses PV stenosis;  
• The use of anticoagulation up to the procedure (including up to transseptal 
puncture) is per standard of care of the investigator. Information on anticoagulation 
therapy, pre and post repeat procedure will be collected in the eCRF. 
It is recommended that heparin is administered prior to or immediately following 
transseptal puncture during ablation procedure and adjusted to achieve and maintain 
an ACT of at least 300 seconds. The ACT levels should be checked at a 15-30 
minutes interval during the duration of the procedure. 
• If a 3D mapping system is used for this repeat procedure, additional info should be 
collected on the location and number of gaps; 
• Rhythm at the beginning (12-lead ECG) and the end of the repeat procedure 
(documented by means of a post-ablation EGM/12-lead ECG); 
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• Reportable Adverse Events, including resolution of ongoing events, if 
applicable/Device Deficiencies; 
In cases of a pre-existing and unresolved phrenic nerve palsy the subject should be 
assessed to evaluate if the event resolved (method per investigator’s discretion); 
• Protocol deviations, if applicable. 
 
Study Completion 
All TREATMENT subjects will be followed for 12 months after the index procedure. Data 
collection will continue up to the point of the Month 12 follow-up visit, including the Holter 
monitor. The End of Study eCRF will have to be completed at study completion. 
 
Source Documents 
It is preferable that original source documents are maintained, when available. In lieu of 
original source documents, certified copies are required to be maintained.  A certified copy 
is a copy (irrespective of the type of media used) of the original record that has been verified 
(i.e., by a dated signature or by generation through a validated process) to have the same 
information, including data that describe the context, content, and structure, as the original. 
Source documentation includes but is not limited to those items noted in Table 10.14-1. 
Table 10.14-1: Source Documentation Requirements 
Requirement 
Disposition 
Informed Consent documentation process 
Retain at Center 
Medical history documents pertaining to eligibility 
criteria 
Retain at Center 
Documentation of demographics data 
Retain at Center 
Physical assessment 
Retain at Center 
Medication regimen and Changes 
Retain at Center  
Medical history 
Retain at Center 
Documentation of isolation confirmation for each 
Pulmonary Vein 
Retain at Center 
Printed and signed PDF Console Export Case Data 
Retain in subject binder 
12-Lead ECGs data including ongoing rhythm 
Retain at Center 
Signed Technical Source Form 
Retain in subject binder 
Imaging, per standard of care 
Retain at Center 
Holter report 
Retain in subject binder 
Adverse Events 
Retain at Center 
In the event of a subject death (if requested: 
• 
Death narrative 
• 
Relevant medical records 
• 
Death Certificate 
• 
Autopsy report 
 
 
Submit one copy to BSC, 
Retain one copy at center 
 
 
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11. Statistical Considerations 
 Endpoints 
 Primary Safety Endpoint 
The primary safety endpoint will be evaluated by the safety event free rate at 12 months 
post-index procedure.  
Primary safety events will consist of a composite of the following  device and procedure-
related and device-related adverse events.  
Acute primary safety endpoint events, events occurring up to 7 days post-index procedure 
or hospital discharge, whichever is later, include:  
• 
Death 
• 
Myocardial infarction (MI) 
• 
Persistent gastroparesis/injury to vagus nerve 
• 
Transient ischemic attack (TIA) 
• 
Stroke/Cerebrovascular accident (CVA) 
• 
Thromboembolism/ Air embolism* 
• 
Cardiac tamponade/perforation 
• 
Pneumothorax 
• 
Serious vascular access complications** 
• 
Pulmonary edema/heart failure 
• 
AV block not attributable to medication effect or vasovagal reaction 
 
* Thromboembolic or air embolic events collected in the study refer to any occlusion of blood vessel(s) that 
results in clinical symptoms  
** Defined as prolongation of hospitalization, requirement of surgical intervention or blood transfusion 
 
 
Chronic primary safety endpoint events, events occurring through 12 months post-index 
procedure, include: 
• 
Atrial esophageal fistula 
• 
Pulmonary vein stenosis (≥ 70% reduction of diameter) 
• 
Symptomatic pericardial effusion  
• 
Persistent Phrenic nerve injury*** 
 
***A non-recovered phrenic nerve injury at 12 months post-index procedure will count as a chronic primary 
endpoint. The study will collect information on phrenic nerve palsy observed before the end of the index 
procedure and, in case it occurred, will track information for potential recovery during the study visits. 
11.1.1.1. Hypotheses 
For all Cohorts: 
Ho:  The primary safety endpoint event-free rate at 12 months post procedure ≤ 86% 
Ha:  The primary safety endpoint event-free rate at 12 months post procedure > 86% 
 
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11.1.1.2. Sample Size  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
i  
 
 
11.1.1.3. Statistical Methods 
The 12 month (365-day) primary safety event-free rate will be calculated using Kaplan-
Meier methodology. Subjects who withdraw from the study prior to 12 months without 
experiencing an event will be censored on the date of withdrawal.  The 95% one-sided 
lower confidence limit of the observed safety event-free rate will be compared to the 
performance goal of 86%. If the lower confidence limit is greater than the performance 
goal, the null hypothesis will be rejected. The lower confidence limit will be calculated as 
the pointwise confidence limit using the log-log methodology. 
 Primary Effectiveness Endpoint 
The primary effectiveness endpoint will be evaluated by the failure-free rate at 12 months 
post-index procedure in each cohort.  
 
Failure defined as: 
• 
Failure to achieve acute procedural success* in the index procedure;  
• 
More than one repeat procedure during the blanking period (within 90 days 
post-index procedure); 
• 
Documented atrial fibrillation, or new onset of atrial flutter or atrial 
tachycardia event (≥ 30 seconds in duration or from a 10 second 12-lead 
ECG) between days 91 and days 365 post-index procedure**. 
• 
Any of the following interventions for atrial fibrillation, or new onset of 
atrial flutter or atrial tachycardia between days 91 and days 365 post-index 
procedure: 
• 
Repeat procedure 
• 
Electrical and/or pharmacological cardioversion for AF/AFL/AT  
• 
Prescribed a higher dose of any AAD*** documented at baseline or 
a new AAD*** not documented at baseline  
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* Acute procedural success is defined as isolation of the all pulmonary veins or anatomical equivalents 
achieved with the POLARx Cryoablation balloon at the end of the index procedure and as demonstrated at 
minimum by entrance block using the Cryo Mapping Catheter (Other techniques of assessment are per 
investigator’s discretion) 
** Subjects will be monitored for recurrences of the arrhythmias by means of clinical visits, ECG and 24-
hour Holter monitoring. Recurrences documented with other devices only (eg. ILR, PM, ICD, CRT) will not 
be counted as primary effectiveness endpoint events 
*** AADs for endpoint will consist of all Class I/III and any Class II/IV medications taken for control of 
AF/AT/AFL recurrence   
11.1.2.1. Hypotheses 
Ho:  The failure-free rate at 12 months post procedure ≤ 50% 
Ha:  The failure-free rate at 12 months post procedure > 50% 
 
11.1.2.2. Sample Size  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
11.1.2.3. Statistical Methods 
The 12 month (365-day) primary effectiveness failure-free rate will be calculated using 
Kaplan-Meier methodology. Subjects who withdraw from the study prior to 12 months 
without experiencing an event will be censored on the date of withdrawal.  The 95% one-
sided lower confidence limit of the observed effectiveness failure-free rate in each cohort 
will be compared to the corresponding performance goal. If the lower confidence limit is 
greater than the performance goal, the null hypothesis will be rejected. The lower 
confidence limit will be calculated as the pointwise confidence limit using the log-log 
methodology. 
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 Data Analyses 
 Secondary Effectiveness Endpoint 
Documentation and rate of acute procedural success (definition see section 11.1.2.). 
Electrical isolation of a PV is demonstrated at minimum by entrance block using the Cryo 
Mapping Catheter (Other techniques of assessment are per investigator’s discretion). 
Information on isolation method used per site standard of care will be collected  with a 
minimum by entrance block in all PVs or anatomical equivalents. Additional data, if 
available, will be collected on Exit Block or Conduction Block verification using 3D 
mapping. 
 
 Interim Analyses  
No formal interim analyses are planned for the purpose of stopping the study early for 
declaring effectiveness or for futility. Analysis of each endpoint will be performed when 
all applicable data for that endpoint has been collected. Analyses of acute data (procedural 
safety and acute procedural success) may be performed and used for publication purposes 
after completion of study enrollment, index procedure, 7 day and 3 month follow-up of all 
subjects. A study report will be completed when the first 199 De Novo treatment subjects 
with paroxysmal atrial fibrillation qualifying for primary endpoint analyses will complete 
the follow-up of 12 months. 
 Subgroup Analyses 
Additional ancillary analyses on specific subgroup of subjects, may be presented. 
These analyses will include but not limited to the following: 
• Age (<60 versus ≥ 60 years); 
• Gender (Male versus Female); 
• Monitoring (Subjects with data from continuous ECG recording systems (eg. ILR, 
PM, ICD, CRT) versus those without). 
 Pooling Analysis 
Center-to-center heterogeneity will be assessed for the primary endpoints by performing a 
random effects logistic regression analysis.  Centers with less than five enrollments will be 
combined to form “supercenters”. Small centers will be combined until the newly created 
supercenter has five enrollments, and then a new supercenter will be created. Centers will 
be deemed to be heterogeneous if the variance of the random center effect is found to 
significantly differ from zero.  A significance level of 15% will be used for this test. 
 Multivariable Analyses 
For each primary endpoint, univariate analyses of the following covariates will be 
performed, and any found to be significantly associated with the outcome at the .15 alpha 
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level will be included as covariates in a multivariate regression model. Backward selection 
with 0.15 alpha level stay criterion will be used to determine the final multivariate model.  
The list of baseline covariates includes, but is not necessarily limited to: 
• Subject demographics (e.g. age, gender) 
• Subject baseline characteristics (e.g. LVEF and LA diameter) 
• Procedural techniques (e.g., esophageal temperature monitoring,) 
 
An additional multivariable analysis will be performed to assess on the effect of cryo dosing 
parameters on acute (procedure duration, dwell time, acuite success, acute adverse events)  
and chronic parameters (freedom from effectiveness failure). Cryo dosing parameters to be 
assessed for use in the model will be considered: number of cryo applications, time to 
isolation,  ablation duration, sequence of veins approached and consecutive applications in 
the same vein. Additional subject variables such as PV anatomy and baseline characteristics 
will also be assessed for inclusion in the model. 
 
 Additional Analyses 
Additional analyses include, but are not limited to:  
• Procedure times: LA dwell time*, total ablation time, number of cryo applications 
per vein, time to thaw, total fluoroscopy time and total procedure time;  
• Time-To-Isolation per ablation application, if available; 
• Freedom from recurrence of individual types of atrial arrhythmias (AF, AFL, AT) 
between days 91 and days 365 post-index procedure; 
• Analysis of ablation techniques (i.e. segmental approach to left common trunk, 
additional linear ablations, etc.); 
• Analysis of different anaesthesia techniques (General anaesthesia with or without 
intubation versus sedation) 
• Freedom from recurrence in subjects with non-common anatomical configurations 
of PV (e.g. left common trunk); 
• Freedom from primary effectiveness failure evaluated in subgroups of subjects 
(termination of AAD versus continuation of AAD after blanking period); 
• For the subgroup of subjects undergoing 3D mapping with the Boston Scientific 
mapping Rhythmia system and performing a post-procedural map, map 
information will be collected to determine lesion locations; 
• For subjects that will undergo repeat ablation during the course of the clinical 
follow-up, anatomical location of ablations gaps will be assessed. 
* LA dwell time is defined as time from the Cryoablation Catheter introduced in the left atrium (LA) to the 
last time of Cryoablation Catheter exiting the LA. 
 
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 Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the analyses will 
be documented in an amended Statistical Analysis Plan approved prior to performing the 
analyses. Changes from the planned statistical methods after performing the analyses will 
be documented in the clinical study report along with a reason for the deviation. 
 
 General Statistical Methods 
 Analysis Sets 
Effectiveness endpoint analyses will use all available data from all eligible TREATMENT 
subjects. Eligible TREATMENT subjects for the primary effectiveness endpoint includes 
all TREATMENT subjects who do not have an implantable continuous ECG recording 
system (eg. Pacemakers, arrhythmia loop recording systems, ICD, CRT). Eligible 
TREATMENT subjects for the secondary effectiveness endpoint will include all 
TREATMENT subjects. 
Primary safety endpoint analyses will use data from all available TREATMENT subjects. 
Safety analysis for ATTEMPT subjects will be limited to the Acute primary safety endpoint 
events (per definition in section 6.2.1.).  
 Control of Systematic Error/Bias 
Selection of subjects will be made from the Investigator’s population. All subjects that have 
signed the ICF will be enrolled in the study.   
 Number of Subjects per Investigative Site 
To avoid any center effect and bias, one center will initially not be allowed to enroll more 
than 10% of the 199 subjects (20 subjects) meeting enrollment criteria. Enrollment up to a 
total of 30 subjects meeting the enrollment criteria during the enrollment period will be 
allowed after sponsor approval. Enrollment of an amount of study subjects in excess of 
such approved number of 30 total subjects must first be approved by Sponsor, notified to 
Institution’s IRB/EC/REB, as applicable, and requires an amendment of exhibit A of the 
clinical study agreement. 
 
 
12. Data Management 
 Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) 
system, recommended within 10 business days. 
The clinical database will reside on a production server hosted by Medidata EDC System. 
All changes made to the clinical data will be captured in an electronic audit trail and 
available for review by the sponsor or its representative. The associated Rave software and 
database have been designed to meet regulatory compliance for deployment as part of a 
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validated system compliant with laws and regulations applicable to the conduct of clinical 
studies pertaining to the use of electronic records and signatures. Database backups are 
performed regularly. 
The Investigator provides his/her electronic signature on the appropriate electronic case 
report forms (eCRFs) in compliance with local regulations. A written signature on printouts 
of the eCRFs must also be provided if required by local regulation. Changes to data 
previously submitted to the sponsor require a new electronic signature by the Investigator 
acknowledging and approving the changes. 
Visual and/or electronic data review will be performed to identify possible data 
discrepancies. Manual and/or automatic queries will be created in the Medidata EDC 
system and will be issued to the site for appropriate response. Site staff will be responsible 
for resolving all queries in the database in a timely manner. 
CRF Completion Guidelines will be created by Boston Scientific and provided to all sites.  
 
 Data Retention 
The Principal Investigator or his/her designee or Investigational site will maintain all 
essential study documents and source documentation that support the data collected on the 
study subjects in compliance with applicable regulatory requirements.   
The Principal Investigator or his/her designee will take measures to prevent accidental or 
premature destruction of these documents. If for any reason the Principal Investigator or 
his/her designee withdraws responsibility for maintaining these essential documents, 
custody must be transferred to an individual who will assume responsibility and BSC must 
receive written notification of this custodial change. Sites are required to inform Boston 
Scientific in writing where paper or electronic files are maintained in case files are stored 
off site and are not readily available. 
 Technical Source Forms 
The Technical Source Form (TSF) is the approved document to capture protocol required 
data elements that are not duplicated in any other source documents. This form requires 
review and approval by the investigator and is to be used by the study sites as a source 
document. 
Collection and completion of all information on the Technical Source Form is the 
responsibility of the appropriately delegated site personnel.  
At the conclusion of the procedure, the completed technical source form must be signed 
(and initialed as needed) by the following people: 
• 
the Delegated Site Personnel completing the forms; 
• 
the Delegated Investigator conducting and/or supervising the case. 
13. Deviations 
An Investigator must not make any changes or deviate from this protocol, except to protect 
the life and physical well-being of a subject in an emergency. An investigator shall notify 
the sponsor and the reviewing EC of any deviation from the investigational plan to protect 
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the life or physical well-being of a subject in an emergency, and those deviations which 
affect the scientific integrity of the clinical study. Such notice shall be given as soon as 
possible, but no later than 5 working days after the emergency occurred, or per prevailing 
local requirements, if sooner than 5 working days.  
All deviations from the investigational plan, with the reason for the deviation and the date 
of occurrence, must be documented and reported to the sponsor using EDC. Sites may also 
be required to report deviations to the EC, per local guidelines and government regulations.  
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, 
appropriate corrective and preventive actions (including EC notification, site re-training, or 
site discontinuation/termination) will be put into place by the sponsor. 
 
14. Compliance 
 Statement of Compliance 
This study will be conducted in accordance with the spirit of ISO 14155 (Clinical 
Investigation of Medical Devices for Human Subjects – Good Clinical Practice), the 
relevant parts of the ICH Guidelines for Good Clinical Practices, ethical principles that 
have their origins in the Declaration of Helsinki, and applicable individual country laws 
and regulations. The study shall not begin until the required approval/favorable opinion 
from the EC and/or regulatory authority has been obtained, if appropriate. Also, the study 
shall not begin prior to issuance of the site Authorization to Enroll, as provided by the 
sponsor. Any additional requirements imposed by the EC or regulatory authority shall be 
followed, if appropriate.  
 Investigator Responsibilities 
The Principal Investigator of an investigational site is responsible for ensuring that the 
study is conducted in accordance with the Clinical Study Agreement, the clinical 
investigation plan, the spirit of ISO 14155, ethical principles that have their origins in the 
Declaration of Helsinki, any conditions of approval imposed by the reviewing EC, and 
prevailing local and/or country laws and/or regulations, whichever affords the greater 
protection to the subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following.  
• Prior to beginning the study, sign the Clinical Study Agreement and comply with the 
Investigator responsibilities as described in such Agreement.   
• Provide his/her qualifications and experience to assume responsibility for the proper 
conduct of the study and that of key members of the site team through up-to-date 
curriculum vitae or other relevant documentation and disclose potential conflicts of 
interest, including financial, that may interfere with the conduct of the clinical study or 
interpretation of results. 
• Make no changes in or deviate from this protocol, except to protect the life and physical 
well-being of a subject in an emergency; document and explain any deviation from the 
approved protocol that occurred during the course of the clinical study. 
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• Create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all clinical-
study-related records are retained per requirements. 
• Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
sponsor in the CRFs and in all required reports. 
• Record, report, and assess (seriousness and relationship to the device/procedure) every 
adverse event as applicable per the protocol and observed device deficiency. 
• Report to sponsor, per the protocol requirements, all SAEs and device deficiencies that 
could have led to a SADE and potential/USADE or UADE. 
• Report to the EC and regulatory authorities any SAEs and device deficiencies that could 
have led to a SADE and potential/USADE or UADE, if required by applicable laws or 
regulations or this protocol or by the EC, and supply BSC with any additional requested 
information related to the safety reporting of a particular event. 
• Allow the sponsor to perform monitoring and auditing activities, and be accessible to 
the clinical research monitor or auditor and respond to questions during monitoring 
visits or audit(s). 
• Allow and support regulatory authorities and the EC when performing auditing 
activities. 
• Ensure that informed consent is obtained in accordance with applicable laws, this 
protocol and local EC requirements. 
• Provide adequate medical care to a subject during and after a subject’s participation in 
a clinical study in the case of adverse events, as described in the Informed Consent 
Form (ICF). 
• Inform the subject of the nature and possible cause of any adverse events experienced. 
• As applicable, provide the subject with necessary instructions on proper use, handling, 
storage, and return of the device when it is used/operated by the subject. 
• Inform the subject of any new significant findings occurring during the clinical study, 
including the need for additional medical care that may be required. 
• Provide the subject with well-defined procedures for possible emergency situations 
related to the clinical study, and make the necessary arrangements for emergency 
treatment, including decoding procedures for blinded/masked clinical studies, as 
needed. 
• Ensure that clinical medical records are clearly marked to indicate that the subject is 
enrolled in this clinical study. 
• Ensure that, if appropriate, subjects enrolled in the clinical study are provided with 
some means of showing their participation in the clinical study, together with 
identification and compliance information for concomitant treatment measures (contact 
address and telephone numbers shall be provided). 
• Inform, with the subject’s approval or when required by national regulations, the 
subject’s personal physician about the subject’s participation in the clinical study. 
• Make all reasonable efforts to ascertain the reason(s) for a subject’s premature 
withdrawal from clinical study while fully respecting the subject’s rights. 
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• Ensure that an adequate study site team and facilities exist and are maintained and 
documented during the clinical study. 
 Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to 
conducting the informed consent process, the Principal Investigator or trained sub-
investigator is responsible for providing appropriate training, ensuring delegates are 
competent to perform the tasks they have been delegated and ensuring adequate supervision 
of those to whom tasks are delegated. Where there is a sub-investigator at a site, the sub-
investigator should not be delegated the primary supervisory responsibility for the site. The 
investigator is accountable for regulatory violations resulting from failure to adequately 
supervise the conduct of the clinical study.  
 Ethics Committee 
The investigational site will obtain the written and dated approval/favorable opinion of the 
EC for the clinical study before recruiting subjects and implementing all subsequent 
amendments, if required. 
A copy of the written EC and/or competent authority (CA) approval of the protocol (or 
permission to conduct the study) and ICF, must be received by the sponsor before 
recruitment of subjects into the study. Prior approval must also be obtained for other 
materials related to subject recruitment or which will be provided to the subject. 
 
Any amendment to the protocol will require review and approval by the EC before the 
changes are implemented to the study.  All changes to the ICF will be EC approved; a 
determination will be made regarding whether a new ICF needs to be obtained from 
participants who provided consent, using a previously approved ICF.  
Annual EC approval and renewals will be obtained throughout the duration of the study as 
required by applicable local/country laws or regulations or EC requirements. Copies of the 
study reports and the EC continuance of approval must be provided to the sponsor.  
 Sponsor Responsibilities 
All information and data sent to BSC concerning subjects or their participation in this study 
will be considered confidential by BSC and will be kept confidential in accordance with all 
applicable laws and regulations. Only authorized BSC personnel and/or a BSC 
representative including, but not limited to Contract Research Organization (CRO), will 
have access to this information. Authorized regulatory personnel have the right to inspect 
and copy all records pertinent to this study. Study data collected during this study may be 
used by BSC for the purposes of this study, publication, and to support future research 
and/or other business purposes, such as overseeing and improving the performance of its 
device, new medical research and proposals for developing new medical products and 
procedures. All data used in the analysis and reporting of this study or shared with a third-
party researcher will be without identifiable reference to specific subjects. 
Information received during the study will not be used to market to subjects; subject names 
will not be placed on any mailing lists or sold to anyone for marketing purposes.  
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 Role of Boston Scientific Representatives 
Boston Scientific personnel can provide technical support to the investigator and other 
health care personnel (collectively HCP) as needed during index procedure, testing required 
by the protocol, and follow-ups. Support may include HCP training, addressing HCP 
questions, or providing clarifications to HCPs concerning the operation of BSC 
equipment/devices (including programmers, analyzers, and other support equipment). 
At the request of the investigator and while under investigator supervision, BSC personnel 
may operate equipment during index procedure, assist with the conduct of testing specified 
in the protocol, and interact with the subject to accomplish requested activities.  
Typical tasks may include the following: 
• Setting up, calibrating and/or operating parameters to investigator-requested settings of 
the Console during the preparation and execution of the mapping and ablation 
procedure; 
• Clarifying device behavior, operation or diagnostic output as requested by the 
investigator or other health care personnel; 
• Interaction with Boston Scientific noninvasive equipment (Console and applicable 
accessories) and interpretation of information contained therein to support the 
collection of required information by the delegated site staff; 
• Print out reports/export data directly from the console and provide original printouts or 
electronic data reports to clinical site as source documentation; 
• Provide technical expertise/support to subjects during office visits and/or during 
teleconference calls/electronic communications with the principal investigator or their 
delegated site staff and the subject.  
 
In addition, BSC personnel may perform certain activities to ensure study quality. These 
activities may include the following: 
• Observing testing or medical procedures to provide information relevant to protocol 
compliance 
• Reviewing collected data and study documentation for completeness and accuracy 
 
Boston Scientific personnel will not do the following.  
• Practice medicine; 
• Provide medical diagnosis or treatment to subjects; 
• Discuss a subject’s condition or treatment with a subject; 
• Record data on source documents; 
• Independently collect critical study data (defined as primary or secondary endpoint 
data); 
• Enter data in electronic data capture systems or on paper case report forms. 
 
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 Insurance  
Where required by local/country regulation, proof and type of insurance coverage, by BSC 
for subjects in the study will be obtained. 
15. Monitoring 
Monitoring will be performed during the study to assess continued compliance with the 
protocol and applicable regulations. In addition, the clinical research monitor verifies that 
study records are adequately maintained, that data are reported in a satisfactory manner 
with respect to timeliness, adequacy, and accuracy, and that the Principal Investigator 
continues to have sufficient staff and facilities to conduct the study safely and effectively. 
The Principal Investigator/institution guarantees direct access to original source documents 
by BSC personnel, their designees, and appropriate regulatory authorities. 
The study may also be subject to a quality assurance audit by BSC or its designees, as well 
as inspection by appropriate regulatory authorities. It is important that the Principal 
Investigator and relevant study personnel are available during on-site monitoring visits or 
audits and that sufficient time is devoted to the process. 
16. Potential Risks and Benefits 
 Instructions for Use 
Please refer to the Instructions for Use for an overview of anticipated adverse (device) 
effects, and risks associated to the commercial device(s).   
 Risks associated with Participation in the Clinical Study 
There are no specific tests outside those recommended as standard practice for catheter 
ablation of AF required by this clinical study protocol. Therefore, there is no foreseen 
increased risk to subjects for participating in the study. 
 Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
using the devices in accordance with their applicable Instructions for Use, performing 
procedures in the appropriate hospital environment, following recommended standard 
practices/guidelines, adherence to subject selection criteria, close monitoring of the 
subject's physiologic status during research procedures and/or follow-ups and by promptly 
supplying BSC with all pertinent information required by this protocol. 
 Anticipated Benefits 
Subjects may or may not receive any benefit from participating in this study as compared 
to the current standard of care received for treatment of AF.  Potential benefits of the 
Cryoablation System for the subject may include the following: 
• 
Complete or partial reduction in symptoms related to AF 
• 
Complete or partial reduction in the number of cardioversions, medications a 
subject is taking, and in the number of hospitalizations related to AF 
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 Risk to Benefit Rationale, if applicable 
Risk management activities, including Hazard Analyses (HA) and Failure Mode Effects 
Analyses (FMEA), have been performed on the Cryoablation System, steerable sheath and 
extension cable to identify and analyze known and foreseeable hazards (in both normal and 
fault conditions) and reasonably foreseeable sequences or combinations of events that could 
result from using this product and the risks associated with each hazard.  Mitigations have 
been implemented in the design, processes, and/or labeling and directions for use of the 
product to reduce the residual risk of each hazard as necessary and practicable. The HA has 
been reviewed and approved and the remaining risks are acceptable when weighed against 
the intended benefits to the subject. 
17. Safety Reporting 
 Reportable Events by investigational site to Boston Scientific 
It is the responsibility of the investigator to assess and report to BSC any event which occurs 
in any of following categories of reportable events: 
• All Serious Adverse Events, including all events leading to death; 
• All Thromboembolic Events; 
• All Study Procedure Related AEs (index and repeat procedure); 
• All BSC commercialized device-related adverse events; 
• All Study Device-Related Adverse Events; 
• All Study Related Device Deficiencies; 
• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device 
Effects previously not defined in the IFU. 
 
Any reportable adverse event (per definition above), experienced by the study subject after 
written informed consent must be recorded in the eCRF. 
Whenever possible, the medical diagnosis should be reported as the Event Term instead of 
individual symptoms. If it is unclear whether or not an event fits one of the above 
categories, or if the event cannot be isolated from the device or procedure, it should be 
submitted as an adverse event and/or device deficiency. 
Death should not be recorded as an SAE but should only be reflected as an outcome of one 
(1) specific SAE (see Table 17.2-1 for Safety definitions). 
If the subject experiences a new arrhythmia between index procedure and end of study, and 
the investigator considers this adverse event to be procedure related, it needs to be reported. 
The following clinical events will not be considered adverse events for this clinical study:  
• 
Pre-existing diseases or conditions (including AF, AFL, AT) will not be reported as 
adverse events unless there has been a substantial increase in severity or frequency 
of the problem as compared to the subject’s baseline which cannot be attributed to 
the expected progression of the disease or condition;  
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• 
A recurrence of an arrhytmia should be reported on the “AF recurrence” CRF and 
should not be recorded as an adverse event, unless it meets seriousness criteria as 
per table 17.2-1; 
• 
Pre-planned hospitalizations at time of enrollment or for a pre-existing condition;  
• 
If an additional ablation procedure is required, this additional ablation procedure 
should not be considered as an Adverse Event, unless associated with subject 
worsening condition or a new diagnosis. If the investigator considers this event to 
be related to any procedure, the event needs to be reported. In this case, the 
additional ablation procedure should be reported in the Adverse Event eCRF as 
corrective action of the specific Procedure Related Adverse Event reported for the 
worsening condition or new diagnosis. 
 
Refer to Instructions for Use for the known risks associated with the commercial device(s). 
 
 Definitions and Classification 
Adverse event definitions are provided in Table 17.2-1. Administrative edits were made on 
the safety definitions from ISO 14155 and MEDDEV 2.7/3 for clarification purposes. 
 
Table 17.2-1: Safety Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
 
 
 
 
Any untoward medical occurrence, unintended disease or injury, or any 
untoward clinical signs (including an abnormal laboratory finding) in 
subjects, users or other persons, whether or not related to the study 
medical device.  
NOTE 1: This includes events related to the study medical device or 
comparator. 
NOTE 2: This definition includes events related to the procedures 
involved. 
NOTE 3: For users or other persons, this definition is restricted to events 
related to the study medical device.  
Adverse Device Effect (ADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
Adverse event related to the use of the study medical device 
NOTE 1: This includes any adverse event resulting from 
insufficiencies or inadequacies in the instructions for use, the 
deployment, the implantation, the installation, the operation, or any 
malfunction of the study medical device. 
NOTE 2: This definition includes any event resulting from use error 
or intentional abnormal use of the study medical device. 
Serious Adverse Event (SAE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
Note: This definition meets the reporting objectives and requirements of 
ISO 14155 and MEDDEV 2.7/3. 
Adverse event that: 
a) Led to death, 
b) Led to  serious deterioration in the health of the subject as defined by 
either: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, 
or 
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Table 17.2-1: Safety Definitions 
Term 
Definition 
3) in-patient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization, or 
4) medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body structure or 
a body function 
c) Led to fetal distress, fetal death, or a congenital abnormality or birth 
defect. 
NOTE 1: Planned hospitalization for a pre-existing condition, or a 
procedure required by the clinical investigational plan, without a serious 
deterioration in health, is not considered a serious adverse event.  
Serious Adverse Device Effect 
(SADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 
Unanticipated Adverse Device 
Effect (UADE) 
 
Ref: 21 CFR Part 812 
 
Any serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including 
a supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or 
welfare of subjects.   
Unanticipated 
Serious 
Adverse 
Device 
Effect 
(USADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
 
Serious adverse device effect which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk analysis 
report. 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been identified 
in the risk analysis report. 
Device Deficiency 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
An inadequacy of the study medical device related to its identity, quality, 
durability, reliability, safety or performance. This may include 
malfunctions, use error, or inadequacy in the information supplied by the 
manufacturer. 
 
 Relationship to Device(s) 
The Investigator must assess the relationship of the reportable AE to the device or 
procedure. See criteria in Table 17.3-1:  
 
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Table 17.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
Not Related 
Ref: MEDDEV 2.7/3 
Relationship to the device or procedures can be excluded when: 
- the event is not a known side effect of the product category the device belongs 
to or of similar devices and procedures; 
- the event has no temporal relationship with the use of the study device or the 
procedures; 
- the serious event does not follow a known response pattern to the medical device 
(if the response pattern is previously known) and is biologically implausible; 
- the discontinuation of medical device application or the reduction of the level 
of activation/exposure - when clinically feasible – and reintroduction of its use 
(or increase of the level of activation/exposure), do not impact on the serious 
event; 
- the event involves a body-site or an organ not expected to be affected by the 
device or procedure;  
- the serious event can be attributed to another cause (e.g. an underlying 
or concurrent illness/ clinical condition, an effect of another device, drug, 
treatment or other risk factors); 
- the event does not depend on a false result given by the study device used for 
diagnosis, when applicable; harms to the subject are not clearly due to use error; 
- In order to establish the non-relatedness, not all the criteria listed above might 
be met at the same time, depending on the type of device/procedures and the 
serious event. 
Unlikely Related 
Ref: MEDDEV 2.7/3 
The relationship with the use of the device seems not relevant and/or the event 
can be reasonably explained by another cause, but additional information may be 
obtained. 
Possibly Related 
Ref: MEDDEV 2.7/3 
The relationship with the use of the study device is weak but cannot be ruled out 
completely. Alternative causes are also possible (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). 
Cases were relatedness cannot be assessed or no information has been obtained 
should also be classified as possible. 
Probably Related 
Ref: MEDDEV 2.7/3 
The relationship with the use of the study device seems relevant and/or the event 
cannot be reasonably explained by another cause, but additional information may 
be obtained. 
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Table 17.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
Causal Relationship 
Ref: MEDDEV 2.7/3 
The serious event is associated with the study device or with procedures beyond 
reasonable doubt when: 
- the event is a known side effect of the product category the device belongs to 
or of similar devices and procedures; 
- the event has a temporal relationship with the study device use/application or 
procedures; 
- the event involves a body-site or organ that 
-the study device or procedures are applied to; 
-the study device or procedures have an effect on; 
- the serious event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
- the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
- other possible causes (e.g. an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled 
out; 
- harm to the subject is due to error in use; 
- the event depends on a false result given by the study device used for diagnosis, 
when applicable; 
- In order to establish the relatedness, not all the criteria listed above might be 
met at the same time, depending on the type of device/procedures and the serious 
event. 
 
 Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 17.4-1. 
Adverse events and device deficiencies must always be reported through the eCRF system. 
In the event that an alternative method of reporting is necessary (i.e. the eCRF system is 
unavailable), please report the adverse event or device deficiency to Boston Scientific by 
sending the Event Notification Form via email to the following email address: 
 
 
  
 
 
 
 
 
 
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Table 17.4-1: Investigator reporting Requirements 
Event Classification 
Communication Method  
Communication 
Timeline 
post-market 
studies*  
(MEDDEV 2.12/2:  
GUIDELINES ON A MEDICAL DEVICE 
VIGILANCE SYSTEM) 
Unanticipated Adverse Device 
Effect / Unanticipated Serious 
Adverse Device Effect  
 
Complete AE eCRF page 
with all available new and 
updated information.  
• 
Within 1 business day of first becoming 
aware of the event. 
• 
Terminating at the end of the study. 
 
 
Provide all relevant source 
documentation 
(de-
identified/ pseudonymized) 
for reported event.  
• 
Upon request of sponsor.  
Serious Adverse Event  
Complete AE eCRF page 
with all available new and 
updated information.  
• 
Within 10 business days after becoming 
aware of the event or as per local/regional 
regulations.  
• 
All death events must be reported within 3 
calendar days 
• 
Reporting required through the end of the 
study 
Provide all relevant source 
documentation 
(de-
identified/ pseudonymized) 
for reported event.  
• 
Upon request of sponsor  
Serious 
Adverse 
Device 
Effects 
Complete AE eCRF page 
with all available new and 
updated information. 
• 
Within 2 business days of first becoming 
aware of the event or as per local/regional 
regulations. 
• 
Reporting required through the end of the 
study 
Provide all relevant source 
documentation 
(de-
identified/ pseudonymized) 
for reported event.  
• 
Upon request of sponsor  
Device 
Deficiencies 
(including but not limited to 
failures, malfunctions, and 
product nonconformities) 
Note:  Any Device Deficiency 
that might have led to a serious 
adverse event if a) suitable 
action had not been taken or b) 
intervention had not been 
made or c) if circumstances 
had been less fortunate is 
considered a reportable event. 
Complete DD eCRF with 
all 
available 
new 
and 
updated information.  
• 
Within 2 business days of first becoming 
aware of the event. Reporting required 
through the end of the study 
Provide all relevant source 
documentation 
(de-
identified/ pseudonymized) 
for reported event. 
• 
Upon request of sponsor 
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Event Classification 
Communication Method  
Communication 
Timeline 
post-market 
studies*  
(MEDDEV 2.12/2:  
GUIDELINES ON A MEDICAL DEVICE 
VIGILANCE SYSTEM) 
Adverse 
Event 
including 
Adverse Device Effects 
Complete AE eCRF page, 
which 
contains 
such 
information as date of AE, 
treatment of AE resolution, 
assessment of seriousness 
and relationship to the 
device.  
• 
In a timely manner  (e.g. recommend 
within 30 business days) after becoming 
aware of the information 
• 
Reporting required through the end of the 
study 
Provide all relevant source 
documentation 
(de-
identified/ pseudonymized) 
for reported event.  
 
 Boston Scientific Device Deficiencies 
All device deficiencies (including but not limited to failures, malfunctions, use errors, 
product nonconformities, and inadequacy in the information supplied by the manufacturer) 
associated with the study devices will be documented and reported to BSC (as per table 
17.4-1). If possible, the device(s) should be returned to BSC for analysis. Instructions for 
returning the device(s) will be provided upon request. If it is not possible to return the 
device, the investigator should document why the device was not returned and the final 
disposition of the device. Device deficiencies should also be documented in the subject’s 
source records. 
Device deficiencies are not adverse events. However, an adverse event that results from a 
device deficiency, would be recorded as an adverse event on the appropriate eCRF in 
addition to completing a Device Deficiency eCRF. 
 Reporting to Regulatory Authorities  / ECs / Investigators 
BSC is responsible for reporting adverse event information to all participating Principal 
Investigators, ECs and regulatory authorities, as applicable.  
The Principal Investigator is responsible for informing the EC, and regulatory authorities 
of UADEs and SAEs as required by local/regional regulations. 
 
 Subject Death Reporting  
A subject death during the study should be reported to Boston Scientific as soon as possible 
and, in any event, within three (3) calendar days of site notification. The site’s EC must be 
notified of any deaths in accordance with that site’s EC policies and procedures.  
Upon request of sponsor, notification of death must include a detailed narrative (death 
letter) that provides detailed information describing the circumstances surrounding the 
death. A death narrative in the local language is acceptable, if accompanied by a translation 
in English. The details listed below should be addressed in the death narrative, in order for 
BSC to understand the circumstance surrounding the death:  
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• Date and time of death; 
• Place death occurred; 
• Immediate cause of death; 
• Rhythm at the time of death, if known (include any available documentation); 
• Whether the death was related to the study devices, clinical study, procedure, or 
subject condition; 
• Whether or not the death was witnessed; 
• Whether the subject had worsening heart failure; 
• Any other circumstances surrounding the death; 
• Approximate time interval from the initiating event to death (temporal course) – 
items to consider include, but are not limited to: information regarding last time 
subject was seen by investigator, last office visit, etc. 
• Investigator or sub-Investigator signature and date. 
 
Also submit the following documentation, upon request from sponsor:  
If the subject expired in the hospital:  
• A copy of the medical records for that admission (e.g., H&P, consults, test results, 
operative reports, and/or progress notes from the hospital chart); 
• Death certificate (if available); 
• Autopsy report (if applicable); 
 
If the subject expired outside of the hospital (e.g., home): 
• A copy of the most recent clinic visit (if not already submitted to Boston Scientific); 
• Death certificate (if available); 
• If applicable, the Boston Scientific catheters should be returned promptly to Boston 
Scientific CRM/EP for analysis. 
 
18. Informed Consent 
Subject participation in this clinical study is voluntary.  Informed Consent is required from 
each subject or his/her legally authorized representative. The Investigator is responsible for 
ensuring that Informed Consent is obtained prior to the use of any study devices, study-
required procedures and/or testing, or data collection.  
The obtaining and documentation of Informed Consent must be in accordance with the 
principles of the Declaration of Helsinki, ISO 14155, any applicable national regulations, 
and local Ethics Committee and/or Regulatory authority, as applicable. The ICF must be 
accepted by BSC or its delegate (e.g. CRO), and approved by the site’s EC, or central EC, 
if applicable. 
Boston Scientific will provide a study-specific template of the ICF to investigators 
participating in this study. The ICF template may be modified to meet the requirements of 
the investigative site’s EC.  Any modification requires acceptance from BSC prior to use 
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of the form.  The ICF must be in a language understandable to the subject and if needed, 
BSC will assist the site in obtaining a written consent translation. Translated consent forms 
must also have EC approval prior to their use. Privacy language shall be included in the 
body of the form or as a separate form as applicable.   
The process of obtaining Informed Consent shall at a minimum include the following steps, 
as well as any other steps required by applicable laws, rules, regulations and guidelines: 
• be conducted by the Principal Investigator or designee authorized to conduct the 
process,  
• include a description of all aspects of the clinical study that are relevant to the subject’s 
decision to participate throughout the clinical study, 
• avoid any coercion of or undue influence of subjects to participate, 
• not waive or appear to waive subject’s legal rights, 
• use native language that is non-technical and understandable to the subject or his/her 
legal representative, 
• provide ample time for the subject to consider participation and ask questions if 
necessary, 
• ensure important new information is provided to new and existing subjects throughout 
the clinical study.  
The ICF shall always be signed and personally dated by the subject or legal representative 
competent to sign the ICF under the applicable laws, rules, regulations and guidelines and 
by the investigator and/or an authorized designee responsible for conducting the informed 
consent process. If a legal representative signs, the subject shall be asked to provide 
informed consent for continued participation as soon as his/her medical condition allows. 
The original signed ICF will be retained by the site and a copy of the signed and dated 
document and any other written information must be given to the person signing the form.  
Failure to obtain subject consent will be reported by BSC to the applicable regulatory 
authority according to their requirements (e.g., FDA requirement is within 5 working days 
of learning of such an event). Any violations of the informed consent process must be 
reported as deviations to the sponsor and local regulatory authorities (e.g. EC), as 
appropriate. 
If new information becomes available that can significantly affect a subject's future health 
and medical care, that information shall be provided to the affected subject(s) in written 
form via a revised ICF or, in some situations, enrolled subjects may be requested to sign 
and date an addendum to the ICF. In addition to new significant information during the 
course of a study, other situations may necessitate revision of the ICF, such as if there are 
amendments to the applicable laws, protocol, a change in Principal Investigator, 
administrative changes, or following annual review by the EC. The new version of the ICF 
must be approved by the EC. Acceptance by Boston Scientific is required if changes to the 
revised ICF are requested by the site’s EC. The EC will determine the subject population 
to be re-consented. 
 
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19. Committees 
 Safety Monitoring Process 
BSC Safety Trial Operations reviews all reported adverse events and device deficiencies 
on a regular basis and, as required, with BSC Medical Safety per the study specific safety 
plan.  During scheduled monitoring activities, clinical research monitors will support this 
continuous review through their review of source documents and other data information. 
The BSC Medical Safety group includes physicians with expertise in Electrophysiology 
and with the necessary therapeutic and subject matter expertise to evaluate and classify the 
events into the categories outlined above. 
 Steering Committee 
A Steering Committee composed of the sponsor’s Clinical Management and other 
prominent Electrophysiologists from around Europe has been convened for this study.  
Responsibilities for the Committee may include oversight of the overall conduct of the 
study with regard to protocol development, study progress, subject safety, overall data 
quality and integrity, and first line review and final decision making of independent medical 
reviewer recommendations, as well as disseminating any study results through appropriate 
scientific sessions and publications.  Steering Committee members may participate in the 
review and approval of all requests for data analysis, abstract and manuscript preparation, 
and submission.   
20. Suspension or Termination 
22.1 Premature Termination of the Study 
Boston Scientific reserves the right to terminate the study at any stage but intends to 
exercise this right only for valid scientific or business reasons and reasons related to 
protection of subjects.  Investigators, associated ECs, and regulatory authorities, as 
applicable, will be notified in writing in the event of study termination. 
22.1.1 Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the 
following: 
• The occurrence of unanticipated adverse device effects that present a significant or 
unreasonable risk to subjects enrolled in the study. 
• An enrollment rate far below expectation that prejudices the conclusion of the study.  
• A decision on the part of Boston Scientific to suspend or discontinue 
development/marketing of the device. 
22.2 Termination of Study Participation by the Investigator or Withdrawal of EC 
Approval 
Any investigator, or associated EC or regulatory authority may discontinue participation in 
the study or withdraw approval of the study, respectively, with suitable written notice to 
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Boston Scientific. Investigators, associated ECs, and regulatory authorities, as applicable, 
will be notified in writing in the event of these occurrences. 
22.3 Requirements for Documentation and Subject Follow-up 
In the event of premature study termination a written statement as to why the premature 
termination has occurred will be provided to all participating sites by Boston Scientific. 
The EC and regulatory authorities, as applicable, will be notified. Detailed information on 
how enrolled subjects will be managed thereafter will be provided.  
In the event an EC terminates participation in the study, participating investigators, 
associated ECs, and regulatory authorities, as applicable, will be notified in writing. 
Detailed information on how enrolled subjects will be managed thereafter will be provided 
by Boston Scientific. 
In the event a Principal Investigator terminates participation in the study, study 
responsibility will be transferred to another investigator, if possible. In the event there are 
no opportunities to transfer Principal Investigator responsibility; detailed information on 
how enrolled subjects will be managed thereafter will be provided by Boston Scientific. 
The Principal Investigator or his/her designee must return all study-related documents and 
devices, if supplied by Boston Scientific, unless this action would jeopardize the rights, 
safety, or welfare of the subjects. 
22.4 Criteria for Suspending/Terminating a Study Site 
Boston Scientific reserves the right to stop the inclusion of subjects at a study site at any 
time after the study initiation visit if no subjects have been enrolled  for a period beyond 
12 months after site initiation, or if the site has multiple or severe protocol 
violations/noncompliance without justification and/or fails to follow remedial actions. 
In the event of termination of site participation, all devices and testing equipment, as 
applicable, will be returned to BSC unless this action would jeopardize the rights, safety or 
well-being of the subjects. The EC and regulatory authorities, as applicable, will be 
notified. Study participants will be contacted, as applicable, and be informed of changes to 
study visit schedule. 
 
21. Publication Policy 
BSC requires disclosure of its involvement as a sponsor or financial supporter in any 
publication or presentation relating to a BSC study or its results. BSC will submit study 
results for publication (regardless of study outcome) following the conclusion or 
termination of the study. Boston Scientific adheres to the Contributorship Criteria set forth 
in the Uniform Requirements of the International Committee of Medical Journal Editors 
(ICMJE; http://www.icmje.org). In order to ensure the public disclosure of study results in 
a timely manner, while maintaining an unbiased presentation of study outcomes, BSC 
personnel may assist authors and investigators in publication preparation provided the 
following guidelines are followed:  
• All authorship and contributorship requirements as described above must be followed. 
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• BSC involvement in the publication preparation and the BSC Publication Policy should 
be discussed with the Coordinating Principal Investigator(s) and/or Executive/Steering 
Committee at the onset of the project. 
• The First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission.  
The data, analytic methods, and study materials for this clinical study may be made 
available to other researchers in accordance with the Boston Scientific Data Sharing Policy 
(https://www.bostonscientific.com/).  
 
22. Bibliography 
1. January, CT et al., 2014 AHA/ACC/HRS guideline for the management of patients 
with atrial fibrillation:  a report of the American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines and the Heart Rhythm 
Society. J Am Coll Cardiol 2014; 64(21): e1-e76. 
2. Lloyd-Jones, DM et al., Defining and setting national goals for cardiovascular 
health promotion and disease reduction: the American Heart Association's 
strategic Impact Goal through 2020 and beyond. Circulation. 2010 Feb 
2;121(4):586-613. doi: 10.1161/CIRCULATIONAHA.109.192703. Epub 2010 
Jan 20. 
3. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial 
fibrillation: European perspective. Clin Epidemiol. 2014; 6: 213–220.  
4. Friberg J BP, Scharling H. Rising rates of hospital admissions for atrial 
fibrillation. Epidemiology 2003;14 666-672. 
5. Wolf PA BEaBA. Secular trends in the prevalence of atrial fibrillation: The 
framingham study. Am heart J 1996; 131:790-795. 
6. Furburg CD PB, Manolio TA, et al. Prevalence of diagnosed atrial fibrillation in 
elderly subjects. Am J Cardiol. 1995; 74:236-241. 
7. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor 
for stroke: the Framingham Study. Stroke. 1991;22:983–988  
8. Wann S CA, January C, et al. ACC/AHA/HRS focused update on the management 
of patients with atrial fibrillation (2011 writing group members) (updating the 
2006 guideline): A report of the American College of Cardiology 
Foundation/American Heart Association task force on practice guidelines. 
Circulation. 2011; 123:104-123. 
9. Wazni O, Wilkoff, B, Saliba, W. Catheter ablation for atrial fibrillation. New Engl 
J Med. 2011; 365:2296-2304. 
10. Kirchhof P, Benussi S, Kotecha D, Ahlsson , Atar D, Casadei B, Castella M, et al. 
2016 ESC Guidelines for the management of atrial fibrillation developed in 
collaboration with EACTS. Eur Heart J. 2018 Apr 1;39(13):1109 
11. Calkins H, Hindricks G, Cappato R, et al. 2017 HRS/EHRA/ECAS/APHRS/ 
SOLAECE expert consensus statement on catheter and surgical ablation of atrial 
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fibrillation: Executive summary: executive summary. Europace. 2018 Jan 
1;20(1):157-208. 
12. Packer D, Kowal R, Wheelan K, Irwin J, et al. Cryoballoon Ablation of Pulmonary 
Veins for paroxysmal Atrial Fibrillation. JACC, 2013;61:1713‐23. 
13. Kuck KH, Brugada J, Furnkranz A, Metzner A, Ouyang F, Chun KR, Elvan A, 
Arentz T, Bestehorn K, Pocock SJ, Albeneque JP, Tondo C, for the FIRE AND 
ICE Investigators. Cryoballoon or radiofrequency ablation for paroxysmal atrial 
fibrillation. N Engl J Med, 2016;374:2235–2245.Medtronic Press Release, 
“Clinical Trial to Evaluate Medtronic Cryoablation as First‐Line Treatment for 
Patients with Symptomatic Paroxysmal Atrial Fibrillation”, July 11, 2017. 
14. Epstein AE CM, Fogoros RN, et al. Classification of death in antiarrhythmia trials. 
J Am Coll Cardiol 1996; 27:433-442 
 
 
23. Abbreviations and Definitions  
 Abbreviations 
Abbreviations are shown in Table 23.1-1.   
Table 23.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
AAD 
Anti-Arrhythmic Drugs 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AFL 
Atrial Flutter 
AT 
Atrial Tachycardia 
CA 
Competent Authority 
CABG 
Coronary artery bypass grafting 
CRF 
Case Report Form 
CVA 
Cerebrovascular Accident 
DD 
Device Deficiency 
DMS 
Diaphragm Movement Sensor 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ICB 
Inter Connection Box 
ICE 
Intracardiac Echo 
ICF 
Informed Consent Form 
IFU 
Instructions for Use 
LA 
Left Atrium 
MI 
Myocardial Infarction 
MRI 
Magnetic Resonance Imaging 
N2O 
Nitrous Oxide 
PAF 
Paroxysmal Atrial Fibrillation 
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Table 23.1-1: Abbreviations 
Abbreviation/Acronym 
Term 
PeAF 
Persistent Atrial Fibrillation 
PFO 
Patent Foramen Ovale 
PMCF 
Post Market Clinical Follow-up 
PTCA 
Percutaneous transluminal coronary angioplasty 
PV 
Pulmonary Vein 
PV 
Pulmonary Venogram 
PVI 
Pulmonary Vein Isolation 
RA 
Right Atrium 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
TEE 
Trans-esophageal echocardiography 
TIA 
Transient Ischemic Attack 
TSF 
Technical Source Form 
TTE 
Trans-Thoracic echocardiography 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
 Definitions 
Terms are defined in Table 23.2-1. 
Table 23.2-1 Definitions 
Term 
Definition 
Activated 
Coagulation/Clotting 
Time 
ACT is a test that is used to monitor the effectiveness of high dose heparin 
therapy. 
Arterial-Venous Fistula 
Abnormal communication between an artery and a vein. 
Atrioesophageal Fistula 
A connection between the atrium and the lumen of the esophagus. 
Attempt Subject 
Any subject that signs the consent form, and has any study device inserted 
into the body but does not receive any Cryoablation application.  
AV block 
A conduction disturbance that results in the partial inability of an electrical 
impulse generated in the atria to reach the ventricles. 
Blanking Period 
90-day period between ablation procedure and the initiation of the 
Effectiveness Evaluation Period during which up to one additional ablation 
procedure can be performed and subjects can be prescribed antiarrhythmic 
drugs as determined necessary by the investigator. 
Cardiac tamponade/ 
perforation 
 
The development of a significant pericardial effusion during or within 30 
days of undergoing an AF ablation procedure. A significant pericardial 
effusion is one that results in hemodynamic compromise, requires elective 
or urgent pericardiocentesis, or results in a 1-cm or more pericardial 
effusion as documented by echocardiography.  
Embolism 
The sudden blocking of an artery by a clot or foreign material which has 
been brought to its site of lodgment by the blood current. 
Enrolled Subject 
A subject who has given written informed consent to participate in the 
study. 
Hematoma 
A localized collection of blood, usually clotted, in an organ, space or tissue, 
due to a break in the wall of a blood vessel. 
Intent Subject 
Any subject that signs the consent form but does not have any study devices 
inserted into the body. Subjects who are enrolled in the study but do not 
undergo ablation procedure within 90 days from consent signature date 
may not be reconsented and will be withdrawn from the study. 
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Term 
Definition 
In-patient Hospitalization 
Hospitalizations ≥24 hours in duration or <24 hours with medical 
intravenous therapy or surgical intervention 
Myocardial infarction (in 
the context of AF 
ablation) 
The presence of any one of the following criteria:  
(1) detection of ECG changes indicative of new ischemia (new STT wave 
changes or new LBBB) that persist for more than 1 hour;  
(2) development of new pathological Q waves on an ECG;  
(3) imaging evidence of new loss of viable myocardium or new regional 
wall motion abnormality 
Occlusion Grade 
Score 4 = excellent (full retention of contrast medium without visible 
outflow)  
Score 3 = moderate (incomplete occlusion with slight leakage of contrast 
medium)  
Score 2= poor  (presence of sustained and massive leakage of contrast 
medium) 
Score 1 = very poor (immediate rapid outflow from the PV). 
Paroxysmal 
Atrial 
Fibrillation 
(PAF) 
Recurrent symptomatic Atrial Fibrillation that terminates spontaneously or 
with intervention within seven days of onset. 
Pericardial Effusion 
A collection of fluid or blood in the pericardial space around the heart or 
in pleural space around the lungs. 
Pericarditis 
Inflammation of the pericardium surrounding the heart.  Pericarditis should 
be considered a major complication following ablation if it results in an 
effusion 
that 
leads 
to 
hemodynamic 
compromise 
or 
requires 
pericardiocentesis, prolongs hospitalization by more than 48 hours, 
requires hospitalization, or persists for more than 30 days following the 
ablation procedure. 
Pneumothorax 
Collapse of the lung due to an abrupt change in the intrapleural pressure 
within the chest cavity. 
Primary Effectiveness Failure 
A TREATMENT subject with  
• 
 Acute procedure failure 
• 
 More than one repeat procedure during the blanking period 
• 
Documented atrial fibrillation, or new onset of atrial flutter or 
atrial tachycardia event (≥ 30 seconds in duration from an event 
monitor or Holter, or from a 10 second 12-lead ECG) between 
91 and 365 days post index procedure 
Any of the following interventions for atrial fibrillation, or new onset of 
atrial flutter or atrial tachycardia between 91 days and 365 days post index 
procedure: 
• 
Repeat procedure 
• 
Electrical and/or pharmacological cardioversion for AF/AT/AFL 
• 
Prescribed a higher dose of any AAD documented at baseline or 
a new AAD not documented at baseline 
Procedural Success 
Pulmonary vein isolation achieved with the Boston Scientific cryoablation 
system as demonstrated by entrance block at the minimum. 
Prolonged Hospitalization 
Hospitalization ≥72 hours after the study procedure for reasons other than 
anticoagulation 
Pseudoaneurysm 
A dilation of an artery with disruption of one or more layers of its walls. 
Pulmonary 
Vein 
Stenosis 
(Significant) 
 
Pulmonary vein stenosis is defined as a reduction of the diameter of a PV 
or PV branch. For the primary safety endpoint of this study, significant 
pulmonary vein stenosis is defined as symptomatic and requiring 
intervention. 
Pulmonary edema/heart failure 
Ineffective pumping of the heart leading to an accumulation of fluid in the 
lungs. Typical symptoms include shortness of breath with exertion, 
difficulty breathing when lying flat and leg or ankle swelling. 
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Term 
Definition 
Source Data 
All information in original records of clinical findings, observations, or 
other activities in a clinical study, necessary for the reconstruction and 
evaluation of the clinical study (original records or certified copies). 
Source Document 
Printed, optical or electronic document containing source data. Examples: 
Hospital records, laboratory notes, device accountability records, 
radiographs, records kept at the investigation site, and at the laboratories 
involved in the clinical study. 
Stroke/Cerebrovascular accident 
(CVA) 
 
Rapid onset of a focal or global neurological deficit with at least one of the 
following: change in level of consciousness, hemiplegia, hemiparesis, 
numbness or sensory loss affecting one side of the body, dysphasia 
or aphasia, hemianopia, amaurosis fugax, or other neurological signs or 
symptoms consistent with stroke. 
Duration of a focal or global neurological deficit ≥24 hours; OR <24 hours 
if therapeutic intervention(s) were performed (e.g., thrombolytic therapy or 
intracranial angioplasty); OR available neuroimaging documents a new 
hemorrhage or infarct; OR the neurological deficit results in death. 
No other readily identifiable non-stroke cause for the clinical presentation 
(e.g., brain tumor, trauma, infection, hypoglycemia, peripheral lesion, 
pharmacological influences). 
Confirmation of the diagnosis by at least one of the following: neurology 
or neurosurgical specialist; neuroimaging procedure (MRI or CT scan or 
cerebral angiography); lumbar puncture (i.e., spinal fluid analysis 
diagnostic of intracranial hemorrhage) 
Symptomatic AF 
Required symptom(s) of AF that were experienced by the subject, made 
them seek medical attention, and were concurrent with a documented 
episode by ECG, event monitoring and/or Holter monitor. Symptoms may 
have included palpitations, irregular pulse (i.e. rapid, racing, pounding, 
fluttering, bradycardic), dizziness, weakness, chest discomfort, and 
breathlessness. 
Thrombus 
An aggregation of blood factors, primarily platelets and fibrin with 
entrapment of cellular elements, frequently causing vascular obstruction at 
the point of its formation. 
Thromboembolism 
The blockage of a blood vessel lumen by air or solid material such as device 
fragments, blood clot or other tissues that have migrated from another 
anatomic site. 
Transient Ischemic Attack (TIA) 
New focal neurological deficit with rapid symptom resolution (usually 1 to 
2 hours), always within 24 hours; neuroimaging without tissue injury 
Treatment Subject 
Any subject that signs the consent form, and has the specified study devices 
inserted into the body and undergoes protocol specific treatment for the 
intended disease. 
Vagal Nerve Injury/Gastroparesis  
Vagal nerve injury is defined as injury to the vagal nerve that results in 
esophageal dysmotility or gastroparesis.  Vagal nerve injury is considered 
to be a major complication if it prolongs hospitalization, requires 
hospitalization, or results in ongoing symptoms for more than 30 days 
following an ablation procedure 
Vascular access complications 
Development of a hematoma, an AV fistula, or a pseudoaneurysm. A major 
vascular complication is defined as one that requires intervention, such as 
surgical repair or transfusion, prolongs the hospital stay, or requires 
hospital admission. 
 
 
 
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Form/Template 92120219_Rev/Ver C 
          Confidential 
 
 
    POLAR ICE Protocol, 92499974, Rev/Ver B 
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Released
92499974 B.3
POLAR ICE - Study Protocol
E.D: 07/May/2020 Boston Scientific Confidential. Unauthorized use is prohibited.
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