Safety and Effectiveness IDE Trial for Boston Scientific's Cryoballoon in the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial Fibrillation
Phase: NA
Conditions: Paroxysmal Atrial Fibrillation
Sponsor: Boston Scientific Corporation

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Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in 
the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial 
Fibrillation 
FROzEN-AF 
PY004 
CLINICAL INVESTIGATION PLAN 
G190060 
National Clinical Trial (NCT) Identified Number: NCT04133168 
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 Contacts 
Clinical Trial Managers, Protocol Authors 
 
Sarah Kenneweg 
Clinical Trial Manager 
4100 Hamline Ave. N. 
St. Paul, MN 55112 
USA 
Tel. +1 (510) 701- 1351 
Sarah.kenneweg@bsci.com 
 
Sheryl McCammon 
Clinical Trial Manager 
4100 Hamline Ave. N. 
St. Paul, MN 55112 
USA 
Tel. +1 (763) 647- 0113 
Sheryl.McCammon@bsci.com 
 
Elke Sommerijns 
Sr. Clinical Trial Manager 
Guidant Europe, a Boston Scientific Company 
Green Square, Lambroekstraat 5D 
 
1831 Diegem 
Belgium 
Tel. +32 479 76 71 56 
Elke.sommerijns@bsci.com 
 
Coordinating Principal 
Investigator(s) 
Kenneth Ellenbogen, MD 
Kimmerling Professor of Cardiology 
Chair, Division of Cardiology 
VCU Pauley Heart Center 
Medical College of Virginia / VCU School of Medicine 
Gateway Building 
1200E. Marshall Street 
3rd Floor – Electrophysiology Division - Room 3-223 
Richmond, Virginia 23219 
Office (804) 828-7565  
E-mail: kenneth.ellenbogen@vcuhealth.org 

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Executive Steering 
Committee Members 
Ante Anić, MD 
EP lab, Heart Center, 
University Hospital Split, 
Croatia 
A. Starcevica 25 D, 23000 
Zadar, Croatia 
Telephone: +38523240605 
Email: anteanic@gmail.com 
Robin Boisseau 9131 Stony 
Point Parkway Apt 3213 
Richmond, VA 23235. Tel: 
(843) 860-9004   Email: 
Robin.Boisseau@vcuhealth.org 
Arash Aryana, MD, PhD, 
FACC, FHRS 
Medical Director, 
Cardiovascular Services 
Mercy General Hospital 
3941 J Street, Suite #350 
Sacramento, CA 95819 
(916) 453 2684 
E-mail:   
a_aryana@outlook.com 
Nassir Marrouche, MD  
Tulane University School of 
Medicine  
Cardiology 
1430 Tulane Avenue, Box 8548 
New Orleans, LA 70112 
(804) 988-2025                             
Email: 
Nmarrouche@tulane.edu 
 
Suneet Mittal, MD, FACC, 
FHRS 
Director, Electrophysiology 
Associate Chief of Cardiology 
Medical Director, Snyder AF 
Center 
Director, Cardiac Research 
200 West 57th Street, Suite 610 
New York, NY 10019 
(212) HEART DR (432-7837) 
Email: 
MITTSU@Valleyhealth.com 
 
Niraj Varma MD, PhD, FRCP 
Cardiac Pacing & 
Electrophysiology  
Department of Cardiovascular 
Medicine 
Cleveland Clinic 
 9500 Euclid Ave J2-2 
Cleveland, OH 44195  
(216) 444-2142  
Email: varman@ccf.org 
Wilber W. Su, MD, FACC, 
FHRS 
Cardiology and Cardiac 
Electrophysiology 
Banner– University Medical 
Group- Heart Center 
755 E. McDowell Rd, 4th 
Floor 
Phoenix, AZ 85006 
(602) 521-3090 
Email: wilwsu@gmail.com 
This section is intentionally left blank. 
Vendors/Labs/External 
Organizations 
A list of vendors/core laboratories/external organizations 
involved in the trial is maintained by the sponsor.  
 

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Original Release: 30-Jan-2019 
Revision 
Version 
Protocol 
Date 
Template 
number and 
version 
Protocol 
Section 
Modified 
Summary of Changes 
Justification for Modification 
C 
4-Mar-2019 
90702637, 
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NA 
Versions A to C incorporated internal changes prior to 
FDA submission 
NA 
D 
9-May-2019 
90702637, 
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Modifications according to initial FDA IDE review, 
application # G190060, 5 April 2019 
Modifications according to initial FDA IDE review, 
application # G190060, 5 April 2019 
E 
19-Aug-2019 
90702637, 
Rev/Ver AJ 
 
Modifications according to FDA IDE review 3July2019, 
application # G190060, 3 July 2019 
Modifications according to FDA IDE review, application 
# G190060, 3 July 2019 
F 
26-Aug-2019 
90702637, 
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Updated Table Numbering for Tables 14 through 17 
Incorrect table numbering 
G 
18-Sep-2019 
90702637, 
Rev/Ver AJ 
 
Modifications according to FDA IDE review, application 
# G190060, 16 September 2019 
Modifications according to FDA IDE review, application 
# G190060, 16 September 2019 
H 
NovNov-
2020 
90702637, 
Rev/Ver AN 
Throughout 
To comply updated BSC template versions (specifically 
highlighted in green in redlined version) 
Per BSC procedures, primarily driven by ISO 14155 
changes 
H 
Nov-2020 
90702637, 
Rev/Ver AN 
9.1 
Up to 50 sites in North America, Europe and Asia-Pacific 
may participate in this study. Up to 10 sites in Europe may 
contribute to enrollments. 
Europe added as a potential geography for study centers 
within the FROzEN-AF study. 
H 
Nov-2020 
90702637, 
Rev/Ver AN 
9.3.2 
For investigators participating in a geography in which the 
system is not investigational, a roll-in case may not be 
required if BSC can confirm the physician has previously 
treated patients with the system.   
Protocol revision H expands the geography to sites in 
Europe where the product is commercially available. 
H 
Nov-2020 
90702637, 
Rev/Ver AN 
10.2 
For inclusion criteria, “Subjects refractory or intolerant to 
at least one class I or III antiarrhythmic medication,” the 
following clause was added, “or contraindicated to any 
class I or III medications.”  
Providing clarification that subjects have either failed, are 
intolerant or contraindicated to at least one class I or III 
antiarrhythmic medication for inclusion in the study. 
H 
Nov-2020 
90702637, 
Rev/Ver AN 
10.2 
The defined criteria for PAF documentation for inclusion 
criteria was updated to the following:  
Requires documentation of 2 AF symptomatic recurrences 
in the medical file but allows ECG documentation to be 
extended to 12 months. 

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Revision 
Version 
Protocol 
Date 
Template 
number and 
version 
Protocol 
Section 
Modified 
Summary of Changes 
Justification for Modification 
History of recurrent symptomatic paroxysmal atrial 
fibrillation (PAF), defined as atrial fibrillation that 
terminates spontaneously or with intervention (either 
procedure or drug therapy) within seven days of onset. 
Minimum documentation includes the following: 
• 
a physician’s note indicating recurrent self-
terminating atrial fibrillation (AF) which includes 
at least two symptomatic AF episodes within last 
six months from enrollment, and  
• 
one electrocardiographically documented AF 
episode within 12 months prior to enrollment.   
H 
Nov-2020 
90702637, 
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10.3 
Removed the following exclusions: 
• 
Age maximum of 75 years 
• 
Body Mass index (BMI) ≥ 40 
• 
Inclusion criteria defined of >18 years with no 
maximum age limit for the randomized studies 
for which this single-arm trial design is based.   
• 
Exclusion criteria for BMI not included in the 
randomized studies for which this single-arm trial 
design is based. 
H 
Nov-2020 
90702637, 
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12.5.2 
Added language to define that if subject enrolled less than 
3 weeks prior to the procedure, pre-ablation 
anticoagulation must be initiated and maintained from 
point of enrollment to the day of the index procedure and 
that thrombus screening should be performed for these 
subjects.  
Per protocol, enrollment (subject consent) may occur any 
time during the 30 days before the index procedure, and 
clarification added pre-ablation anticoagulation regimen 
for subjects enrolled less than 3 weeks prior to the 
procedure. 
H 
Nov-2020 
90702637, 
Rev/Ver AN 
12.15 
Unforeseen Circumstances section added 
To provide guidance if patient follow-ups are not possible 
due to unforeseen circumstances (e.g. COVID-19).  
I 
Feb-2022 
90702637, 
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Appendix 
27.1 
Addition of Appendix 27.1 – POLARx FIT: FROzEN 
Extension Study 
To include a sub-study establishing the safety and 
effectiveness of Boston Scientific’s POLARx 
Cryoablation System with the POLARx FIT catheter. 
I 
Feb-2022 
90702637, 
Rev/Ver AP 
Title page 
and 
Contact 
Added NCT Identified Number and updated BSC Contact 
Information  
Updated contact information to reflect current BSC Study 
Managers 

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Revision 
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Protocol 
Date 
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number and 
version 
Protocol 
Section 
Modified 
Summary of Changes 
Justification for Modification 
Informatio
n 
I 
Feb-2022 
90702637, 
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Section 7.1 
Expanded Device Specification Tables  
Expanded device specifications to align with tables in 
IFUs 
I 
Feb-2022 
90702637, 
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Section 8.2, 
Table 5 
Added clarification as to which vascular access 
complication events would be considered primary safety 
endpoint events 
To remain consistent with the methods used in the meta-
analysis performed to determine expected rates and an 
appropriate performance goal for the primary safety 
endpoint 

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 Protocol Synopsis 
 
Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in 
the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial 
Fibrillation 
 
FROzEN-AF 
Study 
Objective(s) 
To establish the safety and effectiveness of the Boston Scientific 
Cardiac Cryoablation System for treatment of symptomatic, drug 
refractory, recurrent, paroxysmal atrial fibrillation (AF). 
Test Device  
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”) 
• Diaphragm Movement Sensor (DMS) 
• Related Accessories, as listed in protocol section 7.1.7.  
Control Device 
There are no control devices in this study.  
Planned 
Indication(s) for 
Use  
The Cryoablation System is intended for cryoablation and electrical 
mapping of the pulmonary veins for pulmonary vein isolation (PVI) in 
the ablation treatment of patients with paroxysmal atrial fibrillation 
(PAF). 
Treatment will occur according to the approved indication for use within 
each geography and the defined inclusion/exclusion criteria within the 
protocol. 
Study Design 
Multi-center, open label, prospective, single arm study to document the 
safety and performance of Boston Scientific’s Cryoablation System.  
All subjects fitting the enrollment criteria, signing the consent and 
undergoing the index procedure with the study devices will be followed 
up for twelve (12) months after the index procedure. FROzEN-AF will be 
conducted as a post market study in those regions where the device is 
approved, including Europe. 

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Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in 
the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial 
Fibrillation 
 
FROzEN-AF 
Planned 
Number of 
Subjects 
A maximum of 405 subjects treated with the Cryoablation System will 
be enrolled in the study, inclusive of a maximum of 80 roll-in 
TREATMENT subjects and 325 non roll-in TREATMENT subjects.  
Planned 
Number of 
Investigational 
Sites / Countries 
Up to 50 sites in North America, Europe and Asia-Pacific may 
participate in this study.. At least 50% of the sites and 50% of the 
subjects will enroll in the United States, potentially up to 10% of 
subjects will enroll in 3 to 5 combined sites from Hong Kong and 
Taiwan.  Up to 10 sites in Europe may contribute to enrollments. No 
study site will be allowed to contribute more than 15% of the required 
enrollment.  
Primary Safety 
Endpoint 
Primary safety event free rate at 12 months post 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 or hospital discharge, whichever is later, include:  
• Death 
• Myocardial infarction (MI) 
• Transient ischemic attack (TIA) 
• Stroke/ Cerebrovascular accident (CVA) 
• Vascular access complications 
• Mitral or tricuspid valvular damage 
• Thromboembolism/ Air embolism leading to a life-
threatening event such as a ventricular arrhythmia, stroke, 
pulmonary embolism, or myocardial infarction and, 
thromboembolic events that result in permanent injury, 
require intervention for treatment or prolongs or require 
hospitalization for more than 48 hours 
• Gastroparesis/injury to vagus nerve 
• Pneumothorax 
• Pulmonary edema/heart failure 
• AV block 
 
Cardiac tamponade/perforation, occurring up to 30 days post index 
procedure. 

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Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in 
the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial 
Fibrillation 
 
FROzEN-AF 
 
Chronic primary safety endpoint events, events occurring through 12 
months post procedure, include: 
• Atrial esophageal fistula 
• Severe Pulmonary vein stenosis (≥ 70% reduction in the 
diameter of the PV or PV branch from baseline) 
• Persistent phrenic nerve palsy   
 
 
Primary 
Effectiveness 
Endpoint 
Failure free rate at 12 months post procedure.  
Failure defined as: 
• Failure to achieve acute procedural success in the index 
procedure or repeat procedure during the blanking period  
• Use of amiodarone post index procedure 
• Surgical treatment for AF/AFL/AT post index procedure 
• Use of a non-study ablation catheter for AF targets in the 
index procedure or repeat procedure during the blanking 
period 
• More than one repeat procedure with the POLARx catheter 
during the blanking period (90 days post index procedure) 
• Documented atrial fibrillation, or new onset of atrial flutter 
or atrial tachycardia event [≥ 30 seconds in duration from the 
study specific event monitor, Holter Monitor, or from a 10 
second 12-lead Electrocardiography (ECG)] between days 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 days 
91 post index procedure and 365 days: 
• Repeat procedure 
• Electrical and/or pharmacological cardioversion 
for AF/AFL/AT  
• Prescribed any antiarrhythmic drug (AAD)*  
 
*AADs for endpoint will consist of all Class I/III, including Amiodarone, and any 
Class II/IV medications taken for control of atrial fibrillation (AF)/Atrial tachycardia 
(AT)/Atrial flutter (AFL) recurrence 

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Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in 
the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial 
Fibrillation 
 
FROzEN-AF 
Secondary 
Safety Endpoint 
Safety:  Reportable Adverse Events rates at 12 months. 
Adverse events will be collected at all subject follow-up visits. 
Reportable events include: 
• All Serious Adverse Events 
• All Study Procedure-Related Adverse Events 
• All Study Device-Related Adverse Events 
• All Study Device Deficiencies  
• Unanticipated Adverse Device Effects/Unanticipated Serious 
Adverse 
Device 
Effects 
previously 
not 
defined 
in 
Investigator’s Brochure or DFU 
Secondary 
Effectiveness 
Endpoint 
Rate of acute procedural success defined as the achievement of electrical 
isolation of all PVs by using the POLARx Cardiac Cryoablation system 
only. Electrical isolation of a PV is demonstrated by entrance and exit 
block.  
Additional 
Endpoints 
Additional endpoints and analysis include, but are not limited to:  
• Changes in the quality of life measures (AFEQT and EQ-5D-
5L) between baseline and 12 months follow up 
• Single procedure success defined as freedom from primary 
effectiveness failure without a repeat procedure  
• Duration of LA dwell time, defined as time from the 
Cryoablation Catheter exiting the sheath in the LA to time of 
final PV isolation 
• Total Cryoablation time for the index procedure; 
• Total fluoroscopy time for the index procedure; 
• Total index procedure time. 
• Freedom from recurrence of individual types of atrial 
arrhythmias between 91 and 365 days from index procedure: 
1) AF 2) AT 3) AFL  
• Failure-free rate as defined in primary effectiveness endpoint 
at 6 months post procedure 

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Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in 
the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial 
Fibrillation 
 
FROzEN-AF 
• Failure- free rate as defined in primary effectiveness endpoint 
when considering AF/AT/AFL episodes reported to the 
investigators by study specific (event recorder transmissions, 
12 lead ECG and Holter) and non-study related devices (other 
commercial applications for arrhythmia monitoring and 
detection the subject may access during the study including 
telemetry, other sources of continuous recording etc.) 
PV Stenosis 
Screening 
Substudy 
Screening for PV stenosis with computed tomography (CT) or cardiac 
magnetic resonance imaging (MRI) between 3 and 6 months post ablation 
will be performed in a subgroup of treated subjects. The subgroup will 
include a minimum of 50 subjects enrolled at up to 8 sites. Sites will be 
selected among those that use imaging as a standard-of-care for PV 
stenosis screening after AF ablation. 
• Each site participating in the sub study will enroll a maximum of 
18 substudy subjects.  
Patient 
Disposition and 
Method of 
Assigning 
Patients to 
Treatment 
Any subject that signs the consent form, meets eligibility criteria, has the 
study device inserted into the body and receives Cryoablation therapy 
will be assigned to the TREATMENT group. 
The disposition of all subjects enrolled in the study will be described in 
tables and diagrams.  The data will include number of subjects screened, 
subjects that fail screening, subjects treated and assessed at each follow-
up interval.  Subjects who fail screening, or who do not complete the 
study will be enumerated and the reason(s) for their screening failure or 
discontinuation from the study will be described. 
Follow-up 
Schedule 
Visits schedule:  pre-discharge, Day 7, 3 months (blanking period), 6 
months, 12 months.  
Study Duration Study is expected to last approximately 24 months (9-12 months for 
enrollment period with 12 months follow-up). 
Participant 
Duration 
The study duration for each subject is expected to be approximately 12 
months. 

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Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in 
the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial 
Fibrillation 
 
FROzEN-AF 
Inclusion 
Criteria 
• History of recurrent symptomatic paroxysmal atrial fibrillation 
(PAF), defined as atrial fibrillation that terminates spontaneously or 
with intervention (either procedure or drug therapy) within seven 
days of onset. Minimum documentation includes the following: 
o a physician’s note indicating recurrent self-terminating atrial 
fibrillation (AF) which includes at least two symptomatic AF 
episodes within six months prior to enrollment, and  
o one electrocardiographically documented AF episode within 
12 months prior to enrollment.   
• No amiodarone use within 90 days prior to enrollment 
• Subjects who are indicated for an ablation procedure for paroxysmal 
atrial fibrillation (PAF) according to 2017 HRS expert consensus 
statement on catheter and surgical ablation of atrial fibrillation 
• Subjects refractory or intolerant to at least one class I or III 
antiarrhythmic medication or contraindicated to any class I or III 
medications  
• Subjects who are willing and capable of providing informed consent  
• Subjects who are willing and capable of participating in all testing 
associated with this clinical investigation at an approved clinical 
investigational center 
• 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 
• Any known contraindication to an AF ablation or anticoagulation 
• Continuous AF lasting longer than seven (7) days from onset 
• History of previous left atrial ablation or surgical treatment for AF/ 
AFL/ AT 
• Atrial fibrillation secondary to electrolyte imbalance, thyroid 
disease, or any other reversible or non-cardiac cause 
• Structural heart disease or implanted devices as described below: 

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Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in 
the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial 
Fibrillation 
 
FROzEN-AF 
a. Left ventricular ejection fraction (LVEF) < 40% based on most 
recent transthoracic echocardiogram (TTE) performed ≤180 days 
prior to enrollment * 
b. Left atrial diameter > 5.5 cm OR left atrial volume > 50 ml/m2 
indexed based on the most recent TTE performed ≤ 180 days prior 
to enrollment * 
c. An implanted pacemaker, ICD, CRT device or an arrhythmia 
loop recorder 
d. Previous cardiac surgery: i.e. ventriculotomy or atriotomy 
(excluding atriotomy for CABG) 
e. Previous cardiac valvular surgical or percutaneous procedure, or 
prosthetic valve, including mitral valve clips 
f. Interatrial baffle, closure device, patch, or patent foramen ovale 
(PFO) occluder 
g. Presence of a left atrial appendage occlusion device 
h. Presence of any pulmonary vein stents 
i. Coronary artery bypass graft (CABG), PTCA/ PCI/ coronary 
stent procedures within 90 days prior to enrollment 
j. Unstable angina or ongoing myocardial ischemia 
k. Myocardial infarction within 90 days prior to enrollment 
l. Moderate or severe mitral stenosis [severity assessed on the most 
recent TTE ≤180 days prior to enrollment as pulmonary artery 
systolic pressure >30 mmHg(1)] 
m. Evidence of left atrial thrombus** 
• Any previous history of cryoglobulinemia 
• Stage 3B or higher renal disease (estimated glomerular filtration 
rate, eGFR <45 mL/min) 
• History of blood clotting or bleeding disease 

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Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in 
the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial 
Fibrillation 
 
FROzEN-AF 
• Any prior history of documented cerebral infarct, TIA or systemic 
embolism [excluding a post-operative deep vein thrombosis (DVT)] 
≤180 days prior to enrollment 
• Active systemic infection 
• Pregnant, lactating (current or anticipated during study follow up), or 
women of childbearing potential who are, or plan to become, 
pregnant during the time of the study (method of assessment upon 
physician’s discretion) 
• 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 
• Subjects who in the judgment of the investigator have a life 
expectancy of less than two years  
 
*LVEF and LA diameters obtained ≤180 days prior to enrollment will be 
acceptable, unless a cardiac event has occurred (e.g. MI) between the date of the 
exam and the enrollment date, otherwise a new echocardiogram (trans-thoracic or 
trans-esophageal, or intracardiac echo) must be performed to confirm eligibility 
prior to performing ablation. For TTE, LA anteroposterior diameter measured by 
M-mode from the parasternal long-axis view will be used.  If both LA diameter 
and volume are available, only one meeting eligibility criteria is required. 
 
**The absence of thrombus must be confirmed by means of a trans-esophageal 
echocardiogram (TEE) within 48 hours prior to the procedure or Intracardiac 
Echography (ICE) during the procedure in subjects not adequately anticoagulated 
(see section 12.5.2.) for at least 3 weeks prior to procedure OR with CHA2DS2-VASc 
score (see Appendix 30.4) ≥2 in men  and ≥3 in women OR enlarged LA (≥4.5cm). 
If a thrombus is observed, the subject no longer meets eligibility criteria. When 
screening for thrombus prior to the index procedure, ensure that the 
anticoagulation approach as described in section 12.5.2. is followed until the day 
of the procedure. 
Arrhythmia 
Monitoring 
Strategy 
This study will employ a rhythm surveillance monitoring strategy 
consistent with the recommendations in the 2017 HRS expert consensus 
statement on catheter and surgical ablation of atrial fibrillation. A 

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Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in 
the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial 
Fibrillation 
 
FROzEN-AF 
wearable arrhythmia/event monitor (e.g. Trans-Telephonic Monitor- 
TTM) will be used to assess atrial arrhythmia recurrence (including 
unscheduled visits for symptomatic atrial arrhythmias and 24-hour Holter 
monitoring at 12 months follow up).  
Within the first 90 days after the index ablation procedure subjects will 
be instructed to transmit all symptomatic episodes for detection and 
treatment of early recurrences.  All subjects will be instructed to submit 
at least two transmissions every month after their 3-month follow-up visit 
until their 12- month follow-up. 
All TREATMENT subjects will be provided with 24-Hour Holter 
Monitors at the 12-month follow-up visit.   
Core lab will be utilized for reviewing electrocardiographic recordings 
from the surveillance monitoring, inclusive of data from the wearable 
arrhythmia/event monitors and in-hospital ECGs.  
Statistical Methods  
Primary 
Statistical 
Hypothesis 
Hypothesis for primary safety endpoint  
• 
Ho:  The primary safety endpoint event-free rate at 12 months post 
procedure ≤ 89% 
• 
Ha:  The primary safety endpoint event-free rate at 12 months post 
procedure > 89% 
 
Hypothesis for primary effectiveness endpoint  
• 
Ho:  The 12-month failure-free rate ≤50% 
• 
Ha:  The 12-month failure-free rate > 50% 
The performance goal of 50% is based on the minimum chronic acceptable 
success rate for paroxysmal AF at 12 months follow-up defined in 2017 HRS 
Consensus document  
Statistical Test 
Method 
Primary safety endpoint 
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 

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Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in 
the Treatment of Symptomatic Drug Refractory Paroxysmal Atrial 
Fibrillation 
 
FROzEN-AF 
the observed safety event-free rate will be compared to the performance 
goal of 89%. 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 
For the primary effectiveness endpoint, the Kaplan-Meier 12 month (365-
day) primary effectiveness event-free rate will be calculated. 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 primary effectiveness event-free 
rate will be compared to the performance goal of 50%. 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. 
Sample Size 
Parameters 
The sample size estimate was obtained using the normal approximation 
to the binomial distribution and verified through simulations based on 
Kaplan-Meier methodology. The following assumptions were used in 
the sample size calculation: 
Assumptions 
Primary 
Safety 
Primary 
Effectiveness 
Expected rate 
94% 
60% 
Performance goal 
89% 
50% 
Attrition (per year) 
10% 
10% 
Significance level  (one-sided) 
5% 
5% 
Power 
90% 
90% 
Sample size  
325* 
247* 
*subjects treated with the ablation system 

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Data Collection Schedule 
Procedure/Assessment 
Enrollment 
(up to 30 
days before 
Index 
procedure) 
Baseline 
(up to 30 
days before 
Index 
procedure) 
Index 
Procedure 
(Day 0) 
Blanking Period 
Repeat 
Procedure 
Effectiveness Evaluation Period 
Pre-
Discharge 
(1-7 days 
post 
procedure) 
Day 7 
Follow-up  
Contact      
(+/-1 day) 
Repeat 
Procedure for 
PAF 
 
Month 3 
Follow Up 
(91±14 days) 
Month 6 
Follow Up 
(180±30 
days) 
Month 12 
Follow Up 
(365±30 
days) 
Unscheduled 
Visit 
Informed Consent Process, 
including informed consent 
signature date 
X 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X 
X 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
Blood Tests 
 
X1 
 
 
 
 
 
 
 
 
TTE (medical history) 
 
X2 
 
 
 
 
 
 
 
 
NIH Stroke Scale (NIHSS) 
 
X3 
 
X3 
 
 
 
 
 
 
Neurology Consultation4 
 
 
 
(X)4 
 
 
 
 
 
 
Brain MRI Scan5 
 
 
 
(X)5 
 
 
 
 
 
 
Physical Assessment 
 
X 
 
 
 
 
X 
X 
X 
X 
Physical Assessment with 
Cardiovascular/Pulmonary 
Examination 
 
 
 
X6 
 
 
 
 
 
 
Quality of Life (AFEQT and 
EQ-5D-5L) 
 
X 
 
 
 
 
X 
X 
X 
 
PV Anatomical Assessment 
(CT/MRI) 
 
X7 
 
 
 
 
 
 
 
 
Screening for LA thrombus 
(TEE or ICE) 
 
X 8 
 
 
X8 
 
 
 
 
PV Stenosis Assessment 
(CT/MRI) 
 
 
 
(X)9 
 
 
(X)9 
(X)9 
(X)9 
(X)9 
PV Stenosis Screening 
Substudy (CTMRI) 
 
X 
 
 
 
 
X 
 
 
Procedural Data 
 
 
X 
 
 
X 
 
 
 
 
12-Lead ECG 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Phrenic Nerve Palsy 
Assessment 
 
 
X10 
(X)10 
 
(X)10 
(X)10 
(X)10 
(X)10 
(X)10 
Holter Monitor (24 hours) 
 
 
 
 
 
 
 
 
X 
 
Arrhythmia/Event Monitor  
 
 
 
X 
 
 
X 
X 
X 
X 

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Procedure/Assessment 
Enrollment 
(up to 30 
days before 
Index 
procedure) 
Baseline 
(up to 30 
days before 
Index 
procedure) 
Index 
Procedure 
(Day 0) 
Blanking Period 
Repeat 
Procedure 
Effectiveness Evaluation Period 
Pre-
Discharge 
(1-7 days 
post 
procedure) 
Day 7 
Follow-up  
Contact      
(+/-1 day) 
Repeat 
Procedure for 
PAF 
 
Month 3 
Follow Up 
(91±14 days) 
Month 6 
Follow Up 
(180±30 
days) 
Month 12 
Follow Up 
(365±30 
days) 
Unscheduled 
Visit 
Documentation of 
intervention for AF/AT/AFL 
(if any) 
 
 
 
 
 
X 
X 
X 
X 
X 
Medications 
Prior and current AAD medications and Anticoagulant therapy regimen from Enrollment through End of Study Visit 
Protocol deviations 
From Enrollment through End of Study Visit 
Adverse Event 
Assessment 
Continuous from Enrollment through End of Study Visit 
 
1 Blood tests up to 90 days prior to enrollment, 
2 TTE either new or from medical file, ≤180 days prior to enrollment;  
3 NIH Stroke Scale (NIHSS) performed at baseline and at the pre-discharge visit 
4 Neurology consult is only required if NIH scale worsens from the previous assessment   
5 Brain DW-MRI scan required if neurology consultation determines possibility of new stroke  
6 Physical Assessment at discharge to include a Cardiovascular/Pulmonary Examination including: weight, resting heart rate, systolic and diastolic blood pressure, O2 saturation, lung 
auscultation (includes respiratory rate and respiratory rhythm), and temperature,  
7 Performed before the case (CT/MRI);  
8 TEE within 48 hours prior to the procedure or ICE during procedure 
9 Assessed in case of suspected PV stenosis;  
10Screening for phrenic nerve palsy will be performed during ablation, and prior to leaving the EP lab at the completion of the ablation procedure in all subjects. Assessment at discharge and at 
follow-up visits is only applicable for subjects who had phrenic nerve palsy detected at the index procedure.  
Abbreviations: IP = index procedure, NIH = National Institutes of Health, ECG = electrocardiogram, ICE= Intracardiac Echography; PV=pulmonary vein, TTM = trans-telephonic monitor,  
TTE = trans-thoracic echocardiogram, TEE = trans-esophageal echocardiogram, CT = Computed Tomography, MRI = Magnetic Resonance Imaging, FU = follow-up. 
 
 
 

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 Table of Contents 
1. 
TITLE PAGE  .......................................................................................................................1 
 
PROTOCOL SYNOPSIS .........................................................................................................7 
 
TABLE OF CONTENTS .......................................................................................................19 
 
TABLE OF FIGURES ..........................................................................................................24 
 
TABLE OF TABLES ............................................................................................................25 
 
INTRODUCTION.................................................................................................................26 
 Background ............................................................................................................26 
 Study Rationale .....................................................................................................27 
 
DEVICE DESCRIPTION ......................................................................................................27 
 Boston Scientific Cardiac Cryoablation System.................................................27 
 
POLARx Cryoablation Catheter ...............................................................28 
 
POLARMAP Cryoablation Mapping Catheter .........................................30 
 
POLARSHEATH Cryoablation Steerable Sheath ....................................31 
 
SMARTFREEZE Cryoablation System Console .....................................32 
 
Diaphragm Movement Sensor ..................................................................33 
 
Esophageal Temperature Sensor Cable ....................................................35 
 
Other Cryoablation System Devices .........................................................36 
 
Inter Connection Box ...............................................................36 
 
Console Foot Switch ................................................................36 
 
Cryoablation Cable ..................................................................36 
 
Cryoablation Catheter Extension Cable ...................................36 
 
Cryoablation Mapping Catheter EP Electrical Cable ..............36 
 Intended Use and Contraindications ...................................................................36 
 
POLARx Cryoablation Catheter ...............................................................36 
 
POLARMAP Cryoablation Mapping Catheter .........................................37 
 
POLARSHEATH Cryoablation Steerable Sheath ....................................38 
 
SMARTFREEZE Cryoablation System Console .....................................38 
 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................................39 
 Study Objective .....................................................................................................39 
 Primary Safety Endpoint ......................................................................................39 

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 Primary Effectiveness Endpoint ..........................................................................42 
 Secondary Safety Endpoints: ...............................................................................42 
 Secondary Effectiveness Endpoints: ....................................................................43 
 Additional Endpoints ............................................................................................43 
 
STUDY DESIGN .................................................................................................................44 
 Scale and Duration ................................................................................................45 
 Treatment Assignment ..........................................................................................47 
 
Treatment ..................................................................................................47 
 Justification for the Study Design ........................................................................47 
 
Single-Arm Study design ..........................................................................47 
 
Roll-ins and Non Roll-in Treatment Subjects ...........................................47 
 SUBJECT SELECTION ........................................................................................................48 
 Study Population and Eligibility ..........................................................................48 
 Inclusion Criteria ..................................................................................................48 
 Exclusion Criteria .................................................................................................49 
 SUBJECT ACCOUNTABILITY .............................................................................................51 
 Point of Enrollment ...............................................................................................51 
 Enrollment Controls .............................................................................................51 
 Withdrawal ............................................................................................................51 
 Lost to Follow-Up ..................................................................................................52 
 Subject Status and Classification .........................................................................52 
 End-of-Study Definition........................................................................................54 
 STUDY METHODS .............................................................................................................54 
 Data Collection ......................................................................................................54 
 Study Candidate Screening ..................................................................................56 
 Screening and Enrollment Log .................................................................56 
 Enrollment and Informed Consent......................................................................56 
 Baseline Visit..........................................................................................................57 
 Medications ............................................................................................................59 
 Anti-Arrhythmic Drugs ............................................................................59 
 AADs prior to index procedure ................................................59 

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 AADs post index procedure during the 90-day blanking period
 ..................................................................................................59 
 AADs post 90 days blanking period ........................................59 
 Anticoagulation .........................................................................................59 
 Thrombus Screening .................................................................................61 
 Index (Ablation) Procedure ..................................................................................61 
 General Info ..............................................................................................61 
 Pulmonary Vein Isolation ........................................................62 
 Cryoablation System Preparation ............................................62 
 Cryoablation protocol ..............................................................63 
 PV isolation verification ..........................................................64 
 Additional ablation(s) ..............................................................65 
 Index procedure collected data .................................................................65 
 Pre-Discharge Visit ...............................................................................................67 
 Day 7 Follow-up Contact ......................................................................................68 
 Month 3 Follow-Up Visit ......................................................................................68 
 
Month 6 Follow-Up Visit ........................................................................69 
 
Month 12 Follow-Up Visit ......................................................................70 
 
Unscheduled Visits ..................................................................................70 
 
Additional/Repeat Procedure ................................................................71 
 
Study Completion ...................................................................................72 
 
Unforeseen Circumstances (Natural Disaster/Global Pandemic) ......73 
 
Source Documents ..................................................................................73 
 STATISTICAL CONSIDERATIONS ......................................................................................74 
 Endpoints ...............................................................................................................74 
 Primary Safety Endpoints .........................................................................74 
 Hypotheses ...............................................................................75 
 Sample Size ..............................................................................75 
 Statistical Methods ...................................................................76 
 Secondary Safety Endpoint .......................................................................76 
 Primary Effectiveness Endpoint ...............................................................76 
 Hypotheses ...............................................................................77 
 Sample Size ..............................................................................77 
 Statistical Methods ...................................................................77 
 Secondary Effectiveness Endpoint ...........................................................77 
 General Statistical Methods .................................................................................77 
 Analysis Sets .............................................................................................77 

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 Control of Systematic Error/Bias ..............................................................78 
 Study Success and Control of Type I Error ..............................................78 
 Number of Subjects per Investigative Site ...............................................78 
 Data Analyses ........................................................................................................78 
 Interim Analyses .......................................................................................78 
 Missing Data Analyses .............................................................................78 
 Subgroup Analyses ...................................................................................79 
 Center Pooling Analysis ...........................................................................79 
 Multivariable Analyses .............................................................................79 
 Additional Analyses ..................................................................................79 
 Changes to Planned Analyses ...................................................................80 
 HEALTH ECONOMICS OUTCOMES ...................................................................................80 
 DATA MANAGEMENT .......................................................................................................81 
 Data Collection, Processing, and Review ............................................................81 
 Data Retention .......................................................................................................81 
 Technical Source Forms .......................................................................................81 
 Core Laboratories .................................................................................................82 
 Event and 24-Hour Holter Monitors’ Core Lab .......................................82 
 Event Monitors .........................................................................82 
 24-Hour Holter Monitors .........................................................82 
 ECG Core Lab ..........................................................................................83 
 PV Imaging Core Lab ...............................................................................83 
 Quality of Life (QOL) ...........................................................................................83 
 DEVIATIONS......................................................................................................................84 
 DEVICE/EQUIPMENT ACCOUNTABILITY FOR PRODUCTS LABELLED INVESTIGATIONAL
 
84 
 Investigationally-Labelled Products ....................................................................84 
 Commercially-Labelled Product ..........................................................................85 
 COMPLIANCE ....................................................................................................................85 
 Statement of Compliance ......................................................................................85 
 Investigator Responsibilities ................................................................................86 
 Delegation of Responsibility ....................................................................88 
 Institutional Review Board/Ethics Committee/REB..........................................88 

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 Sponsor Responsibilities .......................................................................................88 
 Role of Boston Scientific Representatives ...............................................89 
 Insurance ................................................................................................................90 
 MONITORING ....................................................................................................................90 
 POTENTIAL RISKS AND BENEFITS ...................................................................................90 
 Anticipated Adverse Events .................................................................................90 
 Risks Associated with the Study Device(s) ..........................................................92 
 Risks associated with Participation in the Clinical Study .................................92 
 Risk Minimization Actions ...................................................................................92 
 Anticipated Benefits ..............................................................................................92 
 Risk to Benefit Rationale ......................................................................................92 
 SAFETY REPORTING .........................................................................................................93 
 Reportable Events by investigational site to Boston Scientific .........................93 
 Definitions and Classification...............................................................................94 
 Relationship to Study Device(s) ...........................................................................96 
 Investigator Reporting Requirements .................................................................98 
 Boston Scientific Device Deficiencies .................................................................100 
 Reporting to Regulatory Authorities / IRBs/ ECs/ REBs/ Investigators .......100 
 Subject Death Reporting ....................................................................................101 
 INFORMED CONSENT ......................................................................................................102 
 COMMITTEES .................................................................................................................103 
 Safety Monitoring Process ..................................................................................103 
 Clinical Events Committee .................................................................................103 
 Data Monitoring Committee ..............................................................................104 
 Executive/ Steering Committee ..........................................................................104 
 SUSPENSION OR TERMINATION......................................................................................105 
 Premature Termination of the Study ................................................................105 
 Criteria for Premature Termination of the Study ....................................105 
 Termination of Study Participation by the Investigator or Withdrawal of IRB 
Approval...............................................................................................................105 

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 Requirements for Documentation and Subject Follow-up ..............................105 
 Criteria for Suspending/Terminating a Study Site ..........................................106 
 STUDY REGISTRATION AND RESULTS POSTING ............................................................106 
 Clinical Investigation Report .............................................................................106 
 PUBLICATION POLICY ....................................................................................................106 
 REIMBURSEMENT AND COMPENSATION FOR SUBJECTS ...............................................107 
 Subject Reimbursement ......................................................................................107 
 Compensation for Subject’s Health Injury.......................................................107 
 BIBLIOGRAPHY ...............................................................................................................107 
 ABBREVIATIONS AND DEFINITIONS ...............................................................................109 
 Abbreviations.......................................................................................................109 
 Definitions ............................................................................................................110 
 APPENDICES ...................................................................................................................113 
 Indications for ablation of PAF according to 2017 HRS expert consensus 
statement on catheter and surgical ablation of atrial fibrillation ...................113 
 Quality of Life Instruments ................................................................................114 
 National Institutes of Health Stroke Assessment .............................................115 
 CHA2DS2-VASc Score for AF ............................................................................115 
 POLARx FIT: FROzEN-AF Extension Study .................................................117 
 
 
 Table of Figures 
Figure 1: POLARx Cryoablation Catheter Distal Tip ............................................................ 29 
Figure 2:  POLARx Cryoablation Catheter Handle ................................................................ 29 
Figure 3:  Mapping Catheter Assembly .................................................................................. 30 
Figure 4:  POLARMAP Cryoablation Mapping Catheter with Electrode Arrangements ...... 30 
Figure 5:  SMARTFREEZE Cryoablation System Console ................................................... 33 
Figure 6:  Diaphragm Movement Sensor (DMS) Data Cryoablation Console Display Phrenic 
Nerve Pacing Signal & Alert ............................................................................... 34 
Figure 7:  Esophagus Temperature Monitoring Data Display ................................................ 35 

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Figure 8:  FROzEN-AF Study Design ................................................................................. 46 
Figure 9:  Indications for catheter ablation of symptomatic atrial fibrillation ...................... 114 
 
 Table of Tables 
Table 1: Cryoablation System ................................................................................................. 28 
Table 2: POLARx Cryoablation Catheter Specifications ....................................................... 29 
Table 3: POLARMAP Cryoablation Mapping Catheter Specifications ................................. 31 
Table 4: POLARSHEATH Cryoablation Steerable Sheath Specifications ............................ 31 
Table 5: Primary Safety Endpoint Components Definitions* ................................................ 40 
Table 6: Overview of Objectives and Endpoints .................................................................... 43 
Table 7: Inclusion Criteria ...................................................................................................... 48 
Table 8: Exclusion Criteria ..................................................................................................... 49 
 
 
 
 
 
 

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 Introduction 
 Background 
Atrial fibrillation (AF) is the most commonly encountered sustained cardiac arrhythmia in 
clinical practice (2). 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 (3). It currently affects approximately 2.3 million people in North America (4).  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 (5,6,7).  Among 
Medicare beneficiaries, incident AF is common and increases as individuals age with incidence 
rates per 1,000 person-years reported at ages 70-74 of 18.8, increasing to 28.8 for persons 75-
79 and 38.3 for persons 80-84. Similarly, the overall prevalence among Medicare beneficiaries 
age 70-74 is about 6% increasing to over 13% for individuals 80 years of age and older (8).   
AF causes symptoms that impair quality of life, increases the risk of stroke fivefold, and 
increases mortality.  
There are multiple therapies in current use for the treatment of AF; however, it is recognized 
that many of these therapies are suboptimal for most patients. Treatment options include 
medical management, pacing, cardioversion, implantable devices, surgery, and ablation 
therapy to eliminate the arrhythmia (9,10.11).  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, 
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 

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cryoablation therapy to treat Paroxysmal Atrial Fibrillation (PAF) has gained significant 
utilization worldwide, with an estimated 370,000 procedures performed to date (14). 
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 in 2018 and its data is being used to obtain CE-mark. 
The data of up to 405 subjects who will undergo treatment with the Boston Scientific 
Cryoablation System for de-novo PAF will be evaluated in this IDE trial. This study seeks to 
obtain approval for the Boston Scientific Cryoablation System in North America.  
 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. Accordingly, the present IDE study aims at collecting 
clinical data to establish the safety and one-year effectiveness profile of the Cryoablation 
System for treatment of symptomatic, drug refractory, recurrent, paroxysmal atrial fibrillation. 
 
 Device Description 
 Boston Scientific Cardiac Cryoablation System  
The Boston Scientific Cardiac Cryoablation System (henceforth “Cryoablation System”) is 
intended for treatment of symptomatic, drug refractory, recurrent, paroxysmal AF.  
The individual devices within the Cryoablation system and their associated model numbers are 
listed in Table 1.  
Treatment will occur according to the approved indication for use within each geography and 
the defined inclusion/exclusion criteria within the protocol. A copy of the DFU will be 
provided in local language as required per national regulations.  
FROzEN-AF will be conducted as a post market study in those regions where the device is 
approved, including Europe. For countries where commercially available, please refer to 
country-specific commercially available DFU.  
 
 

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Table 1: Cryoablation System  
Individual Devices within the System 
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 
Diaphragm Movement Sensor (DMS) 
2314 
Inter Connection Box (ICB) 
2314 
Esophageal Temperature Sensor Cable  
2314 
Cryo-Console Foot Switch 
2314 
Cryo-Cable 
2318 
Cryo-Catheter Extension Cable 
2319 
Cryo Mapping Catheter EP Electrical 
Cable 
2320 
 POLARx Cryoablation Catheter 
The Cryoablation Catheter 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 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 

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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.  
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: POLARx Cryoablation Catheter Distal Tip 
 
Figure 2:  POLARx Cryoablation Catheter Handle 
 
Table 2: POLARx Cryoablation Catheter Specifications 
Catheter Shaft Size 
11.8 Fr 
Catheter Overall Length 
134 cm 
Catheter Tip Outer Diameter (OD) 9 Fr 
Compatible Introducer Sheath 
Compatible with POLARSHEATH Sheath 12F 
Steerable Sheath 
Guidewire Lumen Inner Diameter 
(ID) 
Compatible with POLARMAP Mapping Catheter and 
guidewires ≤ 0.035 
Inflated Balloon Dimensions 
Diameter 
28 mm 

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Catheter 
Effective Length  
99 cm 
 
Short Tip 
5 mm 
 
Long Tip 
12 mm 
Thermocouples 
Internal to Balloon 
Environmental Parameters 
Storage 
15°C to 25°C (59°F to 77°F)  
 
Transit 
-30°C to 60°C (-22°F to 140°F) 
15% to 90% relative humidity 
 
Operation 
15°C to 30°C (59°F to 86°F) 
 
 POLARMAP Cryoablation Mapping Catheter 
The POLARMAP Cryoablation Mapping Catheter is a single-use, sterile, multi-electrode, 
diagnostic catheter designed to map cardiac signals during ablation procedures.  The catheter 
is 20mm in diameter with 8 evenly spaced radiopaque electrodes.  The proximal end of the 
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 Cryoablation Mapping Catheter also allows for 
delivery of pacing stimuli used in the interpretation of PV isolation (PVI).   
 
Figure 3:  Mapping Catheter Assembly 
 
Figure 4:  POLARMAP Cryoablation Mapping Catheter with Electrode Arrangements 
 
 

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Table 3: POLARMAP Cryoablation Mapping Catheter Specifications 
POLARMAP Shaft Size 
3.3 Fr (1.1 mm or 0.043 inches) 
Compatible Mating Device 
Minimum Internal Diameter 
3.4 Fr. (1.2 mm or 0.044 inches) 
Loop Diameter 
20 mm (0.79 inches) 
POLAR Shaft Length 
Overall 166: cm 
Effective: 149 cm 
Electrodes 
8 electrodes 
Electrode Size  
1 mm 
Electrode Spacing 
6 mm 
Environmental Parameters 
Storage 
15°C to 25°C (59°F to 77°F) 
Transit 
-30°C to 60°C (-22°F to 140°F) 
15% to 90% relative humidity 
 
Operation 
15°C to 30°C (59°F to 86°F) 
 
 POLARSHEATH Cryoablation Steerable Sheath 
The POLARSHEATH Cryoablation 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. 
 
As a component of the Cryoablation System, the Cryoablation 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 4: POLARSHEATH Cryoablation Steerable Sheath Specifications 
Sheath Overall Length 
82 cm (32.3 in) 
 
Sheath Usable Length 
68 cm (26.8 in) 
 
Sheath Inner Diameter 
12.7 Fr 
 
Sheath Outer Diameter 
15.9 Fr 
 
Usable Dilator Length 
85 cm (33.5 in) 
 
Radiopaque Markers 
2.5mm proximal to 
sheath tip 
 
Guidewire Compatibility 
0.81 mm (0.032 in) and 
0.89 mm (0.035 in) 
 
Environmental Parameters 
Storage 
15° C to 25° C 
(59° F to 77° F) 

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Transit 
-30° C to 60° C 
(-22° F to 140° F) 
15% to 90% 
relative humidity 
 
Operation 
15° C to 30° C 
(59° F to 86° F) 
 
 
 SMARTFREEZE Cryoablation System Console 
The SMARTFREEZE Cryoablation System 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 and 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:  SMARTFREEZE Cryoablation System Console 
 
Integration between the Cryoablation Catheter and the Console includes monitoring catheter 
as well as console functionality, aided by a number of accessory devices that make up the 
overall system such as: power cords, extension cables, connection box, foot switch, 
diaphragmatic movement sensor, esophageal temperature sensor cable. In addition, the system 
incorporates a number of non-medical device items such as a scavenging hose, wrench, and 
nitrous oxide tank.   
 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 Cryoablation 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 patient’s chest and assess 
the patient’s diaphragmatic movement during the period within the procedure that requires the 
physician’s full attention (when ablation is occurring). 

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It has been reported with cryoablation balloon technology that the incidence of phrenic nerve 
injury ranges from 2.7% - 11.2% 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 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 Cryoablation Console and 
sends data to be displayed on the Cryoablation Console’s user interface (see Figure 6 below). 
 
 
Figure 6:  Diaphragm Movement Sensor (DMS) Data Cryoablation 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 a 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.  

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 Esophageal Temperature Sensor Cable 
Esophageal temperature monitoring is a frequently used technique; used more so 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 incidence of esophageal ulceration is 
generally reversible, with a reported incidence of 17% of patients. 
 
As noted above, 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 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. 
 
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. The 
measured esophageal temperature turns the measurement display from “Blue” to “Red” if the 
temperature probe falls below a physician pre-set value (see Figure 7 below). This feature 
potentially reduces adverse events such as esophageal ulcerations and fistulas. This is a 
redundant 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  

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 Other Cryoablation System Devices 
 Inter Connection Box 
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. 
 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. 
 Cryoablation 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.  
 Cryoablation Catheter Extension Cable 
The Cryoablation Catheter Extension Cable is a sterile, single-use cable that provides the 
connectivity between the Cryoablation Catheter and the Console ICB.  
 Cryoablation Mapping Catheter EP Electrical Cable 
The EP Electrical Cable is a sterile, single-use accessory for the Cryo Mapping Catheter and 
is designed to interface (connect) the Cryoablation Mapping Catheter with standard EP 
recording systems.  
 Intended Use and Contraindications 
The Cryoablation System is intended for treatment of symptomatic, drug refractory, 
recurrent, paroxysmal AF. 
 POLARx Cryoablation Catheter 
The POLARx Cryoablation Catheter is a single use, flexible, over-the wire balloon catheter 
intended to ablate cardiac tissue. 
Use of the Cryoablation Catheter is contraindicated as follows: 
• In patients with an active systemic infection, as this may increase the risk for 
endocarditis and sepsis. 
• In patients with a myxoma or an intracardiac thrombus, as the catheter could 
precipitate an embolic event. 
• In patients with a prosthetic valve (mechanical or tissue) 

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• In the ventricle of the heart where the device may become entrapped in a valve or 
chordae structures. 
• In patients with a recent ventriculotomy or atriotomy, as this may increase the risk of 
cardiac perforation or embolic event. 
• In patients with pulmonary vein stents, as the catheter may dislodge or damage the 
stent. 
• In patients with cryoglobulinemia, as the cryoablation application may lead to 
vascular injury. 
• In conditions where insertion into or manipulation in the atrium is unsafe, as this may 
increase the risk of perforation or systemic embolic event. 
• In patients with intra-atrial septal patch or surgical intervention in or adjacent to the 
intra-atrial septum. 
• In patients with an interatrial baffle or patch, as the transseptal puncture could fail to 
close. 
• In patients with hypercoagulopathy or an inability to tolerate anticoagulation therapy 
during an electrophysiology procedure 
• In patients with a contraindication to an invasive electrophysiology procedure where 
insertion or manipulation of a catheter in the cardiac chambers is deemed unsafe. 
 POLARMAP Cryoablation Mapping Catheter 
During an ablation procedure when PVs are isolated, the Cryoablation Mapping Catheter is 
intended to obtain electrograms and provide pacing in cardiac structures in the atrial regions 
of the heart. 
 Use of the POLARMAP Mapping Catheter is contraindicated as follows:  
• In patients with an active systemic infection as this may increase the risk for 
endocarditis and sepsis.  
• In patients with a myxoma or an intracardiac thrombus as the catheter could 
precipitate an embolic event.  
• In patients with a prosthetic heart valve (mechanical or tissue).  
• In the ventricle of the heart where the device may become entrapped in a valve or 
chordae structures.  
• In patients with a recent ventriculotomy or atriotomy as this may increase the risk 
of cardiac perforation or embolic event.  
• In patients with pulmonary vein stents as the catheter may dislodge or damage the 
stent. 
• In patients with cryoglobulinemia as the cryoablation application may lead to 
vascular injury. 
• In conditions where insertion into or manipulation in the atrium is unsafe as this 
may increase the risk of perforation or systemic embolic event. 
• In patients with intra-atrial septal patch or other surgical intervention in or 
adjacent to the intra-atrial septum. 
• In patients with a contraindication to an invasive EP procedure where insertion or 
manipulation of a catheter in the cardiac chambers is deemed unsafe. 

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 POLARSHEATH Cryoablation Steerable Sheath 
The Cryoablation Steerable Sheath is intended to facilitate the placement of diagnostic and/ 
or therapeutic intracardiac devices during percutaneous catheter ablation procedures. The 
sheath deflection facilitates catheter positioning. 
Use of the POLARSHEATH is contraindicated as follows: 
• In patients with an active systemic infection as this may increase the risk for 
endocarditis and sepsis. 
• In patients where vascular access is unobtainable, or the femoral vein is known to be 
obstructed. 
• In conditions where insertion into or manipulation in the atrium is unsafe as this may 
increase the risk of perforation or systemic embolic event. 
• In the ventricle of the heart where the device may become entrapped in a valve or 
chordae structures. 
• In patients with a prosthetic heart valve (mechanical or tissue) 
• In patients with a recent ventriculotomy or atriotomy as this may increase the risk of 
cardiac perforation or embolic event. 
• In patients with pulmonary vein stents as the sheath may dislodge or damage the stent. 
• In patients with an interatrial baffle or patch as the transseptal puncture could fail to 
close. 
• In patients with hypercoagulopathy or an inability to tolerate anticoagulation therapy 
during an electrophysiology procedure. 
• In patients with a contraindication to an invasive electrophysiology procedure where 
insertion 
 SMARTFREEZE Cryoablation System Console 
The SMARTFREEZE Cryoablation System Console is a component of the Cryoablation 
System which is intended for cryoablation and electrical mapping of the pulmonary veins for 
pulmonary vein isolation (PVI) in the ablation treatment of paroxysmal atrial fibrillation. 
 
Use of the SMARTFREEZE Cryoablation System is contraindicated as follows: 
• 
In patients with an active systemic infection as this may increase the risk for 
endocarditis and sepsis. 
• 
In patients with a prosthetic valve (mechanical or tissue) 
• 
In patients with a myxoma or an intracardiac thrombus as the catheter could 
precipitate an embolic event. 
• 
In the ventricle of the heart where the device may become entrapped in the valve 
or chordae structures. 
• 
In patients with a recent ventriculostomy or atriotomy because this may increase 
the risk of cardiac perforation or embolic event. 
• 
In patients with pulmonary vein stents as the catheter may dislodge or damage 
the stent. 
• 
In patients with cryoglobulinemia as the application of cryogenic energy may 

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lead to vascular injury. 
• 
In conditions where insertion into or manipulation in the atria is unsafe as this 
may increase the risk of perforation or systemic embolic event. 
• 
In patients with an interatrial baffle or patch as the transseptal puncture could 
fail to close. 
• 
In patients with hyper-coagulopathy or an inability to tolerate anticoagulation 
therapy during an electrophysiology procedure. 
• 
In patients with a contraindication to an invasive electrophysiology procedure 
where insertion or manipulation of a catheter in the cardiac chambers is deemed 
unsafe. 
 
 Study Objectives and Endpoints 
 Study Objective 
To establish the safety and effectiveness of the Boston Scientific Cardiac Cryoablation System 
for treatment of symptomatic, drug refractory, recurrent, PAF. The following endpoints will 
be evaluated to establish the safety and effectiveness of the Cryoablation System for the 
treatment of symptomatic, drug refractory, recurrent, paroxysmal atrial fibrillation. 
 Primary Safety Endpoint  
Primary safety event free rate at 12 months post 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 or hospital 
discharge, whichever is later, include:  
• Death 
• Myocardial infarction 
• Transient ischemic attack (TIA) 
• Stroke/ Cerebrovascular accident (CVA) 
• Vascular access complications 
• Mitral or tricuspid valvular damage 
• Thromboembolism/ Air embolism leading to a life-threatening event such as a 
ventricular arrhythmia, stroke, pulmonary embolism, or myocardial infarction and, 
thromboembolic events that result in permanent injury, require intervention for 
treatment or prolongs or require hospitalization for more than 48 hours 
• Gastroparesis/ injury to vagus nerve 
• Pneumothorax 
• Pulmonary edema/ heart failure 
• AV block 
 

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Cardiac tamponade/perforation, occurring up to 30 days post index procedure. 
 
Chronic primary safety endpoint events, events occurring through 12 months post 
procedure, include: 
• Atrial esophageal fistula 
• Severe pulmonary vein stenosis (≥ 70% reduction in the  diameter of the PV or 
PV branch from baseline) 
• Persistent phrenic nerve palsy* 
 
*A non-recovered phrenic nerve palsy 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. 
Table 5: Primary Safety Endpoint Components Definitions* 
Term 
Definition 
Atrioesophageal Fistula 
An atrioesophageal fistula is defined as a connection between the atrium 
and the lumen of the esophagus. Evidence supporting this diagnosis 
includes documentation of esophageal erosion combined with evidence of 
a fistulous connection to the atrium, such as air emboli, an embolic event, 
or direct observation at the time of surgical repair. A CT scan or MRI scan 
is the most common method of documentation of an atrioesophageal 
fistula. 
AV block 
A conduction disturbance that results in the partial inability of an electrical 
impulse generated in the atria to reach the ventricles. 
Cardiac tamponade/perforation 
Cardiac tamponade/perforation is defined as 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.  
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 left bundle branch block, 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.  
Pericardial Effusion 
A collection of fluid or blood in the pericardial space around the heart or in 
pleural space around the lungs.  
Phrenic nerve palsy 
Phrenic nerve palsy is defined as absent phrenic nerve function as assessed 
by a sniff test. A phrenic nerve palsy is considered to be permanent when it 
is documented to be present 12 months or longer following ablation. 
Pneumothorax 
Collapse of the lung due to an abrupt change in the intrapleural pressure 
within the chest cavity. 
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 
Pulmonary Vein Stenosis 
(Severe) 
Pulmonary vein stenosis is defined as a reduction of the diameter of a PV 
or PV branch. PV stenosis can be categorized as mild <50%, moderate 
50%–70%, and severe ≥70% reduction in the diameter of the PV or PV 
branch. A severe PV stenosis will count toward the primary safety 
endpoint.   
Stroke/Cerebrovascular accident 
(CVA)  
Stroke diagnostic criteria: 
• 
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)  
• 
Stroke: (diagnosis as above, preferably with positive 
neuroimaging study); 
o 
Minor–Modified Rankin score <2 at 30 and 90 days† 
o 
Major–Modified Rankin score ≥2 at 30 and 90 days 
Thromboembolism 
The blockage of a blood vessel lumen by 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. 
Transient ischemic attack: new focal neurological deficit with rapid 
symptom resolution (usually 1 to 2 hours), always within 24 hours; 
neuroimaging without tissue injury 
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 
Vascular access complications include the 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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 Primary Effectiveness Endpoint 
Failure-free rate at 12 months post procedure. 
Failure is defined as: 
• Failure to achieve acute procedural success in the index procedure or repeat 
procedure during the blanking period  
• Use of amiodarone post index procedure  
• Surgical treatment for AF/AFL/AT post index procedure 
• Use of a non-study ablation catheter for AF targets in the index procedure or 
repeat procedure during the blanking period 
• More than one repeat procedure with the POLARx catheter during the blanking 
period (90 days post index procedure) 
• Documented atrial fibrillation, or new onset of atrial flutter or atrial tachycardia 
event (≥ 30 seconds in duration from the study-specific event monitor, Holter 
Monitor, 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 and 365 days post procedure: 
• 
Repeat procedure 
• 
Electrical and/or pharmacological cardioversion for AF/AFL/AT  
• 
Prescribed any anti-arrhythmic drug (AAD)**  
 
*12-lead ECGs performed during scheduled or unscheduled visits and assessed by the ECG 
core lab will count for primary effectiveness endpoint assessment. Additional documentation 
of arrhythmias coming from sources different from those listed above will be collected and 
analyzed separately. 
**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 Safety Endpoints: 
Reportable Adverse Events rates at 12 months. 
Adverse events will be collected at all subject follow-up visits. Reportable events include: 
• All Serious Adverse Events 
• All Study Procedure-Related Adverse Events 
• All Study Device-Related Adverse Events 
• All Study Device Deficiencies  
• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device 
Effects previously not defined in DFU/Investigator’s Brochure 

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 Secondary Effectiveness Endpoints: 
Rate of Acute Procedural Success defined as the achievement of electrical isolation of all 
PVs by using the Cardiac Cryoablation system only.; Electrical isolation of a PV is 
demonstrated by entrance and exit block. 
 Additional Endpoints 
Additional endpoints and analyses include, but are not limited to:  
• Changes in the quality of life measures (AFEQT and EQ-5D-5L) between 
baseline and 12 months follow up 
• Single procedure success, defined as freedom from primary effectiveness failure 
without a repeat procedure 
• Duration of LA dwell time, defined as time from the Cryoablation Catheter 
exiting the sheath in the LA to time of final PV isolation  
• Total Cryoablation time for the index procedure 
• Total fluoroscopy time for the index procedure; 
• Total index procedure time 
• Freedom from recurrence of individual types atrial arrhythmias between 91 and 
365 days post index procedure: 1) AF 2) AT 3) AFL  
• Failure- free rate as defined in primary effectiveness endpoint when considering 
AF/AT/AFL episodes reported to the investigators by study specific (event 
recorder transmissions, 12 lead ECG and Holter) and non-study related devices 
(other commercial applications for arrhythmia monitoring and detection the 
subject may access during the study including telemetry, other sources of 
continuous recording etc.) 
• Freedom from primary effectiveness failure at six (6) months will be included s in 
the final study report as a “proof-of-concept” analysis to potentially show the 
ability to predict 1-year effectiveness results using 6-month effectiveness data 
Table 6: Overview of Objectives and Endpoints 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Establish the safety of the 
Cryoablation System 
 
 
 
Establish the effectiveness of the 
Cryoablation System 
Composite of acute and 12- 
month study specific adverse 
events 
 
Failure- free rate at 12 months 
including failure to achieve 
success at index or repeated 
procedure in blanking period, 
amiodarone post procedure, 
List of events were selected 
from those typically associated 
with catheter ablation of AF.  
 
 
Performance goal and expected 
rates calculated from a meta-
analysis of pivotal and IDE 
studies on AF ablation   

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
documented AF/AT/AFL or 
interventions to treat these 
arrhythmias after blanking 
period, including repeated 
procedures cardioversion or 
pharmacologic treatment 
Secondary 
 
 
Acute procedural success  
Rate of acute procedural 
success defined as the 
achievement of electrical 
isolation of all PVs by using 
the POLARx Cardiac 
Cryoablation System only. 
Electrical isolation of a PV is 
demonstrated by entrance and 
exit block. 
Component of the primary 
effectiveness endpoint 
Adverse events reporting 
 
 
Reportable Adverse Events 
rates at 12 months 
 
 
Complete overview of the safety 
events collected in the study 
Additional 
 
 
Recurrence of individual arrhythmia 
types 
Freedom from recurrence of 
AF/AT/AFL 
 
Component of the primary 
effectiveness endpoint 
Quality of life assessment 
Changes in the quality of life 
measures (AFEQT and EQ-
5D-5L) between baseline and 
12 months follow up 
Consistent with the objective of 
AF ablation to improve quality 
of life and reduce AF-associated 
symptoms 
Single procedure success 
Freedom from primary 
effectiveness failure without a 
repeat procedure  . 
To assess success rate after a 
single procedure 
Establish the effectiveness of the 
Cryoablation System at 6 months 
Failure free rate at 6 months 
post index procedure 
Post hoc ancillary analysis to 
establish if the effectiveness 
profile of the device at 1 year 
could be predicted by 6 months 
data. 
Procedure-related times 
LA dwell time, ablation time, 
fluoroscopy time, index 
procedure time 
 
To relate with published data on 
other AF ablation devices 
 
 Study Design 
The FROzEN-AF study is a prospective, non-randomized, multi-center, investigation being 
conducted to establish the safety and effectiveness of the Cryoablation System in subjects 
with symptomatic, drug refractory, recurrent, paroxysmal atrial fibrillation.  

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 Scale and Duration 
A maximum of 405 subjects treated with the Cryoablation System will be enrolled in the 
study, inclusive of a maximum of 80 roll-in TREATMENT subjects and 325 non roll-in 
TREATMENT subjects undergoing the index ablation procedure (per subject status 
classification, section 11.5) 
Fifty (50) non roll-in TREATMENT subjects will participate in a PV Stenosis Screening 
Substudy at up to 8 study sites. The substudy will include a baseline and a 3 to 6 months 
CT/MRI imaging data post index procedure to evaluate the potential extent of PV stenosis.  
Each site participating to the substudy will enroll a maximum of 18 substudy subjects. 
Up to 50 sites in North America, Europe and Asia-Pacific may participate in this study. At 
least 50% of the  sites and 50% of the subjects will enroll in  the United States and 
potentially up to 10% of  subjects will enroll in  3 to 5 combined sites from Hong Kong and 
Taiwan. Up to 10 sites in Europe may contribute to enrollments. To reduce the impact of 
individual center bias, no study site will be allowed to contribute more than 48 subjects 
(average 15% of the 325 study non roll-in TREATMENT subjects).  
 
The enrollment period for this study is expected to last between 9 to 12 months. Each subject 
will be followed at specified time points after the ablation procedure (index procedure), with 
a follow-up duration of 12 months.  A study subject’s participation will be considered 
complete when all protocol required visits have been completed as indicated in Figure 8.  The 
total study duration is estimated to be approximately 24 months. Subjects may be requested 
to consent to provide long term follow-up data, if needed for post-approval requirements.   
 
 

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Figure 8:  FROzEN-AF Study Design 
 
Yes 
Subject Enrolled 
 
Blanking Period         
≤ 90 days post procedure 
Pre-Discharge          
1-7 days post procedure 
6-Month Follow Up    
180 ± 30 days 
12-Month Follow Up 
365 ± 30 days 
Subject candidate  
screening for 
enrollment 
No 
Patient signed 
informed consent  
                 
Consent Ineligible 
(Screen failure) 
(Screening log) 
  
Roll-in Subject  
Non Roll-in 
Treatment 
Index Procedure  
Day 0 
Recurrence?  
≤90 day)  
1 Repeat Procedure 
(continue follow-up 
schedule) 
Yes 
Patient withdrawn or  
not meeting  selection  
criteria 
Day 7 Follow-up Contact    
Telephone   ± 1 day 

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 Treatment Assignment 
All screened subjects who sign the informed consent will be considered enrolled.  Data will 
be collected during the baseline visit, the ablation (index) procedure, the pre-discharge visit, 
the Day 7 telephone contact/follow up, month 3 follow up, the month 6 follow up and during 
the month 12 follow up. In case unscheduled visits or additional ablation procedures take 
place, this data will also be collected. Please refer to section 12 for an overview of data to be 
collected during these visits. 
Subjects will be classified based on Subject Status and Classification as per section 11.5. 
 Treatment  
All enrolled subjects who undergo the ablation procedure will be treated with the Cryoablation 
System.  
It is recommended that each investigational center will be limited to 2 active ablating 
investigators.  Additional investigators may participate for completion of subject follow-up 
visits if appropriately delegated (section 12.6.1) and trained to complete the assigned tasks.   
 Justification for the Study Design 
 Single-Arm Study design 
Boston Scientific believes that a prospective non-randomized IDE trial with the Cryoablation 
System as treatment device and powered for standard safety and effectiveness objective 
performance criteria is reasonable to obtain approval of the Cryoablation System. 
The rationale for a non-randomized trial includes, the formal equivalence of the system design 
with the existing Medtronic® Arctic Front Advance™ Catheter in terms of delivered therapy 
and temperature profiles, as proven by extensive bench testing done with the Boston Scientific 
Cryoablation System. 
Additionally, the current understanding in the field of catheter ablation of PAF and presence 
of an additional seven products approved by the FDA for the PAF ablation indication from 
four different manufacturers makes the field mature enough to consider a single arm design 
adequate for this study. Inherent limitations of single arm trials compared to a randomized 
clinical trial (RCT) will be addressed by appropriately limiting bias and confounders in the 
present protocol. This includes definition of inclusion/exclusion criteria to match the 
population enrolled in other IDE trials on PAF ablation and taking measures for subject 
screening and arrhythmia recurrence surveillance. 
 Roll-ins and Non Roll-in Treatment Subjects 
To help facilitate investigators’ familiarity with the new investigational system and avoid 
learning curve bias, roll-in subjects will be enrolled at each study site. Each ablating physician 
will need to treat 1 (one) roll-in subject with the Cryoablation System per definition of 
Treatment in section 11.5.  

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After completing the treatment roll-in case, BSC will provide the investigator with 
authorization to proceed with the treatment of the non roll-in subjects. 
 All safety and effectiveness data will be collected and reported for all subjects; however, the 
data will not be included in the endpoint analyses for roll-in cases.   
In order to avoid potential bias, it is recommended the number of authorized active ablating 
physicians per investigational site performing the index procedure is restricted to 2.  
For investigators participating in a geography in which the system is not investigational, a roll-
in case may not be required if the physician has previous experience treating patients with the 
Cryoablation System.   
 Subject Selection  
 Study Population and Eligibility  
Subjects enrolled in the FROzEN-AF study will be clinically indicated for an ablation 
procedure for the treatment of symptomatic, drug refractory, recurrent, paroxysmal atrial 
fibrillation. Subjects should meet the study inclusion/exclusion criteria as outlined below in 
section 10.2 and 10.3. The subjects selected for participation will be from the investigator’s 
general patient population. The investigator or its designee has the responsibility for screening 
all potential subjects and selecting those who meet study inclusion/exclusion. 
 Inclusion Criteria 
Subjects who meet all the following criteria (see Table 7) may be given consideration for 
inclusion in this clinical investigation, provided no exclusion criterion (see section 10.3) is 
met.  
Table 7: Inclusion Criteria 
Inclusion 
Criteria 
• History of recurrent symptomatic paroxysmal atrial fibrillation 
(PAF), defined as atrial fibrillation that terminates spontaneously or 
with intervention (either procedure or drug therapy) within seven 
days of onset. Minimum documentation includes the following: 
o a physician’s note indicating recurrent self-terminating atrial 
fibrillation (AF) which includes at least two symptomatic AF 
episodes within six months prior to enrollment, and  
o one electrocardiographically documented AF episode within 
12 months prior to enrollment.   
• Subjects who are indicated for an ablation procedure for 
paroxysmal atrial fibrillation (PAF) according to 2017 HRS expert 
consensus statement on catheter and surgical ablation of atrial 
fibrillation 

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• No amiodarone use within 90 days prior to enrollment 
• Subjects refractory or intolerant to at least one class I or III 
antiarrhythmic medication or contraindicated to any class I or III 
medications 
• Subjects who are willing and capable of providing informed 
consent  
• Subjects who are willing and capable of participating in all testing 
associated with this clinical investigation at an approved clinical 
investigation center 
• 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 (see Table 8) cannot be included in this 
study or will be excluded from this clinical study. 
Table 8: Exclusion Criteria 
Exclusion 
Criteria 
• Any known contraindication to an AF ablation or anticoagulation 
• Continuous AF lasting longer than seven (7) days from onset 
• History of previous left atrial ablation or surgical treatment for AF/ 
AFL/ AT 
• Atrial fibrillation secondary to electrolyte imbalance, thyroid 
disease, or any other reversible or non-cardiac cause 
• Structural heart disease or implanted devices as described below: 
a. Left ventricular ejection fraction (LVEF) < 40% based on the 
most recent TTE performed ≤180 days prior to enrollment* 
b. Left atrial diameter > 5.5 cm OR left atrial volume > 50 ml/m2 
indexed based on the most recent TTE performed ≤ 180 days prior 
to enrollment* 
c. An implanted pacemaker, ICD, CRT device or an arrhythmia 
loop recorder 
d. Previous cardiac surgery: i.e. ventriculotomy or atriotomy 
(excluding atriotomy for CABG) 
e. Previous cardiac valvular surgical or percutaneous procedure, or 
prosthetic valve, including mitral valve clips 
f. Interatrial baffle, closure device, patch, or PFO occluder 

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g. Presence of a left atrial appendage occlusion device 
h. Presence of any pulmonary vein stents 
i. Coronary artery bypass graft (CABG), PTCA/ PCI/ coronary 
stent procedures within 90 days prior to enrollment 
j. Unstable angina or ongoing myocardial ischemia 
k. Myocardial infarction within 90 days prior to enrollment 
l. Moderate or severe mitral stenosis[severity assessed on the most 
recent TTE ≤180 days prior to enrollment as Pulmonary artery 
systolic pressure >30 mm Hg(1)] 
m. Evidence of left atrial thrombus** 
• Any previous history of cryoglobulinemia 
• Stage 3B or higher renal disease (estimated glomerular filtration 
rate, eGFR <45 mL/min) 
• History of blood clotting or bleeding disease 
• Any prior history of documented cerebral infarct, TIA or systemic 
embolism (excluding a post-operative DVT) ≤180 days prior to 
enrollment 
• Active systemic infection 
• Pregnant, lactating (current or anticipated during study follow up), 
or women of childbearing potential who are, or plan to become, 
pregnant during the time of the study (method of assessment upon 
physician’s discretion) 
 
• 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 
 
• Subjects who in the judgment of the investigator have a life 
expectancy of less than two years  
 
*LVEF and LA diameters obtained ≤180 days prior to enrollment will be 
acceptable, unless a cardiac event has occurred (e.g. MI) between the date of the 
exam and the enrollment date, otherwise a new echocardiogram (trans-thoracic or 
trans-esophageal, or intracardiac echo) must be performed to confirm eligibility 
prior to performing ablation. For TTE, the LA anteroposterior diameter measured 
by M-mode from the parasternal long-axis view will be used.  If both LA diameter 
and volume are available, only one meeting eligibility criteria is required. 

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**The absence of thrombus must be confirmed by means of a TEE within 48 hours 
prior to the procedure or ICE during procedure in subjects not adequately 
anticoagulated (see section 12.5.2.) for at least 3 weeks prior to the procedure OR 
with CHA2DS2-VASc score (see Appendix 30.4) ≥2 in men  and ≥3 in women OR 
enlarged LA (≥4.5cm). If a thrombus is observed, the subject no longer meets 
eligibility criteria. When screening for thrombus prior to the index procedure, 
ensure that the anticoagulation approach as described in section 12.5.2. is 
followed until the day of the procedure. 
 Subject Accountability  
 Point of Enrollment 
Subjects who have signed and dated the Informed Consent Form are considered enrolled in 
the study.  All TREATMENT subjects (per definition in section 12.3) will be counted against 
the enrollment ceiling of 325 subjects. 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 SOC can be used to determine pre-eligibility. Study 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 and 
document them for each screened patient in the study Screening and Enrollment Log. 
 Enrollment Controls 
Subject study-specific ID will be generated through the Electronic Data Capture (EDC) system 
used for this study. This database will also be utilized to provide the sites with subject 
classification assignments (including roll-in subjects) once a subject has provided written 
informed consent.  Enrollment controls will be put in place to ensure no more than 48 (average 
15% of the 325 TREATMENT subjects) will occur at a single site.  In addition, BSC will 
communicate the process that will be followed for enrolling subjects as the enrollment ceiling 
of 325 TREATMENT subjects is approached to prevent exceeding this enrollment ceiling.   
 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 investigation, 
the reason(s) shall be reported. If such withdrawal is due to problems related to investigational 
device safety or performance, the investigator shall ask for the subject’s documented 
permission to follow his/her status/condition outside of the clinical study.   
 
Reasons for withdrawal may include physician discretion, subject choice to withdraw, 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. In the 
event a subject does decide to withdraw from the study, every effort should be made to obtain 

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full information on any on-going reportable Adverse Events up to the point of withdrawal.  
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. Data collected 
up to the point of subject withdrawal may be used, unless any local regulations apply which 
require removal of the data.  
If the withdrawal is due to the investigator’s discretion, the investigator is obligated to follow 
all open reportable Adverse Events until they can be considered as closed or chronic. 
All open reportable adverse events should be closed or documented as chronic.  If the 
withdrawal is due to problems related to device safety or performance, the investigator shall 
ask for the subject’s documented permission to follow his/her status/condition. 
Withdrawn subjects will not be replaced. 
All applicable electronic case report forms (eCRFs) up to the point of subject withdrawal/lost 
to follow up and an “End of Study” eCRF must be completed.   
 Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return after documented 
attempts to attend a scheduled visit and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant 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 participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (at minimum 3 telephone calls and a 
certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical 
record or study file.  
• Should the participant continue to be unreachable, he or she will be considered lost to 
follow-up from the study. 
 
All applicable electronic case report forms (eCRFs) up to the point of subject withdrawal/lost 
to follow up and an “End of Study” eCRF must be completed.   
 Subject Status and Classification 
As subjects are evaluated, enrolled and treated in the study, they will be grouped into one of 
the following categories. Categorization will help determine how data gathered from them will 
be stored and evaluated. 
Consent Ineligible (Screening Failures) 

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A subject who has signed informed consent but is found not to meet eligibility criteria will be 
classified as “Consent Ineligible”. There are no Follow Up reporting requirements for consent 
ineligible subjects. Subjects determined to be Consent Ineligible do not count towards the 
enrollment ceiling and will not be used for analysis of the endpoints. The original signed 
Informed Consent must be maintained in the center’s patient file.   A subject Identification 
Number (ID) will be assigned in the EDC system.  
For consent ineligible subjects the following forms must be completed: 
• Enrollment and End of Study  
• Adverse Event forms for any reportable event, as defined in section 21 for any 
adverse event that occurs after signing the Informed Consent, up to the point of 
subject withdrawal 
 
 Roll-in and non roll-in subjects will be further classified as Intent, Attempt, and Treatment as 
described below.  
Intent 
A subject who signs informed consent, meets eligibility criteria, but does not have any 
study investigational devices inserted into the body will be classified as “INTENT”. 
Subjects that are enrolled in the study but do not undergo ablation procedure within 30 
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 not count 
towards the enrollment ceiling and will not be used for analysis of the endpoints. The 
original signed Informed Consent must be maintained in the center’s patient file. A 
subject ID will be assigned in the EDC system.  
For intent subjects, at the miniumum the following forms  must be  completed:  
• Enrollment and baseline forms such as, but not limited to: informed consent, 
enrollment information and other related forms; 
• End of Study form; 
• Adverse Event forms for any reportable event, as defined in section 21 for any 
adverse event that occurs after signing the Informed Consent, up to the point of 
subject withdrawal 
Attempt 
A subject who signs informed consent, meets eligibility criteria, and has any study 
device inserted into the body but does not receive any Cryoablation application will be 
classified as “ATTEMPT.” Attempt subjects do not count towards the enrollment 
ceiling. Attempt subjects and will be used for analysis of the primary and secondary 
safety endpoint and additional analyses of safety data but will not be used for analysis 
of the primary and secondary effectiveness endpoints or additional analyses of 
effectiveness data (additional analysis include subgroup, multivariable, and center 
pooling analyses). The original signed Informed Consent must be maintained in the 

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center’s patient 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 the 12 month visit. All applicable case report 
forms per the protocol will be completed. The original signed Informed Consent and 
any relevant documentation must be maintained in the center’s patient file.  
Treatment 
Any subject that signs the consent form, meets eligibility criteria 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 follow-up schedule 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 patient file. 
It is the investigational sites’s responsibility to list all Screen Failures, Consent Ineligible 
(screening failure), Intent, Attempt and Treatment subjects on the Screening and Enrollment 
Log.  
 End-of-Study Definition  
A clinical trial is considered completed when participants are no longer being examined or the 
last participant’s last study visit has occurred. The end of the study is defined as completion of 
the last visit or procedure shown in the Data Collection Schedule in the trial globally.  
 
 Study Methods 
 Data Collection 
Each Treatment subject will be followed at index procedure, at pre-discharge visit, at the month 
3 follow up, at the month 6 follow up and at 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. If the subject needs to undergo an additional ablation procedure in the LA 
during the follow-up period, then this additional ablation procedure will need to be captured in 
the EDC database. The data collection schedule is shown in Table 9.

 
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 Table  9:  Data Collection Schedule 
 
 
Procedure/Assessm
ent 
Enroll
ment 
(up to 
30 days 
before 
Index 
procedur
e) 
Baseli
ne 
(up to 
30 days 
before 
Index 
procedur
e) 
Index 
Proced
ure 
(Day 
0) 
Blanking Period 
Repeat 
Procedur
e 
Effectiveness Evaluation Period 
Pre-
Dischar
ge 
(1-7 
days 
post 
procedu
re) 
Day 7 
Follow-
up 
Contact  
(+/-1 
day) 
Repeat 
Procedur
e for 
PAF 
 
Mont
h 3 
Follow 
Up 
(91±14 
days) 
Mont
h 6 
Follow 
Up 
(180±
30 
days) 
Month 
12 
Follow 
Up 
(365±30 
days) 
Unsched
uled 
Visit 
Informed Consent 
Process, including 
informed consent 
signature date 
X 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X 
X 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
Blood Tests 
 
X1 
 
 
 
 
 
 
 
 
TTE (medical 
history) 
 
X2 
 
 
 
 
 
 
 
 
NIH Stroke Scale 
(NIHSS) 
 
X3 
 
X3 
 
 
 
 
 
 
Neurology 
Consultation4 
 
 
 
(X)4 
 
 
 
 
 
 
Brain MRI Scan5 
 
 
 
(X)5 
 
 
 
 
 
 
Physical 
Assessment 
 
X 
 
 
 
 
X 
X 
X 
X 
Physical 
Assessment with 
Cardiovascular/Pul
monary 
Examination 
 
 
 
X6 
 
 
 
 
 
 
Quality of Life 
(AFEQT and EQ-
5D-5L) 
 
X 
 
 
 
 
X 
X 
X 
 
PV Anatomical 
Assessment 
(CT/MRI) 
 
X7 
 
 
 
 
 
 
 
 
Screening for LA 
Thrombus (TEE or 
ICE) 
 
X 8 
 
 
X8 
 
 
 
 
PV Stenosis 
Assessment 
(CT/MRI) 
 
 
 
(X)9 
 
 
(X)9 
(X)9 
(X)9 
(X)9 
PV Stenosis 
Screening Substudy 
(CT/MRI) 
 
X 
 
 
 
 
X 
 
 
Procedural Data 
 
 
X 
 
 
X 
 
 
 
 
12-Lead ECG 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Phrenic Nerve 
Palsy Assessment 
 
 
X10 
(X)10 
 
(X)10 
(X)10 
(X)10 
(X)10 
X10 
Holter Monitor (24 
hours) 
 
 
 
 
 
 
 
 
X 
 
Arrhythmia/Event 
Monitor  
 
 
 
X 
 
 
X 
X 
X 
X 

 
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Procedure/Assessm
ent 
Enroll
ment 
(up to 
30 days 
before 
Index 
procedur
e) 
Baseli
ne 
(up to 
30 days 
before 
Index 
procedur
e) 
Index 
Proced
ure 
(Day 
0) 
Blanking Period 
Repeat 
Procedur
e 
Effectiveness Evaluation Period 
Pre-
Dischar
ge 
(1-7 
days 
post 
procedu
re) 
Day 7 
Follow-
up 
Contact  
(+/-1 
day) 
Repeat 
Procedur
e for 
PAF 
 
Mont
h 3 
Follow 
Up 
(91±14 
days) 
Mont
h 6 
Follow 
Up 
(180±
30 
days) 
Month 
12 
Follow 
Up 
(365±30 
days) 
Unsched
uled 
Visit 
Documentation of 
Intervention for 
AF/AT/AFL (if any) 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
Medications 
Prior and current AAD medications and Anticoagulant therapy regimen from Enrollment through End of Study Visit 
Protocol Deviations 
From Enrollment through End of Study Visit 
Adverse Event 
Assessment 
Continuous from Enrollment through End of Study Visit 
 
1 Blood tests up to 90 days prior to enrollment, 
2 TTE either new or from medical file, ≤180 days prior to enrollment; 
3 NIH Stroke Scale (NIHSS) performed at baseline and the pre-discharge visit.  
4 Neurology consult is only required if NIH scale worsens from the previous assessment   
5 Brain DW-MRI scan required if neurology consultation determines possibility of new stroke  
6 Physical assessment at discharge will also include a cardiovascular/pulmonary examination:  weight, resting heart rate, systolic and 
diastolic blood pressure, O2 saturation, lung auscultation (includes respiratory rate and respiratory rhythm), and temperature   
7 Performed before the case (CT/MRI);  
8 TEE 48 hours prior to the procedure or ICE during the procedure  
9 Assessed in case of suspected PV stenosis;  
10Screening for phrenic nerve palsy will be performed during ablation, and prior to leaving the EP lab at the completion of the ablation 
procedure in all subjects. Assessment at discharge and at follow-up visits is only applicable for subjects who had phrenic nerve palsy 
detected at the index procedure.  
Abbreviations: IP = index procedure, NIH = National Institutes of Health, ECG = electrocardiogram, ICE= Intracardiac Echograp
PV=pulmonary veins, TTM = trans-telephonic monitor,  
TTE = trans-thoracic echocardiogram, TEE = trans-esophageal echocardiogram, CT = Computed Tomography, MRI = Magnetic Resona
Imaging, FU = follow-up. 
 Study Candidate Screening 
Investigators are responsible for screening all subjects and selecting those who are appropriate 
for study inclusion. The subjects selected for participation should be from the investigator’s 
general patient population.  The investigator is expected to follow standard of care testing to 
diagnose and screen subjects for inclusion in the study. 
 Screening and Enrollment Log 
A Screening and Enrollment Log will be maintained to document select information about 
candidates who fail to meet the general and specific selection criteria, including those 
enrolled in the study and classified either as Consent Ineligible, Intent, Attempt or Treatment 
subjects. 
 Enrollment and Informed Consent 
Subjects who provide consent are considered enrolled in the study. In order to determine 
eligibility of a subject, the investigator or designee needs to implement the consent process 
and verify/document the subject meets the inclusion/exclusion criteria. Informed consent is 

 
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required for all subjects prior to their participation in the study. No study-specific procedures 
should 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 personally signed and dated by 
the subject. 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 30 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 11.5).  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 will be made 
available for review at Interim Monitoring Visits (IMVs). 
For additional information regarding the informed consent process, refer to section 22. 
 Baseline Visit 
Enrolled subjects will have baseline data collected. The data collection at baseline includes: 
• Visit date 
• Documentation of Informed Consent process, including Informed Consent Form 
signature date  
• Check of Eligibility Criteria*  
• Demographic data, including: age at time of consent, gender, race and ethnicity 
• Physical assessment including: weight, height, resting heart rate, systolic and diastolic 
blood pressure  
• Rhythm at time of visit (by means of a 12-lead ECG) 
• Medical history, including, but not limited to:  
o Evidence of PAF in the medical history should be documented as per the inclusion 
criteria. Treatment history (drug, cardioversion, etc.) should be documented.   
o Underlying cardiovascular disease, if any; including but not limited to 
hypertension, dyslipidemia, coronary artery disease 
o Prior history of cardiac events including: acute myocardial infarction, CVA, or TIA  
o Prior surgical interventions and/or cardiac procedures including: Percutaneous 
Trans Catheter Angioplasty (PTCA), Coronary Artery Bypass Graft (CABG), 
pacemaker (PM) implantation, implantable cardioverter-defibrillator (ICD) 
implant, Cardiac Resynchronization Therapy (CRT) implant, cardiac valve 
interventions, left atrial appendage closure (LAAC), patent foramen ovale (PFO) 
intervention, heart transplant or procedures for implantation of other intracardiac 
devices  
o Detailed history of all arrhythmias  

 
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o Non-cardiac comorbidities, including but not limited to: Chronic Obstructive 
Pulmonary Disease, Diabetes, Hepatic Disease, Neurologic Disease, Renal 
Disease, Bleeding Disorders/Clot disorders, Sleep Disordered Breathing 
• The following instrumental assessments will be performed or data from existing 
information will be collected: 
o TTE (most recent, either assessed at baseline visit or from medical file if date if not 
> 180 days prior to enrollment). Data will include: LVEF, left atrial diameter or left 
atrial volume**, pulmonary artery pressure**  
o Cardiac MRI or spiral CT scan, to assess PV anatomy and PV dimension.  
o TEE or ICE to rule out presence of left atrial thrombus. See section 12.5.2. 
Anticoagulation, Thrombus Screening. 
In the event a subject has an adverse event related to the TTE, TEE, ICE or CT/MRI 
scan, they shall remain in the study until the event is resolved. 
• Pregnancy test (urine or blood), if applicable*** 
• Blood tests**** 
• Quality of Life assessment through AFEQT and EQ-5D-5L questionnaires  
• Conduct a baseline National Institute of Health Stroke Scale (NIHSS), see Appendix 
30.2. 
• AAD history and most recent dose prior to enrollment; stop date of amiodarone (if 
applicable)  
• Current AAD and anticoagulation medication regimen  
• Reportable Adverse Events, if applicable 
• Protocol Deviations, if applicable 
 
* LVEF and LA diameters obtained ≤ 180 days prior to enrollment will be acceptable, unless 
a cardiac event has occurred (e.g. MI) between the date of the exam and the enrollment date, 
otherwise a new echocardiogram (trans-thoracic or trans-esophageal, or intracardiac echo) 
must be performed to confirm eligibility prior to performing ablation. LA anteroposterior 
diameter measured by M-mode from the parasternal long-axis view will be used.  If both LA 
diameter and volume are available, only one meeting eligibility criteria is required.  
**Moderate to Severe mitral stenosis (severity will be assessed as pulmonary artery systolic 
pressure > 30 mmHg). 
***A pregnancy test (method of assessment per investigators’ discretion) must be performed 
for women of childbearing potential. Women of child bearing potential will be required to 
verify entrance criteria prior to the procedure by providing documentation of a negative 
pregnancy test.  A negative pregnancy test conducted as standard of care within 7 days prior 
to enrollment will be acceptable. 
****Laboratory blood tests (other than a pregnancy blood test) obtained ≤ 90 days prior to 
enrollment will be acceptable.  

 
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 Medications 
 Anti-Arrhythmic Drugs 
 AADs prior to index procedure 
Inclusion criteria require the subject to be refractory or intolerant to at least one class I or III 
antiarrhythmic medication and amiodarone to be stopped three months before 
enrollment.  Prior and current AAD therapy will be collected in the EDC system. 
If applicable, administration of amiodarone and stop date will be entered in EDC. 
 AADs post index procedure during the 90-day blanking period 
Blanking period is defined as the time between Index procedure and 90 days post Index 
procedure. Post-procedure AADs are allowed per physician’s discretion during the blanking 
period. New AADs should not be prescribed unless considered medically necessary.  If 
treatment with AAD is prescribed during the blanking period, it is recommended that a Class 
I or III AAD be selected according to the ACC/AHA/ESC 2014 Guidelines for the 
Management of Patients with AF.  No amiodarone use is permitted post procedure. After the 
index procedure, the investigator should remove subjects from AADs to appropriately assess 
the subject for early arrhythmia recurrence that may require a repeat ablation procedure within 
the blanking period (on or before day 90). 
 AADs post 90 days blanking period 
Investigators must stop administration of AADs for any atrial tachyarrhythmia after the 
blanking period. If the investigator determines that the subject must be prescribed any dose of 
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/AT/AFL recurrence.   
Treatment with Class II/IV medications for conditions other than control of atrial arrhythmia 
recurrence is also permitted and will be documented.  Every effort should be made to keep 
those drugs at a stable dose over the entire course of the study.   
 Anticoagulation 
The following anticoagulation protocol is required for this study. An adequate anticoagulation 
regimen is represented by one of the 4 approaches listed in the paragraph titled “Pre-ablation”. 
Pre-ablation. 
Physicians can follow either an uninterrupted anticoagulation approach (Recommended), 
based on uninterrupted warfarin or NOAC, or minimally interrupted NOAC or an interrupted 
anticoagulation approach with adequate bridge with LMWH (Low Molecular Weight 
Heparin). 
• Uninterrupted anticoagulation approach (recommended) includes one of the following 
options: 

 
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1) Uninterrupted treatment with warfarin or NOAC*, requiring continued 
treatment including the day of the index procedure  
2) Minimally interrupted NOAC, requiring continued treatment but allowing to 
stop NOAC 12 to 24 hours before the index procedure (e.g. holding the morning 
dose the day of the procedure) 
• Interrupted anticoagulation approach includes one of the following options. 
3) If patient is on Warfarin, this should be stopped 5 days prior to the ablation 
procedure and bridged with LMWH. LMWH should be stopped 12 hours prior 
ablation. 
4) If patient is on NOAC, this should be stopped 5 days prior to the ablation 
procedure and bridged to Warfarin or bridged with LMWH. LMWH should be 
stopped 12 hours prior ablation. At the time NOAC is stopped, INR value should 
be checked, if applicable, to ensure the Time of Therapeutic Range (TTR) are 
achieved with normalized ratio (INR) between 2.0 and 3.0. 
 
* Includes any of the FDA approved NOAC (dabigatran, edoxaban, apixaban or rivaroxaban) 
 Anticoagulation guidelines that pertain to cardioversion of AF should be adhered.  
If at the time of enrollment, a patient has not been anticoagulated as defined above in the pre-
ablation anticoagulation, anticoagulation must be initiated and maintained from point of 
enrollment to the time of the index procedure. In the event that the patient has not been 
anticoagulated for at least 3 weeks prior to the index procedure, thrombus screening must be 
conducted as outlined in Section 12.5.3.  
 
Intra ablation:  
• Heparin should be administered prior to transseptal puncture during AF catheter 
ablation procedures and adjusted to achieve and maintain an ACT of at least 300 
seconds. The ACT level should be checked at 10-15 minute intervals until therapeutic 
anticoagulation is achieved, and then at 15–30 minute intervals for the duration of the 
procedure.  
After ablation:  
• Systemic anticoagulation with warfarin or a NOAC is recommended for at least 2 
months post catheter ablation of AF. 
• Adherence to AF anticoagulation guidelines is recommended for patients who have 
undergone an AF ablation procedure, regardless of the apparent success or failure of 
the procedure.  
Decisions regarding continuation of systemic anticoagulation more than 2 months post 
ablation should be based on the patient's stroke risk profile and not on the perceived 
success or failure of the ablation procedure. 

 
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  Thrombus Screening 
The absence of thrombus must be confirmed by means of a TEE within 48 hours prior to 
the procedure or ICE during the procedure in subjects not adequately anticoagulated (see 
section 12.5.2) for at least 3 weeks prior to procedure OR with CHA2DS2-VASc score (see 
Appendix 30.4) ≥2 in men and ≥3 in women OR enlarged LA (≥4.5cm). When screening 
for thrombus prior to the index procedure, ensure that the anticoagulation approach as 
described in Section 12.5.2 is followed until the day of the procedure. 
 Index (Ablation) Procedure 
 General Info 
• Authorized ablating physicians 
 
The study-related ablation procedure, from transseptal access in the left atrium until end of 
the ablation procedure must be performed by investigators trained in Electrophysiology 
(EP), trained to the FROzEN-AF clinical protocol and authorized by BSC to handle 
investigational devices. The index ablation procedure must be performed within 30 days 
of a subject’s enrollment into the study.  To avoid potential bias, it is recommended the 
number of active ablating physicians performing the index procedure per investigational 
site is restricted to 2. Boston Scientific will therefore authorize a maximum of 2 active 
ablating physicians per site except in regions where the Cryoballoon System is 
commercially available. 
 
• De novo procedures 
For the purposes of this protocol, de novo procedures are defined as AF procedures in 
which there has been no prior ablation in the Left Atrium (LA). According to subject 
selection criteria, all Index procedures in this study are de-novo as history of previous left 
atrial ablation or surgical treatment for AF/ AFL/ AT constitute an exclusion criterion. 
• Esophagus management  
Esophagus management must be performed by means of temperature monitoring via the 
Console using commercially available products. A commercially available temperature 
probe compatible with the Cryoablation system, will be used with measurements acquired 
and displayed through the Console. If the esophageal temperature falls below 20°C during 
cryoablation applications, the ablation will be stopped until esophageal temperature returns 
to baseline. 
• Phrenic nerve activity monitoring 
o Index Procedure: 
 During ablation phrenic nerve activity monitoring will be performed. 
The phrenic nerve will be paced with a focal or circular catheter, higher 
than the ablation position during all right sided vein ablations. If a 
reduction in phrenic response is detected, the operating physician will 

 
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continue to closely monitor phrenic nerve activity and pacing capture, 
and will consider immediately interrupting cryoablation  
 After ablation, prior to leaving the EP lab, fluoroscopy of diaphragm 
movement will be performed at the completion of the ablation procedure 
o Discharge: 
 All patients presenting with phrenic nerve palsy at the end of the index 
procedure will be re-assessed at the discharge visit for phrenic nerve 
palsy via sniff test or an inhalation-exhalation chest radiography of the 
diaphragm 
o At Follow-up Visits: 
 Patients with unresolved phrenic nerve palsy detected at discharge visit, 
should be assessed by means of sniff test or an inhalation -exhalation 
chest radiography of the diaphragm to evaluate if the event resolved 
• Three-dimensional electroanatomic mapping 
3D electro-anatomical mapping is not recommended in this study. If 3D mapping is 
performed, a commercially available device will be used, and the following information 
will be collected: mapping catheter, 3D mapping system and mapping times. 
 Pulmonary Vein Isolation  
The goal of the ablation procedure is electrical isolation of all clinically relevant PVs.  
Electrical isolation of the veins must be demonstrated by entrance and exit block.  
If the subject is in AF prior to the ablation, it will be up to the physician’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. 
 Cryoablation System Preparation  
The Console will create a record for each ablation attempted, including Ablation Duration, 
Cryoballoon Temperature, Esophagus Temperature (if connected) and DMS activity data. In 
order to accurately capture information relevant to the study, the following information must 
be input into the Console at each index procedure: 
 
Prior to Ablation:   
• On the subject information screen, enter the subject’s identification (code provided by 
the EDC system when enrolling the patient) and the operating physician name. 
• For the purpose of this study, the DMS must 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, 

 
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ICE) should always be applied during right pulmonary vein ablations. The DMS is 
not intended as a substitute for such standard of care methods.       
1. Place a disposable ECG electrode just below the right side costal cartilage. 
2. Snap the DMS onto the electrode. 
3. Ask the patient to cough and verify that signal is visible on the console screen. 
Adjust the position of the electrode if necessary. 
Prior to performing the ablation, pace the phrenic nerve with a focal or 
circular catheter positioned superior to the ablation location (e.g. superior 
vena cava). Adjust the pacing settings and catheter location as necessary to 
attain phrenic nerve capture. Typically, high output at 20 mA and 800 – 1000 
milliseconds (ms) may be needed. 
NOTE:  Avoid or minimize use of paralytics if general anesthesia is used as 
paralytics may interfere with pacing capture of the phrenic nerve. 
4. While pacing the phrenic nerve, adjust the DMS gain and sensitivity levels 
within the Settings screen to maximize the DMS signal level in the display 
window. Reduce the gain if the DMS signal appears saturated. Stop pacing 
until needed for the ablation.  
5. Set the DMS threshold (within the Settings screen) for which the DMS 
notification will be displayed. The suggested DMS threshold setting is 65%, 
but. the threshold can be adjusted per physician discretion. 
• 
The movement amplitude measured by the DMS at the initiation of 
cryoablation is used as the baseline value and is displayed as 100%. 
• 
If the phrenic nerve pacing response decreases during cryoablation, the 
DMS amplitude will correspondingly decrease. The console will display 
the DMS amplitude as a percentage of the baseline value. For example, 
80% displayed on the console indicates the DMS amplitude is 80% of the 
baseline valve and that movement amplitude is reduced by 20%.  
6. In case of a DMS notification, continue to closely monitor phrenic nerve 
activity and pacing capture, and consider immediately interrupting 
cryoablation.  
 
During Each Ablation Application:   
• Annotate the ablation site, mark the Time-To-Isolation, and set the Ablation Duration.  
 Cryoablation protocol   
The ablation procedure should follow this recommended sequence: Prepare patient with 
conscious sedation or general anaesthesia. Prepare the vascular access sites per physician 
preference. Follow anticoagulation protocol in section 12.5.2. 

 
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1. Intracardiac echo (ICE) may be performed to support the procedure. Record any 
observation of cardiac structural damage, any evidence of pericardial effusion, or any 
visible anomalies on the CRF. 
2. Place additional diagnostic catheters, for example in the coronary sinus or for pacing 
the phrenic nerve, at the discretion of the physician. 
3. Per institutional protocol, complete transseptal access (single or double).  
4. Baseline the fluoroscopy exposure time.  
5. Per the DFU, prepare the steerable sheath. Insert the steerable sheath over the 
guidewire and advance the sheath across the atrial septum. 
6. Per the DFU, prepare the cryoablation catheter and the mapping catheter. Insert the 
mapping catheter into the cryoablation catheter. Insert the Cryoablation Catheter into 
the steerable sheath and advance it into the left atrium. 
7. Baseline the LA dwell time. 
8. Advance the mapping catheter into the targeted PV and attain baseline electrograms, 
including confirming conduction between LA and PV. 
9. Inflate the cryoballoon and occlude the targeted PV. Confirm and grade the occlusion 
using fluoroscopy with contrast injection.  
10. Position the esophagus temperature probe as directly posterior to the cryoballoon as 
possible.  
11. If the selected vessel is a right PV, start phrenic nerve pacing prior to starting the 
cryoablation. 
12. Start the cryoablation and observe the electrograms for changes in conduction. 
Identify Time-To-Isolation and set ablation duration as required by the dosing 
strategy document (document 92355401 provided separately). Investigators may 
apply a different dosing than the one provided in this document for reasons including 
technical difficulties, anatomical challenges, or concerns for subject welfare.   
13. Upon completing the ablation, determine if entrance and exit block were achieved. If 
entrance and exit block are not confirmed, ablate the PV again as required by the 
dosing strategy document (document 92355401). Investigators may apply a different 
dosing than the one provided in this document for reasons including technical 
difficulties, anatomical challenges, or concerns for subject welfare.  If entrance and 
exit block are confirmed, reposition the system to target another PV. 
 PV isolation verification  
Electrograms from the POLARMAP mapping catheter will be used to assess entrance and 
exit block into/from the PVs. The PV will only be considered isolated if entrance and exit 
block are confirmed. Electrogram data must be documented.  

 
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 Additional ablation(s) 
Additional ablation of non-PV foci that initiate AF (including locations in the LA, RA, or 
SVC), targeting complex fractionated electrograms or ganglionated plexi or performing left 
atrial mitral isthmus or roof lines are not allowed in this protocol.  
Additional ablation of the cavo-tricuspid isthmus (CTI) with a conventional market approved 
RF catheter is allowed only in case a typical atrial flutter is documented in prior patient history 
or occurs during the case (either spontaneously or inducible). 
The Cryoablation System cannot be used for the ablation of other arrhythmia(s)/additional 
line(s) or applications outside the PVs. 
It is not allowed to perform concomitant procedures during the ablation procedure (e.g. ICD 
implant, PM, LAAC).   
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.   
If at any time during the ablation procedure the investigator is unable to continue the ablation 
with the designated investigational catheter (for the PV isolation), the investigator may 
consider the case a procedural failure and complete the case with a device determined best for 
the subject.  The point at which failure was determined as well as the rationale must be 
documented.  A protocol deviation will be documented in the EDC system. 
 Index procedure collected data 
The following data related to the procedure will be collected: 
• Date of procedure 
• Identification of all investigational study devices:  
o Cryoablation Catheter  
o Cryo Mapping Catheter  
o Cryo Steerable Sheath  
o Console and all investigational accessory devices 
• Identification of non-study devices if applicable:  
o Additional sheaths/introducers used during the procedure including 
manufacturer, model and type 
o Additional catheter(s) used during the case other than Cryoablation Catheter 
including manufacturer, model, and type (e.g. mapping catheter and CS 
catheter) 
o Mapping system and mapping catheter (manufacturer and model); if 
RHYTHMIA HDx™ is used (manufacturer, model and software version)  

 
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• 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 access to left atrium single or double transseptal 
• Method of evaluating phrenic nerve function and determining when intervention is 
needed 
• Collection of ACT levels 
 
Specific to the PVI ablation the following information will be collected: 
• Pre-ablation electrograms with baseline entrance and exit conduction for each PV 
• Occlusion score for each cryo application 
• Time-to-Isolation (if achieved), minimum balloon temperature, and duration of each 
cryo application.  
• Total number and total duration of cryo applications per PV 
• Post-ablation electrograms of entrance/exit block for each PV 
   
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 
• Total Cryoablation time (duration of all cryo applications) 
• Duration of LA dwell time defined as time from the Cryoablation Catheter exiting the 
sheath in the LA to time of final PV isolation. 
• 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 through fluoroscopy of diaphragm movement. 
• Protocol Deviations, if applicable 
 
After removal from the subject, all investigational catheters should be inspected by the 
investigational site staff, and if any abnormalities are noted on the catheter, it must be 
documented.  All investigational catheters, steerable sheaths and extension cables opened 
and/or used during the procedure must be returned to the sponsor.  Failure to return an 

 
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investigational device will result in a protocol deviation. All other control ablation or 
diagnostic catheters may be disposed of per standard EP practice. All adverse experiences 
with a BSC product, including those commercially available, during the ablation procedure 
must be promptly reported to BSC and documented on the eCRF. 
 
• The Export Case Data (the data collected through the Console) will be saved and 
stored to external media, as provided by the sponsor; 
• Console Report 
• The EP Lab Procedure Report will be printed and stored in the center’s patient file.  
Please refer to Table 10 for an overview of source document requirements. 
 Pre-Discharge Visit 
The pre-discharge follow-up visit (1 to 7 days post procedure) should be done before hospital 
discharge, but 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. 
The data collection at Pre-Discharge includes: 
• Date of visit 
• Physical assessment with cardiovascular/pulmonary examination including: 
o Weight,  
o Resting heart rate,  
o Systolic and diastolic blood pressure,  
o O2 saturation, 
o Lung auscultation (includes respiratory rate and respiratory rhythm),  
o Temperature 
• Rhythm at time of visit (by means of a 12-lead ECG)  
• Conduct an NIH Stroke Scale (NIHSS)  (see Appendix 30.2) 
• In cases of phrenic nerve palsy at the index procedure, patients should be assessed by 
means of a sniff test or an inhalation-exhalation chest radiography of the diaphragm 
to evaluate if the event resolved  
• Provide subjects with arrhythmia/event monitor and operating instructions; 
• Perform a cardiac MRI or spiral CT if PV stenosis is suspected at any time 
throughout the follow-up period. Recommend using the same imaging modality used 
at baseline 
• New, discontinued or changes to current medication regimen 
• Reportable Adverse Events, including resolution of ongoing events, if applicable 
• Protocol Deviations, if applicable 

 
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If the NIH stroke scale demonstrates new abnormal findings when compared with the pre-
procedure assessment, the subject will have a neurology consultation. A brain DW-MRI scan 
is required if neurology consultation determines possibility of new stroke. The DW MRI scan 
sequences required will be performed within the local guidelines associated with brain MRI 
scan. The following parameters for the DW-MRI are recommended in order to allow 
comparability of potential findings across patients: 
• 1.5T MRI imaging equipment 
• 
Diffusion-weighted imaging technique  
• 5mm slice thickness 
 Day 7 Follow-up Contact 
A telephone contact will occur at 7 days post-procedure (7 days±1 day). If the patient is still 
hospitalized the 7 days follow-up will be performed as in-hospital visits.  The data collection 
at the day 7 follow-up includes: 
• Date of visit 
• New, discontinued or changes to in current medication regime 
• Reportable Adverse Events, including resolution of ongoing events, if applicable 
• Protocol Deviations, if applicable 
In cases of in-hospital visit and phrenic nerve palsy at the index procedure, patients should be 
assessed by means of sniff-test or inhalation-exhalation chest radiography of the diaphragm to 
evaluate if the event resolved.  
 Month 3 Follow-Up Visit 
This visit should be completed at 3 months post-procedure (91 days±14 days).  Due to the 
range for the visit completion and the endpoint requirement for medication, AAD medication 
changes made during the three-month follow-up visit will be counted as being made within the 
blanking period, but efforts should be made to remove subjects from AADs by eight weeks 
post-procedure to allow for complete washout. The data collection at the 3-month follow-up 
includes: 
• Date of visit 
• Physical assessment including weight, resting heart rate, systolic and diastolic blood 
pressure 
• Rhythm at time of visit (by means of a 12-lead ECG) 
• Quality of Life Instruments (AFEQT and EQ-5D-5L) 
• Review of any symptomatic transmissions (arrhythmia/event monitor such as a TTM) 
• Documentation of any intervention for AF/AT/AFL (e.g. Repeat Procedure, 
Cardioversion), if applicable 

 
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• Perform a cardiac MRI or spiral CT if planned at 3 months as part of the PV stenosis 
screening substudy. Use the same imaging modality used at baseline.  
• For sites not participating in the PV stenosis substudy, perform a cardiac MRI or 
spiral CT if PV stenosis is suspected at any time throughout the follow-up period. 
Recommend using the same imaging modality used at baseline. 
• New, discontinued or changes to current medication regimen 
• Reportable Adverse Events, including resolution of ongoing events, if applicable; in 
particular: 
o In cases of a pre-existing and unresolved phrenic nerve palsy the patient 
should be assessed by means of a sniff test or an inhalation-exhalation chest 
radiography of the diaphragm to evaluate if the event resolved  
• Protocol Deviations, if applicable 
 Month 6 Follow-Up Visit  
This visit should be completed at 6 months post-procedure (180 days±30 days).  The data 
collection at the month 6 follow-up includes: 
• Date of visit 
• Physical assessment including weight, resting heart rate, systolic and diastolic blood 
pressure; 
• Rhythm at time of visit (by means of a 12-lead ECG) 
• Quality of Life Instruments (AFEQT and EQ-5D-5L) 
• Review of any symptomatic or asymptomatic transmissions (arrhythmia/event 
monitor such as TTM) 
• Documentation of any intervention for AF/AT/AFL (e.g. Repeat Procedure, 
Cardioversion), if applicable 
• Perform a cardiac MRI or spiral CT at any point in time during the 3 to 6 months 
follow-up as part of the PV stenosis screening substudy. Use the same imaging 
modality used at baseline   
• For sites which are not part of the PV stenosis screening substudy, perform a cardiac 
MRI or spiral CT if PV stenosis is suspected at any time throughout the follow-up 
period. Recommend using the same imaging modality used at baseline  
• New, discontinued or changes to current medication regimen 
• Reportable Adverse Events, including resolution of ongoing events, if applicable; in 
particular: 

 
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• In cases of phrenic nerve palsy at the index procedure, patients should be assessed by 
means of a sniff test or an inhalation-exhalation chest radiography of the diaphragm 
to evaluate if the event resolved  
• Protocol Deviations, if applicable 
 Month 12 Follow-Up Visit 
Investigators will assess subject status at 12 months (365 days±30 days) post index 
procedure. The data collection at the month 12 follow-up includes: 
• Date of visit 
• Physical assessment including weight, resting heart rate, systolic and diastolic blood 
pressure; 
• Rhythm at time of visit (by means of a 12-lead ECG) 
• Quality of Life Instruments (AFEQT and EQ-5D-5L) 
• Review of any symptomatic or asymptomatic transmissions (arrhythmia/event 
monitor such as TTM) 
•  24-hour Holter monitor data recorded with the study specific TTM   
Note: While wearing the Holter monitor, subjects should also make every attempt to 
capture the symptomatic episode with the TTM 
• Documentation of any intervention for AF/AT/AFL (e.g. Repeat Procedure, 
Cardioversion), if applicable 
• Perform a cardiac MRI or spiral CT if PV stenosis is suspected. Recommend using 
the same imaging modality used at baseline  
• New, discontinued or changes to in current medication regime 
• Reportable Adverse Events, including resolution of ongoing events, if applicable; in 
particular: 
o In cases of phrenic nerve palsy at the index procedure, patients should be 
assessed by means of a sniff test or an inhalation-exhalation chest radiography 
of the diaphragm to evaluate if the event resolved  
• Protocol Deviations, if applicable 
 Unscheduled Visits 
An unscheduled follow-up visit is any subject visit triggered by subject symptoms that is not 
already defined as one of the study visits. 
If subjects experience symptoms associated with cardiac arrhythmias (e.g. palpitations, 
lightheadedness, syncope, dyspnea) during the first 12 months, they will be instructed to record 
the arrhythmia on the event monitor.  The investigator will review the information transmitted 

 
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and will contact the subject to schedule an additional office visit if deemed necessary per 
investigator’s decision.   
In addition to determining the best course of action for the subject (repeat ablation, medication 
adjustment), during the visit, the following will be collected:  
• Date of visit 
• Physical assessment including: weight, resting heart rate, systolic and diastolic blood 
pressure 
• Rhythm at time of visit (by means of a 12-lead ECG) 
• Review of any symptomatic or asymptomatic transmissions (arrhythmia/event 
monitor, such as TTM)  
• Documentation of any intervention for AF/AT/AFL (e.g. Repeat Procedure, 
Cardioversion), if applicable 
• Perform a cardiac MRI or spiral CT at any point in time during the 3 to 6 month 
follow-up as part of the PV stenosis screening substudy. Use the same imaging 
modality used at baseline   
• For sites not part of the PV stenosis screening substudy, perform a cardiac MRI or 
spiral CT if PV stenosis is suspected at any time throughout the follow-up period. 
Recommend using the same imaging modality used at baseline 
• New, discontinued or changes to current medication regimen 
• Reportable Adverse Events, including resolution of ongoing events, if applicable; in 
particular: 
o In cases of phrenic nerve palsy at the index procedure, patients should be 
assessed by means of a sniff test or an inhalation-exhalation chest radiography 
of the diaphragm to evaluate if the event resolved  
• Protocol Deviations, if applicable 
 Additional/Repeat Procedure 
In case an additional procedure (including but not limited to a repeat ablation procedure for 
PAF) occurs during the month 12 follow-up period, the data of this procedure will be entered 
in the ‘Additional/ Repeat Procedure’ eCRF.  In case this additional procedure is an ablation 
procedure (for the same, or different arrhythmias or for an unsuccessful ablation of the 
arrhythmia presented at index procedure), detailed information about this additional ablation 
procedure will be entered in the ‘Additional/Repeat Procedure’ eCRF: 
• Was the additional ablation procedure performed in the LA? If yes, TEE or ICE to 
rule out presence of left atrial thrombus.  *** 
• For additional ablation procedures performed in the LA: was this additional ablation 
procedure performed to treat AF?  If no, specify the arrhythmia type. 

 
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It is known that a repeat ablation procedure for PAF may be necessary in certain 
subjects after the index ablation procedure due to recurrences of PAF or other 
tachyarrhythmias requiring treatment.  One repeat ablation procedure for PAF is 
allowed within the blanking period if considered medically necessary due to patient’s 
intolerability of the PAF. If the repeated ablation procedure occurs during the 
blanking period (within 90 days of the Index procedure) it is recommended to use the 
Cryoablation system. Use of a non-study device for AF re-ablation during blanking 
period constitutes a failure for the effectiveness endpoint.   Data for the repeat 
ablation procedure will be collected in the eCRF. 
Subjects must follow the same anticoagulation requirements as defined for the index 
procedure in section 12.5.2 prior to proceeding with the repeat ablation procedure for 
PAF.  
• If a 3D mapping system is used for this additional procedure, additional info will be 
collected  
• Reportable Adverse Events, including resolution of ongoing events, if applicable; in 
particular: 
o In cases of phrenic nerve palsy at the index procedure, patients should be 
assessed by means of a sniff test or an inhalation-exhalation chest radiography 
of the diaphragm to evaluate if the event resolved  
• Protocol deviations, if applicable 
The appropriate type of pre-procedure imaging (CT/MRI) is to be determined by the 
investigator.  As available, the PV images must be reviewed against the pre-ablation imaging 
from the index procedure to rule out PV stenosis from the index ablation procedure.   
 Study Completion 
Each Treatment subject will be followed until the month 12 follow-up. Participation in the 
study is considered complete upon completion of the month 12 follow-up. 
A participant is considered to have completed the study if he or she has completed all phases 
of the study including the last visit or the last scheduled procedure shown in the Data Collection 
Schedule. 
 
In case of premature termination of the study, please refer to section 24.  
Following termination/completion of the study, subjects will be managed according to local 
institution practice.  
Sites will need to document and complete the “End of Study” CRF to signify study 
completion. 

 
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 Unforeseen Circumstances (Natural Disaster/Global Pandemic) 
There may be unforeseen circumstances that occur during the course of the study, such as a 
natural disaster or a global pandemic (e.g. COVID-19) that prevents a subject from attending 
study visits during the required follow-up window. While every attempt should be made to 
avoid disruptions in collecting study data, it is important to collect as much data as possible, 
by any available means and from any available resources. This may include obtaining records 
from an outside clinic, hospital or other healthcare facility that is not IRB/EC/REB approved.  
In the event that study data must be collected remotely, every effort should be made to 
collect the data within the study visit window, if possible. Critical data collected during the 
study includes any procedure or device related adverse events, recurrence of any 
AF/AT/AFL, and a Cardiac CT or MRI (if PV stenosis is suspected). Event monitors and 24- 
hour Holter monitors can be used to detect any recurrence of AF/AT/AFL. If a Cardiac CT or 
MRI is required because PV stenosis is suspected, the Cardiac CT or MRI may be performed 
at another healthcare facility and the window to conduct this test may be extended by up to 
one month (30 days) following the normal study visit window.  
 
 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 the Table below.  
Table 10: Source Documentation Requirements 
Requirement 
Disposition 
Screening and enrollment log 
Retain at Center 
Informed consent documentation process 
Retain at Center 
Medical history documents pertaining to eligibility 
criteria 
Retain at Center 
Documentation of demographics data 
Retain at Center 
Pregnancy, if applicable 
Retain at Center 
Physical assessment  
Retain at Center 
Cardiovascular/pulmonary examination 
Retain at Center 
Medication Regimen and Changes 
Retain at Center  
Medical history 
Retain at Center 
Quality of Life Instruments (AFEQT and EQ-5D-5L) 
Retain at Center 

 
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Requirement 
Disposition 
NIH Stroke Scale Assessments 
Retain original at center and submit copies and all 
associated source documents if a change in scale is 
observed from baseline 
If determined necessary, neurological consultation 
and brain MRI (DW-MRI) 
Retain originals at center and submit all source 
documents and copy of complete scan to BSC  
Imaging 
Retain at Center 
12-Lead ECGs data including ongoing rhythm 
Retain at Center 
Imaging, per standard of care 
Retain at Center 
Recording System Print-Outs, showing entrance/exit 
block for each Pulmonary Vein 
Retain at Center 
Pre-ablation electrograms with baseline entrance and 
exit conduction for each PV 
Retain at Center 
Recording lab logs, showing the time of 
entrance/exit block  
Retain at Center 
Signed Technical Source Form 
Retain at Center 
Console Report 
Retain at Center 
 
Console Export Case Data 
Retain at Center 
Submit one copy to BSC 
Printed EP Lab Procedure Report  
Retain at Center 
Adverse Events 
Retain at Center 
In the event of a patient death: 
• 
Death narrative 
• 
Relevant medical records 
• 
Death Certificate 
• 
Autopsy report 
Events be adjudicated by CEC: 
• 
Relevant medical records 
 
 
Submit one copy to BSC, 
Retain one copy at center 
 
 Statistical Considerations 
 Endpoints 
 Primary Safety Endpoints 
The expected safety event rate for the primary safety endpoint has been estimated by 
performing a meta-analysis on recently completed IDE studies (see Table 11). Although 
referring to the first-generation Cryoballoon (Arctic Front™ Balloon, Medtronic®), the STOP-
AF IDE study was included in the model as it is the only reported IDE study that utilizes a 
cryoablation balloon. Event rates and their 95% confidence intervals were estimated from 

 
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SSED, primary publications or results disclosed on clinicaltrials.gov and calculated based on 
the occurrence of the events that constitute the primary safety endpoint defined in this protocol. 
 
Table 11: Meta-Analysis to Determine Expected rate and 95% CI for Primary Safety 
Endpoint 
 
The overall safety event rate from this meta-analysis is 6.05%. All the studies passed their pre-
specified primary safety endpoint and established that the device under study exhibited an 
acceptable safety profile. In conclusion, BSC proposes a primary safety endpoint expected 
event rate of 6% (94% event-free rate). A performance goal for the primary safety endpoint 
was derived using the sum of the 95% upper confidence bound of the meta-analysis rate and a 
margin of indifference that is 50% of the upper confidence bound (7.2% + 0.5*7.2%). This 
resulted in a performance goal of 11% (89% event-free rate). 
 Hypotheses 
Ho:  The primary safety endpoint event-free rate at 12 months post procedure ≤89% 
Ha:  The primary safety endpoint event-free rate at 12 months post  procedure >89%  
 Sample Size  
Minimum of 325 non roll-in TREATMENT subjects treated with the Cryoablation System.   
Additionally, all ATTEMPT subjects will be included in the primary safety endpoint 
analysis. 
The sample size estimate was obtained using the normal approximation to the binomial 
distribution and verified through simulations based on Kaplan-Meier methodology. The 
following assumptions were used in the sample size calculation: 
Assumptions 
Primary 
Safety 
Expected rate 
94% 

 
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Performance goal 
89% 
Attrition (per year) 
10% 
Significance level  (one-sided) 
5% 
Power 
90% 
Patients after attrition 
325 
 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 89%. 
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. 
 Secondary Safety Endpoint 
Reportable Adverse Events rates at 12 months. 
Adverse events will be collected at all subject follow-up visits. Reportable events include: 
• All Serious Adverse Events 
• All Study Procedure-Related Adverse Events 
• All Study Device-Related Adverse Events 
• All Study Device Deficiencies  
• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device 
Effects previously not defined in DFU/Investigator’s Brochure 
 Primary Effectiveness Endpoint 
An effectiveness performance goal of 50% has been chosen based on the minimum chronic 
acceptable success rate for paroxysmal AF at 12-month follow-up defined in 2017 HRS 
Consensus document (ref). When considering recurrence of AF/AT/AFL, obtained in the 
pivotal trials on Cryoablation (STOP AF and FIRE & ICE) the starting point for the estimate 
failure-free rate was set as the one obtained for the second generation cryoballoon (FIRE & 
ICE: 66%), Effectiveness results are not easily poolable as aggregate  from recent IDE studies 
on AF ablation to difference in methodology and definitions found in the selected trials when 
evaluating the freedom from AF/AT/AFL recurrences off AADs after 3-months blanking 
period. Accordingly, an estimate of the failure-free rate taking into account recurrence of 
symptomatic and asymptomatic events has been estimated from the data of the recently 
concluded ZERO-AF trial from Boston Scientific, that led to the choice of 60% was based on 
as expected rate.  

 
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 Hypotheses 
Ho:  The 12-month failure-free rate ≤ 50% 
Ha:  The 12-month failure-free rate >50% 
 Sample Size  
Two hundred forty-nine non roll-in TREATMENT subjects treated with the Cryoablation 
System. 
The sample size estimate was obtained using the normal approximation to the binomial 
distribution and verified through simulations based on Kaplan-Meier methodology. The 
following assumptions were used in the sample size calculation: 
 
Assumptions 
Primary Effectiveness 
paroxysmal 
Expected rate 
60% 
Performance goal 
50% 
Attrition (per year) 
10% 
Significance level  (one-sided) 
5% 
Power 
90% 
Patients after attrition 
249 
 Statistical Methods 
For the primary effectiveness endpoint, the Kaplan-Meier 12 month (365-day) primary 
effectiveness event-free rate will be calculated. 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 primary effectiveness event-free rate will be 
compared to the performance goal of 50%. 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. 
 Secondary Effectiveness Endpoint 
Rate of Acute Procedural Success defined as the achievement of electrical isolation of all 
PVs by using the Cardiac Cryoablation system only. Electrical isolation of a PV is 
demonstrated by entrance and exit block. 
 General Statistical Methods 
 Analysis Sets 
Each primary endpoint analysis will use all available data from all non roll-in TREATMENT 
subjects. 

 
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 Control of Systematic Error/Bias 
Selection of patients will be made from the Investigator’s population. All patients meeting the 
eligibility criteria and having signed the ICF will be eligible for enrollment in the study.  
Control and reduction of potential bias associated with a single-arm study design have been 
taken into account by considering a series of measures including but not limited to: 
• 
defining inclusion and exclusion criteria to represent a population similar to the one 
enrolled in recently completed trials on AF ablation; 
• 
implementing a screening log to document reason(s) for screening failure and a pre-
specified analysis on screening failures; 
• 
employing a rhythm surveillance monitoring strategy that is equivalent to that used in 
recent PAF IDE studies and consistent with the relevant recommendation in the HRS 
consensus document;  
• 
utilizing core lab for reviewing electrocardiographic recordings from study specific 
rhythm surveillance monitoring after the blanking period. 
 Study Success and Control of Type I Error 
As this study was designed to address the safety and effectiveness of the Boston Scientific 
Cardiac Cryoablation System, there is one primary safety endpoint and one primary 
effectiveness endpoint.  Both the primary endpoints must pass in order for study success to 
be achieved.  Each primary endpoint would be tested at a significance level of 5% while still 
maintaining the overall Type I error level at no greater than 5%.  This follows the 
methodology of the Intersection-Union Test (IUT).  If all primary endpoints for a given study 
are passed, then the secondary effectiveness endpoint will be tested at alpha = 0.05. 
 Number of Subjects per Investigative Site 
To avoid any center effect and bias, one center will not be authorized to enroll more than 48 
subjects (15% of the minimum 325 enrollment total of non roll-in TREATMENT subjects). 
 Data Analyses 
 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. 
 Missing Data Analyses  
Because endpoints will be analyzed using Kaplan-Meier methodology, all TREATMENT 
subjects will contribute data to the primary effectiveness endpoint and all TREATMENT and 
ATTEMPT subjects will contribute data to the primary safety endpoint. A tipping point 
analysis will be done to assess the potential impact of missing data in INTENT and ATTEMPT 

 
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subjects for the primary effectiveness endpoint and in INTENT subjects for the primary safety 
endpoint. 
In the tipping point analysis, missing data subjects will be assigned as either having or not 
having an endpoint event. All possible combinations of success and failure in these subject’s 
data will be evaluated along with the actual observed data to find the point at which the 
endpoint would have failed. 
 Subgroup Analyses 
An analysis will be performed for the primary endpoints to determine whether significant 
differences exist in endpoint results between subgroups.  The list of covariates (with applicable 
subgroups in parentheses) includes the following: 
• Sex (Female vs. Male) 
• Age at time of consent (subjects > 60 years vs subjects ≤60 years) 
• Geography (International vs. United States) 
• Enrollment criteria (protocol versions A-G vs. subsequent protocol versions)  
Each subgroup covariate will be included as a single independent variable in a logistic 
regression model with the primary endpoint outcome as the dependent variable and a test for 
significance at the 15% level will be performed.  
In addition to subgroup analyses, descriptive statistics of subject demographic and baseline 
characteristics will be presented for each subgroup listed in this section. 
 Center 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 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,) 
 Additional Analyses 
 Additional endpoints and analyses include, but are not limited to:  

 
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• Changes in the quality of life measures (AFEQT and EQ-5D-5L) between baseline 
and 12 months follow up 
• Single procedure success, defined as freedom from primary effectiveness failure 
without a repeat procedure  
• Duration of LA dwell time, defined as time from the Cryoablation Catheter exiting 
the sheath in the LA to time of final PV isolation;  
• Total Cryoablation time for the index procedure; 
• Total fluoroscopy time for the index procedure; 
• Total index procedure time; 
• Freedom from recurrence of individual types atrial arrhythmias between 91 and 365 
days post index procedure: 1) AF 2) AT 3) AFL;  
• Failure- free rate as defined in primary effectiveness endpoint when considering 
AF/AT/AFL episodes reported to the investigators by study specific (event recorder 
transmissions, 12 lead ECG and Holter) and non-study related devices (other 
commercial applications for arrhythmia monitoring and detection the subject may 
access during the study including telemetry, other sources of continuous recording 
etc.); 
Freedom from primary effectiveness failure at six (6) months will be included in the final 
study report as a “proof-of-concept” analysis to potentially show the ability to predict 1-year 
effectiveness results using 6-month effectiveness data. 
 
 
 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. 
 Health Economics Outcomes 
A formal health economics analysis may be completed as part of this trial study, given 
meaningful clinical results are obtained. This will take into consideration complication rates, 
quality of life, and resource utilization. The EQ-5D, generic quality of life measure, will be 
used to assess health utilities. We may estimate costs associated with the health care utilization 
measures at all sites. These inputs may be used in health economics analysis performed. 
 

 
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 Data Management 
 Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) system.  
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(s). The associated Rave software and database have 
been designed to meet regulatory compliance for deployment as part of a 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 EDC system and will be issued to the 
site for appropriate response. Site staff will be responsible for resolving all queries in the 
database. 
Data transfers from other systems such as core labs and electronic questionnaires will be 
coordinated by Boston Scientific.  
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 sponsor-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. 

 
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Collection and completion of all information on the Technical Source Form is the 
responsibility of the appropriately delegated site personnel. If available, the console operator 
will provide the delegated site personnel with the study related data collected during the case 
directly from the console. 
At the conclusion of the procedure, the completed technical source form must be signed (and 
initialed as needed) by the following people: 
• 
Delegated Site Personnel completing the forms 
• 
Delegated Investigator conducting and/or supervising the case 
• 
Console operator supporting the case 
 Core Laboratories 
 Event and 24-Hour Holter Monitors’ Core Lab 
 Event Monitors 
A Core Lab will provide the center and/or subject all necessary instructions and/or materials 
related to the use of the event monitor.  Only TREATMENT subjects will be provided with 
an event monitor, such as a Trans-Telephonic Monitor (TTM), either prior to discharge from 
the hospital or will be sent to the subject’s residence immediately following discharge.  All 
events will be analyzed by the centralized research company to determine if the episodes are 
associated with arrhythmia recurrence.  The Core Lab will make this information accessible 
to the Investigator center for concurrence.  If there is discordance in arrhythmia classification 
between the Core Lab and the investigator, a third-party cardiologist will be used for final 
rhythm determination. 
Within the first 90 days (3 months) after the index ablation procedure (blanking period), 
TREATMENT subjects will be instructed to transmit all symptomatic episodes for detection 
and/or treatment of early recurrences.  After the subject’s 3-month follow-up visit, subjects 
will be instructed to send at least two transmissions per month (either symptomatic or 
asymptomatic) through the 12-month follow-up to ensure continued reporting compliance. If 
subjects experience symptoms associated with cardiac arrhythmias (e.g. palpitations, 
lightheadedness, syncope, dyspnea), they will be instructed to transmit a recording. Such 
recording will count towards the required transmission of that period. The Core Lab will work 
with the investigational site to ensure reporting compliance.   
All event monitors must be returned to the centralized research company upon completion of 
a subject’s 12-month follow-up or withdrawal from the study.   
 24-Hour Holter Monitors 
All TREATMENT subjects will be provided with 24-Hour Holter Monitors at the 12-month 
follow-up visit.   
Investigational centers will be trained on the set-up of the monitors and will provide the 
subjects with the instructions necessary to complete the test.  If a subject has a symptomatic 
episode while wearing the Holter Monitor, they will be strongly encouraged to report the 

 
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symptoms to their physician.  Once the Holter Monitor is returned to the centralized research 
company, the monitor will be analyzed for all symptomatic and asymptomatic arrhythmia 
episodes, and investigators will be informed of the results.   
 ECG Core Lab 
To ensure objective assessment of rhythm monitoring data, 12-lead ECG tracings obtained 
beyond 3 months post-procedure will be reviewed by an independent core lab. 
 PV Imaging Core Lab 
As part of the PV Imaging sub-study, a core lab will be contracted to review the baseline and 
follow-up CT/MRI scans for assessment of PV diameter narrowing and determination of 
severe PV stenosis.  The Core Lab will report the degree of narrowing (None, mild 50%, 
moderate 50-70%, severe ≥70%) in the follow-up scan compared to baseline.  All results will 
be provided both to BSC and to the investigator for adverse event reporting, if applicable. 
If PV stenosis is a suspected adverse event for subjects not partaking in the PV Imaging sub-
study, the PV Imaging core lab will also review the pre-ablation and post-ablation PV images 
collected on non-sub-study subjects to assess the degree of narrowing of the PV diameter for 
the Primary Safety Endpoint.  If it is determined that the baseline diameter of the vein of 
interest is not visually identifiable from the pre-ablation image, the PV Imaging core lab will 
measure the diameter of the vein before and after the narrowing region to determine the 
percentage change.  The results of the analysis will be provided to the investigator for 
submission of an adverse event, if applicable.  All necessary data will be provided to the study’s 
independent clinical events committee (CEC) for adjudication of the submitted adverse event, 
with a definition of severe PV stenosis being defined as ≥70% reduction in diameter from 
baseline. 
 Quality of Life (QOL) 
Clinical trials increasingly recognize the value of including patient reported outcome measures 
in their design. To understand the impact of atrial fibrillation ablation procedures on patient’s 
quality of life, the quality of life instruments used for the trial will be the EQ-5D-5L for a 
generic questionnaire and the AFEQT for disease specific. Subjects will be asked to complete 
the questionnaires at the Enrollment visit as well as at the three, six, and 12-month follow-ups.   
The Atrial Fibrillation Effect on Quality of Life (AFEQT) was developed to evaluate disease-
specific quality of life for patients with atrial fibrillation. The 20-item questionnaire is 
subdivided into three domains: symptoms, daily activities, and treatment concerns with 
responses provided on a seven-point Likert scale.  
The EQ-5D, generic quality of life measure, will be used to assess health utilities. It is a 
descriptive system of health-related quality of life states consisting of five dimensions 
(mobility, self-care, usual activities, pain/discomfort, anxiety/depression) each of which can 
take one of five responses. The responses record five levels of severity (no problems/slight 
problems/moderate problems/severe problems/extreme problems) within a particular EQ-5D 
dimension. 

 
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 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 IRB/EC/REB, and the regulatory authority if applicable, of any 
deviation from the investigational plan to protect the life or physical well-being of a subject in 
an emergency, and those deviations which affect the scientific integrity of the clinical 
investigation. 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 eCRF. Sites may also be 
required to report deviations to the IRB/EC/REB, 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 IRB/FDA notification, site re-training, or site 
discontinuation/termination) will be put into place by the sponsor. 
 
 Device/Equipment Accountability for Products Labelled 
Investigational 
 Investigationally-Labelled Products 
The investigational devices/equipment shall be securely maintained, controlled, and used only 
in this clinical study. Investigational equipment shall be returned in the condition in which it 
was provided, reasonable wear and tear excepted. 
For investigationally-labelled items, the principal investigator or an authorized designee shall 
do the following: 
• Securely maintain and control access to these items to ensure they are used only 
in this clinical study and only per the protocol.  
• Ensure the storage environment for these items is appropriate for maintaining 
conditions per the items’ labeling (e.g. temperature, humidity, etc., as applicable)  
• Return remaining items upon Sponsor request and in the condition in which they 
were provided, reasonable wear and tear excepted. 
The sponsor shall keep records to document the physical location of all investigationally-
labelled devices/ equipment from shipment of investigational devices from BSC or designated 
facility/equipment to the investigation sites until return or disposal. 

 
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The principal investigator or an authorized designee shall maintain accurate and timely Device 
Accountability Records documenting the receipt, use, return and disposal of the investigational 
devices/equipment, which shall include the following 
• Date of receipt 
• Identification and quantity of each investigational device/piece of equipment (examples 
of identification: batch number, serial number or unique code) 
• Expiry date, as applicable 
• Date or dates of use 
• Subject identification 
• Date on which the investigational device/piece of equipment was returned/explanted 
from subject, if applicable 
• Date of return (and number) of unused, expired, or malfunctioning investigational 
devices/equipment, if applicable. 
 
 Commercially-Labelled Product 
The principal investigator or an authorized designee shall maintain accurate and timely Device 
Accountability Records documenting the use and out of service of the devices/equipment, 
which shall include the following: 
• Identification and quantity of each investigational device/piece of equipment (examples 
of identification: batch number, serial number or unique code) 
• Date or dates of use 
• Subject identification 
• Date on which the device/piece of equipment was out of service. 
 
 
 Compliance 
 Statement of Compliance 
This clinical investigation is financed by the study sponsor. Before the investigational site 
can be “Authorized to Enroll,” the investigational site must enter into a Clinical Study 
Agreement with the sponsor that details the financing of the study as well as the rights and 
obligations of the investigational site and the investigator. 
 

 
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This study will be conducted in accordance with 21 CFR 814.20 part 56, part 50 and part 812 
or 813, 45 CFR part 46, ISO 14155Clinical Investigation of Medical Devices for Human 
Subjects - Good Clinical Practice, 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 IRB and 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 IRB 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, 
21 CFR 814.20 part 56, part 50 and part 812 or 813, ISO 14155 Clinical Investigation of 
Medical Devices for Human Subjects - Good Clinical Practice, any conditions of approval 
imposed by the reviewing IRB/EC/REB, 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.   
• Prior to beginning the study, sign the Investigator Brochure Signature Page (if 
applicable) and Protocol Signature page documenting his/her agreement to conduct 
the study in accordance with the protocol. 
• 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 
investigation. 
• 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-investigation-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  reportable events. 

 
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• Report to the IRB/EC/REB 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 IRB/EC/REB, 
and supply BSC with any additional requested information related to the safety 
reporting of a particular event 
• Maintain the device accountability records and control of the investigationnally-
labelled device, ensuring that the investigationally-labelled device is used only by 
authorized/designated users and in accordance with this protocol and 
instructions/directions for use 
• 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 IRB/EC/REB when performing 
auditing activities 
• Ensure that informed consent is obtained in accordance with applicable laws, this 
protocol and local IRB/EC/REB 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 investigational device when it is used/operated by 
the subject 
• Inform the subject of any new significant findings occurring during the clinical 
investigation, 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, 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 investigation are provided 
with some means of showing their participation in the clinical investigation, 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 
investigation 

 
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• Make all reasonable efforts to ascertain the reason(s) for a subject’s premature 
withdrawal from clinical investigation while fully respecting the subject’s rights 
• Ensure that an adequate investigation site team and facilities exist and are maintained 
and documented during the clinical investigation.  
All investigators will provide their qualifications and experience to assume responsibility 
for their delegated tasks 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. 
 
 Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to conducting 
the informed consent process, the Principal Investigator is responsible for providing 
appropriate training, ensuring that the individuals 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.  
 Institutional Review Board/Ethics Committee/REB 
The investigational site will obtain the written and dated approval/favorable opinion of the 
IRB/EC/REB for the clinical investigation before recruiting subjects and implementing all 
subsequent amendments, if required. 
A copy of the written IRB/EC/REB and FDA approval or local authority if applicable of the 
protocol (or permission to conduct the study) and ICF, must be received by the sponsor before 
recruitment of subjects into the study and shipment of investigational product/equipment. 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 IRB/EC/REB before 
the changes are implemented to the study.  All changes to the ICF will be IRB/EC/REB 
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 
IRB/EC/REB approval and renewals will be obtained throughout the duration of the study as 
required by applicable local state laws or regulations or IRB/EC/REB requirements. Copies of 
the study reports and the IRB continuance of approval must be provided to the sponsor. 
 Sponsor Responsibilities 
BSC has extensive experience conducting global clinical trials. 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 

 
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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.  
 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 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 the 
Cryoablation System and other support equipment). 
At the request of the investigator and while under investigator supervision, BSC personnel may 
operate equipment during ablation 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 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 clinical 
protocol compliance. 
• Reviewing collected data and study documentation for completeness, accuracy and 
compliance. 

 
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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 without the approval and 
presence of the investigator 
• Collect critical study data without review and approval of the ablating physician 
• Enter data in electronic data capture systems or study medical data into paper forms 
 Insurance  
Where required by local/country regulation, proof and type of insurance coverage, by BSC 
for subjects in the study will be obtained. 
 
 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 sponsor will put a plan in place to document the specific monitoring requirements.  
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 or remote monitoring visits or audits 
and that sufficient time is devoted to the process. 
 
 Potential Risks and Benefits 
 Anticipated Adverse Events  
Subjects participating in this study are subject to the same risks shared by all patients 
undergoing an ablation procedure for treatment of PAF.  Since the handling characteristics of 
the Cryoablation System are designed to be similar to those of other approved catheters for AF 
ablation, it is anticipated that the rate of catheter-related complications in this study will be 
similar to those reported from catheter ablations performed with approved catheter ablation 
systems.  The protocol-required testing for this study uses standard techniques that are 
routinely used for the treatment and management of subjects with drug refractory PAF. 

 
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Based upon the current literature and BSC reports on adverse events with an ablation catheter, 
the Table below includes an alphabetical list of the possible anticipated adverse events and 
possible adverse device effects associated with ablation with a cryoballoon  ablation catheter 
for the treatment of PAF. Occurrence of any of the listed events could lead to prolonged 
hospitalization for the subject.   
The following anticipated adverse events (AE) and adverse device effects (ADE) have been 
identified for this study: 
Table 12: Potential Adverse Events and Adverse Device Effects for PAF Ablation and 
Study Device 
Access site complications 
Headache 
Allergic reaction  
Heart failure 
Anemia 
Hematoma 
Arrhythmias  
Hemothorax  
Bleeding/Hemorrhage 
Hemodynamic instability  
Blurred vision 
Hypertension/Hypotension 
Cardiac perforation 
Inadvertent injury to adjacent structures 
Cardiac/pulmonary arrest 
Infection 
Catheter entrapment 
Myocardial infarction  
Cerebrovascular accident (CVA) 
Nerve weakness/palsy/injury (i.e. phrenic/ vagus) 
Chest discomfort/pain or pressure 
Pericarditis 
Complete heart block 
(transient/permanent) 
Pneumothorax 
Complications of sedative 
agents/anesthesia/medications 
Pseudoaneurysm 
Coronary artery spasm 
Pulmonary complications (i.e. edema, pulmonary 
hypertension, pleuritis, pneumonia) 
Cough 
Pulmonary vein stenosis 
Death 
Radiation injury/exposure 
Diaphragmatic paralysis 
Renal insufficiency/failure 
Dizziness or lightheadedness 
Respiratory Depression 
Edema 
Residual atrial septal defect (ASD) 
Pericardial effusion/pleural effusion 
Skin burns (i.e. radiation/defibrillator/ 
cardioverter) 
Elevated cardiac enzymes 
ST segment Elevation 
Embolism (venous/arterial) (i.e.  air, 
gas, thrombo, pulmonary)  
Sore Throat 
Endocarditis 
Tamponade 
Esophageal injury 
Thrombus/thrombosis  
Fever 
Transient ischemic attack (TIA) 
Exacerbation of existing conditions 
Valvular damage 
Fatigue 
Vasospasm 
Fistula (arterial-venous, atrial-
esophageal) 
Visual disturbances 

 
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Gastroparesis 
Vasovagal reactions 
 
Vessel trauma (i.e. injury/ulceration/ perforation/ 
dissection/rupture) 
 
 Risks Associated with the Study Device(s)  
Benchtop studies, pre-clinical research and a CE Mark clinical study have demonstrated that 
the System is safe for human use. All potential risks have been evaluated and mitigation 
strategies have been implemented to reduce potential risks to acceptable levels. 
 Risks associated with Participation in the Clinical Study 
There are no specific tests outside those recommended as standard practice for catheter ablation 
of PAF required by this clinical study protocol. Therefore, there is no foreseen increased risk 
to subjects for participating in the FROzEN-AF 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 Directions for Use, performing the 
procedures following recommended standard practices/guidelines, performing procedures in 
the appropriate hospital environment, 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 PAF. Potential benefits of the 
Cryoablation System for the subject may include the following: 
• Complete or partial reduction in symptoms related to PAF 
• Complete or partial reduction in the number of cardioversions, medications a subject is 
taking, and in the number of hospitalizations related to PAF 
 Risk to Benefit Rationale 
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 

 
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reviewed and approved and the remaining risks are acceptable when weighed against the 
intended benefits to the subject. 
 
 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: 
Reportable Events: 
• All Serious Adverse Events; 
• All Events Leading to Death  
• All Thromboembolic Events 
• All Procedure Related AEs inclusive of AEs related to the assessments (TTE, TEE, 
ICE or CT/MRI scan) listed in section 12.4. 
• All BSC commercialized diagnostic catheter-related events 
• All Cryoablation System Device Related Adverse Events; 
• All Device Deficiencies related to the study device; 
• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device Effects 
previously not defined in the DFU/IB and ICF. 
•  
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 AE but should only be reflected as an outcome of one (1) 
specific SAE (see Table 13 for Safety Definitions). 
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. 
If the patient experiences a new arrhythmia between the index procedure and the end of study, 
and the investigator considers this Adverse Event to be procedure related, it needs to be 

 
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reported. Refer to Investigator’s Brochure or DFU as appropriate for the known risks 
associated with the study device(s). 
Pre-existing diseases or conditions will not be reported as adverse events unless there has been 
a substantial increase in severity or frequency of the problem which cannot be attributed to the 
expected progression of the disease or condition. 
The Boston Scientific Medical Safety group will provide safety oversight by reviewing and 
classifying individual events that are reported to the sponsor. Routine aggregate safety reviews 
will be conducted to ensure subject safety. 
Refer to section 20 for the known risks associated with the study device(s). 
 Definitions and Classification 
Adverse event definitions are provided in the Table below.  Administrative edits were made 
on the safety definitions from ISO 14155 and MEDDEV 2.7/3 for clarification purposes. 
 
Table 13: 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, in the context of a clinical investigation, 
whether or not related to the investigational medical device and whether 
anticipated or unanticipated. 
NOTE 1: This includes events related to the investigational 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 investigational medical device.  
Adverse Device Effect (ADE) 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
Adverse event related to the use of an investigational 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 investigational 
medical device. 
NOTE 2: This definition includes any event resulting from use error or 
intentional misuse of the investigational 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 led to any of the following: 
a) death, 
b) 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, 
including chronic diseases or 

 
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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) 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 
assessment. 
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 assessment. 
Serious Health Threat 
 
Ref: ISO 14155 
 
Signal from any adverse event or device deficiency that indicates an 
imminent risk of death or a serious deterioration in the health in subjects, 
users or other persons, and that requires prompt remedial action 
for other subjects, users or other persons. 
Note 1: This would include events that are of significant and unexpected nature 
such that they become alarming as a potential serious health hazard or possibility 
of multiple deaths occurring at short intervals. 
Device Deficiency 
 
Ref: ISO 14155 
 
Ref: MEDDEV 2.7/3  
An inadequacy of an investigational medical device (defined as the study 
device/Cryoablation System) related to its identity, quality, durability, 
reliability, usability, safety or performance. This may include 
malfunctions, use error, or inadequacy in the information supplied by the 
manufacturer. 
NOTE 1: Device deficiencies include malfunctions, use errors, and 
inadequacy in the information supplied by the manufacturer including 
labelling. 
NOTE 2: This definition includes device deficiencies related to the 
investigational medical device or the comparator. 

 
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Term 
Definition 
The following definitions will be used for defining hospitalization or prolongation of hospitalization for SAE 
classification purposes: 
Hospitalizations  
Hospitalization does not include: 
• 
emergency room visit that does not result in in-patient admission  
Note: although an emergency room visit does not itself meet the 
definition for hospitalization, it may meet other serious criteria 
(e.g. medical or surgical intervention to prevent permanent 
impairment or damage) 
• 
elective and pre-planned treatment/surgery for a pre-existing 
condition that is documented in the subject’s record at the time of 
consent/enrollment 
• 
admission for social reasons and/or respite care in the absence of 
any deterioration in the subject’s general condition (e.g. subject is 
homeless, caregiver relief) 
• 
pre-planned, protocol-specified admission related to the clinical 
study (e.g. procedure required by protocol) 
Prolongation of hospitalization  
In-patient admission to the hospital that is prolonged beyond the expected 
standard duration for the condition under treatment. 
Note: new adverse events occurring during the hospitalization are 
evaluated to determine if they prolonged hospitalization or meet another 
SAE criteria. 
 
 
 
 Relationship to Study Device(s) 
The Investigator must assess the relationship of the reportable AE to the study device and/or 
study procedure, see criteria in Table 14. 
 

 
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Table 14: 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, comparator 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 investigational 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 investigational 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. 
 
 

 
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Possibly Related 
Ref: MEDDEV 2.7/3 
The relationship with the use of the investigational device or comparator, or the 
relationship with procedures 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 investigational device or comparator, or the 
relationship with procedures seems relevant and/or the event cannot be reasonably 
explained by another cause, but additional information may be obtained. 
Causal Relationship 
Ref: MEDDEV 2.7/3 
The serious event is associated with the investigational 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 investigational device use/application 
or procedures; 
- the event involves a body-site or organ that 
-the investigational device or procedures are applied to; -the 
investigational 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 investigational 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 
adverse event. 
 Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 15. 
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: 
 
FROZENAF.safety@bsci.com 

 
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Table 15: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline pre-market studies 
(MEDDEV 2.7/3:  
CLINICAL INVESTIGATIONS: SERIOUS 
ADVERSE EVENT REPORTING UNDER 
DIRECTIVES 90/385/EEC AND 93/42/EEC) 
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, as 
requested by sponsor.  
• 
Upon request of sponsor.  
Serious Adverse Event  
Complete AE eCRF page 
with all available new and 
updated information.  
• 
Within 3 calendar 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 
Serious Adverse Device Effects 
 
Complete AE eCRF page 
with all available new and 
updated information. 
• 
Within 3 calendar 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.  
• 
When documentation is available 
• 
At sponsor request.  
Device Deficiencies (including 
but not limited to failures, 
malfunctions, and product 
nonconformities) 
Note:  Any Investigational 
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 
Complete Device 
Deficiencies eCRF with all 
available new and updated 
information.  
• 
Within 3 calendar 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 pre-market studies 
(MEDDEV 2.7/3:  
CLINICAL INVESTIGATIONS: SERIOUS 
ADVERSE EVENT REPORTING UNDER 
DIRECTIVES 90/385/EEC AND 93/42/EEC) 
or c) if circumstances had been 
less fortunate is considered a 
reportable event. 
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 10 
business days) after becoming aware of the 
information 
• Reporting required through end of study 
• Upon sponsor request 
Provide all relevant source 
documentation (de-
identified/pseudonymized) 
for reported event, as 
requested by sponsor.  
* Please note that pre-market studies are clinical studies with investigational devices or with medical devices that 
bear the regulatory approval and are not being used for the same approved indications. 
 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 (Cryoablation System) will be documented and reported to BSC. If 
possible, the device(s) should be returned to BSC for analysis. Instructions for returning the 
study catheters will be provided in the Site Initiation Visit slides. 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 failures and malfunctions should also be documented in the 
subject’s medical record. 
Device deficiencies (including but not limited to failures, malfunctions, and product 
nonconformities) are not adverse events. However, a reportable event that results from a device 
failure or malfunction, would be recorded as an adverse event on the appropriate eCRF. 
For Device Deficiencies, the investigator must assess and report if the device deficiency could 
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. 
 Reporting to Regulatory Authorities / IRBs/ ECs/ REBs/ Investigators 
BSC is responsible for reporting adverse event information to all participating Principal 
Investigators, IRBs/ECs/REBs and regulatory authorities, as applicable.  

 
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The Principal Investigator is responsible for informing the IRB/EC/REB, 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 IRB/EC/REB 
must be notified of any deaths in accordance with that site’s IRB/EC/REB policies and 
procedures.  
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:  
• 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 catheter, clinical investigation, procedure, or 
patient condition  
• Whether or not the death was witnessed  
• Whether the patient 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:  
If the patient 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 patient 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)   

 
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The Clinical Events Committee (CEC) must review information regarding subject deaths for  
events listed in section 23.2. 
 
 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 investigational devices, 
study-required procedures and/or testing, or data collection. 
The obtaining and documentation of Informed Consent must be in accordance with 21 CFR 
814.20 part 56, part 50 and part 812 or 813, ISO 14155: Clinical Investigation of Medical 
Devices for Human Subjects - Good Clinical Practice and Japan Medical Device GCP, ethical 
principles that have their origins in the Declaration of Helsinki, and applicable individual 
country laws and any applicable national regulations, IRB/EC/REB 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 IRB/EC/REB, or central IRB/EC/REB, 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 IRB/EC/REB.  Any modification requires acceptance from BSC prior to 
use 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 IRB/EC/REB 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. 
 

 
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The ICF shall always be signed and personally dated by the subject and by the investigator 
and/or an authorized designee responsible for conducting the informed consent process. 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. IRB/EC/REB), 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 IRB/EC/REB. The new version of the ICF must be approved 
by the IRB/EC/REB. Acceptance by Boston Scientific is required if changes to the revised ICF 
are requested by the site’s IRB/EC/REB. The IRB/EC/REB will determine the subject 
population to be re-consented. 
 
 Committees 
 Safety Monitoring Process 
To promote early detection of safety issues, the Clinical Events Committee and Data 
Monitoring Committee will provide evaluations of safety events. Success of this program 
requires dynamic collection of unmonitored data as soon as the event is reported. During 
regularly scheduled monitoring activities, clinical research monitors will support the dynamic 
reporting process through their review of source document and other data information.  
The BSC personnel from the Medical Safety and Safety Trial Operation Teams review safety 
data as it is reported by the sites throughout the duration of the study. The BSC Medical Safety 
group includes health care providers with expertise in Electrophysiology and with the 
necessary therapeutic and subject matter expertise to evaluate and classify the events into the 
categories outlined above. 
 Clinical Events Committee  
A Clinical Events Committee (CEC) is an independent group of individuals with pertinent 
expertise that will adjudicate events reported by study investigators and their relationship 
toward the primary endpoints. 
• All Deaths 

 
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• All Adverse Events included in the composite primary safety endpoint per Section 8.2 
of Protocol 
• All Adverse Event that are potentially related to the procedure or any of the devices 
included in the POLARx Cardiac Cryoablation System 
• All unanticipated device effects. 
• Other events at the discretion of BSC 
 
Committee members will include practitioners of Electrophysiology (EP), and/ or Cardiology, 
as well as other experts with the necessary therapeutic and subject matter expertise to 
adjudicate the event categories outlined above.  A complete description of CEC 
responsibilities, qualifications, membership, and committee procedures will be outlined in the 
CEC charter.   
The CEC will review a safety event dossier, prepared by BSC, which may include copies of 
subject source documents provided by study sites, core lab results and independent reviewer 
information as available for the above listed events.  For purposes of determining inclusion 
into the primary safety endpoint, the CEC will adjudicate all the above listed events as to their 
level of seriousness and relation to the ablation procedure and/or catheter. The death 
classification system that will be used by the CEC was developed using the NASPE policy36, 
as well as definitions from Epstein et al. (15)  and O'Connor et al. (16).    All supporting source 
documentation provided by the center will be sent to the CEC for adjudication as defined in 
the CEC charter. 
 Data Monitoring Committee 
A Data Monitoring Committee (DMC) is responsible for the oversight review of all AEs. The 
DMC will include leading experts in Electrophysiology and Biostatistics who are not 
participating in the study and who have no affiliation with BSC.  During the course of the 
study, the DMC will review accumulating safety data to monitor the incidence of AEs sent to 
the CEC and other trends that would warrant modification or termination of the study. 
Responsibilities, qualifications, membership, and DMC procedures will be included in the 
DMC Charter. 
Any DMC recommendation for study modification or termination because of concerns over 
subject safety or issues relating to data monitoring or quality control will be submitted in 
writing to BSC and the study Principal Investigator for consideration and final decision.  If the 
DMC at any time determines that a potentially serious risk exists to subjects in this study, the 
DMC chairman will immediately notify both BSC and the Principal Investigator. 
 Executive/ Steering Committee 
A Steering Committee composed of the sponsor’s Clinical Management, the study Principal 
Investigator, other prominent Electrophysiologists from around the globe and a patient who 
underwent an electrophysiology procedure has been convened for this study.  Responsibilities 
for the Committee include oversight of the overall conduct of the study with regards to protocol 
development, study progress, subject safety, overall data quality and integrity, and first line 

 
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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.   
 Suspension or Termination 
 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 IRBs, and regulatory authorities, as applicable, will be 
notified in writing in the event of study termination. 
  
Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the following. 
• Suspicion of an unacceptable risk, including serious health threat. In this case, the 
sponsor shall suspend the clinical investigation while the risk is assessed. The sponsor 
shall terminate the clinical investigation if an unacceptable risk which cannot be 
controlled is confirmed. 
• Instructions by the IRB/EC/ REB or regulatory authorities to suspend or terminate the 
clinical investigation. 
• 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 of the 
device. 
 Termination of Study Participation by the Investigator or Withdrawal of IRB 
Approval 
Any investigator, or associated IRB or regulatory authority may discontinue participation in 
the study or withdraw approval of the study, respectively, with suitable written notice to Boston 
Scientific. Investigators, associated IRBs, and regulatory authorities, as applicable, will be 
notified in writing in the event of these occurrences. 
 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 
IRB and regulatory authorities, as applicable, will be notified. Detailed information on how 
enrolled subjects will be managed thereafter will be provided.  

 
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In the event an IRB terminates participation in the study, participating investigators, associated 
IRB, 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 
investigational product to Boston Scientific, unless this action would jeopardize the rights, 
safety, or welfare of the subjects. 
 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 6 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 study 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 IRB and regulatory authorities, as applicable, will be notified. 
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
 
 Study Registration and Results Posting 
This research-study is registered on http://www.ClinicalTrials.gov, as required by U.S. Law 
and other jurisdictions.  
 Clinical Investigation Report 
Study results will be made available in accordance with the legal requirements and the 
recognized ethical principles, in accordance with the Boston Scientific Policy. A Clinical 
Investigation Report will be made available to all investigators, IRB/EC/ REB and regulatory 
authorities, as applicable in accordance with the Boston Scientific Policy and local 
requirements.  As applicable, an abbreviated Clinical Investigation Report will be made 
available on a publicly accessible database. 
 
 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 may 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 

 
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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. 
• 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 trial may be made available to 
other researchers in accordance with the Boston Scientific Data Sharing Policy 
(https://www.bostonscientific.com/).  
 
 Reimbursement and Compensation for Subjects 
 Subject Reimbursement 
Travel and other expenses incurred by subjects as a result of participation in the study may be 
reimbursed in accordance with pertinent country laws and regulations and per the study site’s 
regulations.   
 Compensation for Subject’s Health Injury 
Boston Scientific will purchase an insurance policy to cover the cost of potential health 
injury for study subjects, if required by applicable law.  
 
 Bibliography 
1. Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G, Flachskampf 
F, Hall R, Iung B, Kasprzak J, Nataf P, Tornos P, Torracca L, Wenink A, Task Force 
on the Management of Valvular Hearth Disease of the European Society of 
Cardiology., and ESC Committee for Practice Guidelines. Guidelines on the 
management of valvular heart disease: The Task Force on the Management of 
Valvular Heart Disease of the European Society of Cardiology. Eur Heart J. 2007 
Jan;28(2):230-68.   
2. 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 

 
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Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J 
Am Coll Cardiol 2014; 64(21): e1-e76. 
3. 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. 
4. Feinberg WM BJ, Laupacis A, et al. Prevalence, age distribution and gender in 
patients with atrial fibrillation; analysis and implications. Arch Intern Med. 1995;155: 
469-473.  
5. Friberg J BP, Scharling H. Rising rates of hospital admissions for atrial fibrillation. 
Epidemiology 2003;14 666-672. 
6. Wolf PA BEaBA. Secular trends in the prevalence of atrial fibrillation: The 
framingham study. Am heart J 1996; 131:790-795. 
7. Furburg CD PB, Manolio TA, et al. Prevalence of diagnosed atrial fibrillation in 
elderly subjects. Am J Cardiol. 1995; 74:236-241. 
8. Piccini JP, Hammill BG, Sinner MF, et al. Incidence and Prevalence of Atrial 
Fibrillation and Associated Mortality Among Medicare Beneficiaries, 1993-2007. 
Circulation Cardiovascular Quality and Outcomes. 2012;5(1):85-93. 
doi:10.1161/CIRCOUTCOMES.111.962688. 
9. 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. 
10. Fuster V RL, Cannom DS, et al. ACCF/AHA/ESC 2006 guidelines for the 
management of patients with atrial fibrillation: Executive summary.  A report of the 
American College of Cardiology/American Heart Association task force on practice 
guidelines and the European Society of Cardiology committee for practice guidelines 
(writing committee to revise the 2001 guidelines for the management of patients with 
atrial fibrillation): Developed in collaboration with the North American Society of 
Pacing and Electrophysiology. Circulation. 2006;114: e257-e354. 
11. Wazni O, Wilkoff, B, Saliba, W. Catheter ablation for atrial fibrillation. New Engl J 
Med. 2011; 365:2296-2304.Calkins H, Hindricks G, Cappato R, et al. 
2017 HRS/EHRA/ECAS/APHRS/ SOLAECE expert consensus statement on catheter 
and surgical ablation of atrial 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 

 
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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 
15. O’Connor CM CP, Miller AB, et al. Effect of amlodipine on mode of death among 
patients with advanced heart failure in the praise trial. Am J Cardiol 1998; 82:881-
887 
16. Reference of the consensus document: Calkins H, Hindricks G, Cappato R, et al. 
2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter 
and surgical ablation of atrial fibrillation: Executive summary. 2018 Europace. 
 
 Abbreviations and Definitions  
 Abbreviations 
Abbreviations are shown in Table 16. 
 
Table 16: Abbreviations 
Abbreviation/Acronym 
Term 
AAD 
Anti-Arrhythmic Drug 
AF 
Atrial Fibrillation 
AFL 
Atrial Flutter 
AT 
Atrial Tachycardia 
CABG 
Coronary artery bypass grafting 
CRT 
Cardiac Resynchronization Therapy 
CVA 
DFU 
Cerebral Vascular Accident 
Directions for Use 
DMS 
Diaphragm Movement Sensor 
DVT 
Deep Vein Thrombosis 
EDC 
Electronic Data Capture 
EP 
Electrophysiology 
HRS 
Heart Rhythm Society 
IB 
Investigator’s Brochure 
ICB 
Inter Connection Box 
ICD 
Implantable Cardioverter Defibrillator 
ICF 
Informed Consent Form 
LA  
Left Atrium 
LVEF  
Left Ventricular Ejection Fraction 
MRI  
Magnetic Resonance Imaging 
PAF  
Paroxysmal Atrial Fibrillation 
PE 
Pulmonary Embolism 

 
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Abbreviation/Acronym 
Term 
PTCA 
Percutaneous transluminal coronary angioplasty 
PV 
Pulmonary Veins 
PVI 
Pulmonary Vein Isolation 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
TEE 
Trans-esophageal echocardiography 
TIA 
Transient Ischemic Attack 
 
 
 Definitions 
Terms are defined in Table 17.  
Table 17: 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, meets eligibility criteria 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 
procedures 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 is eligible for enrollment and signs an informed consent 
document 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 30 days from consent signature 
date may not be reconsented and will be withdrawn from the study. 
In-patient Hospitalization 
Hospitalizations ≥24 hours in duration or <24 hours with medical 
intravenous therapy or surgical intervention 

 
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Term 
Definition 
Activated Coagulation/Clotting 
Time 
ACT is a test that is used to monitor the effectiveness of high dose heparin 
therapy. 
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 
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  
• 
Failure to achieve acute procedural success in the index 
procedure or repeat procedure during the blanking period  
• 
Use of amiodarone post index procedure 
• 
Surgical treatment for AF/AFL/AT post index procedure 
• 
Use of a non-study ablation catheter for AF targets in the index 
procedure or repeat procedure during the blanking period 
• 
 More than one repeat procedure during the blanking period 
(90 days post procedure) 
• 
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 any AAD 
Acute Procedural Success 
Rate of acute procedural success defined as the achievement of electrical 
isolation of all PVs by using  the POLARx CardiacCryoablation system 
only. Electrical isolation of a PV is 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. 

 
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Term 
Definition 
Activated Coagulation/Clotting 
Time 
ACT is a test that is used to monitor the effectiveness of high dose heparin 
therapy. 
Pulmonary Vein Stenosis 
(Severe) 
 
Severe PV stenosis is defined as ≥ 70% reduction in the  diameter of the 
PV or PV branch from baseline measure. For this study a severe PV 
stenosis will count toward the primary safety endpoint.  
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. 
Source Data 
All information in original records of clinical findings, observations, or 
other activities in a clinical investigation, 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 

 
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Term 
Definition 
Activated Coagulation/Clotting 
Time 
ACT is a test that is used to monitor the effectiveness of high dose heparin 
therapy. 
Treatment Subject 
Any subject that signs the consent form, meets eligibility criteria 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. 
 
 Appendices 
 Indications for ablation of PAF according to 2017 HRS expert consensus statement 
on catheter and surgical ablation of atrial fibrillation 
Indications 
Recommendation 
class 
Level of Evidence 
Symptomatic AF refractory 
or intolerant to at least 
one Class I or III 
antiarrhythmic medication 
Paroxysmal: Catheter 
ablation is recommended. 
I 
A 
Symptomatic AF prior to 
initiation of 
antiarrhythmic therapy 
with a Class I or III 
antiarrhythmic medication 
Paroxysmal: Catheter 
ablation is reasonable 
IIa 
B-R 
 

 
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Figure 9:  Indications for catheter ablation of symptomatic atrial fibrillation                      
Shown in this figure are the indications for catheter ablation of symptomatic paroxysmal, 
persistent, and long-standing persistent AF. The Class for each indication based on 
whether ablation is performed after failure of antiarrhythmic drug therapy or as 
first-line therapy is shown. 
 Quality of Life Instruments 
Clinical trials increasingly recognize the value of including patient reported outcome 
measures in their design. To understand the impact of atrial fibrillation ablation procedures 
on patient’s quality of life, the quality of life instruments used for the trial will be the EQ-5D-
5L for a generic questionnaire and the AFEQT for disease specific. Subjects will be asked to 
complete the questionnaires at the Enrollment visit as well as at the three, six, and 12- month 
follow-ups.   
The EQ-5D, generic quality of life measure, will be used to assess health utilities. It is a 
descriptive system of health-related quality of life states consisting of five dimensions 
(mobility, self-care, usual activities, pain/discomfort, anxiety/depression) each of which can 
take one of five responses. The responses record five levels of severity (no problems/slight 
problems/moderate problems/severe problems/extreme problems) within a particular EQ-5D 
dimension. 

 
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The Atrial Fibrillation Effect on Quality of Life (AFEQT) was developed to evaluate disease-
specific quality of life for patients with atrial fibrillation. The 20-item questionnaire is 
subdivided into three domains: symptoms, daily activities, and treatment concerns with 
responses provided on a seven-point Likert scale. 
 National Institutes of Health Stroke Assessment 
The NIH Stroke Scale (NIHSS) is an assessment tool which quantifies stroke related 
neurological deficit.  This assessment must be conducted in person to provide valuable 
information on stroke severity.   
An Investigator or appropriately trained and delegated site staff designee will administer NIH 
Stroke Scale assessment prior to the index ablation procedure (Baseline) and again at the pre-
discharge visit (1-7 days post the ablation procedure).  All individuals conducting the 
assessment will be required to become certified on administration of the assessment and 
provide BSC with documentation of certification prior to assessment completion with 
subjects.    
Investigational sites will be provided with instructions for assessment completion for the test.  
They will be instructed to administer stroke scale items in the order listed on the form.  
Scores should reflect what the subject does, not what the clinician thinks the subject can do. 
The clinician should record answers while administering the exam and work quickly.  Except 
where indicated, the subject should not be coached.  If a worsening score is noted from the 
previous assessment, the Investigator must follow the additional requirements defined 
throughout Section 12.7.  
 CHA2DS2-VASc Score for AF 
The CHA2DS2-VASc score is used for risk stratification of ischemic stroke in patients with 
nonvalvular atrial fibrillation. 
 
Condition 
Points 
 C   Congestive heart failure (or Left ventricular systolic dysfunction) 
1 
 H 
 Hypertension: blood pressure consistently above 140/90 mmHg (or treated 
hypertension on medication) 
1 
 A2  Age ≥75 years 
2 
 D 
 Diabetes Mellitus 
1 
 S2  Prior Stroke or TIA or thromboembolism 
2 
 V 
 Vascular disease (e.g. peripheral artery disease, myocardial infarction, 
aortic plaque) 
1 
 A 
 Age 65–74 years 
1 
 Sc  Sex category (i.e. female sex) 
1 
 

 
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 POLARx FIT: FROzEN-AF Extension Study 
The Clinical Investigational Plan for the POLARx FIT: FROzEN-AF Extension Study will 
be provided under separate cover. 

 
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POLARx FIT: FROzEN-AF Extension Study 
Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in the 
Treatment of Symptomatic Drug Refractory Paroxysmal Atrial Fibrillation 
 
CLINICAL INVESTIGATION PLAN 
Appendix 30.5  
(to Protocol 92348334 Rev I) 
 
 
G190060 
 
National Clinical Trial (NCT) Identified Number: NCT04133168 
 
 
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  
BSC Clinical Contact 
Clinical Trial Managers, Protocol Authors 
Sheryl McCammon 
Clinical Trial Manager 
4100 Hamline Ave. N. 
St. Paul, MN 55112 
USA 
Tel. +1 (763) 647- 0113 
Sheryl.McCammon@bsci.com  
 
Sarah Kenneweg 
Clinical Trial Manager 
4100 Hamline Ave. N. 
St. Paul, MN 55112 
USA 
Tel. +1 (510) 701- 1351 
Sarah.kenneweg@bsci.com 
 
Elke Sommerijns 
Sr. Clinical Trial Manager 
Guidant Europe, a Boston Scientific Company 
Green Square, Lambroekstraat 5D 
 
1831 Diegem 
Belgium 
Tel. +32 479 76 71 56 
Elke.sommerijns@bsci.com 
Coordinating Principal 
Investigator(s) 
Kenneth Ellenbogen, MD 
Kimmerling Professor of Cardiology 
Chair, Division of Cardiology 
VCU Pauley Heart Center 
Medical College of Virginia / VCU School of Medicine 
Gateway Building 
1200E. Marshall Street 
3rd Floor – Electrophysiology Division - Room 3-223 
Richmond, Virginia 23219 
Office (804) 828-7565  
E-mail: kenneth.ellenbogen@vcuhealth.org 
Executive Steering 
Committee Members 
Ante Anić, MD 
EP lab, Heart Center, University 
Hospital Split, Croatia 
Robin Boisseau 9131 Stony 
Point Parkway Apt 3213 
Richmond, VA 23235. Tel: 
(843) 860-9004   Email:  

 
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A. Starcevica 25 D, 23000 
Zadar, Croatia 
Telephone: +38523240605 
Email: anteanic@gmail.com 
Robin.Boisseau@vcuhealth.org 
Arash Aryana, MD, PhD, 
FACC, FHRS 
Medical Director, 
Cardiovascular Services 
Mercy General Hospital 
3941 J Street, Suite #350 
Sacramento, CA 95819 
(916) 453 2684 
E-mail:   
a_aryana@outlook.com 
Nassir Marrouche, MD  
Tulane University School of 
Medicine  
Cardiology 
1430 Tulane Avenue, Box 8548 
New Orleans, LA 70112 
(804) 988-2025                              
Email: Nmarrouche@tulane.edu 
Suneet Mittal, MD, FACC, 
FHRS 
Director, Electrophysiology 
Associate Chief of Cardiology 
Medical Director, Snyder AF 
Center 
Director, Cardiac Research 
200 West 57th Street, Suite 610 
New York, NY 10019 
(212) HEART DR (432-7837) 
Email: 
MITTSU@Valleyhealth.com 
Niraj Varma MD, PhD, FRCP 
Cardiac Pacing & 
Electrophysiology  
Department of Cardiovascular 
Medicine 
Cleveland Clinic 
 9500 Euclid Ave J2-2 
Cleveland, OH 44195  
(216) 444-2142  
Email: varman@ccf.org 
Wilber W. Su, MD, FACC, 
FHRS 
Cardiology and Cardiac 
Electrophysiology 
Banner– University Medical 
Group- Heart Center 
755 E. McDowell Rd, 4th Floor 
Phoenix, AZ 85006 
(602) 521-3090 
Email: wilwsu@gmail.com 
This section is intentionally left blank. 
Vendors/Labs/External 
Organizations 
A list of vendors/laboratories/external organizations involved in the 
trial is maintained by the sponsor.  
 
 
 
 

 
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Original Release: February 21, 2022 
Current Version: February 21, 2022 
 
Revision 
Version 
Protocol Date 
Template number and 
version 
Protocol Section 
Modified 
Summary of 
Changes 
 
Justification for 
Modification 
A 
February 23, 
2022 
90702637 Rev/Ver AP 
NA-Initial Release 
NA-Initial Release 
NA-Initial Release 
 
 
 
 
 
 
 

 
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2. Protocol Synopsis 
POLARx FIT: FROzEN-AF Extension Study  
Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in the 
Treatment of Symptomatic Drug Refractory Paroxysmal Atrial Fibrillation 
 
Appendix 30.5  
(to Protocol 92348334 Rev I) 
Study Objective(s) 
To establish the safety and effectiveness of Boston Scientific’s 
POLARx Cryoablation System with the POLARx FIT catheter models 
for treatment of symptomatic, drug refractory, recurrent, paroxysmal 
atrial fibrillation (AF).  
Planned 
Indication(s) for 
Use  
The POLARx Cryoablation System is intended for cryoablation and 
electrical mapping of the pulmonary veins for pulmonary vein isolation 
(PVI) in the ablation treatment of patients with paroxysmal atrial 
fibrillation (PAF).  
Treatment will occur according to the approved indication for use 
within each geography and the defined inclusion/exclusion criteria 
within the protocol. 
Test Device and 
sizes, if applicable  
The individual devices within the Cryoablation system are as follows: 
• POLARx FIT™ Cryoablation Catheter (Cryoablation Catheter) 
• SMARTFREEZE™ Console (Console) 
• POLARMAP™ Catheter (Cryoablation Mapping Catheter) 
• POLARSHEATH™ Steerable Sheath (Cryoablation Steerable 
Sheath) 
• Diaphragm Movement Sensor (DMS) 
• Inter Connection Box (ICB) 
• Esophageal Temperature Sensor Cable 
• Other Cryoablation System Devices as listed in Section 7.1.7 
 
POLARx FIT catheter models included in this trial allow treatment to 
be applied at either 28 mm or 31 mm balloon size per physician 
discretion. The POLARx Cryoablation Catheter models assessed in the 
FROzEN-AF study do not have the capability to increase their diameter 
to 31 mm balloon size. 

 
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POLARx FIT: FROzEN-AF Extension Study  
Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in the 
Treatment of Symptomatic Drug Refractory Paroxysmal Atrial Fibrillation 
 
Appendix 30.5  
(to Protocol 92348334 Rev I) 
Control Device and 
device sizes, if 
applicable 
There are no control devices in this extension study. 
Study Design 
Multi-center, open label, prospective, single arm study to document the 
safety and performance of Boston Scientific’s Cryoablation System 
with the POLARx FIT catheter models.  
All subjects fitting the enrollment criteria, signing the consent and 
undergoing the index procedure with the study devices will be followed 
up for twelve months after the index procedure.  
Due to the similarities between the POLARx and POLARx FIT 
catheters, the safety and effectiveness data from subjects treated with 
POLARx (“FROZEN-AF subjects”) may be pooled with the safety and 
effectiveness data from subjects treated with POLARx FIT catheter 
models (“POLARx FIT subjects”). The data will be submitted for 
product approvals once 3 months of follow-up data is available for 
POLARx FIT subjects. 
Planned Number of 
Subjects 
A maximum of 75 subjects will be enrolled and treated with the 
POLARx FIT balloon size at 31 or 28 mm (based on clinical 
judgement) to achieve 50 subjects in the 31 mm TREATMENT group 
(subjects who receive at least one cryoablation applied at the 31 mm 
configuration). 
Planned Number of 
Investigational Sites 
/ Countries 
Up to 20 sites in North America may participate in this study. To reduce 
the impact of individual center bias, each site participating in the 
extension study will enroll and treat a maximum of 18 subjects with 
cryoablation applied at the 31 mm configuration. 
Primary Safety 
Endpoint 
Primary Safety Endpoint at 3 Months  
The primary safety endpoint at 3 months is defined as the safety event-
free rate at 3 months post-procedure. 

 
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POLARx FIT: FROzEN-AF Extension Study  
Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in the 
Treatment of Symptomatic Drug Refractory Paroxysmal Atrial Fibrillation 
 
Appendix 30.5  
(to Protocol 92348334 Rev I) 
Primary safety events at 3 months will consist of a composite of the 
following procedure-related and/or device-related adverse events.  
Events through 7 days post index procedure or hospital discharge, 
whichever is later, unless denoted as events counting through 3 months 
post index procedure. 
• Death 
• Myocardial infarction (MI) 
• Major Vagal Nerve Injury/Gastroparesis  
• Transient ischemic attack (TIA) 
• Stroke/Cerebrovascular accident (CVA) 
• Thromboembolism 
• Cardiac tamponade/perforation* 
• Pneumothorax 
• Major vascular access complications 
• Pulmonary edema/heart failure 
• AV block** 
• Atrial esophageal fistula** 
• Severe pulmonary vein stenosis (≥70% reduction in the diameter 
of the PV or PV branch from baseline)*** 
• Persistent phrenic nerve palsy ****  
*Cardiac tamponade/perforation occurring up to 30 days post-index-procedure will 
count as primary safety endpoint events. 
**AV block not attributable to medication effect or vasovagal reaction. 
***Atrial esophageal fistula and severe pulmonary vein stenosis occurring up to 3 
months post-index-procedure will count as primary safety endpoint events. 
****Phrenic nerve palsy not resolved at the end of the 3 months follow up will count 
as primary safety endpoint event. 
Secondary Safety 
Endpoint 
Secondary Safety Endpoint at 12 Months 
The secondary safety endpoint at 12 months is defined as the safety event-
free rate at 12 months post-procedure.   
Secondary safety events at 12 months will consist of a composite of the 
following procedure-related and/or device-related adverse events. 

 
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POLARx FIT: FROzEN-AF Extension Study  
Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in the 
Treatment of Symptomatic Drug Refractory Paroxysmal Atrial Fibrillation 
 
Appendix 30.5  
(to Protocol 92348334 Rev I) 
The following events will be counted through 7 days post index 
procedure or hospital discharge, whichever is later: 
• Death 
• Myocardial infarction (MI) 
• Major Vagal Nerve Injury/Gastroparesis  
• Transient ischemic attack (TIA) 
• Stroke/Cerebrovascular accident (CVA) 
• Thromboembolism 
• Pneumothorax 
• Major vascular access complications 
• Pulmonary edema/heart failure 
• AV block* 
The following events will be counted through 30 days post index 
procedure: 
• Cardiac tamponade/perforation  
And the following events will be counted through 12 months post index 
procedure: 
• Atrial esophageal fistula 
• Severe pulmonary vein stenosis (≥70% reduction in the diameter 
of the PV or PV branch from baseline)  
• Persistent phrenic nerve palsy** 
* AV block not attributable to medication effect or vasovagal reaction. 
**A non-recovered phrenic nerve palsy at 12 months occurring post index procedure 
will count toward the endpoint. The study will collect information on phrenic nerve 
palsy observed before the end of the index procedure and, in case of occurrence, will 
track information for potential recovery during the study visits. 
Tertiary Safety 
Endpoint 
Reportable Adverse Events rates at 12 months. 
Adverse events will be collected at all subject follow-up visits. 
Reportable events include: 
• All Serious Adverse Events 
• All Study Procedure-Related Adverse Events 

 
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POLARx FIT: FROzEN-AF Extension Study  
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Appendix 30.5  
(to Protocol 92348334 Rev I) 
• All Study Device-Related Adverse Events 
• All Study Device Deficiencies 
• Unanticipated Adverse Device Effects/Unanticipated Serious 
Adverse Device Effects previously not defined in IFU 
Primary 
Effectiveness 
Endpoint 
Rate of acute procedural success defined as the achievement of 
electrical isolation of all PVs by using the POLARx Cardiac 
Cryoablation System with the POLARx FIT cryoablation balloon 
catheter models (with treatment applied at 28 mm or 31 mm balloon 
size per physician discretion). Electrical isolation of a PV is 
demonstrated by entrance and exit block. 
Secondary 
Effectiveness 
Endpoint 
Failure free rate at 12 months post procedure. 
Failure defined as: 
• Failure to achieve acute procedural success in the index 
procedure or repeat procedure during the blanking period 
• Use of amiodarone post index procedure 
• Surgical treatment for AF/AFL/AT post index procedure 
• Use of a non-study ablation catheter for AF targets in the index 
procedure or repeat procedure during the blanking period 
• More than one repeat procedure with the Cryoablation System 
during the blanking period (90 days post index procedure) 
• Documented atrial fibrillation, or new onset of atrial flutter or 
atrial tachycardia event [≥ 30 seconds in duration from the study 
specific event monitor, Holter Monitor, or from a 10 second 12-
lead Electrocardiography (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 days 91 post 
index procedure and 365 days: 
• Repeat procedure 
• Electrical and/or pharmacological cardioversion for AF/AFL/AT 
• Prescribed any antiarrhythmic drug (AAD)* 

 
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POLARx FIT: FROzEN-AF Extension Study  
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Appendix 30.5  
(to Protocol 92348334 Rev I) 
*AADs for endpoint will consist of all Class I/III, including Amiodarone, and 
any Class II/IV medications taken for control of atrial fibrillation (AF)/Atrial 
tachycardia (AT)/Atrial flutter (AFL) recurrence 
Additional 
Endpoints 
 
Additional endpoints and analysis include, but are not limited to: 
• Changes in the quality-of-life measures (AFEQT and EQ-5D- 
5L) between baseline and 12 months follow up 
• Single procedure success, defined as freedom from failure at 12 
months post procedure as defined in the secondary effectiveness 
endpoint without a repeat procedure 
• Duration of LA dwell time, defined as time from the 
Cryoablation Catheter exiting the sheath in the LA to time of 
final PV isolation 
• Total Cryoablation time for the index procedure 
• Total fluoroscopy time for the index procedure 
• Total index procedure time 
• Freedom from recurrence of individual types of atrial 
arrhythmias between 91 and 365 days from index procedure: 1) 
AF 2) AT 3) AFL 
• Failure- free rate as defined in secondary effectiveness endpoint 
when considering AF/AT/AFL episodes reported to the 
investigators by study specific (event recorder transmissions, 12 
lead ECG and Holter) and non-study related devices (other 
commercial applications for arrhythmia monitoring and 
detection the subject may access during the study including 
telemetry, other sources of continuous recording etc.) 
Method of 
Assigning Patients 
to Treatment 
Any subject that signs the consent form, meets eligibility criteria, has 
the study device inserted into the body and receives Cryoablation 
therapy with the Cryoablation System with the POLARx FIT 
cryoablation balloon catheters will be assigned to the TREATMENT 
group. 
The disposition of all subjects enrolled in the study will be described in 
tables and diagrams.  The data will include number of subjects 
screened, subjects that fail screening, subjects treated and assessed at 

 
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Appendix 30.5  
(to Protocol 92348334 Rev I) 
each follow-up interval.  Subjects who fail screening, or who do not 
complete the study will be enumerated and the reason(s) for their 
screening failure or discontinuation from the study will be described. 
Follow-up Schedule Visit schedule:  pre-discharge, Day 7, 3 months (blanking period), 6 
months, 12 months. 
Study Duration 
Enrollment is expected to be completed in approximately 5 months; 
therefore the total sub-study duration is estimated to be approximately 
17 months. 
Participant 
Duration 
The study duration for each subject is expected to be approximately 12 
months. 
Inclusion Criteria 
• History of recurrent symptomatic paroxysmal atrial fibrillation 
(PAF), defined as atrial fibrillation that terminates spontaneously or 
with intervention (either procedure or drug therapy) within seven 
days of onset. Minimum documentation includes the following: 
o a physician’s note indicating recurrent self-terminating atrial 
fibrillation (AF) which includes at least two symptomatic 
AF episodes within six months prior to enrollment, and  
o one electrocardiographically documented AF episode within 
12 months prior to enrollment.   
• No amiodarone use within 90 days prior to enrollment 
• Subjects who are indicated for an ablation procedure for 
paroxysmal atrial fibrillation (PAF) according to 2017 HRS expert 
consensus statement on catheter and surgical ablation of atrial 
fibrillation 
• Subjects refractory or intolerant to at least one class I or III 
antiarrhythmic medication or contraindicated to any class I or III 
medications  

 
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Appendix 30.5  
(to Protocol 92348334 Rev I) 
• Subjects who are willing and capable of providing informed 
consent  
• Subjects who are willing and capable of participating in all testing 
associated with this clinical investigation at an approved clinical 
investigational center 
• 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 
• Any known contraindication to an AF ablation or anticoagulation 
• Continuous AF lasting longer than seven (7) days from onset 
• History of previous left atrial ablation or surgical treatment for AF/ 
AFL/ AT 
• Atrial fibrillation secondary to electrolyte imbalance, thyroid 
disease, or any other reversible or non-cardiac cause 
• Structural heart disease or implanted devices as described below: 
a. Left ventricular ejection fraction (LVEF) < 40% based on most 
recent transthoracic echocardiogram (TTE) performed ≤180 days 
prior to enrollment * 
b. Left atrial diameter > 5.5 cm OR left atrial volume > 50 ml/m2 
indexed based on the most recent TTE performed ≤ 180 days prior 
to enrollment * 
c. An implanted pacemaker, ICD, CRT device or an active 
arrhythmia loop recorder 
d. Previous cardiac surgery: i.e. ventriculotomy or atriotomy 
(excluding atriotomy for CABG) 
e. Previous cardiac valvular surgical or percutaneous procedure, or 
prosthetic valve, including mitral valve clips 
f. Interatrial baffle, closure device, patch, or patent foramen ovale 
(PFO) occluder 

 
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POLARx FIT: FROzEN-AF Extension Study  
Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in the 
Treatment of Symptomatic Drug Refractory Paroxysmal Atrial Fibrillation 
 
Appendix 30.5  
(to Protocol 92348334 Rev I) 
g. Presence of a left atrial appendage occlusion device 
h. Presence of any pulmonary vein stents 
i. Coronary artery bypass graft (CABG), PTCA/ PCI/ coronary 
stent procedures within 90 days prior to enrollment 
j. Unstable angina or ongoing myocardial ischemia 
k. Myocardial infarction within 90 days prior to enrollment 
l. Moderate or severe mitral stenosis [severity assessed on the 
most recent TTE ≤180 days prior to enrollment as pulmonary 
artery systolic pressure >30 mmHg (1)] 
m. Evidence of left atrial thrombus** 
• Any previous history of cryoglobulinemia 
• Stage 3B or higher renal disease (estimated glomerular filtration 
rate, eGFR <45 mL/min) 
• History of blood clotting or bleeding disease 
• Any prior history of documented cerebral infarct, TIA or systemic 
embolism [excluding a post-operative deep vein thrombosis (DVT)] 
≤180 days prior to enrollment 
• Active systemic infection 
• Pregnant, lactating (current or anticipated during study follow up), 
or women of childbearing potential who are, or plan to become, 
pregnant during the time of the study (method of assessment upon 
physician’s discretion) 
• 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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POLARx FIT: FROzEN-AF Extension Study  
Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in the 
Treatment of Symptomatic Drug Refractory Paroxysmal Atrial Fibrillation 
 
Appendix 30.5  
(to Protocol 92348334 Rev I) 
• Subjects who in the judgment of the investigator have a life 
expectancy of less than two years  
*LVEF and LA diameters obtained ≤180 days prior to enrollment will be 
acceptable, unless a cardiac event has occurred (e.g. MI) between the date of the 
exam and the enrollment date, otherwise a new echocardiogram (trans-thoracic 
or trans-esophageal, or intracardiac echo) must be performed to confirm 
eligibility prior to performing ablation. For TTE, LA anteroposterior diameter 
measured by M-mode from the parasternal long-axis view will be used.  If both 
LA diameter and volume are available, only one meeting eligibility criteria is 
required. 
 
**The absence of thrombus must be confirmed by means of a trans-esophageal 
echocardiogram (TEE) within 48 hours prior to the procedure or Intracardiac 
Echography (ICE) during the procedure in subjects not adequately 
anticoagulated (see Section 12.5.2) for at least 3 weeks prior to procedure OR 
with CHA2DS2-VASc score (see Appendix 27.4) ≥2 in men and ≥3 in women OR 
enlarged LA (≥4.5cm). If a thrombus is observed, the subject no longer meets 
eligibility criteria. When screening for thrombus prior to the index procedure, 
ensure that the anticoagulation approach as described in Section 12.5.2 is 
followed until the day of the procedure. 
Arrhythmia 
Monitoring Strategy 
This study will employ a rhythm surveillance monitoring strategy 
consistent with the recommendations in the 2017 HRS expert consensus 
statement on catheter and surgical ablation of atrial fibrillation. A 
wearable arrhythmia/event monitor (e.g. Trans-Telephonic Monitor- 
TTM) will be used to assess atrial arrhythmia recurrence (including 
unscheduled visits for symptomatic atrial arrhythmias and 24-hour 
Holter monitoring at 12 months follow up).  
Subjects will be instructed to transmit all symptomatic episodes for 
detection and treatment of early recurrences.  At least two transmissions 
every month are to be made. 
All TREATMENT subjects will be provided with 24-Hour Holter 
Monitors at the 12-month follow-up visit.   
Core lab will be utilized for reviewing electrocardiographic recordings 
from the surveillance monitoring, inclusive of data from the wearable 
arrhythmia/event monitors and in-hospital ECGs. 

 
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FROzEN-AF Extension Study, 92797269 
 
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POLARx FIT: FROzEN-AF Extension Study  
Safety and Effectiveness IDE trial for Boston Scientific’s Cryoballoon in the 
Treatment of Symptomatic Drug Refractory Paroxysmal Atrial Fibrillation 
 
Appendix 30.5  
(to Protocol 92348334 Rev I) 
Statistical Methods  
Primary Statistical 
Hypothesis 
Statistical considerations were not utilized in the design of this 
extension study and no statistical hypothesis was defined. 
Analysis of the primary endpoints for submission to FDA will occur 
after 3 months of follow-up data is available for POLARx FIT subjects. 
Analysis of each endpoint will be performed when all applicable data 
for that endpoint has been collected. 
Statistical Test 
Method 
Analysis of study data will use descriptive statistical methods. 
Sample Size 
Parameters 
No power estimates were used to drive sample size calculations. 
 
 
 
 

 
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3. Table of Contents 
1. 
TITLE PAGE  ........................................................................................................................ 1 
2. 
PROTOCOL SYNOPSIS .......................................................................................................... 5 
3. 
TABLE OF CONTENTS ........................................................................................................ 16 
4. 
TABLE OF FIGURES ........................................................................................................... 27 
5. 
TABLE OF TABLES ............................................................................................................. 27 
6. 
INTRODUCTION ................................................................................................................. 29 
6.1. Background ............................................................................................................. 29 
6.2. Study Rationale ...................................................................................................... 30 
7. 
DEVICE DESCRIPTION ....................................................................................................... 31 
7.1. Boston Scientific Cardiac Cryoablation System ................................................. 31 
7.1.1. 
POLARx FIT Cryoablation Catheters ....................................................... 32 
7.1.2. 
POLARMAP Cryoablation Mapping Catheter .......................................... 34 
7.1.3. 
POLARSHEATH Cryoablation Steerable Sheath ..................................... 35 
7.1.4. 
SMARTFREEZE Cryoablation System Console ...................................... 36 
7.1.5. 
Diaphragm Movement Sensor ................................................................... 38 
7.1.6. 
Esophageal Temperature Sensor Cable ..................................................... 39 
7.1.7. 
Other Cryoablation System Devices .......................................................... 40 
3.1.1.1. 
Inter Connection Box ................................................................ 40 
3.1.1.2. 
Console Foot Switch ................................................................. 40 
3.1.1.3. 
Cryoablation Cable ................................................................... 41 
3.1.1.4. 
Cryoablation Catheter Extension Cable .................................... 41 
3.1.1.5. 
Cryoablation Mapping Catheter EP Electrical Cable ............... 41 
7.2. Intended Use and Contraindications .................................................................... 41 
7.2.1. 
POLARx FIT Cryoablation Catheter ......................................................... 41 
7.2.2. 
POLARMAP Cryoablation Mapping Catheter .......................................... 42 
7.2.3. 
POLARSHEATH Cryoablation Steerable Sheath ..................................... 42 
7.2.4. 
SMARTFREEZE Cryoablation System Console ...................................... 43 
8. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................... 45 
8.1. Study Objective ...................................................................................................... 45 
8.2. Primary Safety Endpoint ....................................................................................... 45 

 
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8.3. Primary Effectiveness Endpoint ........................................................................... 48 
8.4. Secondary Safety Endpoints: ................................................................................ 48 
8.5. Secondary Effectiveness Endpoints: ..................................................................... 49 
8.6. Tertiary Safety Endpoints: .................................................................................... 49 
8.7. Additional Endpoints ............................................................................................. 50 
9. 
STUDY DESIGN .................................................................................................................. 52 
9.1. Scale and Duration ................................................................................................. 52 
9.2. Treatment Assignment........................................................................................... 54 
9.2.1. 
Treatment ................................................................................................... 54 
9.3. Justification for the Study Design ......................................................................... 54 
9.3.1. 
Extension Study ......................................................................................... 54 
9.3.2. 
Treatment Subjects .................................................................................... 55 
10. SUBJECT SELECTION ......................................................................................................... 56 
10.1. Study Population and Eligibility ........................................................................... 56 
10.2. Inclusion Criteria ................................................................................................... 56 
10.3. Exclusion Criteria .................................................................................................. 57 
11. SUBJECT ACCOUNTABILITY .............................................................................................. 59 
11.1. Point of Enrollment ................................................................................................ 59 
11.2. Enrollment Controls .............................................................................................. 60 
11.3. Withdrawals ........................................................................................................... 60 
11.4. Lost to Follow-Up ................................................................................................... 61 
11.5. Subject Status and Classification .......................................................................... 61 
11.6. End-of-Study Definition ........................................................................................ 63 
12. STUDY METHODS .............................................................................................................. 63 
12.1. Data Collection ....................................................................................................... 63 
12.2. Study Candidate Screening ................................................................................... 66 
12.3. Enrollment and Informed Consent ...................................................................... 66 
12.4. Baseline Visit .......................................................................................................... 66 
12.5. Medications ............................................................................................................. 68 
12.5.1. Anti-Arrhythmic Drugs ............................................................................. 68 

 
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12.5.1.1. AADs prior to index procedure ................................................. 68 
12.5.1.2. AADs post index procedure during the 90-day blanking period68 
12.5.1.3. AADs post 90 days blanking period ......................................... 69 
12.5.2. Anticoagulation .......................................................................................... 69 
12.5.3. Thrombus Screening .................................................................................. 70 
12.6. Index (Ablation) Procedure ................................................................................... 70 
12.6.1. General Info ............................................................................................... 70 
3.1.1.6. 
Pulmonary Vein Isolation ......................................................... 72 
3.1.1.7. 
Cryoablation System Preparation ............................................. 72 
3.1.1.8. 
Cryoablation protocol ............................................................... 74 
3.1.1.9. 
PV isolation verification ........................................................... 75 
3.1.1.10. Additional ablation(s) ............................................................... 76 
12.6.2. Index procedure collected data .................................................................. 76 
12.7. Pre-Discharge Visit ................................................................................................ 78 
12.8. Day 7 Follow-Up Contact ...................................................................................... 79 
12.9. Month 3 Follow-Up Visit ....................................................................................... 80 
12.10. 
Month 6 Follow-Up Visit ......................................................................... 80 
12.11. 
Month 12 Follow-Up Visit ....................................................................... 81 
12.12. 
Unscheduled Visits ................................................................................... 82 
12.13. 
Additional/Repeat Procedure ................................................................. 83 
12.14. 
Study Completion .................................................................................... 84 
12.15. 
Unforeseen Circumstances (Natural Disaster/Global Pandemic) ....... 84 
12.16. 
Source Documents ................................................................................... 85 
13. STATISTICAL CONSIDERATIONS ....................................................................................... 86 
13.1. Endpoints ................................................................................................................ 86 
13.1.1. Primary Safety Endpoint ............................................................................ 86 
13.1.1.1. Hypotheses ................................................................................ 87 
13.1.1.2. Sample Size ............................................................................... 87 
13.1.1.3. Statistical Methods .................................................................... 87 
13.1.2. Primary Effectiveness Endpoint ................................................................ 87 
13.1.2.1. Hypotheses ................................................................................ 87 
13.1.2.2. Sample Size ............................................................................... 88 
13.1.2.3. Statistical Methods .................................................................... 88 
13.2. General Statistical Methods .................................................................................. 88 
13.2.1. Analysis Sets .............................................................................................. 88 

 
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13.2.2. Control of Systematic Error/Bias ............................................................... 88 
13.2.3. Number of Subjects per Investigative Site ................................................ 89 
13.3. Data Analyses ......................................................................................................... 89 
13.3.1. Interim Analyses ........................................................................................ 89 
13.3.2. Justification of Pooling .............................................................................. 89 
13.3.3. Changes to Planned Analyses .................................................................... 89 
14. HEALTH ECONOMICS OUTCOMES .................................................................................... 89 
15. DATA MANAGEMENT ........................................................................................................ 90 
15.1. Data Collection, Processing, and Review ............................................................. 90 
15.2. Data Retention ........................................................................................................ 91 
15.3. Technical Source Forms ........................................................................................ 91 
15.4. Core Laboratories .................................................................................................. 91 
15.4.1. Event and 24-Hour Holter Monitors’ Core Lab ........................................ 91 
15.4.1.1. Event Monitors.......................................................................... 91 
15.4.1.2. 24-Hour Holter Monitors .......................................................... 92 
15.4.2. ECG Core Lab ........................................................................................... 92 
15.4.3. PV Stenosis Imaging.................................................................................. 92 
15.5. Quality of Life (QOL) ............................................................................................ 92 
16. DEVIATIONS ...................................................................................................................... 93 
17. ACCOUNTABILITY FOR STUDY PRODUCTS ....................................................................... 93 
17.1. Investigationally-Labelled Products ..................................................................... 93 
17.2. Commercially Labelled Products ......................................................................... 94 
18. COMPLIANCE ..................................................................................................................... 95 
18.1. Statement of Compliance ....................................................................................... 95 
18.2. Investigator Responsibilities ................................................................................. 95 
18.2.1. Delegation of Responsibility ..................................................................... 97 
18.3. Institutional Review Board/ Ethics Committee ................................................... 97 
18.4. Sponsor Responsibilities ........................................................................................ 98 
18.4.1. Role of Boston Scientific Representatives ................................................ 98 
18.5. Insurance ................................................................................................................. 99 

 
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19. MONITORING ..................................................................................................................... 99 
20. POTENTIAL RISKS AND BENEFITS .................................................................................. 100 
20.1. Anticipated Adverse Events ................................................................................ 100 
20.2. Risks Associated with the Study Device(s) ......................................................... 101 
20.3. Risks associated with Participation in the Clinical Study ................................ 101 
20.4. Risk Minimization Actions .................................................................................. 102 
20.5. Anticipated Benefits ............................................................................................. 102 
20.6. Risk to Benefit Rationale ..................................................................................... 102 
21. SAFETY REPORTING ........................................................................................................ 102 
21.1. Reportable Events by investigational site to Boston Scientific ........................ 102 
21.2. Definitions and Classification ............................................................................. 103 
21.3. Relationship to Study Device(s) .......................................................................... 106 
21.4. Investigator Reporting Requirements ................................................................ 107 
21.5. Device Deficiencies ............................................................................................... 109 
21.6. Reporting to Regulatory Authorities / IRBs / ECs / REBs/ Investigators ...... 110 
21.7. Subject Death Reporting ..................................................................................... 110 
22. INFORMED CONSENT....................................................................................................... 111 
23. COMMITTEES .................................................................................................................. 112 
23.1. Safety Monitoring Process ................................................................................... 112 
23.2. Clinical Events Committee .................................................................................. 113 
23.3. Data Monitoring Committee ............................................................................... 113 
23.4. Executive/ Steering Committee ........................................................................... 114 
24. SUSPENSION OR TERMINATION ...................................................................................... 114 
24.1. Premature Termination of the Study ................................................................. 114 
24.1.1. Criteria for Premature Termination of the Study ..................................... 114 
24.2. Termination of Study Participation by the Investigator or Withdrawal of IRB/ 
EC /REB Approval ............................................................................................... 115 
24.3. Requirements for Documentation and Subject Follow-up ............................... 115 
24.4. Criteria for Suspending/Terminating a Study Site ........................................... 115 

 
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25. STUDY REGISTRATION AND RESULTS ............................................................................ 116 
25.1. Study Registration ................................................................................................ 116 
25.2. Clinical Investigation Report .............................................................................. 116 
25.3. Publication Policy ................................................................................................. 116 
26. REIMBURSEMENT AND COMPENSATION FOR SUBJECTS ................................................ 117 
26.1. Subject Reimbursement....................................................................................... 117 
26.2. Compensation for Subject’s Health Injury ....................................................... 117 
27. BIBLIOGRAPHY ................................................................................................................ 117 
28. ABBREVIATIONS AND DEFINITIONS ................................................................................ 119 
28.1. Abbreviations ....................................................................................................... 119 
28.2. Definitions ............................................................................................................. 120 
29. APPENDICES .................................................................................................................... 123 
29.1. Indications for ablation of PAF according to 2017 HRS expert consensus 
statement on catheter and surgical ablation of atrial fibrillation .................... 123 
29.2. Quality of Life Instruments ................................................................................. 124 
29.3. National Institutes of Health Stroke Assessment .............................................. 125 
29.4. CHA2DS2-VASc Score for AF ............................................................................ 125 
 
 
 
1. 
TITLE PAGE  ........................................................................................................................ 1 
2. 
PROTOCOL SYNOPSIS .......................................................................................................... 5 
3. 
TABLE OF CONTENTS ........................................................................................................ 16 
4. 
TABLE OF FIGURES ........................................................................................................... 27 
5. 
TABLE OF TABLES ............................................................................................................. 27 
6. 
INTRODUCTION ................................................................................................................. 29 
6.1. Background ............................................................................................................. 29 
6.2. Study Rationale ...................................................................................................... 30 

 
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7. 
DEVICE DESCRIPTION ....................................................................................................... 31 
7.1. Boston Scientific Cardiac Cryoablation System ................................................. 31 
7.1.1. 
POLARx FIT Cryoablation Catheters ....................................................... 32 
7.1.2. 
POLARMAP Cryoablation Mapping Catheter .......................................... 34 
7.1.3. 
POLARSHEATH Cryoablation Steerable Sheath ..................................... 35 
7.1.4. 
SMARTFREEZE Cryoablation System Console ...................................... 36 
7.1.5. 
Diaphragm Movement Sensor ................................................................... 38 
7.1.6. 
Esophageal Temperature Sensor Cable ..................................................... 39 
7.1.7. 
Other Cryoablation System Devices .......................................................... 40 
3.1.1.1. 
Inter Connection Box ................................................................ 40 
3.1.1.2. 
Console Foot Switch ................................................................. 40 
3.1.1.3. 
Cryoablation Cable ................................................................... 41 
3.1.1.4. 
Cryoablation Catheter Extension Cable .................................... 41 
3.1.1.5. 
Cryoablation Mapping Catheter EP Electrical Cable ............... 41 
7.2. Intended Use and Contraindications .................................................................... 41 
7.2.1. 
POLARx FIT Cryoablation Catheter ......................................................... 41 
7.2.2. 
POLARMAP Cryoablation Mapping Catheter .......................................... 42 
7.2.3. 
POLARSHEATH Cryoablation Steerable Sheath ..................................... 42 
7.2.4. 
SMARTFREEZE Cryoablation System Console ...................................... 43 
8. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................... 45 
8.1. Study Objective ...................................................................................................... 45 
8.2. Primary Safety Endpoint ....................................................................................... 45 
8.3. Primary Effectiveness Endpoint ........................................................................... 48 
8.4. Secondary Safety Endpoints: ................................................................................ 48 
8.5. Secondary Effectiveness Endpoints: ..................................................................... 49 
8.6. Tertiary Safety Endpoints: .................................................................................... 49 
8.7. Additional Endpoints ............................................................................................. 50 
9. 
STUDY DESIGN .................................................................................................................. 52 
9.1. Scale and Duration ................................................................................................. 52 
9.2. Treatment Assignment........................................................................................... 54 
9.2.1. 
Treatment ................................................................................................... 54 
9.3. Justification for the Study Design ......................................................................... 54 
9.3.1. 
Extension Study ......................................................................................... 54 

 
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9.3.2. 
Treatment Subjects .................................................................................... 55 
10. SUBJECT SELECTION ......................................................................................................... 56 
10.1. Study Population and Eligibility ........................................................................... 56 
10.2. Inclusion Criteria ................................................................................................... 56 
10.3. Exclusion Criteria .................................................................................................. 57 
11. SUBJECT ACCOUNTABILITY .............................................................................................. 59 
11.1. Point of Enrollment ................................................................................................ 59 
11.2. Enrollment Controls .............................................................................................. 60 
11.3. Withdrawals ........................................................................................................... 60 
11.4. Lost to Follow-Up ................................................................................................... 61 
11.5. Subject Status and Classification .......................................................................... 61 
11.6. End-of-Study Definition ........................................................................................ 63 
12. STUDY METHODS .............................................................................................................. 63 
12.1. Data Collection ....................................................................................................... 63 
12.2. Study Candidate Screening ................................................................................... 66 
12.3. Enrollment and Informed Consent ...................................................................... 66 
12.4. Baseline Visit .......................................................................................................... 66 
12.5. Medications ............................................................................................................. 68 
12.5.1. Anti-Arrhythmic Drugs ............................................................................. 68 
12.5.1.1. AADs prior to index procedure ................................................. 68 
12.5.1.2. AADs post index procedure during the 90-day blanking period68 
12.5.1.3. AADs post 90 days blanking period ......................................... 69 
12.5.2. Anticoagulation .......................................................................................... 69 
12.5.3. Thrombus Screening .................................................................................. 70 
12.6. Index (Ablation) Procedure ................................................................................... 70 
12.6.1. General Info ............................................................................................... 70 
3.1.1.6. 
Pulmonary Vein Isolation ......................................................... 72 
3.1.1.7. 
Cryoablation System Preparation ............................................. 72 
3.1.1.8. 
Cryoablation protocol ............................................................... 74 
3.1.1.9. 
PV isolation verification ........................................................... 75 
3.1.1.10. Additional ablation(s) ............................................................... 76 
12.6.2. Index procedure collected data .................................................................. 76 

 
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12.7. Pre-Discharge Visit ................................................................................................ 78 
12.8. Day 7 Follow-Up Contact ...................................................................................... 79 
12.9. Month 3 Follow-Up Visit ....................................................................................... 80 
12.10. 
Month 6 Follow-Up Visit ......................................................................... 80 
12.11. 
Month 12 Follow-Up Visit ....................................................................... 81 
12.12. 
Unscheduled Visits ................................................................................... 82 
12.13. 
Additional/Repeat Procedure ................................................................. 83 
12.14. 
Study Completion .................................................................................... 84 
12.15. 
Unforeseen Circumstances (Natural Disaster/Global Pandemic) ....... 84 
12.16. 
Source Documents ................................................................................... 85 
13. STATISTICAL CONSIDERATIONS ....................................................................................... 86 
13.1. Endpoints ................................................................................................................ 86 
13.1.1. Primary Safety Endpoint ............................................................................ 86 
13.1.1.1. Hypotheses ................................................................................ 87 
13.1.1.2. Sample Size ............................................................................... 87 
13.1.1.3. Statistical Methods .................................................................... 87 
13.1.2. Primary Effectiveness Endpoint ................................................................ 87 
13.1.2.1. Hypotheses ................................................................................ 87 
13.1.2.2. Sample Size ............................................................................... 88 
13.1.2.3. Statistical Methods .................................................................... 88 
13.2. General Statistical Methods .................................................................................. 88 
13.2.1. Analysis Sets .............................................................................................. 88 
13.2.2. Control of Systematic Error/Bias ............................................................... 88 
13.2.3. Number of Subjects per Investigative Site ................................................ 89 
13.3. Data Analyses ......................................................................................................... 89 
13.3.1. Interim Analyses ........................................................................................ 89 
13.3.2. Justification of Pooling .............................................................................. 89 
13.3.3. Changes to Planned Analyses .................................................................... 89 
14. HEALTH ECONOMICS OUTCOMES .................................................................................... 89 
15. DATA MANAGEMENT ........................................................................................................ 90 
15.1. Data Collection, Processing, and Review ............................................................. 90 
15.2. Data Retention ........................................................................................................ 91 

 
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15.3. Technical Source Forms ........................................................................................ 91 
15.4. Core Laboratories .................................................................................................. 91 
15.4.1. Event and 24-Hour Holter Monitors’ Core Lab ........................................ 91 
15.4.1.1. Event Monitors.......................................................................... 91 
15.4.1.2. 24-Hour Holter Monitors .......................................................... 92 
15.4.2. ECG Core Lab ........................................................................................... 92 
15.4.3. PV Stenosis Imaging.................................................................................. 92 
15.5. Quality of Life (QOL) ............................................................................................ 92 
16. DEVIATIONS ...................................................................................................................... 93 
17. ACCOUNTABILITY FOR STUDY PRODUCTS ....................................................................... 93 
17.1. Investigationally-Labelled Products ..................................................................... 93 
17.2. Commercially Labelled Products ......................................................................... 94 
18. COMPLIANCE ..................................................................................................................... 95 
18.1. Statement of Compliance ....................................................................................... 95 
18.2. Investigator Responsibilities ................................................................................. 95 
18.2.1. Delegation of Responsibility ..................................................................... 97 
18.3. Institutional Review Board/ Ethics Committee ................................................... 97 
18.4. Sponsor Responsibilities ........................................................................................ 98 
18.4.1. Role of Boston Scientific Representatives ................................................ 98 
18.5. Insurance ................................................................................................................. 99 
19. MONITORING ..................................................................................................................... 99 
20. POTENTIAL RISKS AND BENEFITS .................................................................................. 100 
20.1. Anticipated Adverse Events ................................................................................ 100 
20.2. Risks Associated with the Study Device(s) ......................................................... 101 
20.3. Risks associated with Participation in the Clinical Study ................................ 101 
20.4. Risk Minimization Actions .................................................................................. 102 
20.5. Anticipated Benefits ............................................................................................. 102 
20.6. Risk to Benefit Rationale ..................................................................................... 102 
21. SAFETY REPORTING ........................................................................................................ 102 
21.1. Reportable Events by investigational site to Boston Scientific ........................ 102 

 
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21.2. Definitions and Classification ............................................................................. 103 
21.3. Relationship to Study Device(s) .......................................................................... 106 
21.4. Investigator Reporting Requirements ................................................................ 107 
21.5. Device Deficiencies ............................................................................................... 109 
21.6. Reporting to Regulatory Authorities / IRBs / ECs / REBs/ Investigators ...... 110 
21.7. Subject Death Reporting ..................................................................................... 110 
22. INFORMED CONSENT....................................................................................................... 111 
23. COMMITTEES .................................................................................................................. 112 
23.1. Safety Monitoring Process ................................................................................... 112 
23.2. Clinical Events Committee .................................................................................. 113 
23.3. Data Monitoring Committee ............................................................................... 113 
23.4. Executive/ Steering Committee ........................................................................... 114 
24. SUSPENSION OR TERMINATION ...................................................................................... 114 
24.1. Premature Termination of the Study ................................................................. 114 
24.1.1. Criteria for Premature Termination of the Study ..................................... 114 
24.2. Termination of Study Participation by the Investigator or Withdrawal of IRB/ 
EC /REB Approval ............................................................................................... 115 
24.3. Requirements for Documentation and Subject Follow-up ............................... 115 
24.4. Criteria for Suspending/Terminating a Study Site ........................................... 115 
25. STUDY REGISTRATION AND RESULTS ............................................................................ 116 
25.1. Study Registration ................................................................................................ 116 
25.2. Clinical Investigation Report .............................................................................. 116 
25.3. Publication Policy ................................................................................................. 116 
26. REIMBURSEMENT AND COMPENSATION FOR SUBJECTS ................................................ 117 
26.1. Subject Reimbursement....................................................................................... 117 
26.2. Compensation for Subject’s Health Injury ....................................................... 117 
27. BIBLIOGRAPHY ................................................................................................................ 117 
28. ABBREVIATIONS AND DEFINITIONS ................................................................................ 119 
28.1. Abbreviations ....................................................................................................... 119 

 
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28.2. Definitions ............................................................................................................. 120 
29. APPENDICES .................................................................................................................... 123 
29.1. Indications for ablation of PAF according to 2017 HRS expert consensus 
statement on catheter and surgical ablation of atrial fibrillation .................... 123 
29.2. Quality of Life Instruments ................................................................................. 124 
29.3. National Institutes of Health Stroke Assessment .............................................. 125 
29.4. CHA2DS2-VASc Score for AF ............................................................................ 125 
 
 
4. Table of Figures 
Figure 1: POLARx FIT Cryoablation Catheter Distal Tip .................................................... 33 
Figure 2:  POLARx FIT Cryoablation Catheter Handle ........................................................ 33 
Figure 3:  POLARMAP Cryoablation Mapping Catheter Assembly .................................... 34 
Figure 4:  POLARMAP Cryoablation Mapping Catheter with Electrode Arrangements .. 34 
Figure 5:  SMARTFREEZE Cryoablation System Console ................................................... 37 
Figure 6:  Diaphragm Movement Sensor (DMS) Data Cryoablation Console Display 
Phrenic Nerve Pacing Signal & Alert .................................................................... 39 
Figure 7:  Esophagus Temperature Monitoring Data Display ............................................... 40 
Figure 8:  Extension Study of FROzEN-AF: Study Design .................................................... 53 
Figure 9:  Indications for catheter ablation of symptomatic atrial fibrillation .................. 124 
 
5. Table of Tables 
Table 1:  Cryoablation System .................................................................................................. 31 
Table 2:  POLARx FIT Cryoablation Catheter Specifications .............................................. 33 
Table 3:  POLARMAP Cryoablation Mapping Catheter Specifications .............................. 35 
Table 4:  POLARSHEATH Cryoablation Steerable Sheath Specifications .......................... 36 
Table 5:  Safety Endpoint Components Definitions ................................................................ 46 
Table 6:  Overview of Objectives and Endpoints ..................................................................... 51 
Table 7:  Inclusion Criteria ........................................................................................................ 57 

 
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Table 8:  Exclusion Criteria ....................................................................................................... 57 
Table 9:  Data Collection Schedule............................................................................................ 63 
Table 10:  Source Documentation Requirements .................................................................... 85 
Table 11:  Potential Adverse Events and Adverse Device Effects for PAF Ablation and 
Study Device ........................................................................................................... 100 
Table 12:  Safety Definitions .................................................................................................... 104 
Table 13:  Criteria for Assessing Relationship of Study Device or Procedure to Adverse 
Event ....................................................................................................................... 106 
Table 14:  Investigator Reporting Requirements .................................................................. 108 
Table 15:  Abbreviations .......................................................................................................... 119 
Table 16:  Definitions ................................................................................................................ 120 
 
 
 
 

 
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6. Introduction 
6.1. Background 
Atrial fibrillation (AF) is the most commonly encountered sustained cardiac arrhythmia in 
clinical practice (2). 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 
(3). It currently affects approximately 2.3 million people in North America (4).  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 (5,6,7).  Among Medicare beneficiaries, 
incident AF is common and increases as individuals age with incidence rates per 1,000 person-
years reported at ages 70-74 of 18.8, increasing to 28.8 for persons 75-79 and 38.3 for persons 
80-84. Similarly, the overall prevalence among Medicare beneficiaries age 70-74 is about 6% 
increasing to over 13% for individuals 80 years of age and older (8).   
AF causes symptoms that impair quality of life, increases the risk of stroke fivefold, and 
increases mortality.  
There are multiple therapies in current use for the treatment of AF; however, it is recognized that 
many of these therapies are suboptimal for most patients. Treatment options include medical 
management, pacing, cardioversion, implantable devices, surgery, and ablation therapy to 
eliminate the arrhythmia (9,10,11).  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, 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.  
Two studies have been completed with the currently approved cryoablation technology (Arctic 
Front™/ Arctic Front Advance™ Cryoablation Balloon, Medtronic®) 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 

 
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with the means to address the fast‐growing patient numbers. Balloon catheter cryoablation 
therapy to treat Paroxysmal Atrial Fibrillation (PAF) has gained significant utilization 
worldwide. 
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 with the POLARx cryoablation system was completed in 2018 and the 
system obtained CE-mark in 2020. The POLARx cryoablation system is currently commercially 
available in Europe / Middle East, Australia / New Zealand, Japan, and other select countries.  
Good occlusion of the pulmonary vein and intimate contact between the balloon and atrial tissue 
are critical for successful pulmonary vein isolation with cryoablation.  
Despite the clinical effectiveness of the standard 28 mm diameter cryoballoon (both POLARx 
and Arctic Front Advance balloons are 28 mm), physicians have consistently communicated a 
desire for a larger diameter balloon to improve occlusion in a variety of clinical scenarios (15, 
16).  
BSC has developed POLARx FIT which gives users the capability to increase the balloon 
diameter of POLARx from 28 mm to 31 mm on demand. The FIT feature is available on 
POLARx FIT catheter models. This additional capability has been developed without any 
physical changes to the POLARx catheter or SMARTFREEZE console and without sacrificing 
existing capabilities of the POLARx Cryoablation System studied in FROzEN-AF.   
6.2. Study Rationale 
The data of up to 75 subjects who will undergo treatment with the Boston Scientific 
Cryoablation System for de-novo PAF will be evaluated in this extension study of FROzEN-AF.  
This extension study is a prospective, non-randomized, multi-center, investigation being 
conducted to establish the safety and effectiveness of Boston Scientific’s POLARx Cryoablation 
System with the POLARx FIT catheter models in subjects with symptomatic, drug refractory, 
recurrent, paroxysmal atrial fibrillation. The aim of the trial is to collect data with the POLARx 
Cryoablation System using the POLARx FIT catheter models with treatment applied at 28 mm or 
31 mm balloon size per physician discretion. This study seeks to obtain approval for the Boston 
Scientific Cryoablation System with the POLARx FIT catheter models in North America. 

 
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7. Device Description 
7.1. Boston Scientific Cardiac Cryoablation System 
The Boston Scientific Cardiac Cryoablation System (henceforth “Cryoablation System”) is 
intended for treatment of symptomatic, drug refractory, recurrent, paroxysmal AF. The 
individual devices within the Cryoablation system and their associated model numbers to be used 
in this extension study of FROzEN-AF are listed in Table 1. The individual devices listed in 
Table 1 must be used together and it is not allowed to combine investigational with non-
investigational devices.   
Treatment will occur according to the approved indication for use and the defined 
inclusion/exclusion criteria within the protocol. A copy of the IFU will be provided in local 
language as required per national regulations. 
This extension study of FROzEN-AF will be conducted as a pre-market study in the US.  
Table 1:  Cryoablation System  
Individual Devices within the System 
Model Number 
POLARx FIT™ Cryoablation Catheter (Cryoablation Catheter) 
2315 (Short tip and long 
tip) 
SMARTFREEZE™ Console (Console) 
2314 
POLARMAP™ Catheter (Cryoablation Mapping Catheter) 
2317 (20mm) 
POLARSHEATH™ Steerable Sheath (Cryoablation Steerable 
Sheath) 
2316 
Diaphragm Movement Sensor (DMS) 
2314 
Inter Connection Box (ICB) 
2314 
Esophageal Temperature Sensor Cable  
2314 
Cryoablation -Console Foot Switch 
2314 
Cryoablation -Cable 
2318 
Cryoablation -Catheter Extension Cable 
2319 
Cryoablation Mapping Catheter EP Electrical Cable 
2320 
 

 
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7.1.1. POLARx FIT Cryoablation Catheters 
The POLARx FIT Cryoablation Catheters are additional models (Short Tip and Long Tip) of the 
POLARx cryoablation balloon catheters that are part of the POLARx cryoablation system being 
investigated in this extension study.  
The POLARx FIT catheter models are physically identical to the POLARx models (used in the 
FROzEN-AF study) and differ only in the model number programmed into the EEPROM (i.e. 
electronic identifier) of the catheter.  
Identical to the POLARx Cryoablation Catheter, the POLARx FIT catheter is a single use, flexible, 
over-the-wire balloon catheter used to ablate cardiac tissue. The POLARx FIT 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 FIT. The 
Cryoablation catheter connects to the Console with a Cryoablation 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 Cryoablation Mapping Catheter circular 
mapping catheter deployed within the guidewire lumen during ablation procedures.  
During an electrophysiology (EP) ablation procedure, the Cryoablation catheter (including the 
Cryoablation Mapping Catheter) is inserted through the Cryoablation Steerable Sheath 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 Cryoablation 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.  
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  
 

 
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Figure 1: POLARx FIT Cryoablation Catheter Distal Tip 
 
Figure 2:  POLARx FIT Cryoablation Catheter Handle 
 
Table 2:  POLARx FIT Cryoablation Catheter Specifications 
Catheter Shaft Size 
11.8 Fr 
Catheter Overall Length 
134 cm 
Catheter Tip Outer Diameter (OD) 
9 Fr 
Compatible Introducer Sheath 
Compatible with POLARSHEATH Sheath 12F 
Steerable Sheath 
Guidewire Lumen Inner Diameter 
(ID) 
Compatible with POLARMAP Mapping Catheter and 
guidewires ≤ 0.035 
Inflated Balloon Dimensions 
Diameter 
28/31 mm 
 
Catheter 
Effective Length  
99 cm 
 
Short Tip 
5 mm 
 
Long Tip 
12 mm 
Thermocouples 
Internal to Balloon 
Environmental Parameters 
Storage 
15°C to 25°C (59°F to 77°F)  
 
Transit 
-30°C to 60°C (-22°F to 140°F) 
15% to 90% relative humidity 
 
Operation 
15°C to 30°C (59°F to 86°F) 
*The POLARx Cryoablation Catheter models assessed in the FROzEN-AF study do not have the 
capability to increase their diameter to 31 mm balloon size. 

 
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7.1.2. POLARMAP Cryoablation Mapping Catheter 
This section identically matches the Cryoablation Mapping Catheter Section (Section 5.1.2) of 
the FROzEN-AF protocol (92348334). 
 
The POLARMAP Cryoablation Mapping Catheter is a single-use, sterile, multi-electrode, 
diagnostic catheter designed to map cardiac signals during ablation procedures.  The catheter is 
20mm in diameter with 8 evenly spaced radiopaque electrodes.  The proximal end of the 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 Cryoablation Mapping Catheter also allows for delivery of pacing stimuli 
used in the interpretation of PV isolation (PVI).   
 
Figure 3:  POLARMAP Cryoablation Mapping Catheter Assembly 
 
Figure 4:  POLARMAP Cryoablation Mapping Catheter with Electrode Arrangements 
 
 

 
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Table 3:  POLARMAP Cryoablation Mapping Catheter Specifications 
POLARMAP Shaft Size 
3.3 Fr (1.1 mm or 0.043 inches) 
Compatible Mating Device 
Minimum Internal Diameter 
3.4 Fr. (1.2 mm or 0.044 inches) 
Loop Diameter 
20 mm (0.79 inches) 
POLAR Shaft Length 
Overall 166: cm 
Effective: 149 cm 
Electrodes 
8 electrodes 
Electrode Size  
1 mm 
Electrode Spacing 
6 mm 
Environmental Parameters 
Storage 
15°C to 25°C (59°F to 77°F) 
Transit 
-30°C to 60°C (-22°F to 140°F) 
15% to 90% relative humidity 
 
Operation 
15°C to 30°C (59°F to 86°F) 
 
7.1.3. POLARSHEATH Cryoablation Steerable Sheath 
This section identically matches the Cryoablation Steerable Sheath Section (Section 5.1.3) of the 
FROzEN-AF protocol (92348334). 
The POLARSHEATH Cryoablation 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. 
 
As a component of the Cryoablation System, the Cryoablation 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. 
 
 

 
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Table 4:  POLARSHEATH Cryoablation Steerable Sheath Specifications 
Sheath Overall Length 
82 cm (32.3 in) 
 
Sheath Usable Length 
68 cm (26.8 in) 
 
Sheath Inner Diameter 
12.7 Fr 
 
Sheath Outer Diameter 
15.9 Fr 
 
Usable Dilator Length 
85 cm (33.5 in) 
 
Radiopaque Markers 
2.5mm proximal to 
sheath tip 
 
Guidewire Compatibility 
0.81 mm (0.032 in) and 
0.89 mm (0.035 in) 
 
Environmental Parameters 
Storage 
15° C to 25° C 
(59° F to 77° F) 
 
Transit 
-30° C to 60° C 
(-22° F to 140° F) 
15% to 90% 
relative humidity 
 
Operation 
15° C to 30° C 
(59° F to 86° F) 
7.1.4. SMARTFREEZE Cryoablation System Console 
The SMARTFREEZE Cryoablation System 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 and 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:  SMARTFREEZE Cryoablation System Console 
 
Integration between the Cryoablation Catheter and the Console includes monitoring catheter as 
well as console functionality, aided by a number of accessory devices that make up the overall 
system such as: power cords, extension cables, connection box, foot switch, diaphragmatic 
movement sensor, esophageal temperature sensor cable. In addition, the system incorporates a 
number of non-medical device items such as a scavenging hose, wrench, and nitrous oxide tank.   
When connected to a SMARTFREEZE Cryoablation System Console the new EEPROM number 
in the POLARx FIT catheter makes the “FIT” feature button available in the user interface. This 
feature lets users increase the balloon diameter from 28 mm to 31 mm if desired. The FIT feature 
has been incorporated as an optional-use tool within the existing POLARx workflow. The system 
always first inflates the balloon to the standard diameter of 28 mm. Following inflation, the system 
will increase the balloon diameter to 31 mm when the FIT button is pressed. During the 
cryoablation application, the SMARTFREEZE system delivers the same freezing power to both 
the standard and larger diameter balloons (as demonstrated by equivalent temperature on the 
balloon surface). The balloon diameter will return to the standard 28 mm upon the next inflation. 
For ablations using the POLARx FIT catheter with the balloon inflated to the standard diameter, 
the POLARx Cryoablation System is physically, functionally, and operationally identical to that 
currently used in the FROzEN-AF study.   

 
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7.1.5. Diaphragm Movement Sensor 
This section identically matches the Diaphragm Movement Sensor Section (Section 5.1.5) of the 
FROzEN-AF protocol (92348334). 
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 Cryoablation 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 patient’s chest and assess 
the patient’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 phrenic nerve injury 
ranges from 2.7% - 11.2% 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 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 Cryoablation Console and 
sends data to be displayed on the Cryoablation Console’s user interface (see Figure 6). 
 

 
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Figure 6:  Diaphragm Movement Sensor (DMS) Data Cryoablation 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 a 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.  
7.1.6. Esophageal Temperature Sensor Cable 
Esophageal temperature monitoring is a frequently used technique; used more so 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 incidence of esophageal ulceration is generally 
reversible, with a reported incidence of 17% of patients. 
As noted above, 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 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. Multisensor 

 
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probes and CIRCA S-CATH™ esophageal temperature probes are not compatible with the 
POLARx Cryoablation System and are therefore not permitted under this protocol.  
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. The measured 
esophageal temperature turns the measurement display from “Blue” to “Red” if the temperature 
probe falls below a physician pre-set value (see Figure 7 below). This feature potentially reduces 
adverse events such as esophageal ulcerations and fistulas. This is a redundant 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  
 
7.1.7. Other Cryoablation System Devices 
This section identically matches the Other Cryoablation System Devices Section (Section 5.1.7) 
of the FROzEN-AF protocol (92348334). 
3.1.1.1.Inter Connection Box 
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. 
3.1.1.2.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. 

 
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3.1.1.3.Cryoablation Cable 
The Cryoablation 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.  
3.1.1.4.Cryoablation Catheter Extension Cable 
The Cryoablation Catheter Extension Cable is a sterile, single-use cable that provides the 
connectivity between the Cryoablation Catheter and the Console ICB.  
3.1.1.5.Cryoablation Mapping Catheter EP Electrical Cable 
The EP Electrical Cable is a sterile, single-use accessory for the Cryoablation Mapping Catheter 
and is designed to interface (connect) the Cryoablation Mapping Catheter with standard EP 
recording systems.  
7.2. Intended Use and Contraindications 
This section identically matches the Intended Use and Contraindications Section (Section 5.2) of 
the FROzEN-AF protocol (92348334), with the exception that the Cryoablation Catheter 
referenced in this protocol is the POLARx FIT Cryoablation Catheter.  
The Cryoablation System is intended for treatment of symptomatic, drug refractory, recurrent, 
paroxysmal AF. 
7.2.1. POLARx FIT Cryoablation Catheter 
The POLARx FIT Cryoablation Catheter is a single use, flexible, over-the wire balloon catheter 
intended to ablate cardiac tissue. 
Use of the Cryoablation Catheter is contraindicated as follows: 
• In patients with an active systemic infection, as this may increase the risk for endocarditis 
and sepsis. 
• In patients with a myxoma or an intracardiac thrombus, as the catheter could precipitate 
an embolic event. 
• In patients with a prosthetic valve (mechanical or tissue) 
• In the ventricle of the heart where the device may become entrapped in a valve or 
chordae structures. 
• In patients with a recent ventriculotomy or atriotomy, as this may increase the risk of 
cardiac perforation or embolic event. 
• In patients with pulmonary vein stents, as the catheter may dislodge or damage the stent. 
• In patients with cryoglobulinemia, as the cryoablation application may lead to vascular 
injury. 
• In conditions where insertion into or manipulation in the atrium is unsafe, as this may 
increase the risk of perforation or systemic embolic event. 

 
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• In patients with intra-atrial septal patch or surgical intervention in or adjacent to the intra-
atrial septum. 
• In patients with an interatrial baffle or patch, as the transseptal puncture could fail to 
close. 
• In patients with hypercoagulopathy or an inability to tolerate anticoagulation therapy 
during an electrophysiology procedure 
• In patients with a contraindication to an invasive electrophysiology procedure where 
insertion or manipulation of a catheter in the cardiac chambers is deemed unsafe. 
7.2.2. POLARMAP Cryoablation Mapping Catheter 
This section identically matches the Cryoablation Mapping Catheter Section (Section 5.2.2) of 
the FROzEN-AF protocol (92348334). 
During an ablation procedure when PVs are isolated, the Cryoablation Mapping Catheter is 
intended to obtain electrograms and provide pacing in cardiac structures in the atrial regions of 
the heart. 
 Use of the POLARMAP Mapping Catheter is contraindicated as follows:  
• In patients with an active systemic infection as this may increase the risk for 
endocarditis and sepsis.  
• In patients with a myxoma or an intracardiac thrombus as the catheter could 
precipitate an embolic event.  
• In patients with a prosthetic heart valve (mechanical or tissue).  
• In the ventricle of the heart where the device may become entrapped in a valve or 
chordae structures.  
• In patients with a recent ventriculotomy or atriotomy as this may increase the risk of 
cardiac perforation or embolic event.  
• In patients with pulmonary vein stents as the catheter may dislodge or damage the 
stent. 
• In patients with cryoglobulinemia as the cryoablation application may lead to 
vascular injury. 
• In conditions where insertion into or manipulation in the atrium is unsafe as this may 
increase the risk of perforation or systemic embolic event. 
• In patients with intra-atrial septal patch or other surgical intervention in or adjacent to 
the intra-atrial septum. 
• In patients with a contraindication to an invasive EP procedure where insertion or 
manipulation of a catheter in the cardiac chambers is deemed unsafe. 
7.2.3. POLARSHEATH Cryoablation Steerable Sheath 
This section identically matches the Cryoablation Steerable Sheath Section (Section 5.2.3) of the 
FROzEN-AF protocol (92348334). 

 
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The Cryoablation Steerable Sheath is intended to facilitate the placement of diagnostic and/ or 
therapeutic intracardiac devices during percutaneous catheter ablation procedures. The sheath 
deflection facilitates catheter positioning. 
Use of the POLARSHEATH is contraindicated as follows: 
• In patients with an active systemic infection as this may increase the risk for endocarditis 
and sepsis. 
• In patients where vascular access is unobtainable, or the femoral vein is known to be 
obstructed. 
• In conditions where insertion into or manipulation in the atrium is unsafe as this may 
increase the risk of perforation or systemic embolic event. 
• In the ventricle of the heart where the device may become entrapped in a valve or chordae 
structures. 
• In patients with a prosthetic heart valve (mechanical or tissue) 
• In patients with a recent ventriculotomy or atriotomy as this may increase the risk of cardiac 
perforation or embolic event. 
• In patients with pulmonary vein stents as the sheath may dislodge or damage the stent. 
• In patients with an interatrial baffle or patch as the transseptal puncture could fail to close. 
• In patients with hypercoagulopathy or an inability to tolerate anticoagulation therapy 
during an electrophysiology procedure. 
• In patients with a contraindication to an invasive electrophysiology procedure where 
insertion or manipulation of a catheter in the cardiac chambers is deemed unsafe. 
7.2.4. SMARTFREEZE Cryoablation System Console 
This section identically matches the Console Section (Section 5.2.4) of the FROzEN-AF protocol 
(92348334). 
The SMARTFREEZE Cryoablation System Console is a component of the Cryoablation System 
which is intended for cryoablation and electrical mapping of the pulmonary veins for pulmonary 
vein isolation (PVI) in the ablation treatment of paroxysmal atrial fibrillation. 
 
Use of the SMARTFREEZE Cryoablation System is contraindicated as follows: 
• 
In patients with an active systemic infection as this may increase the risk for 
endocarditis and sepsis. 
• 
In patients with a prosthetic valve (mechanical or tissue) 
• 
In patients with a myxoma or an intracardiac thrombus as the catheter could 
precipitate an embolic event. 
• 
In the ventricle of the heart where the device may become entrapped in the valve 
or chordae structures. 
• 
In patients with a recent ventriculostomy or atriotomy because this may increase 
the risk of cardiac perforation or embolic event. 
• 
In patients with pulmonary vein stents as the catheter may dislodge or damage the 
stent. 

 
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• 
In patients with cryoglobulinemia as the application of cryogenic energy may lead 
to vascular injury. 
• 
In conditions where insertion into or manipulation in the atria is unsafe as this may 
increase the risk of perforation or systemic embolic event. 
• 
In patients with an interatrial baffle or patch as the transseptal puncture could fail 
to close. 
• 
In patients with hyper-coagulopathy or an inability to tolerate anticoagulation 
therapy during an electrophysiology procedure. 
• 
In patients with a contraindication to an invasive electrophysiology procedure 
where insertion or manipulation of a catheter in the cardiac chambers is deemed 
unsafe. 
 
 

 
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8. Study Objectives and Endpoints 
A complete overview of objectives and endpoints is provided in Table 6. 
8.1. Study Objective  
To establish the safety and effectiveness of Boston Scientific’s Cryoablation System with the 
POLARx FIT catheter models for treatment of symptomatic, drug refractory, recurrent, 
paroxysmal atrial fibrillation (AF). 
8.2. Primary Safety Endpoint  
The primary safety endpoint at 3 months is defined as the safety event-free rate at 3 months post-
procedure. 
 
Primary safety events at 3 months will consist of a composite of the following procedure-related 
and/or device-related adverse events.  
Events will be counted through 7 days post index procedure or hospital discharge, whichever is 
later, unless denoted as events counting through 3 months post index procedure. 
• Death 
• Myocardial infarction (MI) 
• Major Vagal Nerve Injury/Gastroparesis  
• Transient ischemic attack (TIA) 
• Stroke/Cerebrovascular accident (CVA) 
• Thromboembolism 
• Cardiac tamponade/perforation* 
• Pneumothorax 
• Major vascular access complications 
• Pulmonary edema/heart failure 
• AV block** 
• Atrial esophageal fistula*** 
• Severe pulmonary vein stenosis (≥70% reduction in the diameter of the PV or PV branch 
from baseline)*** 
• Persistent phrenic nerve palsy **** 
 
*Cardiac tamponade/perforation occurring up to 30 days post-index-procedure will count as primary safety endpoint 
events 
**AV block not attributable to medication effect or vasovagal reaction. 
***Atrial esophageal fistula, and severe pulmonary vein stenosis occurring up to 3 months post-index-procedure 
will count as primary safety endpoint events 

 
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**** Phrenic nerve palsy not resolved at the end of the 3 months follow up will count as primary safety endpoint 
event. 
Table 5:  Safety Endpoint Components Definitions 
Term 
Definition 
Atrioesophageal Fistula 
An atrioesophageal fistula is defined as a connection between the atrium 
and the lumen of the esophagus. Evidence supporting this diagnosis 
includes documentation of esophageal erosion combined with evidence of 
a fistulous connection to the atrium, such as air emboli, an embolic event, 
or direct observation at the time of surgical repair. A CT scan or MRI scan 
is the most common method of documentation of an atrioesophageal 
fistula. 
AV block 
A conduction disturbance that results in the partial inability of an electrical 
impulse generated in the atria to reach the ventricles. 
Cardiac tamponade/perforation 
Cardiac tamponade/perforation is defined as 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.  
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 left bundle branch block, 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.  
Pericardial Effusion 
A collection of fluid or blood in the pericardial space around the heart or in 
pleural space around the lungs.  
Phrenic nerve palsy 
Phrenic nerve palsy is defined as absent phrenic nerve function as assessed 
by a sniff test. A phrenic nerve palsy is considered to be permanent when it 
is documented to be present 12 months or longer following ablation. 
Pneumothorax 
Collapse of the lung due to an abrupt change in the intrapleural pressure 
within the chest cavity. 
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. 
Pulmonary Vein Stenosis 
(Severe) 
Pulmonary vein stenosis is defined as a reduction of the diameter of a PV 
or PV branch. PV stenosis can be categorized as mild <50%, moderate 
50%–70%, and severe ≥70% reduction in the diameter of the PV or PV 
branch. A severe PV stenosis will count toward the primary safety 
endpoint.   

 
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Term 
Definition 
Stroke/Cerebrovascular accident 
(CVA)  
Stroke diagnostic criteria: 
• 
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)  
• 
Stroke: (diagnosis as above, preferably with positive 
neuroimaging study); 
o 
Minor–Modified Rankin score <2 at 30 and 90 days† 
o 
Major–Modified Rankin score ≥2 at 30 and 90 days 
Thromboembolism 
The blockage of a blood vessel lumen by 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. 
Transient ischemic attack: new focal neurological deficit with rapid 
symptom resolution (usually 1 to 2 hours), always within 24 hours; 
neuroimaging without tissue injury 
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* 
Vascular access complications include the 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.  
 
*Events of vascular access complications and gastroparesis/ injury to vagus nerve will only be considered 
primary safety endpoint events if they meet the criteria for a major complication, per protocol Table 5. Non-
major events of this type will not be considered primary safety endpoint events. This is consistent with the 
methods used in the meta-analysis performed to determine expected rates and an appropriate performance 
goal for the primary safety endpoint (Section 8.2). 
 

 
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8.3. Primary Effectiveness Endpoint 
Rate of acute procedural success defined as the achievement of electrical isolation of all PVs by 
using the POLARx Cardiac Cryoablation System with the POLARx FIT cryoablation balloon 
catheter models (with treatment applied at 28 mm or 31 mm balloon size per physician 
discretion). Electrical isolation of a PV is demonstrated by entrance and exit block. 
8.4. Secondary Safety Endpoints: 
The secondary safety endpoint at 12 months is defined as the safety event-free rate at 12 months 
post-procedure.   
Secondary safety events at 12 months will consist of a composite of the following procedure-
related and/or device-related adverse events. 
The following events will be counted through 7 days post index procedure or hospital discharge, 
whichever is later: 
• Death 
• Myocardial infarction (MI) 
• Major Vagal Nerve Injury/Gastroparesis  
• Transient ischemic attack (TIA) 
• Stroke/Cerebrovascular accident (CVA) 
• Thromboembolism 
• Pneumothorax 
• Major vascular access complications 
• Pulmonary edema/heart failure 
• AV block* 
The following events will be counted through 30 days post index procedure: 
• Cardiac tamponade/perforation  
And the following events will be counted through 12 months post index procedure: 
• Atrial esophageal fistula 
• Severe pulmonary vein stenosis (≥70% reduction in the diameter of the PV or PV branch 
from baseline)  
• Persistent phrenic nerve palsy** 
* AV block not attributable to medication effect or vasovagal reaction. 

 
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**A non-recovered phrenic nerve palsy at 12 months occurring post index procedure will count as a chronic 
endpoint. The study will collect information on phrenic nerve palsy observed before the end of the index procedure 
and, in case of occurrence, will track information for potential recovery during the study visits. 
8.5. Secondary Effectiveness Endpoints: 
Failure free rate at 12 months post procedure. 
Failure defined as: 
• Failure to achieve acute procedural success in the index procedure or repeat procedure 
during the blanking period 
• Use of amiodarone post index procedure 
• Surgical treatment for AF/AFL/AT post index procedure 
• Use of a non-study ablation catheter for AF targets in the index procedure or repeat 
procedure during the blanking period 
• More than one repeat procedure with the Cryoablation System during the blanking period 
(90 days post index procedure) 
• Documented atrial fibrillation, or new onset of atrial flutter or atrial tachycardia event [≥ 
30 seconds in duration from the study specific event monitor, Holter Monitor, or from a 
10 second 12-lead Electrocardiography (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 days 91 post index procedure and 365 days: 
o Repeat procedure 
o Electrical and/or pharmacological cardioversion for AF/AFL/AT 
o Prescribed any antiarrhythmic drug (AAD)* 
*AADs for endpoint will consist of all Class I/III, including Amiodarone, and any Class II/IV 
medications taken for control of atrial fibrillation (AF)/Atrial tachycardia (AT)/Atrial flutter (AFL) 
recurrence. 
8.6. Tertiary Safety Endpoints:  
Reportable Adverse Events rates at 12 months.  
Adverse events will be collected at all subject follow-up visits.  Reportable events include: 
• All Serious Adverse Events 
• All Study Procedure-Related Adverse Events 
• All Study Device-Related Adverse Events 
• All Study Device Deficiencies  

 
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• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device Effects 
previously not defined in IFU. 
8.7. Additional Endpoints 
Additional endpoints and analysis include, but are not limited to: 
• Changes in the quality-of-life measures (AFEQT and EQ-5D- 5L) between baseline and 
12 months follow up 
• Single procedure success, defined as freedom from failure at 12 months post procedure as 
defined in the secondary effectiveness endpoint without a repeat procedure  
• Duration of LA dwell time, defined as time from the Cryoablation Catheter exiting the 
sheath in the LA to time of final PV isolation 
• Total Cryoablation time for the index procedure 
• Total fluoroscopy time for the index procedure 
• Total index procedure time 
• Freedom from recurrence of individual types of atrial arrhythmias between 91 and 365 
days from index procedure: 1) AF 2) AT 3) AFL 
• Failure- free rate as defined in secondary effectiveness endpoint when considering 
AF/AT/AFL episodes reported to the investigators by study specific (event recorder 
transmissions, 12 lead ECG and Holter) and non-study related devices (other commercial 
applications for arrhythmia monitoring and detection the subject may access during the 
study including telemetry, other sources of continuous recording etc.) 
 
 

 
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Table 6:  Overview of Objectives and Endpoints 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Establish the safety of the 
Cryoablation System 
 
 
Establish the acute procedural 
effectiveness of the Cryoablation 
System 
 
Composite of acute and 3- 
month study specific adverse 
events 
 
Rate of acute procedural 
success defined as the 
achievement of electrical 
isolation of all PVs by using 
the POLARx Cardiac 
Cryoablation System with the 
POLARx FIT cryoablation 
balloon catheter models only. 
Electrical isolation of a PV is 
demonstrated by entrance and 
exit block. 
List of events were selected 
from those typically associated 
with catheter ablation of AF.  
 
Component of the secondary 
effectiveness endpoint 
 
 
Secondary 
 
 
Establish the chronic effectiveness of 
the Cryoablation System 
Failure- free rate at 12 months 
including failure to achieve 
success at index or repeated 
procedure in blanking period, 
amiodarone post procedure, 
documented AF/AT/AFL or 
interventions to treat these 
arrhythmias after blanking 
period, including repeated 
procedures cardioversion or 
pharmacologic treatment 
Performance goal and expected 
rates calculated from a meta-
analysis of pivotal and IDE 
studies on AF ablation   
Tertiary 
 
 
 
Adverse events reporting 
Reportable Adverse Events 
rates at 12 months 
Complete overview of the safety 
events collected in the study 
Additional 
 
 
Recurrence of individual arrhythmia 
types 
Freedom from recurrence of 
AF/AT/AFL 
Component of the primary 
effectiveness endpoint 
Quality of life assessment 
Changes in the quality-of-life 
measures (AFEQT and EQ-
5D-5L) between baseline and 
12 months follow up 
Consistent with the objective of 
AF ablation to improve quality 
of life and reduce AF-associated 
symptoms 
Single procedure success 
Freedom from failure at 12 
months post procedure as 
defined in the secondary 
effectiveness endpoint without 
repeat procedure 
To assess success rate after a 
single procedure  
Procedure-related times 
LA dwell time, ablation time, 
fluoroscopy time, index 
procedure time 
To relate with published data on 
other AF ablation devices 

 
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9. Study Design 
This extension study of FROzEN-AF is a prospective, non-randomized, multi-center, 
investigation being conducted to establish the safety and effectiveness of Boston Scientific’s 
POLARx Cryoablation System with the POLARx FIT catheter models in subjects with 
symptomatic, drug refractory, recurrent, paroxysmal atrial fibrillation.  
9.1. Scale and Duration 
A maximum of 75 subjects will be enrolled and treated with the investigational system in the 
study. Subject enrollment will stop once 50 evaluable  
31 mm TREATMENT subjects are accrued (per subject status classification, Section 11.5).  
Up to 20 sites in North America may participate in this study. All sites will be selected from the 
FROzEN-AF study.  To reduce the impact of individual center bias, each site participating in the 
extension study will enroll and treat a maximum of 18 subjects with cryoablation applied at the 
31 mm configuration. 
The enrollment period for this study is expected to last approximately 5 months. Each subject 
will be followed at specified time points after the ablation procedure (index procedure), with a 
follow-up duration of 12 months.  A study subject’s participation will be considered complete 
when all protocol required visits have been completed as indicated in Figure 8.  The total sub-
study duration is estimated to be approximately 17 months. Subjects may be requested to consent 
to provide long term follow-up data, if needed for post-approval requirements. 

 
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Figure 8:  Extension Study of FROzEN-AF: Study Design 
 

 
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9.2. Treatment Assignment 
All screened subjects who sign the informed consent will be considered enrolled.  Data will be 
collected during the baseline visit, the ablation (index) procedure, the pre-discharge visit, the 
Day 7 telephone contact/follow up, month 3 follow up, the month 6 follow up and during the 
month 12 follow up. In case unscheduled visits or additional ablation procedures take place, this 
data will also be collected. Please refer to Section 12 for an overview of data to be collected 
during these visits. 
Subjects will be classified based on Subject Status and Classification as per Section 11.5. 
9.2.1. Treatment  
All enrolled subjects who undergo the ablation procedure will be treated with Boston Scientific’s 
POLARx Cryoablation System (with the POLARx FIT catheter models as Cryoablation 
catheters). The physician will apply treatment at 28 mm or 31 mm balloon size per clinical 
judgement as outlined in Section 12.6.  
It is recommended that each investigational center will be limited to 2 ablating investigators.  
Additional investigators may participate for completion of subject follow-up visits if 
appropriately delegated (Section 12.6.1) and trained to complete the assigned tasks.   
9.3. Justification for the Study Design 
9.3.1. Extension Study  
Boston Scientific proposes a prospective non-randomized IDE extension study with the 
POLARx Cryoablation System (and the POLARx FIT catheter models as Cryoablation catheters) 
as treatment device in order to seek approval of the POLARx Cryoablation System. The rationale 
for a non-randomized extension study can be justified as follows:  
• All aspects of usage, including preparation, introduction, occlusion and ablation with the 
POLARx FIT catheters are identical to POLARx Cryoablation System. The POLARx 
FIT catheter models are physically identical to POLARx models and differ only in the 
model number programmed into the EEPROM (i.e., electronic identifier) of the catheter. 
When connected to a SMARTFREEZE Cryoablation Console the new EEPROM number 
makes the “FIT” feature available. This feature gives users the ability to increase the 
balloon diameter from 28 mm to 31 mm following inflation, when desired. By design, the 
SMARTFREEZE console will always inflate the cryoballoon to the standard size of 28 
mm diameter on the initial inflation. If a physician prefers to apply the 31 mm diameter 
size, the FIT size must be selected on the Console to increase the balloon diameter from 
28 mm to 31 mm. Size selection may vary within patients for each pulmonary vein, 
allowing the physician to select the desired balloon size per treatment. The POLARx FIT 
catheter model leverages the materials and manufacturing assembly processes as the 
POLARx catheter.  

 
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• The POLARx FIT catheter models and POLARx catheters are intended to be used in the 
same patient population. BSC’s POLARx FIT capability gives users both the standard 28 
mm balloon and an option to increase to a larger, 31 mm balloon on demand. The added 
choice of a 31 mm balloon size for the POLARx FIT Catheter will allow physicians to 
provide cryoablation for PV isolation in a larger variety of pulmonary vein geometries 
(i.e., those that might not have been as good a fit using a 28 mm balloon size).  
• The POLARx FIT catheter models and POLARx catheters have been tested to ensure that 
both balloon diameters provide the same therapeutic cooling. This was tested in a bench 
model that allowed measurement and comparison of the balloon surface temperature of 
the POLARx FIT catheter models and POLARx catheters. The comparison study showed 
no statistical difference in the average surface temperature between POLARx FIT at 31 
mm balloon diameter and POLARx at 28 mm.  
• The POLARx FIT catheter models and POLARx catheters are introduced into the body 
the same way and have the same mechanism of deployment-inflation via low pressure 
N2O refrigerant, with the only difference being the pressure and flow rate applied by the 
SMARTFREEZE Console when using the larger diameter balloon. By maintaining the 
same therapeutic cooling for both 28 mm and 31 mm diameters, the safety and 
effectiveness of POLARx FIT to alter cardiac tissue is not expected to differ.  
Due to the similarities between the POLARx and POLARx FIT catheters, the safety and 
effectiveness data from subjects treated with POLARx (“FROZEN-AF subjects”) may be pooled 
with the safety and effectiveness data from subjects treated with POLARx FIT catheter models 
(“POLARx FIT subjects”). The data will be submitted for product approvals once 3 months of 
follow-up data is available for POLARx FIT subjects.  
9.3.2. Treatment Subjects 
Sites participating in the POLARx FIT extension study will be selected from the FROzEN-AF 
study. Only ablating physicians who contributed a roll-in subject during the FROzEN-AF study 
will be selected. No roll-in subjects will be included in this extension study as the ablating 
physicians will already have significant experience with the Boston Scientific Cryoablation 
System from the FROzEN-AF study. 
All subjects treated with the investigational system will be considered as non-roll-in 
TREATMENT subjects. All safety and effectiveness data will be collected and reported for 
these subjects and will be included in the endpoint analyses.  
To reduce the impact of individual center bias, each site participating in the extension study will 
enroll and treat a maximum of 18 subjects with cryoablation applied at the 31 mm 
configuration.  

 
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10. Subject Selection  
10.1. Study Population and Eligibility  
Subjects enrolled in the POLARx FIT extension study of FROzEN-AF study will be clinically 
indicated for an ablation procedure for the treatment of symptomatic, drug refractory, recurrent, 
paroxysmal atrial fibrillation. Subjects should meet the study inclusion/exclusion criteria as 
outlined below in Sections 10.2 and 10.3.  
 
The subjects selected for participation will be from the investigator’s general patient population. 
The investigator or its designee has the responsibility for screening all potential subjects and 
selecting those who meet study inclusion/exclusion. 
 
The Inclusion/Exclusion Criteria outlined below in Section 8.2 and 8.3 identically match the 
Inclusion/Exclusion Criteria listed in Section 8.2 and 8.3 of the FROzEN-AF protocol 
(92348334).  
 
10.2. Inclusion Criteria 
Subjects who meet the following criteria (Table 7) may be given consideration for inclusion in 
this clinical investigation, provided no exclusion criterion (see Section 10.3) is met.  

 
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Table 7:  Inclusion Criteria 
Inclusion 
Criteria 
• History of recurrent symptomatic paroxysmal atrial fibrillation (PAF), 
defined as atrial fibrillation that terminates spontaneously or with 
intervention (either procedure or drug therapy) within seven days of 
onset. Minimum documentation includes the following: 
o a physician’s note indicating recurrent self-terminating atrial 
fibrillation (AF) which includes at least two symptomatic AF 
episodes within six months prior to enrollment, and  
o one electrocardiographically documented AF episode within 12 
months prior to enrollment.   
• Subjects who are indicated for an ablation procedure for paroxysmal 
atrial fibrillation (PAF) according to 2017 HRS expert consensus 
statement on catheter and surgical ablation of atrial fibrillation 
• No amiodarone use within 90 days prior to enrollment 
• Subjects refractory or intolerant to at least one class I or III 
antiarrhythmic medication or contraindicated to any class I or III 
medications 
• Subjects who are willing and capable of providing informed consent  
• Subjects who are willing and capable of participating in all testing 
associated with this clinical investigation at an approved clinical 
investigation center 
• Subjects whose age is 18 years or above, or who are of legal age to give 
informed consent specific to state and national law 
 
 
10.3.  Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 8) cannot be included in this study or 
will be excluded from this clinical study. 
Table 8:  Exclusion Criteria 
Exclusion Criteria 
• Any known contraindication to an AF ablation or anticoagulation 
• Continuous AF lasting longer than seven (7) days from onset 
• History of previous left atrial ablation or surgical treatment for AF/ 
AFL/ AT 
• Atrial fibrillation secondary to electrolyte imbalance, thyroid disease, 
or any other reversible or non-cardiac cause 

 
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• Structural heart disease or implanted devices as described below: 
a. Left ventricular ejection fraction (LVEF) < 40% based on the most 
recent TTE performed ≤180 days prior to enrollment* 
b. Left atrial diameter > 5.5 cm OR left atrial volume > 50 ml/m2 
indexed based on the most recent TTE performed ≤ 180 days prior to 
enrollment* 
c. An implanted pacemaker, ICD, CRT device or an active arrhythmia 
loop recorder 
d. Previous cardiac surgery: i.e., ventriculotomy or atriotomy 
(excluding atriotomy for CABG) 
e. Previous cardiac valvular surgical or percutaneous procedure, or 
prosthetic valve, including mitral valve clips 
f. Interatrial baffle, closure device, patch, or PFO occluder 
g. Presence of a left atrial appendage occlusion device 
h. Presence of any pulmonary vein stents 
i. Coronary artery bypass graft (CABG), PTCA/ PCI/ coronary stent 
procedures within 90 days prior to enrollment 
j. Unstable angina or ongoing myocardial ischemia 
k. Myocardial infarction within 90 days prior to enrollment 
l. Moderate or severe mitral stenosis [severity assessed on the most 
recent TTE ≤180 days prior to enrollment as Pulmonary artery systolic 
pressure >30 mm Hg (1)] 
m. Evidence of left atrial thrombus** 
• Any previous history of cryoglobulinemia 
• Stage 3B or higher renal disease (estimated glomerular filtration rate, 
eGFR <45 mL/min) 
• History of blood clotting or bleeding disease 
• Any prior history of documented cerebral infarct, TIA or systemic 
embolism (excluding a post-operative DVT) ≤180 days prior to 
enrollment 
• Active systemic infection 
• Pregnant, lactating (current or anticipated during study follow up), or 
women of childbearing potential who are, or plan to become, pregnant 

 
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during the time of the study (method of assessment upon physician’s 
discretion) 
 
• 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 
 
• Subjects who in the judgment of the investigator have a life 
expectancy of less than two years  
 
*LVEF and LA diameters obtained ≤180 days prior to enrollment will be acceptable, 
unless a cardiac event has occurred (e.g., MI) between the date of the exam and the 
enrollment date, otherwise a new echocardiogram (trans-thoracic or trans-
esophageal, or intracardiac echo) must be performed to confirm eligibility prior to 
performing ablation. For TTE, the LA anteroposterior diameter measured by M-mode 
from the parasternal long-axis view will be used.  If both LA diameter and volume are 
available, only one meeting eligibility criteria is required. 
 
**The absence of thrombus must be confirmed by means of a TEE within 48 hours 
prior to the procedure or ICE during procedure in subjects not adequately 
anticoagulated (see Section 12.5.2) for at least 3 weeks prior to the procedure OR 
with CHA2DS2-VASc score (see Appendix 27.4) ≥2 in men and ≥3 in women OR 
enlarged LA (≥4.5cm). If a thrombus is observed, the subject no longer meets 
eligibility criteria. When screening for thrombus prior to the index procedure, ensure 
that the anticoagulation approach as described in Section 12.5.2 is followed until the 
day of the procedure. 
11. Subject Accountability 
11.1. Point of Enrollment 
A maximum of 75 subjects will be enrolled and treated with the POLARx FIT balloon size at 31 
or 28 mm (based on clinical judgement) to ensure a minimum of 50 31 mm TREATMENT 
subjects (subjects who receive at least one cryoablation applied at the 31 mm configuration.) are 
enrolled. 
Subjects who have signed and dated the Informed Consent Form are considered enrolled in the 
study.  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 SOC can 
be used to determine pre-eligibility. Study data from exams performed prior to 
consent/enrollment (e.g., TTE) will be collected as medical history data after the subject is 

 
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consented/enrolled in the study.  It is the investigator’s site responsibility to assess eligibility 
criteria before obtaining the Informed Consent Form. 
11.2. Enrollment Controls 
Study-specific subject IDs will be generated through the Electronic Data Capture (EDC) system 
used for this study. This database will also be utilized to provide the sites with subject 
classification assignments once a subject has provided written informed consent.  Enrollment 
controls will be put in place to ensure that each site participating in the extension study will 
enroll and treat a maximum of 18 subjects with cryoablation applied at the 31 mm configuration. 
11.3. Withdrawals 
This section identically matches the Withdrawals Section (Section 9.3) of the FROzEN-AF 
protocol (92348334). 
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 investigation, the 
reason(s) shall be reported. If such withdrawal is due to problems related to investigational 
device safety or performance, the investigator shall ask for the subject’s documented permission 
to follow his/her status/condition outside of the clinical study.   
Reasons for withdrawal may include physician discretion, subject choice to withdraw, 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. In the event 
a subject does decide to withdraw from the study, every effort should be made to obtain full 
information on any on-going reportable Adverse Events up to the point of withdrawal.  
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. Data collected up to the point 
of subject withdrawal may be used, unless any local regulations apply which require removal of 
the data.  
If the withdrawal is due to the investigator’s discretion, the investigator is obligated to follow all 
open reportable Adverse Events until they can be considered as closed or chronic. 
All open reportable adverse events should be closed or documented as chronic.  If the withdrawal 
is due to problems related to device safety or performance, the investigator shall ask for the 
subject’s documented permission to follow his/her status/condition. 
Withdrawn subjects will not be replaced. 
All applicable electronic case report forms (eCRFs) up to the point of subject withdrawal/lost to 
follow up and an “End of Study” eCRF must be completed.   

 
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11.4. Lost to Follow-Up 
This section identically matches the Lost to Follow-Up Section (Section 9.4) of the FROzEN-AF 
protocol (92348334). 
A participant will be considered lost to follow-up if he or she fails to return after documented 
attempts to attend a scheduled visit and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant 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 
participant on the importance of maintaining the assigned visit schedule and ascertain if 
the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (at minimum 3 telephone calls and a 
certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study 
file.  
• Should the participant continue to be unreachable, he or she will be considered lost to 
follow-up from the study. 
 
All applicable electronic case report forms (eCRFs) up to the point of subject withdrawal/lost to 
follow up and an “End of Study” eCRF must be completed.   
11.5. Subject Status and Classification 
As subjects are evaluated, enrolled and treated in the study, they will be grouped into one of the 
following categories. Categorization will help determine how data gathered from them will be 
stored and evaluated. Subjects previously enrolled in the FROZEN-AF study cannot be re-enrolled 
in the POLARx FIT extension study.  
Consent Ineligible (Screening Failures) 
A subject who has signed informed consent but is found not to meet eligibility criteria will be 
classified as “Consent Ineligible”. There are no Follow Up reporting requirements for consent 
ineligible subjects. Subjects determined to be Consent Ineligible do not count towards the 
enrollment ceiling and will not be used for analysis of the endpoints. The original signed Informed 
Consent must be maintained in the center’s patient file.   A subject Identification Number (ID) will 
be assigned in the EDC system.  
For consent ineligible subjects the following forms must be completed: 
• Enrollment and End of Study  
• Adverse Event forms for any reportable event, as defined in Section 21 that occurs after 
signing the Informed Consent, up to the point of subject withdrawal 

 
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INTENT 
A subject who signs informed consent, meets eligibility criteria, but does not have any study 
investigational devices inserted into the body will be classified as “INTENT”. Subjects that are 
enrolled in the study but do not undergo ablation procedure within 30 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 not count towards the 
enrollment ceiling and will not be used for analysis of the endpoints. The original signed Informed 
Consent must be maintained in the center’s patient file. A subject ID will be assigned in the EDC 
system.  
• For intent subjects, at the miniumum the following forms must be completed: Enrollment 
and baseline forms such as, but not limited to, informed consent, enrollment information 
and other related forms 
• End of Study form 
• Adverse Event forms for any reportable event, as defined in Section 21, that occurs after 
signing the Informed Consent, up to the point of subject withdrawal 
ATTEMPT 
A subject who signs informed consent, meets eligibility criteria, and has any study device inserted 
into the body but does not receive any POLARx FIT Cryoablation application will be classified as 
“ATTEMPT.” Attempt subjects do not count towards the enrollment ceiling. Attempt subjects will 
be used for analysis of the primary and secondary safety endpoint and additional analyses of safety 
data but will not be used for analysis of the primary and secondary effectiveness endpoints or 
additional analyses of effectiveness data (additional analysis include subgroup, multivariable, and 
center pooling analyses). The original signed Informed Consent must be maintained in the center’s 
patient 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 through the 12 month visit. All applicable case report forms per 
the protocol will be completed. The original signed Informed Consent and any relevant 
documentation must be maintained in the center’s patient file.  
TREATMENT 
Any subject that signs the consent form, meets eligibility criteria and has the specified study device 
inserted into the body and received at least one POLARx FIT Cryoablation application, regardless 
of the balloon size configuration, will be classified as “TREATMENT”. These subjects are 
followed in accordance with the follow-up schedule 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 75 subject 
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 patient file. 

 
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31 mm TREATMENT 
Any subject that signs the consent form, meets eligibility criteria and has the specified 
study device inserted into the body and received at least one POLARx FIT Cryoablation 
performed using the 31 mm balloon size configuration, will be further classified as “31 mm 
TREATMENT”. A minimum of 50 31mm TREATMENT subjects will be enrolled. 
11.6. End-of-Study Definition  
This section identically matches the End-of-Study Definition Section (Section 9.6) of the 
FROzEN-AF protocol (92348334). 
A clinical trial is considered completed when participants are no longer being examined or the 
last participant’s last study visit has occurred. The end of the study is defined as completion of 
the last visit or procedure shown in the Data Collection Schedule. 
12. Study Methods 
12.1. Data Collection 
Each Treatment subject will be followed at index procedure, at pre-discharge visit, at the month 
3 follow up, at the month 6 follow up and at 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. If the subject needs to undergo an additional ablation procedure in the LA 
during the follow-up period, then this additional ablation procedure will need to be captured in 
the EDC database. The data collection schedule is shown in Table 9.  
 
Table 9:  Data Collection Schedule 
Procedure/Assessme
nt 
Enroll
ment 
(up to 
30 days 
before 
Index 
procedur
e) 
Baseli
ne 
(up to 
30 days 
before 
Index 
procedur
e) 
Index 
Procedu
re 
(Day 
0) 
Blanking Period 
Repeat 
Procedur
e 
Effectiveness Evaluation Period 
Pre-
Dischar
ge 
(0-7 
days 
post 
procedu
re) 
Day 7 
Follow-
up 
Contact 
(+/-1 
day) 
Repeat 
Procedur
e for PAF 
 
Month 
3 Follow 
Up 
(91±14 
days) 
Mont
h 6 
Follow 
Up 
(180±
30 days) 
Month 
12 
Follow 
Up 
(365±30 
days) 
Uns
che
dule
d 
Vi
sit 
Informed Consent 
Process, including 
informed consent 
signature date 
X 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X 
X 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
Blood Tests 
 
X1 
 
 
 
 
 
 
 
 

 
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Procedure/Assessme
nt 
Enroll
ment 
(up to 
30 days 
before 
Index 
procedur
e) 
Baseli
ne 
(up to 
30 days 
before 
Index 
procedur
e) 
Index 
Procedu
re 
(Day 
0) 
Blanking Period 
Repeat 
Procedur
e 
Effectiveness Evaluation Period 
Pre-
Dischar
ge 
(0-7 
days 
post 
procedu
re) 
Day 7 
Follow-
up 
Contact 
(+/-1 
day) 
Repeat 
Procedur
e for PAF 
 
Month 
3 Follow 
Up 
(91±14 
days) 
Mont
h 6 
Follow 
Up 
(180±
30 days) 
Month 
12 
Follow 
Up 
(365±30 
days) 
Uns
che
dule
d 
Vi
sit 
TTE (medical 
history) 
 
X2 
 
 
 
 
 
 
 
 
NIH Stroke Scale 
(NIHSS) 
 
X3 
 
X3 
 
 
 
 
 
 
Neurology 
Consultation4 
 
 
 
(X)4 
 
 
 
 
 
 
Brain MRI Scan5 
 
 
 
(X)5 
 
 
 
 
 
 
Physical Assessment 
 
X 
 
 
 
 
X 
X 
X 
X 
Physical Assessment 
with 
Cardiovascular/Pul
monary 
Examination 
 
 
 
X6 
 
 
 
 
 
 
Quality of Life 
(AFEQT and EQ-
5D-5L) 
 
X 
 
 
 
 
X 
X 
X 
 
PV Anatomical 
Assessment 
(CT/MRI) 
 
X7 
 
 
 
 
 
 
 
 
Screening for LA 
Thrombus (TEE or 
ICE) 
 
X 8 
 
 
X8 
 
 
 
 
PV Stenosis 
Assessment 
(CT/MRI) 
 
 
 
(X)9 
 
 
(X)9 
(X)9 
(X)9 
(X)9 
Procedural Data 
 
 
X 
 
 
X 
 
 
 
 
12-Lead ECG 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
Phrenic Nerve Palsy 
Assessment 
 
 
X10 
(X)10 
 
(X)10 
(X)10 
(X)10 
(X)10 
X10 
Holter Monitor (24 
hours) 
 
 
 
 
 
 
 
 
X 
 
Arrhythmia/Event 
Monitor  
 
 
 
X 
 
 
X 
X 
X 
X 
Documentation of 
Intervention for 
AF/AT/AFL (if any) 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
Medications 
Prior and current AAD medications and Anticoagulant therapy regimen from Enrollment through End of Study Visit 
Protocol Deviations 
From Enrollment through End of Study Visit 
Adverse Event 
Assessment 
Continuous from Enrollment through End of Study Visit 
1 Blood tests up to 90 days prior to enrollment, if applicable. 
2 TTE either new or from medical file, ≤180 days prior to enrollment. 
3 NIH Stroke Scale (NIHSS) performed at baseline and the pre-discharge visit.  
4 Neurology consult is only required if NIH scale worsens from the previous assessment   
5 Brain DW-MRI scan required if neurology consultation determines possibility of new stroke  
6 Physical assessment at discharge will also include a cardiovascular/pulmonary examination:  resting heart rate, systolic and 
diastolic blood pressure, O2 saturation, lung auscultation (includes respiratory rate and respiratory rhythm), and temperature   

 
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7 Performed up to 180 days prior to the index procedure (CT/MRI).  
8 TEE 48 hours prior to the procedure or ICE during the procedure  
9 Assessed in case of suspected PV stenosis.  
10 Screening for phrenic nerve palsy will be performed during ablation, and prior to leaving the EP lab at the completion of the 
ablation procedure in all subjects. Assessment at discharge and at follow-up visits is only applicable for subjects who had phrenic 
nerve palsy detected at the index procedure.  
 
Abbreviations:  
IP = index procedure, NIH = National Institutes of Health, ECG = electrocardiogram, ICE = Intracardiac Echography; PV = 
pulmonary veins, TTM = trans-telephonic monitor, TTE = trans-thoracic echocardiogram, TEE = trans-esophageal 
echocardiogram, CT = Computed Tomography, MRI = Magnetic Resonance Imaging, FU = follow-up. 
 

 
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12.2. Study Candidate Screening 
Investigators are responsible for screening all subjects and selecting those who are appropriate for 
study inclusion. The subjects selected for participation should be from the investigator’s general 
patient population.  The investigator is expected to follow standard of care testing to diagnose and 
screen subjects for inclusion in the study. 
12.3. Enrollment and Informed Consent 
This section identically matches the Enrollment and Informed Consent Section (Section 10.3) of 
the FROzEN-AF protocol (92348334). 
Subjects who provide consent are considered enrolled in the study. To determine eligibility of a 
subject, the investigator or designee needs to implement the consent process and 
verify/document the subject meets the inclusion/exclusion criteria. Informed consent is required 
for all subjects prior to their participation in the study. No study-specific procedures should 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 personally signed and dated by the subject. 
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 30 days post ICF signature. In case 
the index procedure has not been performed within this period, the subject will be classified as 
Intent (see Section 11.5).  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 will be made available for review at Interim 
Monitoring Visits (IMVs). 
For additional information regarding the informed consent process, refer to Section 22. 
12.4. Baseline Visit 
This section identically matches the Baseline Visit Section (Section 10.4) of the FROzEN-AF 
protocol (92348334). 
Enrolled subjects will have baseline data collected. The data collection at baseline includes: 
• Visit date 
• Documentation of Informed Consent process, including Informed Consent Form 
signature date  
• Check of Eligibility Criteria*  
• Demographic data, including age at time of consent, gender, race, and ethnicity 

 
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• Physical assessment including weight, height, resting heart rate, systolic and diastolic 
blood pressure  
• Rhythm at time of visit (by means of a 12-lead ECG) 
• Medical history, including, but not limited to:  
o Evidence of PAF in the medical history should be documented as per the inclusion 
criteria. Treatment history (drug, cardioversion, etc.) should be documented.   
o Underlying cardiovascular disease, if any; including but not limited to hypertension, 
dyslipidemia, coronary artery disease 
o Prior history of cardiac events including acute myocardial infarction, CVA, or TIA  
o Prior surgical interventions and/or cardiac procedures including: Percutaneous Trans 
Catheter Angioplasty (PTCA), Coronary Artery Bypass Graft (CABG), pacemaker 
(PM) implantation, implantable cardioverter-defibrillator (ICD) implant, Cardiac 
Resynchronization Therapy (CRT) implant, cardiac valve interventions, left atrial 
appendage closure (LAAC), patent foramen ovale (PFO) intervention, heart 
transplant or procedures for implantation of other intracardiac devices  
o Detailed history of all arrhythmias  
o Non-cardiac comorbidities, including but not limited to: Chronic Obstructive 
Pulmonary Disease, Diabetes, Hepatic Disease, Neurologic Disease, Renal Disease, 
Bleeding Disorders/Clot disorders, Sleep Disordered Breathing 
• The following instrumental assessments will be performed or data from existing 
information will be collected: 
o TTE (most recent, either assessed at baseline visit or from medical file if date if not > 
180 days prior to enrollment). Data will include: LVEF, left atrial diameter or left 
atrial volume**, pulmonary artery pressure**  
o Cardiac MRI or spiral CT scan, to assess PV anatomy and PV dimension.  
o TEE or ICE to rule out presence of left atrial thrombus. See Section 12.5.2 
Anticoagulation, Thrombus Screening. 
In the event a subject has an adverse event related to the TTE, TEE, ICE or CT/MRI 
scan, they shall remain in the study until the event is resolved. 
• Pregnancy test (urine or blood), if applicable*** 
• Blood tests**** 
• Quality of Life assessment through AFEQT and EQ-5D-5L questionnaires  
• Conduct a baseline National Institute of Health Stroke Scale (NIHSS), see Appendix 
27.3. 
• AAD history and most recent dose prior to enrollment; stop date of amiodarone (if 
applicable)  
• Current AAD and anticoagulation medication regimen  
• Reportable Adverse Events, if applicable 
• Protocol Deviations, if applicable 

 
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* LVEF and LA diameters obtained ≤ 180 days prior to enrollment will be acceptable, unless a 
cardiac event has occurred (e.g., MI) between the date of the exam and the enrollment date, 
otherwise a new echocardiogram (trans-thoracic or trans-esophageal, or intracardiac echo) must 
be performed to confirm eligibility prior to performing ablation. LA anteroposterior diameter 
measured by M-mode from the parasternal long-axis view will be used.  If both LA diameter and 
volume are available, only one meeting eligibility criteria is required.  
**Moderate to Severe mitral stenosis (severity will be assessed as pulmonary artery systolic 
pressure > 30 mmHg). 
***A pregnancy test (method of assessment per investigators’ discretion) must be performed for 
women of childbearing potential. Women of childbearing potential will be required to verify 
entrance criteria prior to the procedure by providing documentation of a negative pregnancy test.  
A negative pregnancy test conducted as standard of care within 7 days prior to enrollment will be 
acceptable. 
****Laboratory blood tests (other than a pregnancy blood test) obtained ≤ 90 days prior to 
enrollment will be acceptable.  
12.5. Medications 
This section identically matches the Medications Section (Section 10.5) of the FROzEN-AF 
protocol (92348334). 
12.5.1. Anti-Arrhythmic Drugs 
12.5.1.1. AADs prior to index procedure 
Inclusion criteria require the subject to be refractory or intolerant to at least one class I or III 
antiarrhythmic medication and amiodarone to be stopped three months before enrollment.  Prior 
and current AAD therapy will be collected in the EDC system. 
If applicable, administration of amiodarone and stop date will be entered in EDC. 
12.5.1.2. AADs post index procedure during the 90-day blanking period 
Blanking period is defined as the time between Index procedure and 90 days post Index procedure. 
Post-procedure AADs are allowed per physician’s discretion during the blanking period. New 
AADs should not be prescribed unless considered medically necessary.  If treatment with AAD is 
prescribed during the blanking period, it is recommended that a Class I or III AAD be selected 
according to the ACC/AHA/ESC 2014 Guidelines for the Management of Patients with AF.  No 
amiodarone use is permitted post procedure. After the index procedure, the investigator should 
remove subjects from AADs to appropriately assess the subject for early arrhythmia recurrence 
that may require a repeat ablation procedure within the blanking period (on or before day 90). 

 
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12.5.1.3. AADs post 90 days blanking period 
Investigators must stop administration of AADs for any atrial tachyarrhythmia after the blanking 
period. If the investigator determines that the subject must be prescribed any dose of 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/AT/AFL recurrence.   
Treatment with Class II/IV medications for conditions other than control of atrial arrhythmia 
recurrence is also permitted and will be documented.  Every effort should be made to keep those 
drugs at a stable dose over the entire course of the study.   
12.5.2. Anticoagulation 
The following anticoagulation protocol is required for this study. An adequate anticoagulation 
regimen is represented by one of the 4 approaches listed in the paragraph titled “Pre-ablation”. 
Pre-ablation. 
Physicians can follow either an uninterrupted anticoagulation approach (Recommended), based 
on uninterrupted warfarin or NOAC, or minimally interrupted NOAC or an interrupted 
anticoagulation approach with adequate bridge with LMWH (Low Molecular Weight Heparin). 
• Uninterrupted anticoagulation approach (recommended) includes one of the following 
options: 
1) Uninterrupted treatment with warfarin or NOAC*, requiring continued treatment 
including the day of the index procedure  
2) Minimally interrupted NOAC, requiring continued treatment but allowing to stop 
NOAC 12 to 24 hours before the index procedure (e.g., holding the morning dose 
the day of the procedure) 
• Interrupted anticoagulation approach includes one of the following options. 
3) If patient is on Warfarin, this should be stopped 5 days prior to the ablation procedure 
and bridged with LMWH. LMWH should be stopped 12 hours prior ablation. 
4) If patient is on NOAC, this should be stopped 5 days prior to the ablation procedure 
and bridged to Warfarin or bridged with LMWH. LMWH should be stopped 12 hours 
prior ablation. At the time NOAC is stopped, INR value should be checked, if 
applicable, to ensure the Time of Therapeutic Range (TTR) are achieved with 
normalized ratio (INR) between 2.0 and 3.0. 
 
* Includes any of the FDA approved NOAC (dabigatran, edoxaban, apixaban or rivaroxaban) 
 Anticoagulation guidelines that pertain to cardioversion of AF should be adhered.  
If at the time of enrollment, a patient has not been anticoagulated as defined above in the pre-
ablation anticoagulation, anticoagulation must be initiated and maintained from point of 
enrollment to the time of the index procedure. If the patient has not been anticoagulated for at least 

 
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3 weeks prior to the index procedure, thrombus screening must be conducted as outlined in Section 
12.5.3.  
 
Intra ablation:  
• Heparin should be administered prior to transseptal puncture during AF catheter ablation 
procedures and adjusted to achieve and maintain an ACT of at least 300 seconds. The ACT 
level should be checked at 10 to 15-minute intervals until therapeutic anticoagulation is 
achieved, and then at 15 to 30-minute intervals for the duration of the procedure.  
After ablation:  
• Systemic anticoagulation with warfarin or a NOAC is recommended for at least 2 months 
post catheter ablation of AF. 
• Adherence to AF anticoagulation guidelines is recommended for patients who have 
undergone an AF ablation procedure, regardless of the apparent success or failure of the 
procedure.  
Decisions regarding continuation of systemic anticoagulation more than 2 months post 
ablation should be based on the patient's stroke risk profile and not on the perceived success 
or failure of the ablation procedure. 
 
12.5.3. Thrombus Screening 
The absence of thrombus must be confirmed by means of a TEE within 48 hours prior to the 
procedure or ICE during the procedure in subjects not adequately anticoagulated (see section 
10.5.2) for at least 3 weeks prior to procedure OR with CHA2DS2-VASc score (see Appendix 
27.4) ≥2 in men and ≥3 in women OR enlarged LA (≥4.5cm). When screening for thrombus prior 
to the index procedure, ensure that the anticoagulation approach as described in Section 12.5.2 is 
followed until the day of the procedure. 
 
12.6. Index (Ablation) Procedure 
12.6.1. General Info 
• Authorized ablating physicians 
 
The study-related ablation procedure, from transseptal access in the left atrium until end of the 
ablation procedure must be performed by investigators trained in Electrophysiology (EP), 
trained to the POLARx FIT extension study protocol, and authorized by BSC to handle 
investigational devices. The index ablation procedure must be performed within 30 days of a 
subject’s enrollment into the study.  To avoid potential bias, it is recommended the number of 

 
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active ablating physicians performing the index procedure per investigational site is restricted 
to 2.  
 
• De novo procedures 
For the purposes of this protocol, de novo procedures are defined as AF procedures in which 
there has been no prior ablation in the Left Atrium (LA). According to subject selection criteria, 
all Index procedures in this study are de-novo as history of previous left atrial ablation or 
surgical treatment for AF/ AFL/ AT constitute an exclusion criterion. 
• Esophagus management  
Esophagus management must be performed by means of temperature monitoring via the 
Console using commercially available products. A commercially available temperature probe 
compatible with the Cryoablation system, will be used with measurements acquired and 
displayed through the Console. Only temperature measurements displayed on the Console will 
be used for esophageal temperature management. If the esophageal temperature falls below 
20°C during cryoablation applications, the ablation will be stopped until esophageal 
temperature returns to baseline. 
• Phrenic nerve activity monitoring 
o Index Procedure: 
 During ablation phrenic nerve activity monitoring will be performed via the 
Console. The phrenic nerve will be paced with a focal or circular catheter, 
higher than the ablation position during all right sided vein ablations. 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  
 After ablation, prior to leaving the EP lab, fluoroscopy of diaphragm 
movement will be performed at the completion of the ablation procedure 
o Discharge: 
 All patients presenting with phrenic nerve palsy at the end of the index 
procedure will be re-assessed at the discharge visit for phrenic nerve palsy 
via sniff test or an inhalation-exhalation chest radiography of the diaphragm 
o At Follow-up Visits: 
 Patients with unresolved phrenic nerve palsy detected at discharge visit, 
should be assessed by means of sniff test or an inhalation -exhalation chest 
radiography of the diaphragm to evaluate if the event resolved 
• Three-dimensional electroanatomic mapping 

 
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3D electro-anatomical mapping is not recommended in this study. If 3D mapping is performed, 
a commercially available device will be used, and the following information will be collected: 
mapping catheter, 3D mapping system and mapping times. 
3.1.1.6.Pulmonary Vein Isolation  
The goal of the ablation procedure is electrical isolation of all clinically relevant PVs.  Electrical 
isolation of the veins must be demonstrated by entrance and exit block.  
If the subject is in AF prior to the ablation, it will be up to the physician’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.  
3.1.1.7.Cryoablation System Preparation  
The individual devices listed in Table 1 must be used together and it is not allowed to combine 
investigational with non-investigational devices. 
The remainder of this section identically matches the Cryoablation System Preparation Section 
(Section 10.6.1.2) of the FROzEN-AF protocol (92348334). 
The Console will create a record for each ablation attempted, including Ablation Duration, 
Cryoballoon Temperature, Esophagus Temperature (if connected) and DMS activity data. To 
accurately capture information relevant to the study, the following information must be input into 
the Console at each index procedure: 
Prior to Ablation:   
• On the subject information screen, enter the subject’s identification (code provided by the 
EDC system when enrolling the patient) and the operating physician name. 
• For this study, the DMS must 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.       
1. Place a disposable ECG electrode just below the right-side costal cartilage. 
2. Snap the DMS onto the electrode. 
3. Ask the patient to cough and verify that signal is visible on the console screen. 
Adjust the position of the electrode if necessary. 
Prior to performing the ablation, pace the phrenic nerve with a focal or circular 
catheter positioned superior to the ablation location (e.g., superior vena cava). 
Adjust the pacing settings and catheter location as necessary to attain phrenic 
nerve capture. Typically, high output at 20 mA and 800 – 1000 milliseconds (ms) 
may be needed. 

 
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NOTE:  Avoid or minimize use of paralytics if general anesthesia is used as 
paralytics may interfere with pacing capture of the phrenic nerve. 
4. While pacing the phrenic nerve, adjust the DMS gain and sensitivity levels within 
the Settings screen to maximize the DMS signal level in the display window. 
Reduce the gain if the DMS signal appears saturated. Stop pacing until needed for 
the ablation.  
5. Set the DMS threshold (within the Settings screen) for which the DMS 
notification will be displayed. The suggested DMS threshold setting is 65%, but 
the threshold can be adjusted per physician discretion. 
• 
The movement amplitude measured by the DMS at the initiation of 
cryoablation is used as the baseline value and is displayed as 100%. 
• 
If the phrenic nerve pacing response decreases during cryoablation, the DMS 
amplitude will correspondingly decrease. The console will display the DMS 
amplitude as a percentage of the baseline value. For example, 80% displayed 
on the console indicates the DMS amplitude is 80% of the baseline valve and 
that movement amplitude is reduced by 20%.  
6. In case of a DMS notification, continue to closely monitor phrenic nerve activity 
and pacing capture, and consider immediately interrupting cryoablation.  
 
Balloon Size Selection: 
Usage of the 31 mm balloon size will be determined by the investigator’s medical judgement, 
for each individual cryotherapy application. It is anticipated that individual study subjects 
may receive cryotherapy applications from both 28 mm and 31 mm balloon diameters during 
their PVI procedure.   
Specifically, investigators must choose which balloon size to utilize for each ablation 
application.  Investigators should use their medical judgement to select the balloon diameter 
that may be effective for treating each individual PV. In determining balloon size selection, 
Investigators should consider the anatomic factors including PV size, geometry, and LA size 
as well as other procedural factors that could affect balloon placement, occlusion quality, and 
tissue contact.  
The SMARTFREEZE console will always inflate the cryoballoon to the current POLARx 
diameter of 28 mm first. For each energy application that the physician chooses to use the 31 
mm balloon, the balloon diameter must be increased from 28 mm to 31 mm by pressing the 
FIT size selection button on the Console. The balloon diameter can only be changed when 
the system is in the “INFLATION” state, prior to initiating “ABLATION”. After increasing 
the balloon diameter to 31 mm, investigators should follow their standard preparation steps, 
including the use of intra-procedure imaging, to ensure appropriate balloon placement and 
occlusion prior to starting cryotherapy. 

 
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During Each Ablation Application:   
• Annotate the ablation site, mark the Time-To-Isolation, and set the Ablation Duration.  
 
3.1.1.8.Cryoablation protocol   
This section identically matches the Cryoablation Protocol Section (Section 10.6.1.3) of the 
FROzEN-AF protocol (92348334), except for step 9.  
All aspects of usage of the POLARx Cryoablation System with POLARx FIT catheters are the 
same as with POLARx catheters (including preparation, introduction, occlusion, and ablation) 
with exception for the optional step of increasing the balloon diameter. 
The ablation procedure should follow this recommended sequence: Prepare patient with 
conscious sedation or general anaesthesia. Prepare the vascular access sites per physician 
preference. Follow anticoagulation protocol in Section 12.5.2. 
1. Intracardiac echo (ICE) may be performed to support the procedure. Record any 
observation of cardiac structural damage, any evidence of pericardial effusion, or any 
visible anomalies on the CRF. 
2. Place additional diagnostic catheters, for example in the coronary sinus or for pacing the 
phrenic nerve, at the discretion of the physician. 
3. Per institutional protocol, complete transseptal access (single or double).  
4. Baseline the fluoroscopy exposure time.  
5. Per the IFU, prepare the steerable sheath. Insert the steerable sheath over the guidewire 
and advance the sheath across the atrial septum. 
6. Per the IFU, prepare the cryoablation catheter and the mapping catheter. Insert the 
mapping catheter into the cryoablation catheter. Insert the POLARx FIT Cryoablation 
Catheter into the steerable sheath and advance it into the left atrium. 
7. Baseline the LA dwell time. 
8. Advance the mapping catheter into the targeted PV and attain baseline electrograms, 
including confirming conduction between LA and PV. Electrocardiographic 
documentation of the subject’s rhythm prior to ablation will be collected. If entrance/exit 
conduction cannot be recorded due to the subject being in AF, no Protocol Deviation will 
be required. 
9. Per the IFU, inflate the cryoballoon in the left atrium, expand the balloon diameter after 
inflation (per physician discretion), and advance the cryoballoon to occlude the targeted 
PV. 

 
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a. Verify the balloon is at an appropriate position for inflation within the left atrium. 
This may be performed using imaging such as fluoroscopy or echocardiography. 
Do not inflate the balloon while it is positioned inside the PV. 
b. Inflate the cryoballoon in the LA while remaining outside the target PV. The 
cryoballoon will always first inflate to a diameter of 28 mm.  
c. Once inflated in the LA, the balloon may be expanded to the 31 mm diameter 
with the FIT size selection button on the SMARTFREEZE Console. Investigators 
shall use their clinical judgement to determine which balloon diameter (28 mm or 
31 mm) to use for the treatment of each individual PV. 
d. Advance the inflated cryoballoon to occlude the targeted PV. Remain in the 
atrium outside the tubular portion of the PV. For best results, maneuver the sheath 
and/or catheter to position the distal portion of the balloon at the PV ostium. 
e. Verify PV occlusion. Verification may be performed with fluoroscopy and 
contrast/saline injection or with other appropriate visualization / assessment 
techniques such as ICE. If the balloon needs to be deflated for repositioning, use 
the slider switch on the POLARx FIT Catheter handle to simultaneously deflate 
and extend the balloon.  
f. Document the occlusion score prior to starting the ablation. Ensure the occlusion 
score was attained for the balloon diameter used for the cryoablation application. 
10. Position the esophagus temperature probe as directly posterior to the cryoballoon as 
possible.  
11. If the selected vessel is a right PV, start phrenic nerve pacing prior to starting the 
cryoablation. 
12. Start the cryoablation and observe the electrograms for changes in conduction. Identify 
Time-To-Isolation and set ablation duration as required by the dosing strategy document 
(document 92355401 provided separately). Investigators may apply a different dosing 
than the one provided in this document for reasons including technical difficulties, 
anatomical challenges, or concerns for subject welfare.   
13. Upon completing the ablation, determine if entrance and exit block were achieved. If 
entrance and exit block are not confirmed, ablate the PV again as required by the dosing 
strategy document (document 92355401). Investigators may apply a different dosing than 
the one provided in this document for reasons including technical difficulties, anatomical 
challenges, or concerns for subject welfare.  If entrance and exit block are confirmed, 
reposition the system to target another PV. 
3.1.1.9.PV isolation verification  
This section identically matches the PV isolation verification Section (Section 10.6.1.4) of the 
FROzEN-AF protocol (92348334). 

 
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Electrograms from the POLARMAP mapping catheter will be used to assess entrance and exit 
block into/from the PVs. The PV will only be considered isolated if entrance and exit block are 
confirmed. Electrogram data must be documented.  
3.1.1.10. 
Additional ablation(s) 
Additional ablation of non-PV foci that initiate AF (including locations in the LA, RA, or SVC), 
targeting complex fractionated electrograms or ganglionated plexi or performing left atrial mitral 
isthmus or roof lines are not allowed in this protocol.  
Additional ablation of the cavo-tricuspid isthmus (CTI) with a conventional market approved RF 
catheter is allowed only in case a typical atrial flutter is documented in prior patient history or 
occurs during the case (either spontaneously or inducible). 
The Cryoablation System cannot be used for the ablation of other arrhythmia(s)/additional line(s) 
or applications outside the PVs. 
It is not allowed to perform concomitant procedures during the ablation procedure (e.g., ICD 
implant, PM, LAAC, arrhythmia loop recorder).   
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.   
If at any time during the ablation procedure the investigator is unable to continue the ablation with 
the designated investigational catheter (for the PV isolation), the investigator may consider the 
case a procedural failure and complete the case with a device determined best for the subject.  The 
point at which failure was determined as well as the rationale must be documented.  A protocol 
deviation will be documented in the EDC system. 
12.6.2. Index procedure collected data 
This section identically matches the Index procedure collected data Section (Section 10.6.2) of 
the FROzEN-AF protocol (92348334), with the exception that the balloon size for each 
cryoablation application will be collected in this extension study.   
The following data related to the procedure will be collected: 
• Date of procedure 
• Identification of all investigational study devices:  
o Cryoablation Catheter  
o Cryoablation Mapping Catheter  
o Cryoablation Steerable Sheath  
o Console and all investigational accessory devices 

 
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• Identification of non-study devices if applicable:  
o Additional sheaths/introducers used during the procedure including manufacturer, 
model, and type 
o Additional catheter(s) used during the case other than Cryoablation Catheter 
including manufacturer, model, and type (e.g., mapping catheter and CS catheter) 
o Mapping system and mapping catheter (manufacturer and model); if RHYTHMIA 
HDx™ is used (manufacturer, model, and software version)  
• 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 access to left atrium single or double transseptal 
• Method of evaluating phrenic nerve function and determining when intervention is 
needed 
• Collection of ACT levels 
 
Specific to the PVI ablation the following information will be collected: 
• Pre-ablation electrograms with baseline entrance and exit conduction for each PV 
• Balloon size for each cryoablation application 
• Occlusion score for each cryoablation application 
• Time-to-Isolation (if achieved), minimum balloon temperature, and duration of each 
cryoablation application.  
• Total number and total duration of cryoablation applications per PV 
• Post-ablation electrograms of entrance/exit block for each PV 
   
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 
• Total Cryoablation time (duration of all cryoablation applications) 
• Duration of LA dwell time defined as time from the Cryoablation Catheter exiting the 
sheath in the LA to time of final PV isolation. 
• Rhythm at end of case (documented by means of a post-ablation EGM/12-lead ECG) 

 
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• 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 through fluoroscopy of diaphragm movement. 
• Protocol Deviations, if applicable 
 
After removal from the subject, all investigational catheters should be inspected by the 
investigational site staff, and if any abnormalities are noted on the catheter, it must be 
documented.  All investigational catheters, steerable sheaths and extension cables opened and/or 
used during the procedure must be returned to the sponsor.  Failure to return an investigational 
device will result in a protocol deviation. All other control ablation or diagnostic catheters may 
be disposed of per standard EP practice. All adverse experiences with a BSC product, including 
those commercially available, during the ablation procedure must be promptly reported to BSC 
and documented on the eCRF. 
 
• The Export Case Data (the data collected through the Console) will be saved and stored 
to external media, as provided by the sponsor 
• Console Report 
• The EP Lab Procedure Report will be printed and stored in the center’s patient file.  
Please refer to Table 10 for an overview of source document requirements. 
12.7. Pre-Discharge Visit 
This section identically matches the Pre-Discharge Visit Section (Section 10.7) of the FROzEN-
AF protocol (92348334), with the exception that weight does not need to be collected as part of 
the physical assessment. 
The pre-discharge follow-up visit (0 to 7 days post procedure) should be done before hospital 
discharge, but 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. 
The data collection at Pre-Discharge includes: 
• Date of visit 
• Physical assessment with cardiovascular/pulmonary examination including: 
o Resting heart rate 
o Systolic and diastolic blood pressure 
o O2 saturation 
o Lung auscultation (includes respiratory rate and respiratory rhythm) 
o Temperature 
• Rhythm at time of visit (by means of a 12-lead ECG)  

 
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• Conduct an NIH Stroke Scale (NIHSS) (see Appendix 29.3) 
• In cases of phrenic nerve palsy at the index procedure, patients should be assessed by 
means of a sniff test or an inhalation-exhalation chest radiography of the diaphragm to 
evaluate if the event resolved  
• Provide subjects with arrhythmia/event monitor and operating instructions (subjects 
known as procedural failures do not need to be assigned an event monitor) 
• Perform a cardiac MRI or spiral CT if PV stenosis is suspected at any time throughout the 
follow-up period. Recommend using the same imaging modality used at baseline 
• New, discontinued or changes to current medication regimen 
• Reportable Adverse Events, including resolution of ongoing events, if applicable 
• Protocol Deviations, if applicable 
If the NIH stroke scale demonstrates new abnormal findings when compared with the pre-
procedure assessment, the subject will have a neurology consultation. A brain DW-MRI scan is 
required if neurology consultation determines possibility of new stroke. The DW MRI scan 
sequences required will be performed within the local guidelines associated with brain MRI scan. 
The following parameters for the DW-MRI are recommended to allow comparability of potential 
findings across patients: 
• 1.5T MRI imaging equipment 
• 
Diffusion-weighted imaging technique  
• 5 mm slice thickness 
12.8. Day 7 Follow-Up Contact 
This section identically matches the Day 7 Follow-Up Contact Section (Section 10.8) of the 
FROzEN-AF protocol (92348334). 
A telephone contact will occur at 7 days post-procedure (7 days±1 day). If the patient is still 
hospitalized the 7 days follow-up will be performed as in-hospital visits.  The data collection at 
the day 7 follow-up includes: 
• Date of visit 
• New, discontinued or changes to in current medication regime 
• Reportable Adverse Events, including resolution of ongoing events, if applicable 
• Protocol Deviations, if applicable 
In cases of in-hospital visit and phrenic nerve palsy at the index procedure, patients should be 
assessed by means of sniff-test or inhalation-exhalation chest radiography of the diaphragm to 
evaluate if the event resolved.  

 
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12.9. Month 3 Follow-Up Visit 
This section identically matches the Month 3 Follow-Up Visit Section (Section 10.9) of the 
FROzEN-AF protocol (92348334) with the exception that weight does not need to be collected as 
part of the physical assessment. 
This visit should be completed at 3 months post-procedure (91 days±14 days).  Due to the range 
for the visit completion and the endpoint requirement for medication, AAD medication changes 
made during the three-month follow-up visit will be counted as being made within the blanking 
period, but efforts should be made to remove subjects from AADs by eight weeks post-procedure 
to allow for complete washout. The data collection at the 3-month follow-up includes: 
• Date of visit 
• Physical assessment including resting heart rate, systolic and diastolic blood pressure 
• Rhythm at time of visit (by means of a 12-lead ECG) 
• In cases of phrenic nerve palsy at the index procedure, patients should be assessed by 
means of a sniff test or an inhalation-exhalation chest radiography of the diaphragm to 
evaluate if the event resolved  
• Quality of Life Instruments (AFEQT and EQ-5D-5L) 
• Review of any symptomatic transmissions (arrhythmia/event monitor such as a TTM) 
• Documentation of any intervention for AF/AT/AFL (e.g., Repeat Procedure, 
Cardioversion), if applicable 
• Perform a cardiac MRI or spiral CT if PV stenosis is suspected at any time throughout the 
follow-up period. Recommend using the same imaging modality used at baseline. 
• New, discontinued or changes to current medication regimen  
o Reminder: AADs must be stopped for any atrial tachyarrhythmia after the 
blanking period, please refer to Section 12.5.1.3 
• Reportable Adverse Events, including resolution of ongoing events, if applicable; in 
particular: 
o In cases of a pre-existing and unresolved phrenic nerve palsy the patient should be 
assessed by means of a sniff test or an inhalation-exhalation chest radiography of 
the diaphragm to evaluate if the event resolved  
• Protocol Deviations, if applicable 
12.10. 
Month 6 Follow-Up Visit 
This section identically matches the Month 6 Follow-Up Visit Section (Section 10.10) of the 
FROzEN-AF protocol (92348334) with the exception that weight does not need to be collected as 
part of the physical assessment. 

 
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This visit should be completed at 6 months post-procedure (180 days±30 days).  The data 
collection at the month 6 follow-up includes: 
• Date of visit 
• Physical assessment including resting heart rate, systolic and diastolic blood pressure 
• Rhythm at time of visit (by means of a 12-lead ECG) 
• Quality of Life Instruments (AFEQT and EQ-5D-5L) 
• Review of any symptomatic or asymptomatic transmissions (arrhythmia/event monitor 
such as TTM) 
• Documentation of any intervention for AF/AT/AFL (e.g., Repeat Procedure, 
Cardioversion), if applicable 
• Perform a cardiac MRI or spiral CT if PV stenosis is suspected at any time throughout the 
follow-up period. Recommend using the same imaging modality used at baseline  
• New, discontinued or changes to current medication regimen 
• Reportable Adverse Events, including resolution of ongoing events, if applicable; in 
particular: 
o In cases of phrenic nerve palsy at the index procedure, patients should be assessed 
by means of a sniff test or an inhalation-exhalation chest radiography of the 
diaphragm to evaluate if the event resolved  
• Protocol Deviations, if applicable 
12.11. 
Month 12 Follow-Up Visit 
This section identically matches the Month 12 Follow-Up Visit Section (Section 10.11) of the 
FROzEN-AF protocol (92348334) with the exception that weight does not need to be collected as 
part of the physical assessment. 
Investigators will assess subject status at 12 months (365 days±30 days) post index procedure. 
The data collection at the month 12 follow-up includes: 
• Date of visit 
• Physical assessment including resting heart rate, systolic and diastolic blood pressure 
• Rhythm at time of visit (by means of a 12-lead ECG) 
• Quality of Life Instruments (AFEQT and EQ-5D-5L) 
• Review of any symptomatic or asymptomatic transmissions (arrhythmia/event monitor 
such as TTM) 
•  24-hour Holter monitor data recorded with the study specific TTM   

 
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Note: While wearing the Holter monitor, subjects should also make every attempt to capture 
the symptomatic episode with the TTM 
• Documentation of any intervention for AF/AT/AFL (e.g., Repeat Procedure, 
Cardioversion), if applicable 
• Perform a cardiac MRI or spiral CT if PV stenosis is suspected. Recommend using the 
same imaging modality used at baseline  
• New, discontinued or changes to in current medication regime 
• Reportable Adverse Events, including resolution of ongoing events, if applicable; in 
particular: 
o In cases of phrenic nerve palsy at the index procedure, patients should be assessed 
by means of a sniff test or an inhalation-exhalation chest radiography of the 
diaphragm to evaluate if the event resolved  
• Protocol Deviations, if applicable 
12.12. 
 Unscheduled Visits 
This section identically matches the Unscheduled Visits Section (Section 10.12) of the FROzEN-
AF protocol (92348334). 
An unscheduled follow-up visit is any subject visit triggered by subject symptoms that is not 
already defined as one of the study visits. 
If subjects experience symptoms associated with cardiac arrhythmias (e.g., palpitations, light-
headedness, syncope, dyspnea) during the first 12 months, they will be instructed to record the 
arrhythmia on the event monitor.  The investigator will review the information transmitted and 
will contact the subject to schedule an additional office visit if deemed necessary per investigator’s 
decision.   
In addition to determining the best course of action for the subject (repeat ablation, medication 
adjustment), during the visit, the following will be collected:  
• Date of visit 
• Physical assessment including resting heart rate, systolic and diastolic blood pressure 
• Rhythm at time of visit (by means of a 12-lead ECG) 
• Review of any symptomatic or asymptomatic transmissions (arrhythmia/event monitor, 
such as TTM)  
• Documentation of any intervention for AF/AT/AFL (e.g., Repeat Procedure, 
Cardioversion), if applicable 
• Perform a cardiac MRI or spiral CT if PV stenosis is suspected at any time throughout the 
follow-up period. Recommend using the same imaging modality used at baseline 

 
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• New, discontinued or changes to current medication regimen 
• Reportable Adverse Events, including resolution of ongoing events, if applicable; in 
particular: 
o In cases of phrenic nerve palsy at the index procedure, patients should be assessed 
by means of a sniff test or an inhalation-exhalation chest radiography of the 
diaphragm to evaluate if the event resolved  
• Protocol Deviations, if applicable 
12.13. 
Additional/Repeat Procedure 
It is recommended to use the Cryoablation system for repeated ablation procedures to treat AF 
(during the blanking period and during the effectiveness evaluation period). 
In case an additional procedure (including but not limited to a repeat ablation procedure for PAF) 
occurs during the month 12 follow-up period, the data of this procedure will be entered in the 
‘Additional/ Repeat Procedure’ eCRF.  In case this additional procedure is an ablation procedure 
(for the same, or different arrhythmias or for an unsuccessful ablation of the arrhythmia 
presented at index procedure), detailed information about this additional ablation procedure will 
be entered in the ‘Additional/Repeat Procedure’ eCRF: 
• Was the additional ablation procedure performed in the LA? If yes, TEE or ICE to rule 
out presence of left atrial thrombus.   
• For additional ablation procedures performed in the LA: was this additional ablation 
procedure performed to treat AF?  If no, specify the arrhythmia type. 
It is known that a repeat ablation procedure for PAF may be necessary in certain subjects 
after the index ablation procedure due to recurrences of PAF or other tachyarrhythmias 
requiring treatment.  One repeat ablation procedure for PAF is allowed within the 
blanking period if considered medically necessary due to patient’s intolerability of the 
PAF. Use of a non-study device for AF re-ablation during blanking period constitutes a 
failure for the effectiveness endpoint.  Data for the repeat ablation procedure will be 
collected in the eCRF. 
Subjects must follow the same anticoagulation requirements as defined for the index 
procedure in Section 12.6 prior to proceeding with the repeat ablation procedure for PAF.  
• If a 3D mapping system is used for this additional procedure, additional info will be 
collected  
• Reportable Adverse Events, including resolution of ongoing events, if applicable; in 
particular: 
o In cases of phrenic nerve palsy at the index procedure, patients should be assessed 
by means of a sniff test or an inhalation-exhalation chest radiography of the 
diaphragm to evaluate if the event resolved  

 
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• Protocol deviations, if applicable 
The appropriate type of pre-procedure imaging (CT/MRI) is to be determined by the investigator.  
As available, the PV images must be reviewed against the pre-ablation imaging from the index 
procedure to rule out PV stenosis from the index ablation procedure.   
12.14. 
Study Completion 
This section identically matches the Study Completion Section (Section 10.14) of the FROzEN-
AF protocol (92348334). 
Each Treatment subject will be followed until the month 12 follow-up. Participation in the study 
is considered complete upon completion of the month 12 follow-up. 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Data Collection 
Schedule, Table 9. 
 
In case of premature termination of the study, please refer to Section 22.1. 
Following termination/completion of the study, subjects will be managed according to local 
institution practice.  
Sites will need to document and complete the “End of Study” CRF to signify study completion. 
12.15. 
Unforeseen Circumstances (Natural Disaster/Global Pandemic) 
This section identically matches the Unforeseen Circumstances Section (Section 10.15) of the 
FROzEN-AF protocol (92348334). 
There may be unforeseen circumstances that occur during the study, such as a natural disaster or 
a global pandemic (e.g., COVID-19) that prevents a subject from attending study visits during 
the required follow-up window. While every attempt should be made to avoid disruptions in 
collecting study data, it is important to collect as much data as possible, by any available means 
and from any available resources. This may include obtaining records from an outside clinic, 
hospital or other healthcare facility that is not IRB/EC/REB approved.  
If study data must be collected remotely, every effort should be made to collect the data within 
the study visit window, if possible. Critical data collected during the study includes any 
procedure or device related adverse events, recurrence of any AF/AT/AFL, and a Cardiac CT or 
MRI (if PV stenosis is suspected). Event monitors and 24- hour Holter monitors can be used to 
detect any recurrence of AF/AT/AFL. If a Cardiac CT or MRI is required because PV stenosis is 
suspected, the Cardiac CT or MRI may be performed at another healthcare facility and the 
window to conduct this test may be extended by up to one month (30 days) following the normal 
study visit window.  

 
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12.16. 
Source Documents 
This section identically matches the Source Documents Section (Section 10.16) of the FROzEN-
AF protocol (92348334). 
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.  
Table 10:  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 
Pregnancy, if applicable 
Retain at Center 
Physical assessment  
Retain at Center 
Cardiovascular/pulmonary examination 
Retain at Center 
Medication Regimen and Changes 
Retain at Center  
Medical history 
Retain at Center 
Quality of Life Instruments (AFEQT and EQ-5D-5L) 
Retain at Center 
NIH Stroke Scale Assessments 
Retain original at center and submit copies and all 
associated source documents if a change in scale is 
observed from baseline 
If determined necessary, neurological consultation 
and brain MRI (DW-MRI) 
Retain originals at center and submit all source 
documents and copy of complete scan to BSC  
Imaging 
Retain at Center 
12-Lead ECGs data including ongoing rhythm 
Retain at Center 
Imaging, per standard of care 
Retain at Center 
Recording System Printouts, showing entrance/exit 
block for each Pulmonary Vein 
Retain at Center 
Pre-ablation electrograms with baseline entrance and 
exit conduction for each PV 
Retain at Center 
Recording lab logs, showing the time of 
entrance/exit block  
Retain at Center 
Signed Technical Source Form 
Retain at Center 

 
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Requirement 
Disposition 
Console Report 
Retain at Center 
 
Console Export Case Data 
Retain at Center 
Submit one copy to BSC 
Printed EP Lab Procedure Report  
Retain at Center 
Adverse Events 
Retain at Center 
In the event of a patient death: 
• 
Death narrative 
• 
Relevant medical records 
• 
Death Certificate 
• 
Autopsy report 
Events be adjudicated by CEC: 
• 
Relevant medical records 
 
 
Submit one copy to BSC, 
Retain one copy at center 
 
13. Statistical Considerations 
13.1. Endpoints 
13.1.1. Primary Safety Endpoint 
The primary safety endpoint at 3 months is defined as the safety event-free rate at 3 months post-
procedure.   
Primary safety events at 3 months will consist of a composite of the following procedure-related 
and/or device-related adverse events.  
Events will be counted through 7 days post index procedure or hospital discharge, whichever is 
later, unless denoted as events counting through 3 months post index procedure. 
• Death 
• Myocardial infarction (MI) 
• Major Vagal Nerve Injury/Gastroparesis  
• Transient ischemic attack (TIA) 
• Stroke/Cerebrovascular accident (CVA) 
• Thromboembolism 
• Cardiac tamponade/perforation* 
• Pneumothorax 
• Major vascular access complications 
• Pulmonary edema/heart failure 
• AV block** 
• Atrial esophageal fistula*** 

 
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• Severe pulmonary vein stenosis (≥70% reduction in the diameter of the PV or PV branch 
from baseline)*** 
• Persistent phrenic nerve palsy****  
*Cardiac tamponade/perforation occurring up to 30 days post-index-procedure will count as primary safety endpoint 
events 
**AV block not attributable to medication effect or vasovagal reaction. 
***Atrial esophageal fistula and severe pulmonary vein stenosis occurring up to 3 months post-index-procedure will 
count as primary safety endpoint events 
**** Phrenic nerve palsy not resolved at the end of the 3 months follow up will count as primary safety endpoint 
event. 
13.1.1.1. Hypotheses 
Statistical considerations were not utilized in the design of this extension study and there are no 
formal hypotheses to be tested for the primary safety endpoint. 
13.1.1.2. Sample Size  
Due to a lack of hypotheses for the objective, the sample size cannot be determined through 
traditional statistical powering techiniques. The chosen sample size of 50 31 mm TREATMENT 
subjects is intended to be a reasonable number to assess the endpoint with a sufficient degree of 
precision. 
13.1.1.3. Statistical Methods 
Analysis of study data will use descriptive statistical methods. For the primary safety endpoint, 
the Kaplan-Meier 3-month primary safety event free rate will be calculated. Subjects who 
withdraw from the study prior to 3-month or have a repeat procedure performed with a non-study 
catheter without experiencing an event will be censored on the date of withdrawal or repeat 
procedure. The observed primary safety event free rate and its 95% confidence limits (calculated 
as the pointwise confidence limit using the log-log methodology) will be provided. 
13.1.2. Primary Effectiveness Endpoint  
The primary effectiveness endpoint is the rate of acute procedural success where acute 
procedural success is defined as the achievement of electrical isolation of all PVs by using the 
Cardiac Cryoablation System with the POLARx FIT cryoablation balloon catheter models (with 
treatment applied at 28 mm or 31 mm balloon size per physician discretion). Electrical isolation 
of a PV is demonstrated by entrance and exit block. 
13.1.2.1. Hypotheses 
Statistical considerations were not utilized in the design of this extension study and there are no 
formal hypotheses to be tested for the primary effectiveness endpoint. 

 
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13.1.2.2. Sample Size  
Due to a lack of hypotheses for the objective, the sample size cannot be determined through 
traditional statistical powering techiniques. The chosen sample size of 50 31 mm TREATMENT 
subjects is intended to be a reasonable number to assess the endpoint with a sufficient degree of 
precision. 
13.1.2.3. Statistical Methods 
Analysis of study data will use descriptive statistical methods. For the primary effectiveness 
endpoint, the binomial acute procedural success rate and Clopper-Pearson 95% confidence limits 
will be presented.  
13.2. General Statistical Methods 
13.2.1. Analysis Sets 
The primary and secondary safety endpoints and additional analyses of safety data will use all 
available data from ATTEMPT and TREATMENT subjects enrolled in POLARx FIT: 
FROZEN-AF Extension study. The primary and secondary effectiveness endpoints and 
additional analyses of effectiveness data will use all available data from TREATMENT subjects.  
Additionally, in order to further evaluate the safety and effectiveness of the POLARx FIT 
catheter when used at its larger size, an analysis will be performed of each primary and 
secondary endpoint including all available data from 31 mm TREATMENT subjects only. 
13.2.2. Control of Systematic Error/Bias 
Selection of patients will be made from the Investigator’s population. All patients meeting the 
eligibility criteria and having signed the ICF will be eligible for enrollment in the study.  Control 
and reduction of potential bias associated with a single-arm study design have been taken into 
account by considering a series of measures including but not limited to: 
• 
defining inclusion and exclusion criteria to represent a population like the one enrolled in 
recently completed trials on AF ablation 
• 
implementing a screening log to document reason(s) for screening failure and a pre-specified 
analysis on screening failures 
• 
employing a rhythm surveillance monitoring strategy that is equivalent to that used in recent 
PAF IDE studies and consistent with the relevant recommendation in the HRS consensus 
document 
• 
utilizing core lab for reviewing electrocardiographic recordings from study specific rhythm 
surveillance monitoring after the blanking period 

 
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13.2.3. Number of Subjects per Investigative Site 
To avoid any center effect and bias, one center will not be authorized to enroll more than 18 
subjects. 
13.3. Data Analyses 
13.3.1. Interim Analyses  
No formal interim analyses are planned for the purpose of stopping the study early for declaring 
effectiveness or for futility.  
An interim report on the 31 mm TREATMENT group is planned for submission to FDA. 
Procedural data on both a per subject and a per pulmonary vein basis, acute procedural success 
data, and 7-day serious adverse events data will be submitted for a sub-set of these subjects as 
well as a summary of the study status and safety for all POLARx FIT: FROZEN-AF Extension 
study subjects available at the time of the report. 
Final analysis of each endpoint will be performed when all applicable data for that endpoint has 
been collected. Analysis of the primary endpoints for submission to FDA occur after all 3-month 
data has been collected on all subjects. 
13.3.2. Justification of Pooling 
Poolability of the FROzEN-AF Extension Study data with the data from the main FROzEN-AF 
study will be assessed for the primary and secondary endpoints of the FROzEN-AF Extension 
Study. The endpoints from the FROzEN-AF Extension study will be evaluated in the FROzEN-
AF study and data from the two studies will be deemed to be poolable if the absolute difference 
in the endpoint rates is found to be less than a clinically meaningful delta. This analysis will 
occur for the FROzEN-AF Extension Study primary endpoints when 3-month data on all 
subjects has been collected and on the FROzEN-AF Extension Study secondary endpoints when 
12-month data on all subjects has been collected. 
13.3.3. 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. 
14. Health Economics Outcomes 
This section identically matches the Health Economics Outcomes Section (Section 12) of the 
FROzEN-AF protocol (92348334). 
 

 
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A formal health economics analysis may be completed as part of this trial study, given 
meaningful clinical results are obtained. This will take into consideration complication rates, 
quality of life, and resource utilization. The EQ-5D, generic quality of life measure, will be used 
to assess health utilities. We may estimate costs associated with the health care utilization 
measures at all sites. These inputs may be used in health economics analysis performed. 
15. Data Management 
Sections 13.1-13.3 identically match sections 13.1-13.3 of the FROzEN-AF protocol (92348334). 
15.1. Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) system.  
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 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. 
All access to the clinical database will be changed to “Read only” after all data is either “Hard 
Locked” or “Entry Locked”. Once acceptance of the final report or finalization of publications 
(as applicable) is received, final database storage and archiving activities can begin. Once all the 
closeout activities are completed a request to IT is submitted to have the “Database Locked” or 
Decommissioned and all database access revoked. 
Data transfers from other systems such as core labs and electronic questionnaires will be 
coordinated by Boston Scientific.  
CRF Completion Guidelines will be created by Boston Scientific and provided to all sites. 

 
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15.2. 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. 
15.3. Technical Source Forms 
The Technical Source Form (TSF) is the sponsor-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. If available, the console operator will provide the 
delegated site personnel with the study related data collected during the case directly from the 
console. 
At the conclusion of the procedure, the completed technical source form must be signed (and 
initialed as needed) by the following people: 
• 
Delegated Site Personnel completing the forms 
• 
Delegated Investigator conducting and/or supervising the case 
• 
Console operator supporting the case 
15.4. Core Laboratories 
15.4.1. Event and 24-Hour Holter Monitors’ Core Lab 
15.4.1.1. Event Monitors 
A Core Lab will provide the center and/or subject all necessary instructions and/or materials 
related to the use of the event monitor.  Only TREATMENT subjects will be provided with an 
event monitor, such as a Trans-Telephonic Monitor (TTM), either prior to discharge from the 
hospital or will be sent to the subject’s residence immediately following discharge.  All events 
will be analyzed by the centralized research company to determine if the episodes are associated 
with arrhythmia recurrence.  The Core Lab will make this information accessible to the 
Investigator center for concurrence.  If there is discordance in arrhythmia classification between 

 
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the Core Lab and the investigator, a third-party cardiologist will be used for final rhythm 
determination. 
Within the first 90 days (3 months) after the index ablation procedure (blanking period), 
TREATMENT subjects will be instructed to transmit all symptomatic episodes for detection 
and/or treatment of early recurrences.  After the subject’s 3-month follow-up visit, subjects will 
be instructed to send at least two transmissions per month (either symptomatic or asymptomatic) 
through the 12-month follow-up to ensure continued reporting compliance. If subjects experience 
symptoms associated with cardiac arrhythmias (e.g., palpitations, lightheadedness, syncope, 
dyspnea), they will be instructed to transmit a recording. Such recording will count towards the 
required transmission of that period. The Core Lab will work with the investigational site to ensure 
reporting compliance.   
All event monitors must be returned to the centralized research company upon completion of a 
subject’s 12-month follow-up or withdrawal from the study.   
15.4.1.2. 24-Hour Holter Monitors 
Each TREATMENT subject will be provided with a 24-Hour Holter Monitor at the 12-month 
follow-up visit.   
Investigational centers will be trained on the set-up of the monitors and will provide the subjects 
with the instructions necessary to complete the test.  If a subject has a symptomatic episode while 
wearing the Holter Monitor, they will be strongly encouraged to report the symptoms to their 
physician.  Once the Holter Monitor is returned to the centralized research company, the monitor 
will be analyzed for all symptomatic and asymptomatic arrhythmia episodes, and investigators will 
be informed of the results.   
15.4.2. ECG Core Lab 
To ensure objective assessment of rhythm monitoring data, 12-lead ECG tracings obtained beyond 
3 months post-procedure will be reviewed by an independent core lab. 
15.4.3. PV Stenosis Imaging 
Images (CT/MRI) collected to assess adverse events associated with symptomatic pulmonary vein 
(PV) stenosis will be assessed by an independent core lab. 
15.5. Quality of Life (QOL) 
Clinical trials increasingly recognize the value of including patient reported outcome measures in 
their design. To understand the impact of atrial fibrillation ablation procedures on patient’s 
quality of life, the quality-of-life instruments used for the trial will be the EQ-5D-5L for a 
generic questionnaire and the AFEQT for disease specific. Subjects will be asked to complete the 
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The Atrial Fibrillation Effect on Quality of Life (AFEQT) was developed to evaluate disease-
specific quality of life for patients with atrial fibrillation. The 20-item questionnaire is 
subdivided into three domains: symptoms, daily activities, and treatment concerns with 
responses provided on a seven-point Likert scale.  
The EQ-5D, generic quality of life measure, will be used to assess health utilities. It is a 
descriptive system of health-related quality of life states consisting of five dimensions (mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression) each of which can take one of 
five responses. The responses record five levels of severity (no problems/slight 
problems/moderate problems/severe problems/extreme problems) within a particular EQ-5D 
dimension. 
16. Deviations 
This section identically matches the Deviations Section (Section 14) of the FROzEN-AF protocol 
(92348334). 
 
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 IRB/EC/REB, and the regulatory authority if applicable, of any 
deviation from the investigational plan to protect the life or physical well-being of a subject in an 
emergency, and those deviations which affect the scientific integrity of the clinical investigation. 
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 eCRF. Sites may also be 
required to report deviations to the IRB/EC/REB, 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 IRB/FDA notification, site re-training, or site 
discontinuation/termination) will be put into place by the sponsor. 
17. Accountability for Study Products  
17.1. Investigationally-Labelled Products 
The investigationally-labelled devices/equipment shall be securely maintained, controlled, and 
used only in this clinical study.  
For investigationally-labelled items, the principal investigator or an authorized designee shall do 
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• Securely maintain and control access to these items to ensure they are used only in 
this clinical study and only per the protocol.  
• Ensure the storage environment for these items is appropriate for maintaining 
conditions per the items’ labeling (e.g., temperature, humidity, etc., as applicable)  
• Return remaining items and equipment upon Sponsor request and in the condition in 
which they were provided, reasonable wear and tear excepted. 
The sponsor shall keep records to document the physical location of all investigationally-labelled 
devices/equipment from shipment of investigational devices from BSC or designated facility to 
the investigation sites until return or disposal. 
The principal investigator or an authorized designee shall keep records documenting the receipt, 
use, return and disposal of the investigationally-labeled devices/equipment, which shall include 
the following: 
• Names of person(s) who received, used, returned or disposed of each item 
• Date of receipt 
• Identification and quantity of each investigational device/piece of equipment (examples 
of identification: batch number, serial number or unique code) 
• Expiry date, as applicable 
• Date or dates of use 
• Subject identification 
• Date on which the investigational device/piece of equipment was returned/explanted from 
subject, if applicable 
• Date of return (and number) of unused, expired, no longer needed, and/or or 
malfunctioning investigational devices/equipment, if applicable 
• Date and documentation of item disposal, as directed by sponsor, if applicable 
• Physical location and conditions of storage 
17.2. Commercially Labelled Products 
As directed by the study case report form, the principal investigator or an authorized designee 
shall keep records documenting the use of commercially labeled devices/equipment in the study, 
which shall include the following: 
• Identification and quantity of each investigational device/piece of equipment (examples of 
identification: batch number, serial number, or unique code) 
• Date or dates of use 
• Subject identification 

 
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18. Compliance 
18.1. Statement of Compliance 
This clinical investigation is financed by the study sponsor. Before the investigational site can be 
“Authorized to Enroll,” the investigational site must enter into a Clinical Study Agreement with 
the sponsor that details the financing of the study as well as the rights and obligations of the 
investigational site and the investigator. 
 
This study will be conducted in accordance with 21 CFR 814.20 part 56, part 50, part 54 and part 
812 or 814.82, ISO 14155 Clinical Investigation of Medical Devices for Human Subjects - Good 
Clinical Practice, 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 IRB and 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 IRB or regulatory authority 
shall be followed, if appropriate.  
18.2. 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, ISO 
14155 Clinical Investigation of Medical Devices for Human Subjects, ethical principles that have 
their origin in the Declaration of Helsinki, any conditions of approval imposed by the reviewing 
IRB/EC/REB, and prevailing local and/or country laws and/or regulations, whichever affords the 
greater protection to the subject. 
• Prior to beginning the study, sign the Clinical Study Agreement and comply with the 
Investigator responsibilities as described in such Agreement.   
• Prior to beginning the study, sign the Investigator Brochure Signature Page (if applicable) 
and Protocol Signature page documenting his/her agreement to conduct the study in 
accordance with the protocol. 
• 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 clinical investigation. 

 
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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-
investigation-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 reportable events. 
• Report to the IRB/EC/REB 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 IRB/EC/REB, and supply BSC with any 
additional requested information related to the safety reporting of a particular event 
• Maintain the device accountability records and control of the investigationally-labelled 
device, ensuring that the investigationally-labelled device is used only by 
authorized/designated users and in accordance with this protocol and 
instructions/directions for use. 
• Allow the sponsor to perform monitoring and auditing activities, 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 IRB/EC/REB when performing auditing 
activities. 
• Ensure that informed consent is obtained in accordance with applicable laws, this 
protocol and local IRB/EC/REB 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 investigational device when it is used/operated by the subject. 
• Inform the subject of any new significant findings occurring during the clinical 
investigation, 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, as needed. 
• Ensure that clinical medical records are clearly marked to indicate that the subject is 
enrolled in this clinical study. 

 
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• Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided 
with some means of showing their participation in the clinical investigation, 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 investigation. 
• Make all reasonable efforts to ascertain the reason(s) for a subject’s premature 
withdrawal from clinical investigation while fully respecting the subject’s rights. 
• Ensure that an adequate investigation site team and facilities exist and are maintained and 
documented during the clinical investigation.  
All investigators will provide their qualifications and experience to assume responsibility for 
their delegated tasks 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. 
18.2.1. Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to conducting the 
informed consent process, the Principal Investigator is responsible for providing appropriate 
training, ensuring delegated personnel are competent to perform the tasks they have been 
delegated and provide 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.  
18.3. Institutional Review Board/ Ethics Committee 
The investigational site will obtain the written and dated approval/favorable opinion of the 
IRB/EC/REB for the clinical investigation before recruiting subjects and implementing all 
subsequent amendments, if required. 
A copy of the written IRB/EC/REB 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 and shipment of investigational product/equipment. 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 IRB/EC/REB before the 
changes are implemented to the study.  All changes to the ICF will be IRB/EC/REB 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 IRB/EC/REB approval and 
renewals will be obtained throughout the duration of the study as required by applicable 

 
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local/country laws or regulations or IRB/EC/REB requirements. Copies of the study reports and 
the IRB/EC/REB continuance of approval must be provided to the sponsor.  
18.4. 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.  
18.4.1. 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 implant, 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 implant or follow-up, 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: 
• Provide instructions for the safe return of investigational products. For potentially 
hazardous items, provide specialized instructions and materials, as applicable. 
• Interrogating the device or programming device parameters to investigator-requested 
settings as well as operating investigational equipment  
• Performing lead diagnostic testing using a Pacing System Analyzer or programmer to 
obtain pacing and sensing thresholds and impedance measurements 
• Clarifying device behavior, operation or diagnostic output as requested by the 
investigator or other health care personnel 
• Assisting with the collection of study data from Pacing System Analyzers, 
programmers, and other equipment 

 
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• Entering technical data on technical source form if the responsible investigator 
verifies and signs the completed form  
• Print out programming reports directly from the programmer and provide original 
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  
• 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 
18.5. Insurance  
Where required by local/country regulation, proof, and type of insurance coverage, by BSC for 
subjects in the study will be obtained. 
19. Monitoring 
This section identically matches the Monitoring Section (Section 17) of the FROzEN-AF protocol 
(92348334). 
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 sponsor will put a plan in place to document the specific monitoring requirements.  

 
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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 or remote monitoring visits or audits and 
that sufficient time is devoted to the process. 
20. Potential Risks and Benefits 
This section identically matches the Potential Risks and Benefits Section (Section 18) of the 
FROzEN-AF protocol (92348334). 
20.1. Anticipated Adverse Events 
Subjects participating in this study are subject to the same risks shared by all patients undergoing 
an ablation procedure for treatment of PAF.  Since the handling characteristics of the 
Cryoablation System are designed to be similar to those of other approved catheters for AF 
ablation, it is anticipated that the rate of catheter-related complications in this study will be 
similar to those reported from catheter ablations performed with approved catheter ablation 
systems.  The protocol-required testing for this study uses standard techniques that are routinely 
used for the treatment and management of subjects with drug refractory PAF. 
 
Based upon the current literature and BSC reports on adverse events with an ablation catheter, 
Table 11 includes an alphabetical list of the possible anticipated adverse events and possible 
adverse device effects associated with ablation with a cryoballoon ablation catheter for the 
treatment of PAF. Occurrence of any of the listed events could lead to prolonged hospitalization 
for the subject.   
 
The following anticipated adverse events (AE) and adverse device effects (ADE) have been 
identified for this study: 
Table 11:  Potential Adverse Events and Adverse Device Effects for PAF Ablation and 
Study Device 
Access site complications 
Headache 
Allergic reaction  
Heart failure 
Anemia 
Hematoma 
Arrhythmias  
Hemothorax  
Bleeding/Hemorrhage 
Hemodynamic instability  
Blurred vision 
Hypertension/Hypotension 
Cardiac perforation 
Inadvertent injury to adjacent structures 
Cardiac/pulmonary arrest 
Infection 
Catheter entrapment 
Myocardial infarction  
Cerebrovascular accident (CVA) 
Nerve weakness/palsy/injury (i.e., phrenic/ vagus) 
Chest discomfort/pain or pressure 
Pericarditis 

 
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Complete heart block 
(transient/permanent) 
Pneumothorax 
Complications of sedative 
agents/anesthesia/medications 
Pseudoaneurysm 
Coronary artery spasm 
Pulmonary complications (i.e., edema, pulmonary 
hypertension, pleuritis, pneumonia) 
Cough 
Pulmonary vein stenosis 
Death 
Radiation injury/exposure 
Diaphragmatic paralysis 
Renal insufficiency/failure 
Dizziness or lightheadedness 
Respiratory Depression 
Edema 
Residual atrial septal defect (ASD) 
Pericardial effusion/pleural effusion 
Skin burns (i.e., radiation/defibrillator/ 
cardioverter) 
Elevated cardiac enzymes 
ST segment Elevation 
Embolism (venous/arterial) (i.e.  air, 
gas, thrombo, pulmonary)  
Sore Throat 
Endocarditis 
Tamponade 
Esophageal injury 
Thrombus/thrombosis  
Fever 
Transient ischemic attack (TIA) 
Exacerbation of existing conditions 
Valvular damage 
Fatigue 
Vasospasm 
Fistula (arterial-venous, atrial-
esophageal) 
Visual disturbances 
Gastroparesis 
Vasovagal reactions 
 
Vessel trauma (i.e., injury/ulceration/ perforation/ 
dissection/rupture) 
 
20.2. Risks Associated with the Study Device(s)  
Benchtop studies, pre-clinical research and a CE Mark clinical study have demonstrated that the 
System is safe for human use. All potential risks have been evaluated and mitigation strategies 
have been implemented to reduce potential risks to acceptable levels. 
20.3. Risks associated with Participation in the Clinical Study 
There are no specific tests outside those recommended as standard practice for catheter ablation of 
PAF required by this clinical study protocol. Therefore, there is no foreseen increased risk to 
subjects for participating in the FROzEN-AF Study. 

 
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20.4. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, using 
the devices in accordance with their applicable Directions for Use, performing the procedures 
following recommended standard practices/guidelines, performing procedures in the appropriate 
hospital environment, 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. 
20.5. 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 PAF. Potential benefits of the Cryoablation 
System for the subject may include the following: 
• Complete or partial reduction in symptoms related to PAF 
• Complete or partial reduction in the number of cardioversions, medications a subject is 
taking, and in the number of hospitalizations related to PAF 
20.6. Risk to Benefit Rationale 
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. 
21. Safety Reporting 
21.1. 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: 
Reportable Events: 
• All Serious Adverse Events 
• All Events Leading to Death  
• All Thromboembolic Events 

 
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• All Procedure Related AEs inclusive of AEs related to the assessments (TTE, TEE, ICE or 
CT/MRI scan) listed in Section 12.4. 
• All BSC commercialized diagnostic catheter-related events 
• All Cryoablation System Device Related Adverse Events 
• All Device Deficiencies 
• Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device Effects 
previously not defined in the IFU/IB and ICF 
• New findings/updates in relation to already reported events 
Whenever possible, the medical diagnosis should be reported as the Event Term instead of 
individual symptoms. 
If it is unclear whether 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 AE but should only be reflected as an outcome of one specific 
SAE (see Table 12 for Safety Definitions). 
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. 
If the patient experiences a new arrhythmia between the index procedure and the end of study, and 
the investigator considers this Adverse Event to be procedure related, it needs to be reported. Refer 
to Investigator’s Brochure or IFU as appropriate for the known risks associated with the study 
device(s). 
Pre-existing diseases or conditions will not be reported as adverse events unless there has been a 
substantial increase in severity or frequency of the problem which cannot be attributed to the 
expected progression of the disease or condition. 
The Boston Scientific Medical Safety group will provide safety oversight by reviewing and 
classifying individual events that are reported to the sponsor. Routine aggregate safety reviews 
will be conducted to ensure subject safety. 
Refer to Section 20 for the known risks associated with the study device(s). 
21.2. Definitions and Classification 
Adverse event definitions are provided in Table 12.  Administrative edits were made on the 
safety definitions from applicable regulations and guidance including (but not limited to) 21 CFR 

 
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Part 812, ISO 14155, and EU MDR 2017/745/MDCG 2020-10/1 Guidance on Safety Reporting 
in Clinical Investigations for clarification purposes. 
 
Table 12:  Safety Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155 
 
Ref: MDCG 2020-10/1 
 
 
 
 
Any untoward medical occurrence, unintended disease or injury, or any 
untoward clinical signs (including an abnormal laboratory finding) in 
subjects, users or other persons, in the context of a clinical investigation, 
whether or not related to the investigational medical device and whether 
anticipated or unanticipated. 
NOTE 1: This includes events related to the investigational 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 investigational medical device.  
Adverse Device Effect (ADE) 
 
Ref: ISO 14155 
 
Ref: MDCG 2020-10/1 
 
Adverse event related to the use of an investigational 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 investigational medical 
device. 
NOTE 2: This definition includes any event resulting from use error or 
intentional misuse of the investigational medical device. 
NOTE 3: This includes ‘comparator’ if the comparator is a medical device. 
Serious Adverse Event (SAE) 
 
Ref: ISO 14155 
 
Ref: MDCG 2020-10/1 
 
Adverse event that led to any of the following: 
a) death, 
b) serious deterioration in the health of the subject, users or other persons as 
defined by either: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, 
including chronic diseases or 
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) fetal distress, fetal death, or a congenital abnormality or birth defect 
including physical or mental impairment. 
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 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 

 
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Term 
Definition 
 
Ref: MDCG 2020-10/1 
 
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: MDCG 2020-10/1 
 
 
 
Serious adverse device effect which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk assessment. 
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 assessment. 
Serious Health Threat 
 
Ref: ISO 14155 
 
Signal from any adverse event or device deficiency that indicates an 
imminent risk of death or a serious deterioration in the health in subjects, 
users or other persons, and that requires prompt remedial action 
for other subjects, users or other persons. 
NOTE 1: This would include events that are of significant and unexpected 
nature such that they become alarming as a potential serious health hazard or 
possibility of multiple deaths occurring at short intervals. 
Device Deficiency 
 
Ref: ISO 14155 
 
Ref: MDCG 2020-10/1 
 
An inadequacy of an investigational medical device (defined as the study 
device/Cryoablation System) related to its identity, quality, durability, 
reliability, usability, safety or performance.  
NOTE 1: Device deficiencies include malfunctions, use errors, and 
inadequacy in the information supplied by the manufacturer including 
labelling. 
NOTE 2: This definition includes device deficiencies related to the 
investigational medical device or the comparator. 
The following definitions will be used for defining hospitalization or prolongation of hospitalization for SAE 
classification purposes: 
Hospitalizations  
Hospitalization does not include: 
• 
emergency room visit that does not result in in-patient admission  
Note: although an emergency room visit does not itself meet the 
definition for hospitalization, it may meet other serious criteria (e.g., 
medical or surgical intervention to prevent permanent impairment or 
damage) 
• 
elective and pre-planned treatment/surgery for a pre-existing 
condition that is documented in the subject’s record at the time of 
consent/enrollment 

 
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Term 
Definition 
• 
admission for social reasons and/or respite care in the absence of any 
deterioration in the subject’s general condition (e.g., subject is 
homeless, caregiver relief) 
• 
pre-planned, protocol-specified admission related to the clinical 
study (e.g., procedure required by protocol) 
Prolongation of hospitalization  
In-patient admission to the hospital that is prolonged beyond the expected 
standard duration for the condition under treatment. 
Note: new adverse events occurring during the hospitalization are evaluated 
to determine if they prolonged hospitalization or meet another SAE criterion. 
 
21.3. Relationship to Study Device(s) 
The Investigator must assess the relationship of the reportable AE to the study device(s) and/or 
study procedure, see criteria in Table 13. 
 
Table 13:  Criteria for Assessing Relationship of Study Device or Procedure to Adverse 
Event 
Classification 
Description 
Not Related 
Ref:  
MDCG 2020-10/1 
Relationship to the device, comparator or procedures can be excluded when: 
- the event has no temporal relationship with the use of the investigational device, or 
the procedures related to the use of the investigational device 
- 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 that cannot 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 investigational device used 
for diagnosis, when applicable. 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. 
 
 

 
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Possibly Related 
Ref:  
MDCG 2020-10/1 
The relationship with the use of the investigational device or comparator, or the 
relationship with procedures 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 where relatedness cannot 
be assessed, or no information has been obtained, should also be classified as possible. 
Probably Related 
Ref:  
MDCG 2020-10/1 
The relationship with the use of the investigational device or comparator, or the 
relationship with procedures seems relevant and/or the event cannot be reasonably 
explained by another cause. 
Causal Relationship 
Ref:  
MDCG 2020-10/1 
The serious event is associated with the investigational 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 investigational device use/application or 
procedures 
- the event involves a body-site or organ that 
-the investigational device or procedures are applied to 
-the investigational 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 investigational 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 adverse 
event 
21.4. Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 14. 
Adverse events and device deficiencies must always be reported through the eCRF system. If 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: 
 
FROZENAF.safety@bsci.com 
 

 
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Table 14:  Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline pre-market studies 
(21 CFR Part 812, MDCG 2020-10/1) 
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, as 
requested by sponsor.  
• 
Upon request of sponsor.  
Serious Adverse Event  
Complete AE eCRF page 
with all available new and 
updated information.  
• 
Immediately, but not later than 3 calendar 
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 
Serious Adverse Device Effects 
 
Complete AE eCRF page 
with all available new and 
updated information. 
• 
Immediately, but not later than 3 calendar 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.  
• 
When documentation is available 
• 
Upon request of sponsor  
Device Deficiencies (including 
but not limited to, 
malfunctions, use errors and 
inadequacy in information 
Complete Device 
Deficiencies eCRF with all 
available new and updated 
information.  
• 
Immediately, but not later than 3 
calendar days of first becoming aware 
of the event.  
• 
Reporting required through the end of 
the study 

 
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Event Classification 
Communication Method  
Communication Timeline pre-market studies 
(21 CFR Part 812, MDCG 2020-10/1) 
supplied by the manufacturer, 
including labeling) 
Note:  Any Device Deficiency 
that might have led to a serious 
adverse event if appropriate 
action had not been taken, 
intervention had not occurred, 
circumstances had been less 
fortunate is considered a 
reportable event. 
Provide all relevant source 
documentation (de-
identified/ pseudonymized) 
for reported event. 
• 
Upon request of sponsor  
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.  
• Adverse Device Effects: In a timely manner but 
not later than 10 business days after becoming 
aware of the information  
• Adverse Events: In a timely manner but 
recommend within 10 business days after 
becoming aware of the information  
• Reporting required through end of study 
• Upon sponsor request 
Provide all relevant source 
documentation (de-
identified/pseudonymized) 
for reported event, as 
requested by sponsor.  
* Please note that pre-market studies are clinical studies with investigational devices or with medical devices that 
bear the regulatory approval and are not being used for the same approved indications. 
 
21.5. 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 (Cryoablation System) will be documented and reported to BSC. If 
possible, the study device(s) should be returned to BSC for analysis. Instructions for returning 
the study catheters will be provided in the Site Initiation Visit slides. 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 failures and malfunctions should also be documented in the 
subject’s medical record. 
Device deficiencies (including but not limited to failures, malfunctions, and product 
nonconformities) are not adverse events. However, a reportable event that results from a device 
failure or malfunction, would be recorded as an adverse event on the appropriate eCRF. 

 
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For Device Deficiencies, the investigator must assess and report if the device deficiency could 
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. 
21.6. Reporting to Regulatory Authorities / IRBs / ECs / REBs/ Investigators 
BSC is responsible for reporting adverse event information to all participating Principal 
Investigators, IRBs/ECs/REBs and regulatory authorities, as applicable.  
The Principal Investigator is responsible for informing the IRB/EC/REB, and regulatory 
authorities of UADEs and SAEs as required by local/regional regulations. 
21.7. 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 IRB/EC/REB must be 
notified of any deaths in accordance with that site’s IRB/EC/REB policies and procedures.  
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, for BSC to understand the circumstance surrounding 
the death:  
• 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 catheter, clinical investigation, procedure, or 
patient condition  
• Whether or not the death was witnessed  
• Whether the patient 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:  
• If the patient expired in the hospital: 

 
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o 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)  
o Death certificate (if available)  
o Autopsy report (if applicable)  
• If the patient expired outside of the hospital (e.g., home):  
o A copy of the most recent clinic visit (if not already submitted to Boston 
Scientific) 
o Death certificate (if available)   
The Clinical Events Committee (CEC) must review information regarding subject deaths for 
events listed in Section 23.2. 
22. Informed Consent 
This section identically matches the Informed Consent Section (Section 20) of the FROzEN-AF 
protocol (92348334). 
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 investigational devices, study-required 
procedures and/or testing, or data collection. 
The obtaining and documentation of Informed Consent must be in accordance with 21 CFR 
814.20 part 56, part 50 and part 812 or 813, ISO 14155: Clinical Investigation of Medical 
Devices for Human Subjects - Good Clinical Practice and Japan Medical Device GCP, ethical 
principles that have their origins in the Declaration of Helsinki, and applicable individual country 
laws and any applicable national regulations, IRB/EC/REB 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 IRB/EC/REB, or central IRB/EC/REB, 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 IRB/EC/REB.  Any modification requires acceptance from BSC prior to use 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 
IRB/EC/REB 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,  

 
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• 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 and by the investigator 
and/or an authorized designee responsible for conducting the informed consent process. 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., IRB/EC/REB), 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 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 IRB/EC/REB. The new version of the ICF must be approved by the IRB/EC/REB. 
Acceptance by Boston Scientific is required if changes to the revised ICF are requested by the 
site’s IRB/EC/REB. The IRB/EC/REB will determine the subject population to be re-consented.  
23. Committees 
This section identically matches the Committees Section (Section 21) of the FROzEN-AF 
protocol (92348334). 
23.1. Safety Monitoring Process 
To promote early detection of safety issues, the Clinical Events Committee and Data Monitoring 
Committee will provide evaluations of safety events. Success of this program requires dynamic 
collection of unmonitored data as soon as the event is reported. During regularly scheduled 

 
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monitoring activities, clinical research monitors will support the dynamic reporting process 
through their review of source document and other data information.  
BSC personnel, from the Medical Safety and Safety Trial Operation Teams, review safety data as 
it is reported by the sites throughout the duration of the study. The BSC Medical Safety group 
includes health care providers with expertise in Electrophysiology and with the necessary 
therapeutic and subject matter expertise to evaluate and classify the events into the categories 
outlined above. 
23.2. Clinical Events Committee 
A Clinical Events Committee (CEC) is an independent group of individuals with pertinent 
expertise that will adjudicate events reported by study investigators and their relationship toward 
the primary endpoints. 
• All Deaths 
• All Adverse Events included in the composite primary safety endpoint per Section 8.2 of 
Protocol 
• All Adverse Event that are potentially related to the procedure or any of the devices 
included in the Cryoablation System, as defined in Table 1. 
• All unanticipated device effects. 
• Other events at the discretion of BSC 
Committee members will include practitioners of Electrophysiology (EP), and/ or Cardiology, as 
well as other experts with the necessary therapeutic and subject matter expertise to adjudicate the 
event categories outlined above.  A complete description of CEC responsibilities, qualifications, 
membership, and committee procedures will be outlined in the CEC charter.   
The CEC will review a safety event dossier, prepared by BSC, which may include copies of 
subject source documents provided by study sites, core lab results and independent reviewer 
information as available for the above listed events.  For purposes of determining inclusion into 
the primary safety endpoint, the CEC will adjudicate all the above listed events as to their level 
of seriousness and relation to the ablation procedure and/or catheter. The death classification 
system that will be used by the CEC was developed using the NASPE policy 36, as well as 
definitions from Epstein et al. (16) and O'Connor et al. (17).    All supporting source 
documentation provided by the center will be sent to the CEC for adjudication as defined in the 
CEC charter. 
 
23.3. Data Monitoring Committee 
A Data Monitoring Committee (DMC) is responsible for the oversight review of all AEs. The 
DMC will include leading experts in Electrophysiology and Biostatistics who are not 

 
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participating in the study and who have no affiliation with BSC.  During the study, the DMC will 
review accumulating safety data to monitor the incidence of AEs sent to the CEC and other 
trends that would warrant modification or termination of the study. Responsibilities, 
qualifications, membership, and DMC procedures will be included in the DMC Charter. 
 
Any DMC recommendation for study modification or termination because of concerns over 
subject safety or issues relating to data monitoring or quality control will be submitted in writing 
to BSC and the study Principal Investigator for consideration and final decision.  If the DMC at 
any time determines that a potentially serious risk exists to subjects in this study, the DMC 
chairman will immediately notify both BSC and the Principal Investigator. 
23.4. Executive/ Steering Committee 
A Steering Committee composed of the sponsor’s Clinical Management, the study Principal 
Investigator, other prominent Electrophysiologists from around the globe and a patient who 
underwent an electrophysiology procedure has been convened for this study.  Responsibilities for 
the Committee include oversight of the overall conduct of the study with regards 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.   
24. Suspension or Termination 
This section identically matches the Suspension or Termination Section (Section 22) of the 
FROzEN-AF protocol (92348334). 
24.1. 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 IRBs/ECs/REBs, and regulatory authorities, as applicable, will be 
notified in writing in the event of study termination.  
24.1.1. Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the following. 
• Suspicion of an unacceptable risk, including serious health threat. In this case, the 
sponsor shall suspend the clinical investigation while the risk is assessed. The sponsor 
shall terminate the clinical investigation if an unacceptable risk which cannot be 
controlled is confirmed. 

 
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• Instructions by the IRB/EC/REB or regulatory authorities to suspend or terminate the 
clinical investigation. 
• 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 of 
the device. 
24.2. Termination of Study Participation by the Investigator or Withdrawal of IRB/ EC 
/REB Approval 
Any investigator, or associated IRB/EC/REB or regulatory authority may discontinue 
participation in the study or withdraw approval of the study, respectively, with suitable written 
notice to Boston Scientific. Investigators, associated IRBs/ECs/REBs, and regulatory authorities, 
as applicable, will be notified in writing in the event of these occurrences. 
24.3. 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 IRB, 
EC/REB 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 IRB, EC/REB terminates participation in the study, participating investigators, 
associated IRB, EC/REB, 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 
investigational product to Boston Scientific, unless this action would jeopardize the rights, 
safety, or welfare of the subjects. 
24.4. 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 6 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 study 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 IRB/EC/REB and regulatory authorities, as applicable, will be 

 
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notified. Study participants will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
25. Study Registration and Results 
This section identically matches the Study Registration and Results Section (Section 23) of the 
FROzEN-AF protocol (92348334). 
25.1. Study Registration 
This research-study is registered on http://www.ClinicalTrials.gov, as required by U.S. Law and 
other jurisdictions. 
25.2. Clinical Investigation Report 
Study results will be made available in accordance with the legal requirements and the 
recognized ethical principles, in accordance with the Boston Scientific Policy. A Clinical 
Investigation Report will be made available to all investigators, IRB/EC/REB and regulatory 
authorities, as applicable in accordance with the Boston Scientific Policy and local requirements.  
As applicable an abbreviated Clinical Investigation Report will be made available on a publicly 
accessible database. 
25.3. 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 may 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). 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. 
• 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 trial may be made available to 
other researchers in accordance with the Boston Scientific Data Sharing Policy 
(https://www.bostonscientific.com/).  

 
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26. Reimbursement and Compensation for Subjects 
This section identically matches the Reimbursement and Compensation for Subjects Section 
(Section 24) of the FROzEN-AF protocol (92348334). 
26.1. Subject Reimbursement 
Travel and other expenses incurred by subjects because of participation in the study will be 
reimbursed in accordance with pertinent country laws and regulations and per the study site’s 
regulations.   
26.2. Compensation for Subject’s Health Injury 
Boston Scientific will purchase an insurance policy to cover the cost of potential health injury for 
study subjects, if required by applicable law.  
27. Bibliography 
This section identically matches the Bibliography Section (Section 25) of the FROzEN-AF 
protocol (92348334). 
1. Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G, Flachskampf F, 
Hall R, Iung B, Kasprzak J, Nataf P, Tornos P, Torracca L, Wenink A, Task Force on the 
Management of Valvular Hearth Disease of the European Society of Cardiology., and 
ESC Committee for Practice Guidelines. Guidelines on the management of valvular heart 
disease: The Task Force on the Management of Valvular Heart Disease of the European 
Society of Cardiology. Eur Heart J. 2007 Jan;28(2):230-68.   
2. 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. 
3. 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. 
4. Feinberg WM BJ, Laupacis A, et al. Prevalence, age distribution and gender in patients 
with atrial fibrillation; analysis and implications. Arch Intern Med. 1995;155: 469-473.  
5. Friberg J BP, Scharling H. Rising rates of hospital admissions for atrial fibrillation. 
Epidemiology 2003;14 666-672. 
6. Wolf PA BEaBA. Secular trends in the prevalence of atrial fibrillation: The framingham 
study. Am heart J 1996; 131:790-795. 

 
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7. Furburg CD PB, Manolio TA, et al. Prevalence of diagnosed atrial fibrillation in elderly 
subjects. Am J Cardiol. 1995; 74:236-241. 
8. Piccini JP, Hammill BG, Sinner MF, et al. Incidence and Prevalence of Atrial Fibrillation 
and Associated Mortality Among Medicare Beneficiaries, 1993-2007. Circulation 
Cardiovascular Quality and Outcomes. 2012;5(1):85-93. 
doi:10.1161/CIRCOUTCOMES.111.962688. 
9. 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. 
10. Fuster V RL, Cannom DS, et al. ACCF/AHA/ESC 2006 guidelines for the management 
of patients with atrial fibrillation: Executive summary.  A report of the American College 
of Cardiology/American Heart Association task force on practice guidelines and the 
European Society of Cardiology committee for practice guidelines (writing committee to 
revise the 2001 guidelines for the management of patients with atrial fibrillation): 
Developed in collaboration with the North American Society of Pacing and 
Electrophysiology. Circulation. 2006;114: e257-e354. 
11. Wazni O, Wilkoff, B, Saliba, W. Catheter ablation for atrial fibrillation. New Engl J Med. 
2011; 365:2296-2304.Calkins H, Hindricks G, Cappato R, et al. 
2017 HRS/EHRA/ECAS/APHRS/ SOLAECE expert consensus statement on catheter 
and surgical ablation of atrial 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. Rahul Bhardwaj, Petr Neuzil , Vivek Y Reddy et al. Balloon-Based Ablation 
Technologies. Card Electrophysiol Clin 2020;12(2):175-185. 
15. Stefan Hartl, Uwe Dorwarth, Benedikt Bunz et al Lessons from individualized 
cryoballoon sizing. Is there a role for the small balloon? J Cardiol. 2017 Oct;70(4):374-
381. 
16. Epstein AE CM, Fogoros RN, et al. Classification of death in antiarrhythmia trials. J Am 
Coll Cardiol 1996; 27:433-442 
17. O’Connor CM CP, Miller AB, et al. Effect of amlodipine on mode of death among 
patients with advanced heart failure in the praise trial. Am J Cardiol 1998; 82:881-887 

 
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18. Reference of the consensus document: Calkins H, Hindricks G, Cappato R, et al. 
2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and 
surgical ablation of atrial fibrillation: Executive summary. 2018 Europace. 
 
28. Abbreviations and Definitions  
This section identically matches the Abbreviations and Definitions Section (Section 26) of the 
FROzEN-AF protocol (92348334). 
28.1. Abbreviations 
Abbreviations are shown in Table 15. 
 
Table 15:  Abbreviations 
Abbreviation/Acronym 
Term 
AAD 
Anti-Arrhythmic Drug 
AF 
Atrial Fibrillation 
AFL 
Atrial Flutter 
AT 
Atrial Tachycardia 
CABG 
Coronary artery bypass grafting 
CRT 
Cardiac Resynchronization Therapy 
DMS 
Diaphragm Movement Sensor 
DVT 
Deep Vein Thrombosis 
EDC 
Electronic Data Capture 
EP 
Electrophysiology 
HRS 
Heart Rhythm Society 
IB 
Investigator’s Brochure 
ICB 
Inter Connection Box 
ICD 
Implantable Cardioverter Defibrillator 
ICF 
IFU 
Informed Consent Form 
Instructions for Use 
LA  
Left Atrium 
LVEF  
Left Ventricular Ejection Fraction 
MRI  
Magnetic Resonance Imaging 
PAF  
Paroxysmal Atrial Fibrillation 
PE 
Pulmonary Embolism 
PTCA 
Percutaneous transluminal coronary angioplasty 
PV 
Pulmonary Veins 
PVI 
Pulmonary Vein Isolation 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
TEE 
Trans-esophageal echocardiography 

 
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Abbreviation/Acronym 
Term 
TIA 
Transient Ischemic Attack 
 
 
28.2. Definitions 
Terms are defined in Table 16.  
Table 16:  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, meets eligibility criteria 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 
procedures 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 is eligible for enrollment and signs an informed consent 
document 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 30 days from consent signature 
date may not be reconsented and will be withdrawn from the study. 
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 
Paroxysmal Atrial Fibrillation 
(PAF) 
Recurrent symptomatic Atrial Fibrillation that terminates spontaneously or 
with intervention within seven days of onset. 

 
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Term 
Definition 
Activated Coagulation/Clotting 
Time 
ACT is a test that is used to monitor the effectiveness of high dose heparin 
therapy. 
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  
• 
Failure to achieve acute procedural success in the index 
procedure or repeat procedure during the blanking period  
• 
Use of amiodarone post index procedure 
• 
Surgical treatment for AF/AFL/AT post index procedure 
• 
Use of a non-study ablation catheter for AF targets in the index 
procedure or repeat procedure during the blanking period 
• 
More than one repeat procedure during the blanking period (90 
days post procedure) 
• 
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 any AAD 
Acute Procedural Success 
Rate of acute procedural success defined as the achievement of electrical 
isolation of all PVs by using the POLARx Cardiac Cryoablation System 
with the POLARx FIT cryoablation balloon catheter models only. 
Electrical isolation of a PV is 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 
(Severe) 
 
Severe PV stenosis is defined as ≥ 70% reduction in the diameter of the 
PV or PV branch from baseline measure. For this study a severe PV 
stenosis will count toward the primary safety endpoint.  
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 
Activated Coagulation/Clotting 
Time 
ACT is a test that is used to monitor the effectiveness of high dose heparin 
therapy. 
Source Data 
All information in original records of clinical findings, observations, or 
other activities in a clinical investigation, 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, meets eligibility criteria and has 
the specified study devices inserted into the body and undergoes protocol 
specific treatment for the intended disease. 

 
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Term 
Definition 
Activated Coagulation/Clotting 
Time 
ACT is a test that is used to monitor the effectiveness of high dose heparin 
therapy. 
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 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. 
 
29. Appendices 
29.1. Indications for ablation of PAF according to 2017 HRS expert consensus 
statement on catheter and surgical ablation of atrial fibrillation 
This section identically matches Section 27.2 of the FROzEN-AF protocol (92348334). 
 
Indications 
Recommendation 
class 
Level of Evidence 
Symptomatic AF refractory or 
intolerant to at least one Class I 
or III antiarrhythmic 
medication 
Paroxysmal: Catheter ablation 
is recommended. 
I 
A 
Symptomatic AF prior to 
initiation of antiarrhythmic 
therapy with a Class I or III 
antiarrhythmic medication 
Paroxysmal: Catheter ablation 
is reasonable 
IIa 
B-R 
 

 
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Figure 9:  Indications for catheter ablation of symptomatic atrial fibrillation 
Shown in Figure 9 are the indications for catheter ablation of symptomatic paroxysmal, 
persistent, and long-standing persistent AF. The Class for each indication based on whether 
ablation is performed after failure of antiarrhythmic drug therapy or as first-line therapy is 
shown. 
29.2. Quality of Life Instruments 
This section identically matches Section 27.3 of the FROzEN-AF protocol (92348334). 
Clinical trials increasingly recognize the value of including patient reported outcome measures in 
their design. To understand the impact of atrial fibrillation ablation procedures on patient’s 
quality of life, the quality-of-life instruments used for the trial will be the EQ-5D-5L for a 
generic questionnaire and the AFEQT for disease specific. Subjects will be asked to complete the 
questionnaires at the Enrollment visit as well as at the three, six, and 12-month follow-ups.   
The EQ-5D, generic quality of life measure, will be used to assess health utilities. It is a 
descriptive system of health-related quality of life states consisting of five dimensions (mobility, 
self-care, usual activities, pain/discomfort, anxiety/depression) each of which can take one of 
five responses. The responses record five levels of severity (no problems/slight 

 
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problems/moderate problems/severe problems/extreme problems) within a particular EQ-5D 
dimension. 
The Atrial Fibrillation Effect on Quality of Life (AFEQT) was developed to evaluate disease-
specific quality of life for patients with atrial fibrillation. The 20-item questionnaire is 
subdivided into three domains: symptoms, daily activities, and treatment concerns with 
responses provided on a seven-point Likert scale. 
29.3. National Institutes of Health Stroke Assessment 
This section identically matches Section 27.4 of the FROzEN-AF protocol (92348334). 
The NIH Stroke Scale (NIHSS) is an assessment tool which quantifies stroke related 
neurological deficit.  This assessment must be conducted in-person to provide valuable 
information on stroke severity.   
An Investigator or appropriately trained and delegated site staff designee will administer NIH 
Stroke Scale assessment prior to the index ablation procedure (Baseline) and again at the pre-
discharge visit (0-7 days post the ablation procedure).  All individuals conducting the assessment 
will be required to become certified on administration of the assessment and provide BSC with 
documentation of certification prior to assessment completion with subjects.    
Investigational sites will be provided with instructions for administering the assessment.  They 
will be instructed to administer stroke scale items in the order listed on the form.  Scores should 
reflect what the subject does, not what the clinician thinks the subject can do. The clinician 
should record answers while administering the exam and work quickly.  Except where indicated, 
the subject should not be coached.  If a worsening score is noted from the previous assessment, 
the Investigator must follow the additional requirements defined throughout Section 12.7.  
29.4. CHA2DS2-VASc Score for AF 
This section identically matches Section 27.5 of the FROzEN-AF protocol (92348334). 
The CHA2DS2-VASc score is used for risk stratification of ischemic stroke in patients with 
nonvalvular atrial fibrillation. 
 
Condition 
Points 
 C   Congestive heart failure (or Left ventricular systolic dysfunction) 
1 
 H 
 Hypertension: blood pressure consistently above 140/90 mmHg (or treated 
hypertension on medication) 
1 
 A2  Age ≥75 years 
2 
 D 
 Diabetes Mellitus 
1 
 S2  Prior Stroke or TIA or thromboembolism 
2 

 
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 V 
 Vascular disease (e.g., peripheral artery disease, myocardial infarction, aortic 
plaque) 
1 
 A 
 Age 65–74 years 
1 
 Sc  Sex category (i.e., female sex) 
1