Effect of a Bigger Cryoballoon on the Total Antral Lesion Size: Evaluation of POLARx FIT
Phase: NA
Conditions: Atrial Fibrillation
Sponsor: Erasmus Medical Center

  
 
 
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Effect of a bigger cryoballoon on the total 
antral lesion size: Evaluation of POLARx FIT 
 
BETTER-FIT 
 
 
CLINICAL INVESTIGATION PLAN 
 
 
 
 
 
 
 
 
 
 
This protocol contains confidential information for use by the Investigator and their 
designated representatives participating in this clinical investigation. The protocol should 
be held confidential and maintained in a secure location.  
 
 

  
 
 
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PROTOCOL TITLE ‘Effect of a bigger cryoballoon on the total antral lesion 
size: evaluation of POLARx FIT’ 
 
Protocol ID 
NL-SCY-20220526 
Acronym 
BETTER-FIT 
Version 
1.3 
Date 
16 August 2023 
Principal investigator (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
Dr. S.C. Yap, MD, PhD 
Department of Cardiology 
Erasmus MC, University Medical Center 
Rotterdam, Rotterdam, the Netherlands 
Email: s.c.yap@erasmusmc.nl 
Tel: +31650031551 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Erasmus MC 
University Medical Center Rotterdam 
Rotterdam, the Netherlands 
Subsidizing party 
Boston Scientific Corporation 
Marlborough, Massachusetts, USA 
Independent expert  
Dr. J.J. Brugts, MD, PhD 
Email: j.brugts@erasmusmc.nl 

  
 
 
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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
Prof. dr. R.A. de Boer, MD, PhD 
Head of the department of Cardiology 
Erasmus MC, University Medical Center  
Rotterdam, the Netherlands 
 
 
Principal Investigator: 
Dr. S.C. Yap, MD, PhD 
Department of Cardiology 
Erasmus MC, University Medical Center  
Rotterdam, the Netherlands 
 
18-Aug-
2023 
 
 

  
 
 
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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 10 
2. 
OBJECTIVES ................................................................................................................. 11 
3. 
STUDY DESIGN ............................................................................................................. 12 
3.1 
STUDY DESIGN .......................................................................................................... 12 
3.2 
ESTIMATED ENROLMENT AND STUDY DURATION .......................................................... 12 
4. 
STUDY POPULATION ................................................................................................... 14 
4.1 
POPULATION (BASE) .................................................................................................. 14 
4.2 
INCLUSION CRITERIA .................................................................................................. 14 
4.3 
EXCLUSION CRITERIA ................................................................................................. 14 
4.4 
SAMPLE SIZE CALCULATION ........................................................................................ 15 
5. 
TREATMENT OF SUBJECTS ........................................................................................ 15 
5.1 
INVESTIGATIONAL PRODUCT/TREATMENT .................................................................... 15 
5.1.1 Periprocedural management ................................................................................ 15 
5.1.2 Transseptal puncture ............................................................................................ 16 
5.1.3 Pre-ablation UHDx mapping ................................................................................. 16 
5.1.4 Ablation procedure ............................................................................................... 16 
5.1.5 Confirmation of complete PVI ............................................................................... 17 
5.1.6 Post-ablation UHDx mapping ............................................................................... 17 
5.1.7 Follow-up after index procedure ........................................................................... 17 
5.1.8 Data collection schedule ...................................................................................... 18 
5.2 
USE OF CO-INTERVENTION (IF APPLICABLE) ................................................................ 18 
5.3 
ESCAPE MEDICATION (IF APPLICABLE) ......................................................................... 18 
6. 
INVESTIGATIONAL PRODUCT ..................................................................................... 19 
6.1 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT ............................................. 19 
6.2 
SUMMARY OF FINDINGS FROM NON-CLINICAL STUDIES ................................................. 20 
6.3 
SUMMARY OF FINDINGS FROM CLINICAL STUDIES ......................................................... 21 
6.4 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS ........................................ 21 
6.5 
DESCRIPTION AND JUSTIFICATION OF ROUTE OF ADMINISTRATION AND DOSAGE ........... 22 
6.6 
DOSAGES, DOSAGE MODIFICATIONS AND METHOD OF ADMINISTRATION ........................ 22 
6.7 
PREPARATION AND LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCT .................. 22 
6.8 
DRUG ACCOUNTABILITY ............................................................................................. 22 

  
 
 
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7. 
NON-INVESTIGATIONAL PRODUCT ........................................................................... 22 
7.1 
NAME AND DESCRIPTION OF NON-INVESTIGATIONAL PRODUCT(S) ................................ 23 
7.2 
SUMMARY OF FINDINGS FROM NON-CLINICAL STUDIES ................................................. 23 
7.3 
SUMMARY OF FINDINGS FROM CLINICAL STUDIES ......................................................... 23 
7.4 
SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS ........................................ 23 
7.5 
DESCRIPTION AND JUSTIFICATION OF ROUTE OF ADMINISTRATION AND DOSAGE ........... 23 
7.6 
DOSAGES, DOSAGE MODIFICATIONS AND METHOD OF ADMINISTRATION ........................ 23 
7.7 
PREPARATION AND LABELLING OF NON INVESTIGATIONAL MEDICINAL PRODUCT .......... 23 
7.8 
DRUG ACCOUNTABILITY ............................................................................................. 23 
8. 
METHODS ...................................................................................................................... 24 
8.1 
STUDY PARAMETERS/ENDPOINTS ............................................................................... 24 
8.1.1 Main study parameter/endpoint ............................................................................ 24 
8.1.2 Secondary study parameters/endpoints (if applicable) ........................................ 24 
8.1.3 Other study parameters (if applicable) ................................................................. 24 
8.2 
RANDOMISATION, BLINDING, AND TREATMENT ALLOCATION .......................................... 24 
8.3 
STUDY PROCEDURES ................................................................................................. 24 
8.3.1 Assessment of antral lesion size .......................................................................... 24 
8.3.2 Proportion of grade 4 occlusion ............................................................................ 26 
8.4 
WITHDRAWAL OF INDIVIDUAL SUBJECTS ...................................................................... 27 
8.4.1 Specific criteria for withdrawal (if applicable) ....................................................... 27 
8.5 
REPLACEMENT OF INDIVIDUAL SUBJECTS AFTER WITHDRAWAL ..................................... 27 
8.6 
FOLLOW-UP OF SUBJECTS WITHDRAWN FROM TREATMENT .......................................... 27 
8.7 
PREMATURE TERMINATION OF THE STUDY .................................................................. 27 
9. 
SAFETY REPORTING .................................................................................................... 28 
9.1 
TEMPORARY HALT FOR REASONS OF SUBJECT SAFETY ................................................ 28 
9.2 
ADVERSE EVENTS AND DEVICE DEFICIENCIES ............................................................ 28 
9.2.1 Definition of Adverse Device Effects (ADE) ......................................................... 30 
9.2.2 Definition of Adverse Events (AE) ........................................................................ 30 
9.2.3 Causality Assessment .......................................................................................... 30 
9.2.4 Definition of Device Deficiency (DD) .................................................................... 31 
9.2.5 Definition of Serious Adverse Events (SAE) ........................................................ 32 
9.2.6 Definition of Serious Adverse Device Effect (SADE) ............................................ 32 
9.2.7 Definition of Unanticipated Serious Adverse Device Effects (USADE) ................ 32 
9.3 
ANNUAL SAFETY REPORT ........................................................................................... 32 
9.4 
FOLLOW-UP OF ADVERSE EVENTS .............................................................................. 33 

  
 
 
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9.5 
DATA SAFETY MONITORING BOARD (DSMB) / SAFETY COMMITTEE ............................. 33 
10. STATISTICAL ANALYSIS .............................................................................................. 34 
10.1 PRIMARY STUDY PARAMETERS ................................................................................... 34 
10.2 SECONDARY STUDY PARAMETERS .............................................................................. 34 
10.3 OTHER STUDY PARAMETERS ...................................................................................... 34 
10.4 INTERIM ANALYSIS (IF APPLICABLE) ............................................................................. 34 
11. ETHICAL CONSIDERATIONS ....................................................................................... 35 
11.1 REGULATION STATEMENT ........................................................................................... 35 
11.2 RECRUITMENT AND CONSENT ..................................................................................... 35 
11.3 OBJECTION BY MINORS OR INCAPACITATED SUBJECTS (IF APPLICABLE) ........................ 35 
11.4 BENEFITS AND RISKS ASSESSMENT, GROUP RELATEDNESS ......................................... 35 
11.5 COMPENSATION FOR INJURY ...................................................................................... 35 
11.6 INCENTIVES (IF APPLICABLE) ...................................................................................... 36 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ............................ 37 
12.1 HANDLING AND STORAGE OF DATA AND DOCUMENTS ................................................... 37 
12.2 MONITORING AND QUALITY ASSURANCE ..................................................................... 37 
12.3 AMENDMENTS ............................................................................................................ 37 
12.4 ANNUAL PROGRESS REPORT ...................................................................................... 37 
12.5 END OF STUDY REPORT ............................................................................................. 38 
12.6 PUBLIC DISCLOSURE AND PUBLICATION POLICY ........................................................... 38 
13. STRUCTURED RISK ANALYSIS ................................................................................... 39 
13.1 POTENTIAL ISSUES OF CONCERN ................................................................................ 39 
13.2 SYNTHESIS ................................................................................................................ 39 
14. REFERENCES ................................................................................................................ 40 
 

  
 
 
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the 
application form that is required for submission to the accredited 
Ethics Committee; in Dutch: Algemeen Beoordelings- en 
Registratieformulier (ABR-formulier) 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
CB 
Cryoballoon 
CCMO 
Central Committee on Research Involving Human Subjects; in 
Dutch: Centrale Commissie Mensgebonden Onderzoek 
DD 
Device Deficiency 
DMS 
Diaphragmatic Movement Sensor 
eCRF 
Electronic Case Report Form 
GDPR 
General Data Protection Regulation; in Dutch: Algemene 
Verordening Gegevensbescherming (AVG) 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
ICE 
Intracardiac Echocardiography 
IFU 
Instructions For Use 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-
ethische toetsingscommissie (METC) 
LA 
Left Atrium 
LAPW 
Left Atrial Posterior Wall 
PV 
Pulmonary Vein 
PVI 
Pulmonary Vein Isolation 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
Sponsor 
The sponsor is the party that commissions the organization or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organization, or 
investigator. A party that provides funding for a study but does not 
commission it is not regarded as the sponsor but referred to as a 
subsidizing party. 
TTE 
Transthoracic Echocardiogram 

  
 
 
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TTI 
Time-to-Isolation 
UAVG 
Dutch Act on Implementation of the General Data Protection 
Regulation; in Dutch: Uitvoeringswet AVG 
UHDx 
Ultrahigh-Density  
USADE 
Unanticipated Serious Adverse Device Effect 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet 
Medisch-wetenschappelijk Onderzoek met Mensen 
 
 

  
 
 
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SUMMARY 
Effect of a bigger cryoballoon on the total antral lesion size: evaluation of POLARx 
FIT - BETTER-FIT 
 
Rationale: The next generation POLARx™ cryoablation balloon (CB) catheter will have 
the option of to deliver cryotherapy with the current balloon size of 28 mm or a new, larger 
31 mm size by changing the inner balloon pressure (POLARxÔ FIT, Boston Scientific). 
Currently, there is no data on the extension of left atrial (LA) lesion formation with the 31 
mm balloon size of the POLARxÔ FIT cryoablation balloon catheter. The hypothesis is 
that a larger CB size results in a wide antral circumferential lesion.  
Objective: The primary objective is to evaluate the antral lesion size using ultrahigh-
density (UHDx) mapping pre- and post-cryoablation with the 31 mm balloon size CB. 
Secondary objectives are the proportion of pulmonary veins (PVs) where a 31 mm CB 
could be positioned to achieve a grade 4 occlusion and the single shot success rate with 
the 31 mm balloon size CB.  
Study design: Single-center, single-arm, prospective study with pre- and post-PVI UHDx 
mapping.  
Study population: Twenty adult patients with paroxysmal AF who are scheduled to 
undergo pulmonary vein isolation (PVI) with a CB. 
Intervention: Patients will undergo pre- and post-ablation UHDx mapping (OrionÔ 
catheter and RhythmiaÔ 3D-mapping system, Boston Scientific) during the index 
procedure. 
Main study parameters/endpoints: The primary endpoint is the extent of the antral 
lesion size. Secondary endpoints are the proportion of PVs with grade 4 occlusion with 
the 31 mm balloon size CB, the single shot success rate of the 31 mm balloon size CB, 
difference in proportion of achieving grade 4 occlusion in comparison to the standard (28 
mm) size.  
Nature and extent of the burden and risks associated with participation, benefit, 
and group relatedness: A UHDx mapping will be acquired before and after complete 
PVI. The procedures will be performed under deep sedation, which is standard practice 
for CB procedures in our institution. The risk of additional mapping is limited. LA mapping 
is a standard diagnostic method for patients undergoing PVI with radiofrequency 
(“standard-of-care”). In the current study, UHDx mapping will now be used in patients 
undergoing PVI with CB. The most important complication of additional intracardiac 
mapping is cardiac tamponade, but this risk is low (<0.5%).  

  
 
 
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1. INTRODUCTION AND RATIONALE 
Pulmonary vein isolation (PVI) is the cornerstone of interventional treatment of 
symptomatic atrial fibrillation (AF). Among the different available single-shot devices, the 
cryoballoon has demonstrated to be as effective and safe as radiofrequency ablation for 
achieving PVI, while being associated with shorter procedure duration and longer 
fluoroscopy time.1-6 Furthermore, cryoballoon ablation seems to be less operator-
dependent than radiofrequency ablation.7  
 
Mid 2020 a novel cryoballoon (CB) was introduced for the treatment of 
paroxysmal AF: the 28 mm POLARx™ catheter (Boston Scientific, Marlborough, MA, 
USA). The initial clinical results with POLARxÔ have shown a similar acute procedural 
efficacy and safety profile as the fourth-generation 28 mm Artic Front Advance Pro™ 
(AFA-Pro) CB catheter (Medtronic, MN, USA).8-17 In contrast to AFA-Pro, the POLARx™ 
CB operates with a constant inner balloon pressure allowing it to maintain a constant size 
throughout inflation and ablation. The procedure time, ablation time and fluoroscopy time 
are similar between POLARxÔ and AFA-Pro.8 One-year freedom from atrial arrhythmias 
was 77% with POLARx™ which is also comparable with AFA-Pro.18 
 
The next generation POLARxÔ CB (POLARx™ FIT) will allow each ablation to 
be performed with either the standard balloon size (28 mm) or an alternative larger size 
(31 mm). The POLARxÔ FIT catheter will expand to the standard balloon size upon every 
inflation. After each inflation and prior to initiating ablation, the user can increase the 
balloon size using the console user interface. The larger size is enabled by increasing the 
inner balloon pressure from 2.5 psi to 7.5 psi (which is still lower than the balloon 
pressure during ablation with AFA-PRO). Currently, there is limited data on the extension 
of left atrial (LA) scar formation with the 31 mm balloon size of the POLARxÔ FIT CB. 
Previous quantitative data have shown that the second-generation 28 mm AFA CB 
creates antral lesions.19 Preliminary data demonstrated that a 31 mm balloon size will 
result in an antral shift in balloon position.20 A wide antral lesion may potentially be 
beneficial for targeting ganglionic plexi and rotational activity near pulmonary vein (PV) 
ostia thereby potentially increasing long-term arrhythmia survival.21 However, there is a 
lack of clinical data on the use of the larger balloon size, and the benefits and limitations 
of the larger balloon size on occluding different pulmonary veins. The primary aim of the 
present study is to evaluate the antral lesion size when performing a cryoablation with the 
31 mm balloon size of the POLARxÔ FIT CB catheter. The secondary aim is to evaluate 
the feasibility of achieving a grade 4 occlusion with this larger balloon size and the single 
shot success.  
 

  
 
 
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2. OBJECTIVES 
The primary objective is to determine the antral lesion area after PVI with a 31 mm 
balloon size POLARxÔ FIT cryoballoon. 
 
The secondary objectives are to determine the proportion of achieving a grade 4 
occlusion, the single shot success rate per PV with the 31 mm balloon size POLARxÔ 
FIT CB and the difference in occlusion quality in comparison to the 28 mm balloon size. 
 
 
 

  
 
 
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3. STUDY DESIGN 
3.1 Study design 
Investigator-initiated, single-center, open label, prospective, single-arm study evaluating 
the 31 mm balloon size of the POLARxÔ FIT cryoballoon. Before and after complete PVI, 
a 3-dimensional ultrahigh-density (UHDx) map will be created. The study population will 
consist of 20 patients undergoing a first PVI with a normal PV anatomy (exclusion of large 
common ostium or supernumerary veins as determined by a preprocedural CT-scan) in 
the Erasmus MC, Rotterdam, the Netherlands. Patients will be seen at the outpatient 
clinic 3 (blanking), 6 and 12 months after the index ablation to assess potential adverse 
events and recurrence of atrial arrhythmias. After the 1-year visit the study will end for the 
individual patient. The study flowchart is depicted in Figure 3.1.1. 
3.2 Estimated enrolment and study duration 
Enrolment in the study is expected to take approximately 8 months. The last patient 
included will be followed for at least 12 months after the index procedure, thus, the total 
duration of the study is expected to be approximately 20 months.  
 
 
 
 
 

  
 
 
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Figure 3.1.1. Study flowchart 
 
 
 
 

  
 
 
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4. STUDY POPULATION 
4.1 Population (base)  
AF is the most common arrhythmia in the general population and is associated with an 
increased risk of stroke, heart failure and mortality. When patients have symptoms 
secondary to AF either a rate or rhythm control strategy is possible. Components of a 
rhythm control strategy consists of the use of antiarrhythmic medication, cardioversion, 
and catheter ablation. When patients have symptomatic AF despite the use of 
antiarrhythmic medication, they are candidates for a catheter ablation. PVI is the 
cornerstone of catheter ablation of AF. In the Erasmus MC, more than 300 patients with 
AF undergo PVI annually of whom approximately 100 patients with a cryoballoon. Most 
patients undergoing PVI with a cryoballoon has paroxysmal AF. This population is the 
target population of the BETTER-FIT study. A maximum of 20 patients will be enrolled in 
the study.   
4.2 Inclusion criteria 
To be eligible to participate in this study, a subject must meet all the following criteria: 
1. History of symptomatic paroxysmal AF 
2. Subjects who are indicated for a PVI according to the 2020 ESC guidelines for the 
diagnosis and management of AF22 
3. Subjects who are willing and capable of providing informed consent 
4. Subjects who are willing and capable of participating in all testing associated with this 
clinical investigation 
5. Subjects whose age is 18 years or above 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
1. Any known contraindication to an AF ablation or anticoagulation 
2. History of previous left atrial ablation or surgical treatment of AF, atrial flutter, or atrial 
tachycardia 
3. AF secondary to electrolyte imbalance, thyroid disease, or any other reversible or non-
cardiac cause 
4. Significant structural heart disease as evidenced by: 
a. Left ventricular ejection fraction <45% based on most recent transthoracic 
echocardiogram (TTE) performed <6 months prior to enrollment 
b. LA diameter >55 mm based on most recent TTE performed <6 months prior to 
enrollment 
c. Previous cardiac surgery 

  
 
 
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d. Previous cardiac valvular surgical or percutaneous procedure 
e. Interatrial baffle, closure device, patch, or occluder 
f. Unstable angina or ongoing myocardial ischemia 
g. Moderate or severe valvular heart disease on most recent TTE performed <6 months 
prior to enrolment 
h. Congenital heart disease 
i. Left atrial thrombus 
5. History of blood clotting or bleeding disease 
6. Stroke or transient ischemic attack <3 months prior to enrollment 
7. Active systemic infection 
8. Common ostium PV >24 mm defined by CT-scan 
9. Pregnant, lactating, or women of childbearing potential who are, or plan to become, 
pregnant during the time of the study 
10. Subjects who are currently enrolled in another investigational study or registry that 
would directly interfere with the current study 
4.4 Sample size calculation 
With 20 patients we can provide a reliable estimate of the antral lesion area with the 31 
mm balloon size of POLARxÔ FIT. A recent study by Gunawardene et al. evaluated the 
antral lesion area in 20 patients who underwent pulmonary vein isolation with a different 
technique (i.e., pulsed field ablation).23 The total circumferential antral lesion areas of the 
left and right sides were 20.5 ± 3.8 and 25.5 ± 5.7 cm2, respectively. The precision 
achieved with 20 patients thus seems adequate to provide a reliable estimate of the antral 
lesion area. Furthermore, the percentage of technical successful placement of the larger 
balloon size and the single freeze success percentage are based on the number of PVs 
(approximately 80 PVs in 20 patients). It is expected that 20 patients will be enrolled in a 
period of 8 months (approximately 30% enrolment rate of target population), thus an 
estimated mean inclusion rate of 2.5 patients per month. 
 
5. TREATMENT OF SUBJECTS 
5.1 Investigational product/treatment 
5.1.1 Periprocedural management 
All patients will receive oral anticoagulation for at least 4 weeks before ablation. Direct 
acting oral anticoagulants are continued in the morning of the procedure. Vitamin K 
antagonists will be continued with a target INR between 2.0 and 2.5. To exclude left atrial 

  
 
 
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thrombi, all patients will undergo a transesophageal echocardiogram just before the 
procedure. 
5.1.2 Transseptal puncture 
Femoral vein punctures will be performed under ultrasound guidance. After placement of 
2 short introducer sheaths (8F and 10F) in the femoral vein, a bolus of intravenous 
heparin (5000 IE) will be given. A transseptal puncture will be performed using a SL1-
sheath (Swartz, Abbott, Abbott Park, IL) and RF transseptal needle (NRG, Bayliss 
Medical, Rouyn-Noranda, Canada) under guidance of intracardiac echocardiography 
(ICE) (ViewFlex Xtra, Abbott). The SL1 sheath will be replaced by the POLARSHEATH™ 
(Boston Scientific). The dilator and guidewire will be slowly pulled out and the sheath is 
flushed thoroughly before introduction of the cryoballoon catheter. After the transseptal 
puncture, the ICE catheter is replaced by a steerable decapolar diagnostic catheter 
(InquiryÔ, 2-5-2 mm spacing, St. Jude Medical). The decapolar catheter is placed in the 
right ventricle (for vagal response) or in the vena cava superior (for phrenic nerve pacing).   
5.1.3 Pre-ablation UHDx mapping 
Mapping will be preferentially performed in sinus rhythm with prior cardioversion of AF if 
required. UHDx mapping will be performed with RHYTHMIA HDx™ mapping system and 
a 64-pole mini-basket mapping catheter (INTELLAMAP ORION™, Boston Scientific). LA 
voltage maps will be constructed with special point density in the antra of PVs. 
5.1.4 Ablation procedure 
After placement of the POLARMAPÔ circular mapping catheter in the target PV, the 
cryoballoon is initially inflated to the standard 28 mm size. The most optimal PV occlusion 
with the 28 mm balloon size will be achieved and the grade of PV occlusion will be 
determined using a semi-quantitative grading (1 – rapid outflow of contrast medium from 
the PV to 4 – complete contrast retention with no observable leak).24 Thereafter, the 
balloon will increase in size to 31 mm and the most optimal PV occlusion will be 
achieved. Again, the grade of PV occlusion will be determined using a semi-quantitative 
grading (grade 0 to 4).24 After optimal PV occlusion with the 31 mm balloon size, a single 
3-minutes cryoapplication will be delivered, irrespective of achieving PV isolation. The 
cryoapplication will be prematurely stopped when the inner balloon temperature is -69ºC. 
If PV isolation is not achieved after the first attempt, subsequent cryoapplications (3 or 4 
minutes depending on TTI) are delivered until achieving isolation. The balloon size during 
subsequent applications can be adjusted according to the preferences of the operator.   

  
 
 
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The order of PVs will be left superior PV, left inferior PV, right inferior PV, and 
right superior PV. During cryoablation of the left-sided PVs, a diagnostic catheter will be 
placed in the right ventricle to provide ventricular pacing in case of a vagal response after 
cryoablation. During cryoablation of the right-sided PVs, high-output right phrenic nerve 
stimulation will be performed using a diagnostic catheter in the right subclavian vein or 
superior vena cava. Diaphragmatic excursion will be checked by a combination of manual 
palpitation and the use of the Diaphragmatic Movement Sensor (DMS). Whenever the 
diaphragmatic excursions decrease, cryoablation will be immediately terminated. The 
following parameters will be noted per cryoapplication: time from ablation till -40 ºC, TTI, 
balloon nadir temperature, thawing time till 0ºC.  
5.1.5 Confirmation of complete PVI 
Electrical isolation of a PV is demonstrated by entrance and exit block. Entrance block is 
defined as the absence of local potentials inside the vein as assessed by the 
POLARMAPÔ circular mapping catheter. Exit block is defined as absence of atrial 
capture while pacing from inside the vein with the POLARMAPÔ circular mapping 
catheter. If a PV shows reconnection, repeat cryoablation will be performed with the goal 
of achieving electrical isolation. This can be performed with the 28 mm or 31 mm balloon 
size per operator discretion. Complete PVI is defined as electrical isolation of all PVs. 
After complete PVI, post-ablation UHDx mapping will be performed.  
5.1.6 Post-ablation UHDx mapping 
After achieving complete PVI, the 64-pole mini-basket mapping catheter will be 
introduced through the POLARSHEATH for repeat mapping. Repeat mapping will be 
preferentially performed in sinus rhythm with prior cardioversion of AF if required. There 
will be no specified waiting time before remapping. LA voltage maps will be constructed 
with special point density in the antra of PVs. Post-ablation LA lesion surface area will be 
assessed as previously described.23 The key parameters that will be collected are 
described in the Methods section. If conduction gaps or PV reconnections are found 
during UHDx mapping, the mapping catheter will be replaced by the POLARxÔ 
cryoablation catheter and additional ablations will be performed to achieve complete PVI. 
Another UHDx map will be constructed after re-isolation.  
5.1.7 Follow-up after index procedure 
The day following the procedure, the groin will be inspected for groin hematoma and a 
transthoracic echocardiogram will be performed to rule out pericardial effusion. Patients 
will be scheduled for an outpatient visit 3, 6 and 12 months after the index procedure. 

  
 
 
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This follow-up schedule is standard of care in the Erasmus MC after a PVI. During these 
visits a physical examination, 12-lead ECG and Holter will be performed. If a PNP 
occurred during the index procedure, a chest X-ray will be performed during the 
outpatient clinic visit. The indication for a repeat AF ablation is according to the discretion 
of the treating physician. During a repeat ablation it is preferable to perform a bipolar 
voltage map to gain insight in the durability of the antral lesion size area.  
5.1.8 Data collection schedule 
Procedure 
Enrollme
nt (up 
to day -
60) 
Baseline 
(up to 
day -60) 
Index 
procedur
e (day 0) 
Month 3 
follow-up 
(91±14 
days) 
Month 6 
follow-up 
(180±30 
days) 
Month 12 
follow-up 
(365±30 
days) 
Unsched
uled visit 
Informed 
consent 
X 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
X 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
Physical 
examination 
 
X 
 
X 
X 
X 
X 
PV anatomical 
assessment (CT) 
 
X 
 
 
 
 
 
TTE 
 
X 
 
 
 
 
 
Screening for LA 
thrombus 
 
 
X 
 
 
 
 
Procedural data 
 
 
X 
 
 
 
 
12-lead ECG 
 
X 
X 
X 
X 
X 
X 
PNP assessment 
 
 
X 
(X)1 
(X)1 
(X)1 
 
Holter monitor 
 
 
 
X 
X 
X 
X 
Documentation 
of repeat 
ablation 
 
 
 
X 
X 
X 
 
Medications 
Prior and current antiarrhythmic medications and anticoagulant therapy regimen from 
enrollment through end of visit study 
Protocol 
deviations 
From enrollment through end of visit study 
Adverse event 
assessment 
Continuous from enrollment through end of visit study 
1 Assessment of follow-up visit is only applicable for subjects who had phrenic nerve palsy detected at the 
index procedure.  
5.2 Use of co-intervention (if applicable) 
N/A 
5.3 Escape medication (if applicable) 
N/A 
 
 
 

  
 
 
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6. INVESTIGATIONAL PRODUCT  
6.1 Name and description of investigational product 
The POLARx™ FIT cryoablation catheter is CE-marked and is indicated for the treatment 
of patients with symptomatic AF. In comparison to the previous generation of POLARx™ 
cryoablation catheter, the POLARx™ FIT cryoablation catheter can apply cryoablation 
treatment with either 28 mm or 31 mm balloon size per operator discretion. The 
POLARx™ FIT catheter will expand to the standard balloon size of 28 mm upon every 
inflation. After each inflation and prior to initiating ablation, the user can increase the balloon 
size using the console user interface. The larger size is enabled by increasing the inner 
balloon pressure from 2.5 psi to 7.5 psi. To ensure the freezing capability of the larger size 
balloon is consistent with the standard size balloon, the nitrous oxide flow rate during ablation 
is increased from 7800 sccm to 8700 sccm. All other aspects of the nitrous oxide delivery and 
control for POLARx™ FIT are unchanged from POLARx™. A detailed overview of the 
hardware components and connections of the POLARx™ FIT cryoablation system is 
provided in Figures 6.1.1. and 6.1.2. The individual devices within the cryoablation 
system and their UPN are listed in Table 6.1.1.  
 
Figure 6.1.1. POLARx™ FIT cryoballoon 
 
 
 
 

  
 
 
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Figure 6.1.2. Overview of all connections of the POLARx™ FIT cryoablation system 
  
 
Table 6.1.1. Cryoablation devices used in the BETTER-FIT study 
Product name 
Product description 
UPN 
POLARx ST  
POLARx Balloon Catheter ST 28mm  
M004CRBS2000 
POLARx LT  
POLARx Balloon Catheter LT 28mm 
M004CRBS2100 
POLARSHEATH™  
POLARSHEATH Steerable Sheath  
M004CRBS3050 
POLARMAP™ 
POLARMAP Mapping Catheter 20mm  
M004CRBS7200 
SMARTFREEZE™  
SMARTFREEZE Cryo Console  
M004CRBS4000 
DMS Sensor 
Diaphragm Movement Sensor  
M004CRBS6110 
Cryo Extension Cable  
SMARTFREEZE Electrical Ext Cable 
M004CRBS5100 
Cryo Cable  
Cryo Gas Cable  
M004CRBS5200 
POLARMAP EGM Pin 
Breakout Cable 
POLARMAP EGM Pin Breakout Cable 
M004CRBS6200 
Interconnection Box 
Interconnection Box  
M004CRBS4110 
Dual Foot Pedal Switch  
Foot Switch  
M004CRBS4200 
 
6.2 Summary of findings from non-clinical studies 
The Instructions For Use (IFU) of the POLARx™ FIT cryoablation catheter is attached as 
supplement material. Because the device is CE marked, available on the market and the 
device is used within its indications, we have not requested a new IB for this study.  

  
 
 
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6.3 Summary of findings from clinical studies 
FROZEN-AF (NCT 041331680) was a multi-center, open label, prospective, single arm 
study to document the safety and performance of Boston Scientific's Cryoablation System 
(IDE trial) which started in June 2020. As a substudy, the efficacy and safety of the 
POLARx™ FIT cryoablation catheter was evaluated in 50 patients.20 Acute isolation was 
achieved in all 50 patients. The novel 31 mm configuration was used in 65% of ablations. 
In the 198 ablations performed at 31mm, 80.8% achieved a grade 4 occlusion. In PVs 
where the first ablation was performed at 31mm the single shot isolation rate was 
significantly higher than in PVs where the first ablation was performed at 28mm (62.1% 
versus 35.3%). Notably, there was only 1 instance of transient phrenic nerve paralysis 
which resolved prior to discharge. Preliminary landmark-based analysis of a subset of 
veins suggests that inflation to 31mm results in a marked antral shift of balloon position. 
 
Figure 6.3.1. Antral shift of balloon position.20 
 
 
 
6.4 Summary of known and potential risks and benefits 
Cryoballoon ablation is a safe and effective tool for the treatment of AF with a high rate of 
durable PVI. A recent large Netherlands Heart Registration (n=13,823) demonstrated that 
CB ablation was associated with less cardiac tamponades (0.3% versus 0.8%) and less 
vascular complications (1.3% versus 1.7%) compared to radiofrequency ablation.25 In 
contrast, CB ablation was associated with a higher risk of phrenic nerve palsy (1.5% 
versus 0.1%). These data are mainly based on the use of the second-generation CB 
(Arctic Front Advance). 
 
There is limited data on the incidence of periprocedural complications when using 
the POLARx™ cryoablation catheter. Studies have shown that the risk of PNP is similar 

  
 
 
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to Arctic Front Advance Pro™.8 Real-world data from 372 patients in the POLAR-ICE 
registry (NCT 04250714) have demonstrated the following complications (Table 9.4.1.). 
It is expected that the POLARx™ FIT cryoablation catheter will have a similar safety 
profile as the POLARx™ cryoablation catheter. As can be appreciated from Table 6.4.1., 
most complications are related to the procedure and not the device itself.  
 
Table 6.4.1. Periprocedural complications in the POLAR-ICE registry (n=388) 
Complication 
Number of patients (%) 
Phrenic nerve palsy 
9 (2.3%) 
Serious vascular access complications 
6 (1.5%) 
Cardiac tamponade  
2 (0.5%) 
Air embolism 
2 (0.5%) 
Persistent gastroparesis 
1 (0.3%) 
Myocardial infarction 
1 (0.3%) 
Stroke  
1 (0.3%) 
Abstract at EHRA 2022, Tilz et al.  
 
6.5 Description and justification of route of administration and dosage 
N/A 
6.6 Dosages, dosage modifications and method of administration 
N/A 
6.7 Preparation and labelling of Investigational Medicinal Product 
N/A 
6.8 Drug accountability 
N/A 
 
7. NON-INVESTIGATIONAL PRODUCT 
N/A. The study doesn’t include a non-investigational product.  

  
 
 
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7.1 Name and description of non-investigational product(s) 
7.2 Summary of findings from non-clinical studies 
7.3 Summary of findings from clinical studies 
7.4 Summary of known and potential risks and benefits 
7.5 Description and justification of route of administration and dosage 
7.6 Dosages, dosage modifications and method of administration 
7.7 Preparation and labelling of Non Investigational Medicinal Product 
7.8 Drug accountability 

  
 
 
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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
- Extent of antral lesion size (continuous variable) directly after cryoablation with a 
31 mm balloon size POLARxÔ FIT cryoablation catheter. Measures of antral 
lesion size are described in paragraph 8.3.1. and Table 8.3.1.1. 
8.1.2 Secondary study parameters/endpoints (if applicable) 
- Proportion of grade 4 occlusion (continuous variable, expressed as %) with a 31 
mm balloon size POLARxÔ FIT cryoablation catheter (on PV level) during 
cryoballoon procedure. 
- Single shot success rate (continuous variable, expressed as %) with a 31 mm 
balloon size POLARxÔ FIT cryoablation catheter (on PV level) during 
cryoballoon procedure. 
- Difference in proportion of grade 4 occlusion with a 28 mm or 31 mm balloon size 
(continuous variable, expressed as %) POLARxÔ FIT cryoablation catheter (on 
PV level) during cryoballoon procedure. 
8.1.3 Other study parameters (if applicable) 
 The cumulative 1-year freedom from atrial arrhythmias after cryoballoon 
ablation will be described using Kaplan-Meier method using a blanking period 
of 3 months. 
8.2 Randomisation, blinding, and treatment allocation 
N/A 
8.3 Study procedures 
8.3.1 Assessment of antral lesion size 
In the pre- and post-ablation UHDx-map, bipolar voltage will be assess using a scar-
cutoff <0.3 mV.23 The following spatial measurements will be  made consistent with 
a previously published method by Gunawardene et al.23: (1) the surface areas of the 
posterior left- and right-sided PV antral isolation, (2) the LAPW surface area with 
voltage pre- and post-ablation, and (3) the distance between the ipsilateral, antral 
levels of isolation at superior, middle and inferior latitudes of the LAPW (Figures 
8.3.1.A,B and D). The surface area of each PV ostium and the area of the circular 
antral ablation lesion was measured around each ipsilateral PV pair (Figure 

  
 
 
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8.3.1.C). Low-voltage areas will be quantified using a bipolar voltage <0.3 mV. The 
scale on the maps will be set from 0.1 to 0.3 mV. The purple region represents 
unablated tissue with a bipolar voltage >0.3 mV. The scar-border zone will be 
represented by bipolar voltages between 0.1-0.3 mV. The PV ostium is located by 
the steep angle between the LA wall and the tubular aspect of the PV.  
 
Figure 8.3.1. Methods for measurements of surface areas and distances in pre- and 
postablation UHDx maps. (A) Pre-ablation UHDx voltage map and measurement of 
LAPW surface area (indicated by the white dots) and pre-ablation superior, middle, and 
inferior line. (B) Postablation UHDx voltage map and measurement of the non-ablated 
LAPW surface area (indicated by the white dots) and postablation superior, middle, and 
inferior line. (C) Measurement of the PV ostia sizes of the LSPV and LIPV and the area of 
the circumferential antral ablation along the ipsilateral lateral PV pair (indicated by the 
whit dots). (D) Measurements of the posterior surface areas of the left- and right-sided 
pulmonary vein antral isolation areas. Modified from Gunawardene et al.23 
 
 
 
 

  
 
 
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Table 8.3.1.1. provides an overview of the key parameters assessing the extent of the 
antral lesion size. 
 
Table 8.3.1.1. UHDx measurements 
Measurement 
Preablation 
Postablation 
Nonablated LAPW surface area (cm2) 
X 
X 
Superior line (mm) 
X 
X 
Middle line (mm) 
X 
X 
Inferior line (mm) 
X 
X 
Total LPV ostia (cm2) 
- LSPV ostia (cm2) 
- LIPV ostia (cm2) 
- LCV ostia (cm2), if applicable 
- 
X 
Total RPV ostia (cm2) 
- RSPV ostia (cm2) 
- RIPV ostia (cm2) 
- RCV ostia (cm2), if applicable 
- 
X 
Left-sided circumferential antral lesion area (cm2) 
- 
X 
Right-sided circumferential antral lesion area (cm2) 
- 
X 
Posterior PV antral isolation area 
- LSPV (cm2) 
- LIPV (cm2) 
- RSPV (cm2) 
- RIPV (cm2) 
- LCV (cm2), if applicable 
- RCV (cm2), if applicable 
- 
X 
Abbreviations: LAPW, left atrial posterior wall; LCV, left common pulmonary vein; LIPV, left 
inferior pulmonary vein; LPV, left pulmonary vein; LSPV, left superior pulmonary vein; RCV, 
right common pulmonary vein; RIPV, right inferior pulmonary vein; RPV, right pulmonary vein; 
RSPV, right superior pulmonary vein. 
8.3.2 Proportion of grade 4 occlusion 
In this study we will evaluate the proportion of grade 4 occlusion (i.e., contrast 
stasis) of the 28 mm and 31 mm balloon size POLARxÔ FIT cryoablation catheter. 
Therefore, cine acquisitions of contrast vein occlusions will be analyzed. Occlusion 
will be categorized by using a previously described scale (1—rapid outflow of 
contrast medium from the PV to 4—complete contrast retention with no observable 
leak).24 Two experienced observers blinded to vein outcome will assess recorded 
venograms.  

  
 
 
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8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for 
urgent medical reasons. 
8.4.1 Specific criteria for withdrawal (if applicable) 
 
 
N/A 
8.5 Replacement of individual subjects after withdrawal 
Enrolled subjects who decide to leave the study before the index procedure will be 
replaced by new subjects.  
8.6 Follow-up of subjects withdrawn from treatment 
Subjects who are withdrawn from the study will continue their follow-up in agreement with 
local practice.  
8.7 Premature termination of the study 
N/A 
 
 
 

  
 
 
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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance with section 10, subsection 4 of the Medical Research Involving Human 
Subjects Act (in Dutch: Wet Medisch-wetenschappelijk Onderzoek met Mensen, WMO), 
the sponsor will suspend the study if there is sufficient ground that continuation of the 
study will jeopardize subject health or safety.  The sponsor will notify the accredited 
METC without undue delay of a temporary halt including the reason for such an action. 
The study will be suspended pending a further positive decision by the accredited METC. 
The investigator will take care that all subjects are kept informed.  
9.2 Adverse Events and Device Deficiencies 
During the clinical investigation, undesired medical events can occur in participating 
patients, which are called adverse events (AEs) in the following. Furthermore, device 
deficiencies (DD) may also be observed. All AEs and DDs of the investigational device 
shall be assessed by the investigator and shall be documented and reported throughout 
the clinical investigation within the timelines defined below (Figure 9.2.1.). According to 
ISO 14155:2020 (third edition) events will be classified based on the definitions below. 
The investigator will report all reportable events to the sponsor without undue delay but 
not later than 3 calendar days after obtaining knowledge of the event (including 
assessment of causal relationship with device or investigational procedure). Reportable 
events are: 
a) Any SAE that has a causal relationship with the investigational device, the 
comparator, or the investigation procedure or where such causal relationship is 
reasonably possible  
b) Any DD that might have led to a SAE if appropriate action had not been taken, 
intervention had not occurred, or circumstances had been less fortunate 
c) Any new findings in relation to any event referred in point (a) and (b) 
The sponsor will report reportable events through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 2 calendar days of first knowledge for 
SAEs that result in death or are life threatening. All other SAEs will be reported within a 
period of maximum 7 calendar days after the sponsor has first knowledge of the SAE. All 
SAE will be reported and will be categorized as related to the device (SADE) or not. 
 
The sponsor will report expedited unanticipated serious adverse device effects 
(USADEs) through the web portal ToetsingOnline to the METC. The expedited reporting 
of USADEs through the web portal ToetsingOnline is sufficient as notification to the 
competent authority. The expedited reporting will occur not later than 15 days after the 
sponsor has first knowledge of the adverse reactions. For fatal or life-threatening cases, 

  
 
 
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the term will be maximal 7 days for a preliminary report with another 8 days for 
completion of the report.  
 
Figure 9.2.1. Adverse events flow 
 
 

  
 
 
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9.2.1 Definition of Adverse Device Effects (ADE) 
An adverse device effect (ADE) (see ISO 14155:2020 3.1) is an adverse event (AE) 
that is related to the use of an investigational medical device. This includes any AE 
resulting from insufficient or inadequate instructions for use or the deployment, 
implantation, installation, or operation, or any malfunctioning of the investigational 
medical device and any event resulting from use error or from intentional misuse of 
the investigational medical device. This includes comparator if the comparator is a 
medical device.  
9.2.2 Definition of Adverse Events (AE) 
An AE is defined (see ISO 14155:2020 3.2) as any untoward medical occurrence, 
unintended disease or injury, or untoward clinical signs (including abnormal 
laboratory findings) in subjects, users, or other persons whether or not related to the 
investigational medical device, and whether anticipated or unanticipated. This 
includes: 
- Events related to the investigational medical device or the comparator 
- Events related to the procedures involved 
- For users or other persons, this definition is restricted to events related to the use 
of investigational medical devices or comparators 
9.2.3 Causality Assessment 
The relationship between the use of the investigational medical device (including the 
medical-surgical procedure) and the occurrence of each AE shall be assessed and 
categorized, considering the presence of confounding factors, such as concomitant 
medication and treatment, the natural history of the underlying disease, other 
concurrent illness, or risk factors. Each AE will be classified according to five 
different levels of causality. The investigator will use the following definitions to 
assess the relationship of the (serious) AE to the investigational medical device or 
procedures and the sponsor will review the investigators categorization: 
- Not related: the relationship to the medical device or procedure can be excluded 
- Unlikely: the relationship with the use of the medical device seems not relevant 
and/or the event can be reasonably explained by another cause, but additional 
information may be obtained. 
- Possible: the relationship with the use of the investigational medical device is 
weak but cannot be ruled out completely. Alternative causes are also possible 
(e.g., an underlying or concurrent illness/clinical condition or/and an effect of 
another device, drug or treatment). Cases where relatedness cannot be 

  
 
 
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assessed, or no information has been obtained should also be classified as 
possible.  
- Probable: the relationship with the use of the investigational medical device 
seems relevant and/or the event cannot be reasonably explained by another 
cause, but additional information may be obtained. 
- Causal relationship: the (serious) event is associated with the investigational 
medical device or with procedures beyond reasonable doubt.  
The investigators will distinguish between the AEs related to the investigational 
medical device and those related to the device procedures (any procedure specific 
to the investigational device). Procedure related events refers to the procedure 
related to the application of the investigational medical device only and therefore not 
to any other procedure for other devices and not to any other procedures or 
treatments applied later throughout the clinical investigation, for instance to treat 
(serious) AEs.  
 
An AE can be related both to the procedure and the investigational medical 
device. Complications of procedures are considered not related if the said 
procedures would have been applied to the patients also in the absence of 
investigational medical device use or application. 
9.2.4 Definition of Device Deficiency (DD) 
Device deficiency (DD) (see ISO 14155:2020 3.19) is defined as inadequacy of a 
medical device with respect to its identity, quality, durability, reliability, usability, 
safety, or performance, including malfunctions, use errors and inadequacy in the 
information supplied by the manufacturer including labelling. This definition includes 
DD related to investigation medical device or the comparator.  
 
DDs of the investigational medical device shall be documented throughout the 
study. DDs which caused an AE are reported on the respective adverse event form. 
In case the DD did not cause an adverse event, the provided DD form shall be used 
to document this “non-medical” event.  
If a DD could have led to a SADE, 
- If either suitable action had not been taken, 
- If intervention had not been made, or 
- If circumstances had been less fortunate, 
The DD is classified as an DD with a SADE potential. 

  
 
 
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9.2.5 Definition of Serious Adverse Events (SAE) 
AEs are classified as serious (see ISO 14155:2020 3.45) if one or more of the 
following consequences are fulfilled: 
a) Led to death 
b) Led to serious deterioration in the health of the subject, users, or other persons 
as defined by one or more of the following: 
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 or prolonged hospitalization, or 
4) Medical or surgical intervention to prevent life-threatening illness or 
injury, or permanent impairment to a body structure or a body function. 
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect 
including physical or mental impairment.  
 
Note: planned hospitalization for a pre-existing condition, or a procedure required by 
the clinical investigation plan (CIP), without serious deterioration in health is not 
considered a SAE. In-patient hospitalization is defined as at least one overnight stay 
(change of date) in a hospital. In case, a patient is only for some hours in the 
hospital (without change of date), this event will not be documented as serious, 
unless one or more other seriousness criteria are fulfilled.  
9.2.6 Definition of Serious Adverse Device Effect (SADE) 
An ADE (see ISO 14155:2020 3.44) that resulted in any of the consequences 
characteristic of a SAE is considered serious.  
9.2.7 Definition of Unanticipated Serious Adverse Device Effects (USADE) 
SADEs (see ISO 14155:2020 3.51) are defined as unanticipated if by their nature, 
incidence, severity, or outcome they have not been identified in the current risk 
assessment. These events must be reported to the sponsor immediately.  
9.3 Annual safety report 
An annual safety report will be submitted to the METC of the Erasmus MC.  
 

  
 
 
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9.4 Follow-up of adverse events 
All SAEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol.  
9.5 Data Safety Monitoring Board (DSMB) / Safety Committee 
A DSMB will not be established given low-risk character of the study and the well-
established safety of the catheters. The principal investigator will be responsible for 
registering and reporting any ADEs, SADE or USADEs to the METC. 
 
 
 
 

  
 
 
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10. STATISTICAL ANALYSIS 
10.1 Primary study parameters 
The primary study parameter is the extent of the antral lesion size. The antral lesion size 
will be established using the parameters as detailed in Table 8.3.1.1. The antral lesioin 
size will be described as absolute and relative measures. Absolute measures include 
nonablated LAPW, superior line, mid line, inferior line, circumferential antral lesion area, 
and posterior PV antral lesion area. Relative measures include the difference between 
the pre- and post-ablation maps regarding the absolute measures expressed as a 
percentage. 
10.2 Secondary study parameters  
The secondary study parameters are the proportion of grade 4 occlusion and the single 
shot success rate. Both will be determined per PV and expressed as frequency and 
percentage (N, %). The difference in the proportion of grade 4 occlusion between the 28 
mm and 31 mm balloon size will be compared using the McNemar test for paired nominal 
data.  
10.3 Other study parameters 
N/A 
10.4 Interim analysis (if applicable) 
N/A 
 

  
 
 
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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki 
(version 2013), ISO 14155: 2020, WMO and other regional and local laws. 
11.2 Recruitment and consent 
Patients who are referred to the study center for a PVI are always seen by a physician on 
a dedicated outpatient clinic to inform them on the procedure, efficacy, and risks of a PVI. 
If the patient is a suitable patient for a PVI with a cryoballoon and the patient gives 
consent for the procedure, they are considered potential study candidates. If they fulfil the 
in- and exclusion criteria as defined in chapter 4, then they will be approached by a 
member of the study team (not treating physician) to explain the study and obtain 
informed consent if the patient is eligible and willing to participate in the study. Informed 
consent will be obtained and documented in writing before a subject is enrolled in the 
clinical study. It is the responsibility of the investigator to ensure that a written informed 
consent is obtained from the subject (or legally acceptable representative) before any 
activity or procedure is undertaken that is not part of routine care. 
11.3 Objection by minors or incapacitated subjects (if applicable) 
N/A 
11.4 Benefits and risks assessment, group relatedness 
The hypothesis is that the larger balloon size of POLARxÔ FIT cryoablation catheter will 
result in a larger antral lesion size. This may have a beneficial effect by reducing the risk 
of recurrence of AF after the index procedure. In general, cryoballoon procedures are 
associated with less periprocedural risks compared to PVI using RF. It is expected that 
the larger balloon size (31 mm versus 28 mm) will not result in a significant increase in 
periprocedural complications. Catheter handling will not change due to the larger balloon 
size. One of the most common complications due to CB procedures is right-sided PNP. It 
is expected that a larger balloon size will have a beneficial effect on the risk of PNP 
because the larger balloon size will prevent placement of the CB too deep in the right-
sided PVs. By having a more antral position of the CB the risk of PNP is decreased.    
11.5 Compensation for injury 
The sponsor has a liability insurance which is in accordance with article 7 of the WMO. 
The sponsor (also) has an insurance which is in accordance with the legal requirements 
in the Netherlands (Article 7 WMO). This insurance provides cover for damage to 
research subjects through injury or death caused by the study. The insurance applies to 

  
 
 
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the damage that becomes apparent during the study or within 4 years after the end of the 
study. 
11.6 Incentives (if applicable) 
Patients included in the study will not receive any financial compensation. Travel costs 
reimbursement is possible (if visits are not part of the routine clinical care).  

  
 
 
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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Data will be handled confidentially and encoded. A subject identification code will be used 
to be able to trace data to an individual subject. This code will not be based on the patient 
initials and birthdate. The key to the code will be safeguarded by the investigator. The 
handling of personal data will comply with the EU General Data Protection Regulation 
(GDPR) and the Dutch Act on Implementation of the General Data Protection Regulation 
(in Dutch: Uitvoeringswet AVG, UAVG). Electronic Case Report Forms (eCRFs) will be 
utilized. Site staff will enter the information required by the protocol onto eCRFs using a 
validated software/ database that conforms to requirements for electronic data capture. 
The subsidiary party, whose headquarters is located in the United States, can only 
access the fully anonymized data upon request. 
12.2 Monitoring and Quality Assurance  
According to the NFU table the risk classification regarding patient risk is considered 
moderate. The risk classification regarding scientific quality is considered negligible. 
Based on this assessment, the frequency of monitoring will be 2 visits per year. For 
details of the monitoring plan, we refer to the local rules in the Erasmus MC for research 
with moderate risk (in Dutch: onderzoek met matig risico).  
12.3 Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- 
the safety or physical or mental integrity of the subjects of the trial; 
- 
the scientific value of the trial; 
- 
the conduct or management of the trial; or 
- 
the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC. Non-substantial amendments 
will not be notified to the accredited METC but will be recorded and filed by the sponsor. 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  

  
 
 
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12.5 End of study report 
The sponsor will notify the accredited METC of the end of the study within a period of 90 
days. The end of the study is defined as the last patient’s last visit. The sponsor will notify 
the METC immediately of a temporary halt of the study, including the reason of such an 
action. In case the study is ended prematurely, the sponsor will notify the accredited 
METC within 15 days, including the reasons for the premature termination. Within one 
year after the end of the study, the investigator/sponsor will submit a final study report 
with the results of the study, including any publications/abstracts of the study, to the 
accredited METC. 
12.6 Public disclosure and publication policy 
The basic principles of the CCMO’s position on the disclosure/ publication of trial results 
obtained from studies involving human subjects will be respected. The results of the study 
will be submitted for publication to peer-reviewed scientific journals independent of the 
subsidiary party. The investigator shall ensure by its best efforts that confidentiality 
interests of the subsidiary party shall be respected. Therefore, the investigator shall 
forward a manuscript of the planned publication at least 30 days prior publication to the 
subsidiary party. The subsidiary party is entitled to examine the manuscript and to make 
comments on it.  
 
To provide transparency and discourage publication bias, the study is registered in the 
www.clinicaltrials.gov before the first inclusion. 
 
 

  
 
 
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13. STRUCTURED RISK ANALYSIS  
13.1 Potential issues of concern 
N/A (see paragraph 13.2) 
13.2 Synthesis 
The POLARxÔ FIT is a CE-marked device and will be used within the registered 
indication for use. Therefore, paragraph 13.1 was skipped. In general, PVI using a 
cryoballoon is considered safer than radiofrequency ablation. This is related that CB 
ablation is associated with lower interoperator variability, shorter learning curve and faster 
procedure times. Our center has extensive experience with cryoballoon procedures and 
have been using the Arctic Front cryoballoon (Medtronic) since 2005. Since 2019 we 
started cryoablation using the novel POLARxÔ cryoablation system as part of the CE 
mark study.18 After the POLARxÔ cryoablation system obtained the CE mark in 2020, we 
have compared the safety of the POLARxÔ to the Arctic Front Advance ProÔ 
cryoablation system in a real-world population and showed no differences in the rate of 
periprocedural complications.13 We also conducted a meta-analysis in 2021 and did not 
show a difference in periprocedural complications between both cryoablation systems.8 
The second generation POLARxÔ cryoablation catheter, POLARxÔ FIT, is identical to its 
predecessor from the perspective of catheter design. The major difference is that 
POLARxÔ FIT can be used as either a standard sized balloon (28 mm) or a slightly larger 
sized (31 mm) balloon. This small increase in balloon size will most likely have no impact 
on periprocedural complications but may have a small effect on positioning of the balloon 
at the antral part of the PVs. This effect is evaluated in the current study. The larger 
balloon may even have a beneficial effect on the risk of PNP because the larger balloon 
size prevents that the balloon will be positioned too deep in the PV. A deeper position in 
the PV is associated with a higher risk of PNP. Finally, in this study we will perform pre- 
and postablation 3D mapping with a 64-pole mini-basket OrionÔ catheter. 3D mapping is 
standard in RF procedures and mapping is not associated with a high risk of cardiac 
perforation. Because the OrionÔ catheter is introduced through the 15.9F 
POLARSHEATHÔ steerable sheath, specific attention will be paid to the risk of air 
ingress because the risk of air ingress is increased when using a smaller catheter in the 
POLARSHEATHÔ. We believe that the increased risk for the subjects in this study is 
negligible.  
 
 
 

  
 
 
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