Multi-electrode Radiofrequency Balloon Catheter Use for the Isolation of the Pulmonary Veins.
Phase: NA
Conditions: Paroxysmal Atrial Fibrillation
Sponsor: Biosense Webster, Inc.

SHINE 
 
Version v.5.0 – Amendment #4 
Protocol# BWI_2017_01 
 
20July2018 
 
Biosense Webster, Inc. 
CONFIDENTIAL 
     Page 1 of 86 
 
 
 
SHINE 
Multi-electrode Radiofrequency Balloon Catheter 
use for the Isolation of the Pulmonary Veins. 
 
 
Protocol Number:  
BWI_2017_01  
 
Sponsor: 
Biosense Webster, Inc., a division of Johnson & Johnson with registered office 
at 33 Technology Drive, Irvine, CA 92618 
 
Operating Company:  
Johnson & Johnson Medical NV/SA with registered office at Leonardo Da 
Vincilaan 15, 1831 Diegem, Belgium, represented by 
 
 
Funded by: 
Biosense Webster, Inc., part of the Johnson & Johnson family of companies 
 
Version: 
5.0 
 
Date: 
20 JUL 2018 
 
      History of Changes: 
Version— Date 
Description 
 
V 1.0 — 1 Sep 2017 
Original Document 

V 2.0 – 13 Dec 2017 
Amendment #1

V 3.0 – 20 Dec 2017 
 
Amendment #2 
 

V 4.0 – 18 Jun 2018 
 
 
Amendment # 3 – finalized by sponsor, 
not submitted to any country/EC. 
. 

V 5.0 – 20 July2018        
Amendment #4
 
The Biosense Webster Multi-electrode RF Balloon Catheter (D-1389-02-SI) and Multi-Electrode Circular Diagnostic 
Catheter (D-1390-01-SI, D-1390-02-SI, D-1390-03-SI) are for investigational device use only and are not 
commercially available anywhere in the world. “Balloon Catheter/Balloon Ablation Catheter” for RF balloon 
catheter and ‘Frontera’ for Circular Diagnostic catheter are internal Biosense Webster project names and other 
than as used in the present clinical investigation, are not intended for any other external use. The final commercial 
or trade name of the Multi-electrode RF Balloon and Circular Diagnostic Catheter may be different. 

SHINE 
 
Version v.5.0 – Amendment #4 
Protocol# BWI_2017_01 
 
20July2018 
 
Biosense Webster, Inc. 
CONFIDENTIAL 
     Page 2 of 86 
 
Table of Contents 
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SHINE 
 
Version v.5.0 – Amendment #4 
Protocol# BWI_2017_01 
 
20July2018 
 
Biosense Webster, Inc. 
CONFIDENTIAL 
     Page 3 of 86 
 
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SHINE 
 
Version v.5.0 – Amendment #4 
Protocol# BWI_2017_01 
 
20July2018 
 
Biosense Webster, Inc. 
CONFIDENTIAL 
     Page 4 of 86 
 
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List of Figures and Tables 
 
FIGURE 6.5.1-A: MULTI-ELECTRODE RF BALLOON CATHETER DISTAL SEGMENT .......................................................... 33 
FIGURE 6.5.1-B: MULTI-ELECTRODE RF BALLOON CATHETER........................................................................................ 34 
FIGURE 6.5.1-C: MULTI-ELECTRODE RF BALLOON CATHETER WITH RADIOPAQUE UNIQUE MARKERS ........................ 35 
FIGURE 6.5.1-D: BALLOON ADVANCEMENT MECHANISM ............................................................................................. 36 
FIGURE 6.5.2-A: CIRCULAR MAPPING CATHETER DEPLOYED VIA THE GUIDEWIRE LUMEN OF RF BALLOON CATHETER
 ............................................................................................................................................................................... 37 
FIGURE 6.5.2-B: DETAILED MULTI-ELECTRODE CIRCULAR DIAGNOSTIC CATHETER SCHEMATIC .................................. 38 
FIGURE 6.5.2-C: LOOP TIP .............................................................................................................................................. 38 
FIGURE 6.5.2-D: CONNECTIVITY OF THE MULTI-ELECTRODE CIRCULAR DIAGNOSTIC CATHETER WITH THE CARTO® 
SYSTEM .................................................................................................................................................................. 39 
FIGURE 6.6.1-A: CONNECTIVITY DIAGRAM OF MULTI-ELECTRODE RF BALLOON CATHETER ........................................ 40 
 
TABLE 8.2.2-A:  INVESTIGATIONAL DEVICE- RECOMMENDED MAXIMUM PARAMETERS ............................................. 45 
TABLE 8.7-A:SUMMARY OF SUBJECT ASSESSMENTS ..................................................................................................... 52 
TABLE 9.1.3-A: PRIMARY ADVERSE EVENTS ................................................................................................................... 54 
TABLE 9.2.1-A: INTENSITY OR SEVERITY DEFINITIONS ................................................................................................... 57 
TABLE 9.2.2-A: ADVERSE EVENT CAUSALITY CLASSIFICATIONS ..................................................................................... 58 
TABLE 9.2.3-A: ADVERSE EVENT OUTCOME CLASSIFICATIONS ...................................................................................... 58 
TABLE 9.2.4-A: PROVIDES A COMPREHENSIVE LIST OF ANTICIPATED AES. ................................................................... 59 
TABLE 9.4.1-A: AE REPORTING REQUIREMENTS ............................................................................................................ 62 
TABLE 19.1.2-A: RESPONSIBILITIES FOR PREPARING AND SUBMITTING REPORTS ........................................................ 78 
 

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Key roles and Responsible Parties 
 
SPONSOR:   
Cardiovascular & Specialty Solutions (CSS) 
Biosense Webster Inc., part of the Johnson & Johnson family of companies 
33 Technology Drive,  
Irvine, CA 92618 
USA 
Tel: +1 800-729-9010 
 
CONTACTS:   
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Whereas, the Clinical Study is sponsored by Biosense Webster Inc., Johnson and Johnson Medical NV/SA 
with registered offices at Leonardo Da Vincilaan 15, 1831 Diegem, Belgium, has been duly appointed by 
the Sponsor to conduct the Clinical Study on its behalf. 
 
The sponsor maintains an updated list of principal investigators, sites, institutions and Contract Research 
Organizations (if applicable). The definitive list shall be integrated into the study report. 
 

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Protocol Summary 
 
Study Name: 
SHINE 
Study Title: 
Multi-electrode Radiofrequency Balloon Catheter use for the isolation of the 
pulmonary veins.  
 
Study Number: 
BWI_2017_01 
Summary: 
This clinical investigation is a prospective, multicenter, single arm clinical evaluation 
utilizing the Biosense Webster multi-electrode radiofrequency balloon catheter and 
the Biosense Webster multi-electrode circular diagnostic catheter. The objective of 
this clinical investigation is to assess the safety and acute effectiveness of the multi-
electrode radiofrequency balloon catheter and multi-electrode circular diagnostic 
catheter (Frontera) when used for the isolation of the pulmonary veins in the 
treatment of Paroxysmal Atrial Fibrillation (PAF).  A maximum of 230 evaluable 
subjects with symptomatic PAF who are candidates for atrial fibrillation ablation will 
be enrolled in this study, excluding roll-in subjects. Subjects will be evaluated at 7 
days, 1, 3, 6 and 12 months following procedure. 40 subjects will be included in the 
Neurological Assessment Evaluable (NAE) subgroup. 
 
Objective: 
The objective of this study is to assess the safety and acute effectiveness of the 
multi-electrode radiofrequency balloon catheter and multi-electrode circular 
diagnostic catheter in the isolation of the atrial pulmonary veins in treatment of 
subjects with PAF.  
 
Endpoint: 
Primary Endpoints: 
 
ACUTE SAFETY 
Incidence of early onset Primary Adverse Events (PAE) (within 7 days of the mapping 
and ablation procedure).  PAEs include the following AEs:  
x
Death*  
x
Atrio-Esophageal Fistula*  
x
Myocardial Infarction 
x
Cardiac Tamponade/perforation 
x
Thromboembolism 
x
Stroke/CVA 
x
TIA 
x
Phrenic Nerve Paralysis  
x
Pulmonary Vein Stenosis*  
x
Major Vascular Access Complication/Bleeding 
*Device or procedure related death, pulmonary vein stenosis and atrio-esophageal 
fistula, that occur greater than one week (7 days) and (≤) less or equal to 90 days 
post-procedure are considered and analyzed as primary AEs.




 

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ACUTE EFFECTIVENESS 
x
Acute procedural success defined as confirmation of entrance block in 
treated PVs after adenosine and/or isoproterenol challenge (with or 
without the use of a focal catheter). 
 
Main Secondary Endpoints: 
x
Incidence of individual PAE from the primary composite 
x
Incidence of Serious Adverse Device Effects (SADEs) 
x
Incidence of Serious Adverse Events (SAEs) within 7 days (early-onset), >7-
30 days (peri-procedural) and >30 days (late onset) of initial ablation 
procedure 
x
Incidence of non-serious adverse events  
x
Incidence of pre-and post-ablation asymptomatic and symptomatic cerebral 
emboli as determined by MRI evaluations. 
x
Frequency, anatomic location, and size (diameter and volume) of cerebral 
emboli by MRI evaluations at baseline, post-ablation and during follow-up. 
x
Incidence of new or worsening neurologic deficits post-ablation and follow-
up, compared to baseline. 
x
Summary of NIHSS scores at baseline, post-ablation and during follow-up. 
x
Summary of MoCA and mRS scores at baseline, 1 month and during further 
follow-up. 
x
Hospitalization for cardiovascular events 
x
Percentage (%) of PVI touch-up by focal catheter among all targeted veins 
and by subject. 
x
Percentage (%) of subjects with use of focal catheter ablations for non-PV 
triggers. 
x
Percentage (%) of subjects with freedom from documented symptomatic 
atrial fibrillation (AF), atrial tachycardia (AT), or atypical (left side) atrial 
flutter (AFL) episodes (episodes >30 seconds on arrhythmia monitoring 
device from day 91 to 180). 
x
Percentage (%) of subjects with freedom from documented atrial fibrillation 
(AF), atrial tachycardia (AT), or atypical (left side) atrial flutter (AFL) 
episodes (episodes >30 seconds on arrhythmia monitoring device from day 
91 to 180). 
x
Percentage (%) of subjects with freedom from documented symptomatic 
atrial fibrillation (AF), atrial tachycardia (AT), or atypical (left side) atrial 
flutter (AFL) episodes (episodes >30 seconds on arrhythmia monitoring 
device from day 91 to 365). 
x
Percentage (%) of subjects with freedom from documented atrial fibrillation 
(AF), atrial tachycardia (AT), or atypical (left side) atrial flutter (AFL) 
episodes (episodes >30 seconds on arrhythmia monitoring device from day 
91 to 365). 
x
Procedural parameters including but not limited to: total procedure and 
ablation time, balloon dwell time, RF application time, time to effect (PVI 
measured by Frontera), number of RF applications, fluoroscopy time and 
dose. 
x
Health economic data, including but not limited to index procedural 
workflow costs, QoL and hospital costs. 

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Roll-in subjects will not be included in the main study analyses, and will be analyzed 
separately
Population 
Subjects diagnosed with symptomatic paroxysmal AF and candidate for RF ablation 
treatment through pulmonary vein isolation.
Study Design 
 
Interventional, Pivotal, Prospective, multicenter, Single Arm Clinical Evaluation 
 
Roll-in Subjects:  
-1 roll-in subject will be included for ablating physicians that participated in the 
RADIANCE Study 
-2 roll-in subjects will be included by ablating physicians that didn’t participate in 
the RADIANCE study and have extensive balloon experience (>15 cases/year) 
-3 roll-in subjects will be included by ablating physicians that didn’t participate in 
the RADIANCE study and don’t have extensive balloon experience (<15 cases/year) 
 
These subjects will not be analyzed for the main study endpoints.  
. 
Clinical Sites 
Up to 20 sites within Europe 
 
Sample Size 
Sample size calculations were performed using performance goals of 15% and 80% 
respectively for the safety and effectiveness endpoint rates. The primary safety and 
effectiveness endpoints will be evaluated using exact tests for binomial proportions 
at a one-sided 5% significance level. 
The sample size for the study is primarily driven by the safety endpoint. An adaptive 
Bayesian design76 will be used to determine the sample size based on the safety 
endpoint alone. Sample size selection interim analyses will be performed after 
inclusion of 80, 130, 180, and 230 evaluable patients (includes all subjects who had 
the study catheter inserted, except roll-ins). Safety outcomes at 30 days will be used 
as a proxy for the primary safety endpoint at each interim analysis. The final safety 
analysis will be based on complete follow-up for the primary safety endpoint for all 
evaluable patients. Predictive probabilities of success will be used to determine 
whether the sample size at each interim analysis will be sufficient or if the trial 
enrollment will continue.  
At the time of each interim analysis, predictive probabilities of success will be 
estimated using the available data from all evaluable subjects, assuming a non-
informative uniform prior distribution for the primary safety rate. Enrollment will 
be stopped if the predictive probability of trial success at any interim is greater 
than 90%, or if the predictive probability of trial success with the maximum 
sample size is less than a futility bound of 6.5%. Otherwise, enrollment will 
continue until the next interim or the final sample size. Analysis of the 
effectiveness endpoint will be performed at the final sample size determined for 
the safety endpoint. Power for the effectiveness endpoint assessment is >80% at 
all sample sizes ≥80 subjects. 
Operating characteristics of the adaptive design were simulated and the Type-I 
error for safety was shown to be less than 5%. In addition, the safety endpoint will 
be adequately powered for a range of safety rates. The simulation results will be 
provided in the Statistical Analysis Plan.  

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Since Type-I errors for both safety and effectiveness are controlled at a 5% level, 
and the study will be successful if both safety and effectiveness objectives are 
met, the overall study Type-I error rate will be controlled at 5%.  
Based on a maximum amount of 20 sites, assuming an average of 2 ablating 
physicians per site, an estimated amount of up to 60 roll-ins will be included in the 
study. 
 
Description of 
Investigational 
Devices 
The Multi-Electrode Radiofrequency (RF) Balloon catheter is intended for use for 
cardiac electrophysiological ablation of pulmonary veins of the atria when used with 
the nMARQ™ Multi-Channel RF Generator, version 2.3.1. 
 
 
 
 
 
  
 
The Multi-Electrode Circular Diagnostic Catheter is indicated for electrophysiological 
recording and stimulation of the atrial region of the heart and is used in conjunction 
with the Multi-Electrode Radiofrequency Balloon Catheter and ancillary equipment. 
 
 
 
 
 
Study Duration 
Approximately 27 Months (enrollment and follow-up) 
 
Participant 
Duration 
Subjects will be followed till 12 months post-procedure 
 
Study Inclusion 
Criteria 
 
1. Diagnosed with Symptomatic Paroxysmal AF. 
2. Selected for AF ablation procedure for pulmonary vein isolation. 
3. Able and willing to comply with uninterrupted per-protocol anticoagulation 
requirements  
4. Age 18-75 years. 
5. Able and willing to comply with all pre-, post- and follow-up testing and 
requirements. 
6. Signed Patient Informed Consent Form. 
 
Study Exclusion 
criteria 
 
1. AF secondary to electrolyte imbalance, thyroid disease, or reversible or non-
cardiac cause. 
2. Previous surgical or catheter ablation for AF. 
3. Anticipated to receive ablation outside the PV ostia and CTI region 
4. Previously diagnosed with persistent, longstanding AF and/or continuous AF > 7 
days, or > 48 hrs terminated by cardioversion. 
5. Any percutaneous coronary intervention (PCI) within the past 2 months. 
6. Valve repair or replacement and presence of a prosthetic valve. 
7. Any carotid stenting or endarterectomy. 

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8. Coronary artery bypass grafting (CABG), cardiac surgery (e.g. ventriculotomy, 
atriotomy), or valvular cardiac surgical or percutaneous procedure within the 
past 6 months. 
9. Documented left atrium (LA) thrombus on baseline/pre-procedure imaging. 
10.LA antero posterior diameter > 50 mm 
11.Any PV with a diameter ≥ 26 mm 
12.Left Ventricular Ejection Fraction (LVEF) < 40%. 
13.Contraindication to anticoagulation (e.g. heparin). 
14.History of blood clotting or bleeding abnormalities. 
15.Myocardial infarction within the past 2 months. 
16.Documented thromboembolic event (including transient ischemic attack [TIA]) 
within the past 12 months. 
17.Rheumatic Heart Disease. 
18.Uncontrolled heart failure or New York Heart Association (NYHA) function class 
III or IV. 
19.Awaiting cardiac transplantation or other cardiac surgery within the next 12 
months.  
20.Unstable angina. 
21.Acute illness or active systemic infection or sepsis. 
22.Diagnosed atrial myxoma or interatrial baffle or patch. 
23.Presence of implanted pacemaker or implantable cardioverter defibrillator (ICD). 
24.Significant pulmonary disease, (e.g. restrictive pulmonary disease, constrictive or 
chronic obstructive pulmonary disease) or any other disease or malfunction of 
the lungs or respiratory system that produces chronic symptoms. 
25.Significant congenital anomaly or medical problem that, in the opinion of the 
investigator, would preclude enrollment in this study. 
26.Women who are pregnant (as evidenced by pregnancy test if pre-menopausal), 
lactating, or who are of child bearing age and plan on becoming pregnant during 
the course of the clinical investigation. 
27.Enrollment in an investigational study evaluating another device, biologic, or 
drug. 
28.Has known pulmonary vein stenosis. 
29.Presence of intramural thrombus, tumor or other abnormality that precludes 
vascular access, or manipulation of the catheter. 
30.Presence of an IVC filter 
31.Presence of a condition that precludes vascular access. 
32.Life expectancy or other disease processes likely to limit survival to less than 12 
months. 
33.Presenting contra-indication for the devices (e.g. TTE, CT, Holter, etc.) used in the 
study, as indicated in the respective instructions for use. 
34.Categorized as a vulnerable population and requires special treatment with 
respect to safeguards of well-being  
 
Additional exclusion criteria for Neurological Assessment Evaluable (NAE) subjects: 
35.Contraindication to use of contrast agents for MRI such as advanced renal 
disease, etc. (at PI discretion) 
36.Presence of iron-containing metal fragments in the body  
37.Unresolved pre-existing neurological deficit. 
 

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1 Background Information and Scientific Rationale 
1.1 Background Information 
 
Atrial Fibrillation (AF) is the most common sustained arrhythmia in humans.  It affects 
anywhere from 0.4% to 1% of the general population, and increases in prevalence with age to 
approximately 8% in patients over 80 years of age.1, 2  The primary clinical benefit of AF 
ablation is improvement in quality of life (QoL) resulting from the elimination of arrhythmia-
related symptoms such as palpitations, fatigue, or effort intolerance.3  In recognition of this, 
the elimination of symptomatic atrial arrhythmias was recommended by the 2017 
HRS/EHRA/ECAS Consensus on Catheter and Surgical Ablation of Atrial Fibrillation.3 The 
opinion of the ECC as expressed in their 2016 AF Management Guidelines is that “Catheter 
ablation of symptomatic paroxysmal AF is recommended to improve AF symptoms in patients 
who have symptomatic recurrences of AF on antiarrhythmic drug therapy and who prefer 
further rhythm control therapy, when performed by an electrophysiologist who has received 
appropriate training and is performing the procedure in an experienced center.”2, 4 
 
The 2017 HRS/EHRA/ECAS consensus statement states that electrical isolation of the 
pulmonary veins (PVs) from the left atrium is the “cornerstone for most AF ablation 
procedures” and that “complete electrical isolation of all PVs should be the goal.”3   Point-by-
point ablation with RF catheters has provided positive results for treating many types of 
supraventricular arrhythmias,5, 6 including PAF.5-11 However, the procedure is technically 
complex and has a long learning curve. Radiofrequency (RF) ablation success is highly 
dependent on operator skill and is associated with a high degree of PV reconnection.12-14 
Additionally, RF ablation carries a major complication rate of roughly 4.5%.15   
 
In order to reduce technical complexity and potentially decrease major complications, balloon 
ablation catheters were developed. Balloon catheters use tissue cooling (cryoballoon), 
heating (hot balloon) or selective destruction with a laser (laser balloon) to create lesions and 
isolate PVs. 
 
The second-generation cryoballoon (CB-2), so-called because of design improvements over 
the original first-generation cryoballoon, uses injected refrigerant to ablate tissue that comes 
in contact with the distal hemisphere of the balloon (cooling zone).  Advantages of this 
technology over point-by-point RF ablation are that it is less complex, has shorter procedure 
times, short operator learning curve16, durable PVI/low rate of AF recurrence,17-20 minimal risk 
of atrioesophageal fistula or PV stenosis, successful ablation even in cases of complicated 
anatomy16,21 and no requirement for 3D mapping.22,23 While the CB-2 often allows single-shot 
PVI,23-25 there is still some operator skill involved and various investigators have developed a 
pull-back technique (incomplete occlusion at the beginning of freezing) to minimize phrenic 
nerve (PN) injury.25-28 In addition, PN pacing is required throughout the procedure on the right 
side so freezing can be immediately aborted if PN palsy (PNP) is observed.19,22,26,27,29  Because 
of this, there is a greater rate of reconduction in the right superior pulmonary vein (RSPV).18  
Investigators who use the CB-2 differ in their recommendation of a “bonus freeze”,18,20,30,31 
optimal dosing of cryoenergy (240 sec22,24 vs. 180 sec25,32 or even less,29,30), minimum 
temperature21, the need for an endoluminal esophageal temperature cutoff29,33,34, and 

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whether both sizes (23 mm and 28 mm16) should be used versus using the larger balloon 
exclusively.19,23,31,34,35 Further disadvantages of this technique are that it is not appropriate for 
focal touch-ups or repeat ablation of conduction gaps,18,20 and that the larger balloon, which 
most investigators seem to prefer16, may not fit an especially narrow PV ostium. 
 
The hot balloon (HB) is a compliant balloon that uses a heated saline/contrast mixture to heat 
the surrounding tissue and generate thermal lesions. Advantages of the HB system over 
conventional RF ablation are the possibility of single-shot PVI36 and reduced risk of 
perforation/mechanical injury to endocardium.37  In addition, the HB can be withdrawn 
immediately if phrenic nerve (PN) capture is lost, in contrast to the CB-2 which can adhere to 
the tissue and make withdrawal difficult.38,39  A disadvantage to this system is that it still 
requires a fair amount of operator skill and finesse,38,39 and the balloon position should be 
checked often by fluoroscopy and repositioned if indentation is noted.39,40  The need for 
esophageal temperature monitoring and, when applicable, cooling40 also increases procedural 
complexity. The need for PN pacing and/or fluoroscopic monitoring of the diaphragm is still 
paramount with this system in order to prevent PNP.39,40  Because central balloon 
temperature, RF time, and the diameter to which the balloon is inflated are all dependent 
upon the thickness of the target ablation tissue (each PV, e.g.),39,40 extensive pre-procedure 
imaging (intracardiac echocardiography [ICE] or 3-D Computed Tomography [CT]) is 
required.39,40 Like the CB-2, HB is not useful for focal touchups or repeat ablation of gaps/ sites 
of reconduction.  To ablate such areas, a conventional irrigated tip RF catheter is still needed.39 
 
The laser balloon (LB) is a compliant balloon that can be inflated to a broad range of diameters 
and contains a central catheter shaft with a fiberoptic endoscope and a second fiber for laser 
energy delivery.  Applications of laser energy last 20-30 seconds and cover a 30o arc with the 
aim of overlapping lesions by 30-50% to achieve transmurality.41,42  Esophageal temperature 
monitoring and PN pacing are still necessary.  An advantage of this technology is that all 
endoscopic images are instantaneously displayed on a separate screen so that any potential 
gaps can be detected in real time.41 The aiming and laser beams can be rotated, advanced, or 
retracted for flexibility in lesion pattern based on PV anatomy. The operator also has the 
ability to titrate laser energy.41  Ablation in or near the blood source requires decreased energy 
output;43 however, the threat of thermocoagulation exists.44  A common finding with LB 
ablation is that long procedure times are required for conventional RF ablation.41,43,45-52 It 
takes anywhere from 25-50 lesions to successfully isolate one PV.45-48,53 Higher energy output 
is associated with decreased procedure time, but at the expense of greater risk of steam pop 
and balloon damage due to overheating.45 A disadvantage inherent to this system is that the 
catheter shaft itself obscures about one fifth of the circumference of the PV ostium, so 
rotation of the catheter is required to complete ablation of the PV.41,48 The same problem of 
obscuring the view occurs with a spiral mapping catheter, so it must be inserted after the 
balloon is deflated; therefore electrical mapping and ablation cannot be performed 
simultaneously.41,52  Furthermore, the endoscopic images are 2-dimensional and therefore do 
not show the level of the ablation line in relationship to the PV ostium.41  The possibility of 
misalignment increases each time the LB is repositioned.52  Finally, since the LB is not designed 
as an over-the-wire device, there may be an increased risk of pericardial tamponade.47,51 
 
A common advantage to all of these balloon ablation systems is good contact with the target 
tissue regardless of individual anatomy. A disadvantage is the difficulty of avoiding healthy or 
already-ablated tissue.   

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1.2 Previous Experience with the multi-electrode RF balloon catheter 
1.2.1
Multi-Electrode RF Balloon Catheter In-Vivo Porcine Beating Heart Model 
 
Refer to IB for detailed section.  
 
The purpose of the study was to verify the safety and performance of the following    
devices in a porcine beating heart model, when simulating a clinical electrophysiology  
procedure (pulmonary vein isolation): 
x
Multi-electrode RF balloon catheter 
x
13.5 F compatible deflectable sheath (Oscor®) 
x
CARTO® 3 software compatible with RF ablation balloon catheter 
 
 The study evaluated the Multi-electrode RF Balloon Catheter and its ability to work in 
conjunction with the nMARQ™ multi-channel RF generator and the CARTO® 3 system, 
COOLFLOW™ irrigation pump, catheter interface cable and standard pacing and recording 
system in a beating heart animal study to demonstrate safety and performance. 
 
Based on the passing results under the study, the safety and performance of the multi-
electrode RF balloon catheter simulating a clinical EP procedure in a porcine beating heart 
model is verified safe for clinical use. 
 
1.2.2
Multi-Electrode Circular Diagnostic Catheter In-Vivo Porcine Beating Heart Model 
 
Refer to IB for detailed section.  
 
The purpose of the study was to verify the performance and safety of the Multi-Electrode 
Circular Diagnostic Catheter in a porcine beating heart model, when simulating a clinical 
electrophysiology procedure with use of following devices: 
 
x
nMARQ™ RF generator 
x
CARTO® 3 system, with software compatible with RF ablation balloon catheter 
x
Catheter Interface Cable 
x
Standard Pacing and recording system 
x
COOLFLOW® Irrigation Pump 
 
The study evaluated the Multi-Electrode Circular Diagnostic Catheter and its ability to work 
in conjunction with the nMARQ™ multi-channel RF generator and the CARTO® 3 system, in a 
beating heart animal study to demonstrate safety and performance. 
 
Gross pathology examination was performed and cardiac tissue was found to be normal. 
There was no evidence of thrombus, dissection, perforation, or other cardiac injury in left 
atrium of both animals where the multi-electrode circular diagnostic catheter was 
manipulated in the pulmonary veins. 

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Based on the results of safety and performance of multi-electrode circular diagnostic 
catheter in conjunction with multi-electrode RF balloon catheter and ancillary equipment, all 
characteristics passed the acceptance criteria. Multi-electrode circular diagnostic catheter is 
verified safe for clinical use and equivalent to the LASSO® catheter in all characteristics. 
 
1.2.3
The RADIANCE Clinical Investigation 
 
A first in human ‘RADIANCE’ study with the Multi-electrode RF Balloon Catheter enrolled 
subjects between December 2, 2016 and March 8, 2017 in Europe. In this feasibility study 40 
subjects with paroxysmal atrial fibrillation were enrolled. One subject (7.1%) was excluded 
prior to RF ablation procedure. In total 39 subjects were treated with the investigational 
Biosense Webster multi-electrode RF balloon catheter. Four different centers with 9 different 
operators participated in the study. 
 
Of the 40 enrolled subjects, 23 (57.5%) were male and 17 (42.5%) were female. The mean age 
for the 40 subjects was 60.7 ± 10.02 years.  The most prevalent medical condition reported at 
baseline was (systemic) hypertension (22/40 (55.0%)). Subjects suffered from symptomatic AF 
for an average of 51.7 ± 49.71 months at baseline.  
 
The primary endpoint was the incidence of primary procedure-related adverse events 
occurring within seven days of the procedure. From the primary safety endpoint, one subject 
(2.5%) experienced an early-onset (<7 days) primary adverse event, Diaphragmatic Paralysis. 
No 
subject 
deaths, 
atrio-esophagael 
fistula, 
myocardial 
infarction, 
cardiac 
tamponade/perforation, heart block, thromboembolism, CVA, TIA, pneumothorax, 
pulmonary edema, pericarditis, major vascular access complication/bleeding, moderate or 
severe pulmonary vein stenosis were reported.  
 
Apart from the primary adverse events, there were 4 serious adverse events (SAE) reported 
as not being related to the investigational device and study procedure. One SAE (prolonged 
hospital stay for esophageal erythema) has been reported as possibly device and definitely 
(causal relationship) procedure related. 
 
Among 39 subjects that underwent post-ablation cerebral MRI examination and 1 or more 
neurological assessment, 9 subjects (23.1%) were observed with new asymptomatic Cerebral 
Embolic (ACE) lesions. For one of these subjects, an air embolism on sheath insertion was 
noted during the procedure. 2/9 subjects had interrupted warfarin treatment. All ACE lesions 
were resolved during follow-up cerebral examination. 
 
All 39 treated subjects underwent a post procedural esophageal endoscopy.  No ulceration 
was observed in any of the cases. Only esophageal erythema was observed in 5 subjects 
(12.8%).   
 
The procedural performance with the device was favorable, with 100 percent of the treated 
pulmonary veins electrically isolated without the need for a focal ablation catheter. 
 

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As a conclusion, results showed the RF balloon catheter was able to achieve facile, efficient 
and safe electrical isolation of all pulmonary veins with a high rate of first-pass isolation and 
infrequent evidence of latent pulmonary vein re-conduction.  
 
 
1.3 Rationale for design of the clinical investigation 
 
The theoretical advantages to the use of the multi-electrode Radiofrequency Balloon Catheter 
in conjunction with multi-electrode Circular Diagnostic Catheter includes the benefits of other 
balloon-based ablation systems, such as high probability of single-shot PVI with minimal 
collateral damage to non-PV structures, but without the drawbacks of excessive heating or 
cooling of the surrounding tissue. The existing limitation of other existing balloon catheters is 
in the fact that these are single ablative elements that deliver identical amounts of energy 
along the full pulmonary vein ostium circumference, which can lead to over-ablation of thin 
tissue, under-ablation of thick tissue, and unnecessary complications.  
 
The Multi-electrode RF balloon catheter has the potential to deliver directionally-tailored 
energy using multiple electrodes and hereby optimizing both safety and efficacy. The current 
study is a pivotal study that utilizes this new technology in human subjects with PAF. This study 
will evaluate the safety and acute effectiveness of the Multi-electrode RF Balloon catheter, 
with the multi-electrode Circular Diagnostic Catheter when being used for PV isolation in 
treatment of atrial fibrillation. The data of the study will be used for CE-mark registration of 
the device.  
 
1.4 Potential Risk and Benefit 
 
1.4.1
Known Potential Risks 
 
Pericarditis: With any balloon-based ablation, pericarditis can occur due to mechanical or 
thermal irritation of the myocardium.48  This tends to be underreported46 as it is usually 
transient and resolves without intervention. 
 
Phrenic nerve palsy (PNP): Injury to the PN may occur as a result of RF application in the 
region of the right pulmonary veins. The reported incidence of PNP varies from 0% to 0.48% 
when RF energy is used for point-by-point ablation.65,66  While the reported incidence of PNP 
following HB ablation (<4%)38-40,54 or LB ablation (≤6%)41-49,51,52,55 is low, the incidence of PNP 
with CB-2 ablation was reported to range from <5%16,18,20,24,30,31,34,35 to 27%, 19,21,23,25-28,30,55-57 
even with continuous phrenic nerve pacing during right-sided ablation and abortion of 
freezing upon loss of capture. In most cases, PNP with CB-2 is a transient complication,22 
recovering before the end of the procedure,19,21,27,35 or, if not, by the time of 
discharge.16,23,26,29,30,57  However, in a few cases it has been observed to persist for 1020,23,31 to 
2025,28 months, suggesting that the injury is permanent.  
 
Atrioesophageal fistula (AEF): The application of RF energy along the posterior left atrium can 
result in thermal injury to the esophagus and the formation of an AEF. AEF is a rare but 

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catastrophic complication of AF ablation that can occur due to the anatomical proximity of 
the esophagus to the posterior wall of the LA and that is associated with a high mortality 
rate.58  AEF has not been observed in clinical experience with the HB or LB.  Only one patient 
(1.8% of 55 patients) presented with AEF in one prospective observational study with the CB-
219 and this was the only case found in 18 series of consecutive procedures totaling over 2000 
patients.16,19-21,23-31,34,35,55-57   
 
While AEF is uncommon with balloon-based ablation systems, damage to the esophagus is 
fairly common.  One study found that superficial thermal lesions developed in 2% of patients 
and thermal ulcerations in 10% of patients following CB-2 ablation.34  Another study showed 
an incidence of esophageal lesions of 3.19% with CB-2.29  Esophageal lesions were reported in 
1-10% of patients following ablation with the HB.39,40,54 Cooling saline is sometimes infused 
into the esophagus during HB ablation,39,40,54 but this carries with it the further risk of 
aspiration.40  Esophageal injury is most often found after LB ablation, with mild thermal lesions 
found in 7%41 to 8%50 of patients and more severe ulcerations found in 5% to 15%.41,50,55  The 
severity of esophageal lesions was greater with LB compared to RF catheter ablation in a head-
to-head study.50 Moreover, esophageal temperatures in excess of 38.5o-39o C necessitating 
cessation of energy delivery and/or repositioning of the balloon occur more than half of the 
time with LB ablation.41,42,45  The clinical significance of esophageal lesions, if any, is not 
known.25,33,34  
 
Many investigators attempt to mitigate esophageal damage by monitoring endoluminal 
temperature during the ablation procedure. A cutoff temperature of 3o C has 100% sensitivity 
and 100% specificity for predicting esophageal thermal lesions following CB-2 ablation.20  
However, esophageal temperature during LB ablation has poor specificity for esophageal 
injury, with no significant correlation between maximal esophageal temperature and 
incidence and severity of esophageal thermal lesions.50 
 
Pulmonary vein stenosis: The risk of pulmonary adverse events (e.g. PV stenosis, thrombus 
and hypertension) associated with an RF ablation procedure targeting the pulmonary veins is 
considered small (<4%).9,10,61-64  PV stenosis has not been reported following CB-2 ablation.  In 
clinical experience with HB ablation, PV stenosis was reported in <2-5% of patients,38-40 and 
was usually asymptomatic.40  Similarly, with LB ablation, PV stenosis is rarely reported.  In one 
study, mild stenosis (up to 25% narrowing of the PVs) was found in 44% of patients and 
moderate stenosis (26-50% narrowing) in 6%; there were no cases of severe stenosis (>50% 
narrowing).47   
 
Thrombus formation: A thrombus may form on the ablation electrode during the application 
of RF current that could become dislodged and embolize to produce stroke, myocardial 
infarction, or other ischemic injury. The risk of thrombus is minimal with CB-2, but 
microthrombi were found in preclinical studies following HB ablation.36  In the clinical setting 
with HB, 5 patients of 238 (2.1%) developed a cerebral infarction.  However, in each case, this 
was attributed to arrhythmia recurrence and insufficient anticoagulation.39  With LB, data 
suggest 
that 
more 
energy 
applications 
and 
higher 
energy 
output 
facilitate 
thermocoagulation.44,53 Thrombus formation following ablation may also occur on the 
endocardium and may produce arterial or pulmonary embolus.  
 
 

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Pericardial effusion/ cardiac tamponade: Cardiac perforation may result in cardiac 
tamponade and may require percutaneous pericardial drainage or surgical repair.  Pericardial 
effusion was reported in 0.6% - 7.3% of patients ablated with CB-2,16,27,35,56 and cardiac 
tamponade in 0.2% - 3%.21,24,25,28  Pericardial effusion may occur at a rate of 15% in patients 
treated with the HB.37  With the LB, LA perforation has occurred from mechanical trauma due 
to a whipping motion of the sheath toward the LA roof after balloon retraction.41,51 Aside from 
these reports, the incidence of pericardial effusion has been <2%47,48 and cardiac tamponade 
5%46-48,51 with the LB.  Significant hemodynamic compromise can result in neurologic injury 
or death.  This risk is greatest in a thin-walled chamber (ie, RA, LA, or RV).  However, the risk 
of perforation due to steam pop is reduced when the minimum amount of energy output 
required to achieve transmurality is used.45   
 
Cerebral ischemic lesions: The incidence of transient ischemic attack (TIA) is <3% following 
CB-2 ablation;25,30,35 however, in most studies imaging for silent ischemic brain lesions was not 
performed.  In one study in which post procedural imaging was obtained, 13.6% of LB-treated 
patients were observed to have new embolic brain lesions, and another 2.3% had diplopia 
secondary to an ischemic lesion.44  There were similar findings of diplopia due to a suspected 
ischemic event (1.4%) in another LB study.46  The incidence of asymptomatic cerebral lesions 
seen on MRI 1-2 days post-procedure in a randomized controlled study was 24% for LB, which 
was not significantly different from RF catheter ablation or first-generation CB.53   
According to HRS guidelines, 2017, Asymptomatic cerebral emboli (ACE) incidence is varying 
from 2%-15% as a complication to AF ablation.  It is defined as an occlusion of a blood vessel 
in the brain due to an embolus that does not result in any acute clinical symptoms and is 
therefore ‘silent’. Emboli can result from a thrombus, gas, air, tissue or fat. Source of micro-
emboli include thrombi, which can develop on sheaths, materials, air introduction through 
sheath or during catheter exchange.  
 
Coronary artery occlusion: RF current may cause occlusion of a coronary artery, either by 
direct thermal damage, spasm, or thrombosis. Research suggests that the risk of coronary 
occlusion is less than 0.5%.59,60 Because coronary arterial occlusion could produce myocardial 
infarction, angina or death, the physician will attempt to restore coronary blood flow through 
pharmacological, catheter and/or surgical intervention as medically indicated. 
 
Heart block: The application of RF current close to the AV node or HIS bundle could damage 
or destroy the normal AV conduction system, producing complete heart block and requiring 
implantation of a permanent pacemaker. 
 
Cardiac perforation: Cardiac perforation may result from catheter manipulation or application 
of RF current (risk is <1%).59,60  This may result in cardiac tamponade and may require 
percutaneous pericardial drainage or surgical repair.  However, the risk of perforation related 
to a deep steam pop is reduced if RF energy is not delivered perpendicular to the wall at power 
above 35 or 40 watts. If the lesion is deeper, the risk of steam pop is higher above 35-40 watts. 
 
Cardiac valve injury: Injury to a cardiac valve may result from catheter manipulation or the 
application of RF current (risk <1%).59,60 This may produce valvular insufficiency and possibly 
require surgical valve replacement.  
 
Vascular access / bleeding complication: Vascular access complication, femoral 

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arteriovenous fistula, hematoma, and pseudoaneurysm are commonly reported following CB-
2 (typically <4%),16,19,21,23-27,30,35,55-57 or LB ablation (<6%).46,49 Arterial or venous injury, including 
arterial dissection, thrombosis, occlusion or hemorrhage at the catheter insertion sites or at 
other sites along the vessels (risk <1%).59,60 These types of injuries may cause hemorrhage, 
hematoma or ischemic injury to an extremity or major organ.  Hemorrhage could occur as a 
result of anticoagulation (risk <0.5%), which may require transfusion.59,60 
 
Radiation exposure: Radiation exposure during the fluoroscopic imaging of the catheters may 
result in an increase in the lifetime risk of developing a fatal malignancy (0.1%) or a genetic 
defect in offspring (0.002%).67-69 
 
Infection: The percutaneous procedure carries risk of infection, either at the catheter 
insertion site or systemically, including endocarditis and septic emboli (risk <0.5%).59,60 This 
risk can be minimized by using standard aseptic technique and, when indicated, by the use of 
antibiotic agents. 
 
Additional contraindications: Additional contraindications for RF ablation include: 
hemodynamic instability, bacteremia, coagulopathy, prosthetic tricuspid valve, intra-atrial or 
venous thrombosis, and pregnancy. A patient could develop an allergic reaction to the local 
anesthetic, sedatives, x-ray dye, heparin, protamine, or other agents administered during the 
procedure (risk <1%).70-75 
 
 
1.4.2
Minimization of Risk 
The criteria for subject selection, methods, personnel, facilities, and training that are specified 
in this study are intended to minimize the risk to subjects undergoing this procedure.  
 
Patient selection:  Subjects will be prescreened carefully prior to enrollment in the study to 
ensure compliance with the inclusion and exclusion criteria.  The exclusion criteria have been 
developed to exclude subjects with a medical history or condition that increases their risk of 
adverse events (refer to Section 4.2 for the Exclusion Criteria).22 
 
Pre-procedure 
imaging: 
Subjects 
must 
have 
a 
pre-procedure 
Transesophageal 
Echocardiogram (TEE) or Intracardiac Echocardiography (ICE) to screen for the presence of LA 
thrombus, which is intended to decrease the potential for thromboembolic complications.   
 
Within procedure safeguards: Investigators highly skilled in intracardiac mapping and AF 
ablation with RF ablation catheters will be selected for participation in the study.  AF ablation 
procedures will be performed in electrophysiology laboratories with the assistance of skilled 
nurses and technicians. Ablating investigators will undergo device training, including a 
combination of didactic and hands-on training using the multi-electrode RF balloon catheter 
in a simulation model, prior to enrolling subjects. 
 
The risk of PNP will be minimized by monitoring the PN with pacing maneuvers before the 
ablation.  Ablation will be stopped immediately if evidence of PN impairment is observed, and 
the balloon will be repositioned.  
 

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The risk of PV stenosis will be minimized by not positioning the balloon within the tubular 
portion of the target PV.  The balloon should not be inflated while the catheter is positioned 
inside the pulmonary vein; rather, it is always to be inflated in the atrium, then positioned at 
the PV ostium. 
 
The risk of ACE will be minimized by implementing an anti-coagulation regimen prior to 
balloon introduction into the left atrium and during procedure to avoid thrombi/emboli during 
procedure. Investigators will be instructed to remove air bubbles prior to insertion and to 
minimize catheter exchange during procedure to mitigate the of risk air introduction.  
 
In order to help prevent esophageal injury, intraluminal esophageal temperature monitoring 
is required for the study. 
 
Post-procedural management: In accordance with the 2016 ESC AF  Management Guidelines2, 
all subjects will be recommended to be maintained on systemic oral anticoagulation therapy 
for at least two months post-procedure, beginning within 6 hours post-procedure.  After two- 
months post-procedure, a decision regarding continuation of systemic anti-coagulation 
agents will be based on the patient risk for thromboembolism. Systemic oral anticoagulation 
will be recommended to be continued beyond two-months post-ablation in patients with 
CHA2DS2-VASc score ≥2. 
 
Safety data during enrollment and follow-up will be closely monitored and evaluated per the 
specific safety management plan for the study. Also, refer to safety section (9) for more 
information on safety management.   
 
1.4.3
Known Potential Benefits 
In patients with atrial fibrillation, elimination of or a reduction in symptoms is a major driving 
force for therapy. The primary clinical benefit of ablation of AF is an improvement in QoL 
resulting from the elimination of arrhythmia-related symptoms such as palpitations, fatigue, 
or effort intolerance.3 The Balloon Type catheter is intended to allow for the ablation of larger 
areas of tissue compared to traditional single tip catheters. Thus, the multi-electrode RF 
balloon catheter should possess the benefit of reduced procedure time, the possibility of 
single-shot-PVI, and fewer catheter exchanges.  
 
Moreover, ablation procedures using Balloon catheters are typically less complex than point-
by-point ablation procedures. By implementing a compliant balloon design, the RF balloon 
Catheter can mold to varied PV anatomy and achieve very good contact with the tissue. This 
allows for easier positioning of the catheter, shorter operator learning curves, faster total 
procedure times, and potentially reduces the amount of power required to create a 
circumferential contiguous lesion in the ostium of the pulmonary vein. 
 
 
 
 
 
 
 

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2 Objectives and Purpose  
 
2.1 Objective 
The primary objective of this clinical investigation is to demonstrate the safety and acute 
effectiveness of the Multi-Electrode Radiofrequency Balloon Catheter in conjunction with the 
multi-electrode circular diagnostic catheter, in the isolation of the atrial pulmonary veins in 
treatment of subjects with paroxysmal atrial fibrillation. Specifically: 
x
To demonstrate the safety based on the proportion of early-onset (within 7 days of 
ablation procedure) primary adverse events. 
x
To demonstrate the acute effectiveness based on the proportion of acute procedural 
success defined as confirmation of entrance block in treated PVs after adenosine and/or 
isoproterenol challenge (with or without the use of a focal ablation catheter). 
 
The major secondary objective of this study is to evaluate the incidence of (serious) adverse 
events during and after procedure up to 12 months following procedure. The need for the use 
of a focal catheter (touch-up) to get to PV isolation will also be evaluated. 
 
2.2 Purpose 
The purpose of this study is to prove that the use of the Multi-Electrode Radiofrequency 
Balloon Catheter, in conjunction with the multi-electrode circular diagnostic catheter, for the 
isolation of the atrial pulmonary veins in treatment of subjects with paroxysmal atrial 
fibrillation is safe and effective. The results of this study will be used for CE-mark registration 
of the Multi-Electrode Radiofrequency Balloon Catheter.  
 
 
 
3 Study Design and Endpoints 
 
3.1 Description of the Study Design 
A roll-in phase of up to 3 subjects per ablating physician with the multi-electrode RF balloon 
catheter will be implemented. The design of the main study will be carried out as an 
interventional, pivotal, prospective, multicenter, single-arm clinical study.  
 
3.1.1
Roll-In Subjects 
 
One key purpose of this study will be to demonstrate the acute effectiveness of the multi-
electrode RF balloon catheter in the absence of confounding evidence that reflects early 
stages of a medical device learning curve. In addition to a requirement for multi-electrode RF 
balloon catheter training prior to each ablating physician’s participation in this study, 
additional experience of the multi-electrode RF balloon use, in the context of this clinical 
investigational plan, would serve to generate a clearer perspective of the multi-electrode RF 

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catheter acute effectiveness in treating PAF subjects. Therefore, to minimize the learning 
curve effect of using the multi-electrode RF balloon catheter, roll-in subjects will be 
prospectively assigned to each ablating physician per the training plan specifically designed 
for this study. 
-1 roll-in subject will be included for ablating physicians that participated in the 
RADIANCE Study 
-2 roll-in subjects will be included by ablating physicians that didn’t participate in the 
RADIANCE study and have extensive balloon experience (>15 cases/year) 
-3 roll-in subjects will be included by ablating physicians that didn’t participate in the 
RADIANCE study and don’t have extensive balloon experience (<15 cases/year), to 
minimize the learning curve effect of  
A subject who is excluded or discontinued will not count toward the roll-in subjects. All roll-in 
subjects will be followed for 12 months post-procedure. The roll-in subjects will be excluded 
from the main study analyses and will be analyzed separately. 
 
 
3.1.2
Main Study 
 
This will be an interventional, pivotal, prospective, multicenter, single-arm safety and acute 
effectiveness clinical evaluation utilizing the Biosense Webster Multi-electrode RF Balloon 
Catheter in combination with the Biosense Webster Multi-Electrode Circular Diagnostic 
Catheter.  
 
Eligible subjects who sign the informed consent form and who comply with all inclusion and 
exclusion criteria will be enrolled and treated with the Multi-Electrode RF balloon catheter in 
conjunction with the multi-electrode circular diagnostic catheter. An adaptive sample size of 
up to 230 evaluable subjects (non roll-in) be included in the main study phase. All study 
subjects (including roll-ins) will be followed-up for 12 months after study procedure. 
 
Planned statistical analyses of these endpoints are described in the Statistical Analysis section 
(section 14) of this clinical investigational plan. 
 
3.1.3
Neurological Assessment Study 
 
A focused neuropathological evaluation will be integrated within the Main Study.  This subset 
of subjects will be included in the neurological assessment evaluable subgroup (NAE). Subjects 
will be assessed for incidences of symptomatic and asymptomatic pre-and post-ablation 
cerebral emboli with either an absence of CNS deficits (asymptomatic) or with emboli-
associated neurological symptoms (symptomatic).  
A prospective evaluation of 40 subjects at participating sites will be included in this 
assessment. The mandatory roll-in subjects will not be eligible for the NAE assessment to 
minimize the confounding influence of a learning curve during early use of a complex medical 
device. Enrollment in the NAE population may be terminated prior to achieving the target 40 
subjects if study enrollment ends early after a planned interim look. 
At participating sites and considering the above caveats, all subjects (non roll-in) who are 
enrolled in the main study will be considered for participation in the NAE, per specific eligibility 
requirements: 

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1. IF a subject satisfies any one of the 3 following conditions he/she will be excluded 
from the NAE: 

Presence of iron-containing metal fragments in the body  

Subject has a contraindication to use of contrast agents for MRI such as advanced 
renal disease etc. (at PI discretion) 

Subject has an unresolved pre-existing neurological deficit. 
2. Subject must provide written informed consent for MRI, NIHSS, MoCA, mRS, and 
general neurological assessments. 
 
3.2 Study Endpoints 
 
3.2.1
Primary Endpoints 
 
x
Acute Safety 
The primary safety endpoint is the incidence of early onset Primary Adverse Events (PAEs) 
(within seven (7) days of the initial mapping and ablation procedure). PAEs include the 
following AEs (refer to Section 9.1.3 for a complete list and definitions): 
Death* 
Stroke/CVA 
Atrio-Esophageal Fistula* 
TIA 
Myocardial Infarction 
Phrenic Nerve Paralysis 
Cardiac Tamponade/perforation 
Pulmonary Vein Stenosis* 
Thromboembolism 
Major Vascular Access Complication/Bleeding 
* Device or procedure related death, pulmonary vein stenosis and atrio-esophageal fistula that occur 
greater than one week (7 days) and (≤) less or equal to 90 days post-procedure are considered and 
analyzed as primary AEs. 
 
x
Acute Effectiveness 
Acute procedural success defined as confirmation of entrance block in treated PVs after 
adenosine and/or isoproterenol challenge (with or without the use of a focal catheter) 
 
3.2.2
Secondary Endpoints 
 
x
Safety: 
- incidence of individual PAE from the primary composite 
- Incidence of Serious Adverse Device Effects (SADEs) 
- Incidence of Serious Adverse Events (SAEs) within 7 days (early onset), >7-30 days 
(peri-procedural) and >30 days (late onset) of initial ablation procedure 
- Incidence of non- serious adverse events 
- Incidence of pre-and post-ablation asymptomatic and symptomatic cerebral 
emboli as determined by MRI evaluations. 
- Frequency, anatomic location, and size (diameter and volume) of cerebral emboli 
by MRI evaluations at baseline, post-ablation and during follow-up. 
- Incidence of new or worsening neurologic deficits, post-ablation and at follow-up, 
compared to baseline. 
- Summary of NIHSS scores at baseline, post-ablation and during follow-up. 

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- Summary of MoCA scores at baseline, 1 month follow-up and during further 
follow-up.    
- Hospitalization for cardiovascular events (with hospitalization defined as 
prolonged stay ≥2 nights post index procedure or in-patient stay not concurrent 
with index procedure ≥ 1 calendar day) 
x
Effectiveness: 
- Percentage (%) of PVI touch-up by focal catheter among all targeted veins and by 
subject.  
- Percentage (%) of subjects with use of focal catheter ablation for non-PV triggers 
- Percentage (%) of subjects with freedom from documented, symptomatic atrial 
fibrillation (AF), atrial tachycardia (AT), or atypical (left side) atrial flutter (AFL) 
episodes (episodes >30 seconds on arrhythmia monitoring device from day 91 to 
180). 
- Percentage (%) of subjects with freedom from documented, atrial fibrillation (AF), 
atrial tachycardia (AT), or atypical (left side) atrial flutter (AFL) episodes (episodes 
>30 seconds on arrhythmia monitoring device from day 91 to 180). 
- Percentage (%) of subjects with freedom from documented, symptomatic atrial 
fibrillation (AF), atrial tachycardia (AT), or atypical (left side) atrial flutter (AFL) 
episodes (episodes >30 seconds on arrhythmia monitoring device from day 91 to 
365). 
- Percentage (%) of subjects with freedom from documented, atrial fibrillation (AF), 
atrial tachycardia (AT), or atypical (left side) atrial flutter (AFL) episodes (episodes 
>30 seconds on arrhythmia monitoring device from day 91 to 365). 
 
x
Additional analyses on procedural characteristics, including but not limited to: 
- Total procedure time, ablation time, RF application time, balloon dwell time, time 
to effect (PVI) 
- Number and time of RF applications per PV location 
- Fluoroscopy time and dose        
 
x
Health economic assessments, including but not limited to: 
- Index procedural workflow costs 
- Hospital costs 
- Quality of Life (AFEQT questionnaire) 
 
Roll-in subjects will not be included in the main study analyses and will be analyzed separately. 
 
 
4 Study Population 
 
4.1 Participant Inclusion Criteria 
Candidates for this study must meet ALL of the following criteria: 
1. Diagnosed with Symptomatic Paroxysmal AF. 
2. Selected for AF ablation procedure for pulmonary vein isolation. 

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3. Able and willing to comply with uninterrupted per-protocol anticoagulation 
requirements  
4. Age 18-75 years  
5. Able and willing to comply with all pre-, post- and follow-up testing and requirements. 
6. Signed Patient Informed Consent Form. 
 
 
 
4.2 Participant Exclusion Criteria 
Candidates will be excluded if ANY of the following criteria apply: 
1. AF secondary to electrolyte imbalance, thyroid disease, or reversible or non-cardiac 
cause. 
2. Previous surgical or catheter ablation for AF. 
3. Anticipated to receive ablation outside the PV ostia and CTI region 
4. Previously diagnosed with persistent, longstanding AF and/or continuous AF > 7 days, 
or > 48 hrs terminated by cardioversion. 
5. Any percutaneous coronary intervention (PCI) within the past 2 months. 
6. Valve repair or replacement and presence of a prosthetic valve. 
7. Any carotid stenting or endarterectomy. 
8. Coronary artery bypass grafting (CABG), cardiac surgery (e.g. ventriculotomy, 
atriotomy), or valvular cardiac surgical or percutaneous procedure within the past 6 
months. 
9. Documented left atrium (LA) thrombus on baseline/pre-procedure imaging. 
10.LA antero posterior diameter > 50 mm  
11.Any PV with a diameter ≥ 26 mm 
12.Left Ventricular Ejection Fraction (LVEF) < 40%. 
13.Contraindication to anticoagulation (e.g. heparin). 
14.History of blood clotting or bleeding abnormalities. 
15.Myocardial infarction within the past 2 months. 
16.Documented thromboembolic event (including transient ischemic attack [TIA]) within 
the past 12 months. 
17.Rheumatic Heart Disease. 
18.Uncontrolled heart failure or New York Heart Association (NYHA) function class III or 
IV. 
19.Awaiting cardiac transplantation or other cardiac surgery within the next 12 months.  
20.Unstable angina. 
21.Acute illness or active systemic infection or sepsis. 
22.Diagnosed atrial myxoma or interatrial baffle or patch. 
23.Presence of implanted pacemaker or, implantable cardioverter defibrillator (ICD), or 
tissue-embedded, iron-containing metal fragments. 
24.Significant pulmonary disease, (e.g. restrictive pulmonary disease, constrictive or 
chronic obstructive pulmonary disease) or any other disease or malfunction of the 
lungs or respiratory system that produces chronic symptoms. 
25.Significant congenital anomaly or medical problem that, in the opinion of the 
investigator, would preclude enrollment in this study. 

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26.Women who are pregnant (as evidenced by pregnancy test if pre-menopausal), 
lactating, or who are of child bearing age and plan on becoming pregnant during the 
course of the clinical investigation. 
27.Enrollment in an investigational study evaluating another device, biologic, or drug. 
28.Has known pulmonary vein stenosis. 
29.Presence of intramural thrombus, tumor or other abnormality that precludes vascular 
access, or manipulation of the catheter. 
30.Presence of an IVC filter 
31.Presence of a condition that precludes vascular access. 
32.Life expectancy or other disease processes likely to limit survival to less than 12 
months. 
33.Presenting contra-indication for the devices (e.g. TTE, CT, Holter, etc.) used in the 
study, as indicated in the respective instructions for use. 
34.Categorized as a vulnerable population and requires special treatment with respect 
to safeguards of well-being  
 
Additional exclusion criteria for Neurological Assessment Evaluable (NAE) subjects: 
35.Contraindication to use of contrast agents for MRI such as advanced renal disease, 
etc. (at PI discretion) 
36.Presence of iron-containing metal fragments in the body  
37.Unresolved pre-existing neurological deficit. 
 
 
4.3 Participant Withdrawal or Termination 
 
4.3.1
Reasons for Withdrawal or Termination 
 
Participants are free to withdraw from participation in the study at any time upon request 
without penalty or loss of benefits to which they may otherwise be entitled. Participants will 
be informed prior to study entry that they are free to withdraw from the study at any time 
and for any reason without prejudice to their future medical care by a physician or the 
institution. 
   
An investigator may terminate a subject’s participation in the study if:  
•
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant  
•
Withdrawal is in the subjects’ best interest 
•
The participant no longer meets eligibility criteria or meets an exclusion criterion 
(either newly developed or not previously recognized) that precludes further study 
participation. 
•
Subject withdraws consent 
•
Subject is lost to follow up 
 
Every subject should be encouraged to remain in the study until they have completed the 
protocol required follow-up period. 

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4.3.2
Handling of Participant Withdrawals or Termination 
 
If a subject is removed or withdraws from the study, the date and reason for withdrawal will 
be recorded on the appropriate electronic case report form (eCRF). If the subject is withdrawn 
due to an adverse event (AE) or serious adverse event (SAE), the Investigator should follow 
the subject until the AE/SAE has resolved or is considered stable.   
 
If a subject is unable to return for an office/clinic visit or cannot be contacted by telephone, 
3 separate telephone calls should be made to obtain subject related safety information. All 
attempts should be documented in the source documents. If the subject does not respond 
to the 3 telephone calls, then the investigator must send a certified letter to the subject. If 
the subject does not respond to the letter, then the subject will be considered “lost to 
follow-up” for the study.   
Subjects who have signed the ICF, but are later found not to be eligible PRIOR to insertion of 
the study catheter can be replaced. Replacement subjects will be recruited and enrolled 
following the same procedures as non-replacement subjects. 

4.4 Subject Enrollment Disposition 
 
x
Enrolled Subjects: Patients who sign the informed consent form. 
x
Evaluable Subjects:  All enrolled subjects who have the study catheter inserted.  
x
Excluded Subjects: Subjects who are enrolled but never undergo insertion of the study 
catheter. Excluded subjects will only be followed between ICF signature and exclusion for 
event reporting. 
x
Roll-In Subjects:  Enrolled Subjects who have the study catheter inserted and RF delivered 
during the roll-In phase of the ablating investigator. These subjects will not be included in 
the main study analyses and will be analyzed separately.   
x
Discontinued Subjects: Enrolled subjects who have the study catheter inserted but do not 
undergo ablation (i.e., no RF energy is delivered with the study catheter).  Discontinued 
subjects will remain in follow-up for 30 days.   
x
Lost to Follow-up Subjects:  Evaluable subjects of which contact is lost after most recent 
visit (despite 3 documented attempts to contact the subject). 
x
Withdrawn / Early Termination Subjects:  Subjects who withdraw consent for study 
participation or are withdrawn by the investigator, are terminated from the study prior to 
completion of all follow-up visits. 
x
Completed Subjects:  Enrolled subjects who have not been excluded, discontinued, 
withdrawn, terminated early, or lost-to-follow-up from the study prior to the final study 
visit. 
 

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5 Responsibilities 
5.1 Investigator Responsibilities 
 
Investigators at each participating clinical site will have the following responsibilities: 
x
Assuring compliance by site personnel with the provisions of the protocol 
x
Providing the Sponsor with: 
o Signed, dated Investigator Agreement 
o Written EC approval letters and EC-approved consent forms 
o Signed, dated Financial Disclosure form for each participating investigator 
o Curriculum vitae for each investigator 
x
Maintain an accurate and current Delegation of Authority log which identifies 
individuals authorized to perform work for the study and assuring compliance by site 
personnel with the provisions of the protocol 
x
Completing the appropriate training on the device (ablating investigators only) and 
the study protocol prior to enrolling and treating subjects 
x
Maintain accurate and current logs for the study such as:  
o Subject log, Device Accountability Log 
x
Obtain initial and amendment (if applicable) EC approval and annual review/approval 
thereafter for the study protocol and informed consent as applicable 
x
Obtain informed consent form and enroll patients 
x
Perform medical procedures 
x
Order tests required by the study protocol 
x
Review pre-procedure imaging pertaining to the pulmonary vein size prior to 
treatment 
x
Follow subjects until the end of the study protocol 
x
Accurately complete and sign eCRFs in a timely manner 
x
Maintain relevant source documentation and allow Sponsor direct access to perform 
monitoring or auditing duties  
x
Maintain records and provide reports according to prevailing regulatory requirements 
x
Share relevant study-related information with delegated study staff 
x
Inform the appropriate entities (e.g., Sponsor, CA, EC) in a timely manner regarding 
the occurrence of AEs and/or product malfunctions. 
x
Making sufficient effort to maintain contact with treated subjects who fail to comply 
with the follow-up requirements 
x
Maintain study records for at least 5 years or as specified per country specific record 
retention requirements after the study is completed and or terminated. The Sponsor 
will notify the Investigator of either of these events. 
x
Complying with EC and Sponsor annual report requirements, including the final 
report. 
 

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5.2 Sponsor Responsibilities 
 
The Sponsor (Biosense Webster, Inc.) will be responsible for the following: 
x
Conduct of pre-study site assessment and approval 
x
Preparation and modification (if applicable) of study documents including but not 
limited to the protocol, CRFs and informed consent  
x
Selection of appropriately qualified and trained individuals, including monitors, to 
conduct the study  
x
Conduct protocol and device training for investigators and research personnel as 
applicable 
x
Set-up of study-specific committees. 
x
Obtain signed study contracts from investigators/hospitals, CROs and other involved 
parties 
x
Ship study devices to each site 
x
Monitor sites for the duration of the study 
x
Maintain study database 
x
Inform investigator of his/her responsibilities  
x
Submit and obtain approval for study from applicable regulatory agencies 
x
Preparation of reports summarizing the status of the study no less than annually.  
These reports will be supplied to the Principal Investigator at each site. 
x
Update Report of Priors, IFU, IB, and Risk Analyses, as applicable 
x
Update investigators on safety issues, if needed 
x
Report to study investigators and regulatory agencies, as required 
x
Have AEs reviewed by the study-specific committees, as required 
x
Communications with the competent authority 
x
Submission of any amendments to the Clinical Study Protocol/Investigational Plan to 
the competent authority. 
 
6 Study Device Description 
 
6.1 Device Acquisition 
After obtaining a fully executed clinical trial agreement and appropriate approvals, the 
sponsor will initiate shipment(s) of investigational devices to the site. The Sponsor will keep 
records of all investigational devices shipped to the site. Approved investigational devices will 
be shipped directly to the site and will be received by the site. Investigators are responsible 
for appropriate logging of the devices received, verification of packing slip information (i.e., 
lot numbers and quantity shipped), date and identity that each device was used in the study, 
disposition information regarding disposal or return to the Sponsor. 
 

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
 

 
 
 
 
 
 
 
 

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8 Study Schedule  
 
8.1 Screening and Informed Consent 
 
Subjects presenting to the institution with symptomatic PAF and considered for an RF ablation 
procedure should be screened by the investigator or designated member of the research team 
for study eligibility per the protocol inclusion and exclusion criteria. Sites will be instructed to 
screen all subjects who require a documented RF ablation procedure for symptomatic PAF 
without regard to sex or race. 
 
The study investigator or designated member of the research team will obtain written 
informed consent from the subject. The patient informed consent procedure must be done 
within 60 days before the actual study procedure takes place. The background of the proposed 
study and the potential benefits and risks of the study should be explained to the subject. The 
subject or legal representative must sign the consent form prior to any study-specific exams 
or tests are provided to them that fall outside of the standard of care. The consent form used 
must have prior approval from the regulatory authorities and study site's Ethics Committee. 
Failure to obtain informed consent renders the subject ineligible for participation in the study. 
 
The investigator and/or designee must also clearly document the process of obtaining 
informed consent in the subject’s source documents. The voluntary process of informed 
consent confirms the subject’s willingness to participate in the study. It’s the investigator’s 
responsibility to ensure that the informed consent process is performed in accordance with 
ICH-GCP and with applicable local and federal regulations. If new information becomes 
available that can significantly affect a subject’s future health and/or medical care, this 
information shall be provided to the subject(s) affected in written form. If relevant, all affected 
subjects shall be asked to confirm their continuing informed consent in writing by dating and 
signing an amended ICF. 
 
Each subject screened for enrollment in the clinical investigation who signs the patient 
informed consent form will be enrolled into the study. Each eligible subject who signs the 
informed consent on the additional neurological assessments and has post-MRI completed 
will be included in the NAE subgroup. No subject should undergo any clinical investigation 
specific tests or examinations that fall outside the standard of care without first signing the 
patient informed consent form for this clinical investigation.   
 
 
8.2 Baseline Evaluation and Procedures 
 
8.2.1
Pre-Procedure/Baseline Assessments 
Below pre-procedure assessments and data collection must be performed prior to the 
ablation procedure.   

Patient Information and Consent (procedure must be done within 60 days of consent) 

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
Demographics (age, gender, etc). 

Medical history, including but not limited to arrhythmia, heart disease, thromboembolic 
events, lung/respiratory problems. 

AF history (first evidence of AF, number of episodes, symptoms, etc). 

NYHA Functional Class Scale. 

CHA2DS2 VASc Score. Subjects will be scored against the CHA2DS2 VASc.  

Medication history: Medication history (cardiac medication, AAD medication, 
anticoagulation regimen and any other clinically significant medication history) shall be 
gathered by interview or from medical records following enrolment but prior to the 
ablation procedure and should be recorded in the eCRF.  

Anticoagulation therapy: Uninterrupted anticoagulation management is mandatory for 
each study subject. For subjects on warfarin/coumadin therapy, subjects shall be 
maintained on Warfarin/Coumadin for at least 3 weeks prior to treatment with an INR ≥ 
2 (to be confirmed maximum 48h hours pre-procedure). Any INR <2 within 3 weeks prior 
to ablation will lead to exclusion of the patient or postponement of the study procedure. 
The results must be available prior to start of procedure.  

Electrocardiogram (12-Lead ECG). Data from 12-lead ECG recordings will be collected if 
available.  

Transthoracic Echo (TTE) to determine the atrial size and LVEF% should be completed 
within 60 days prior to the study ablation procedure.  

Cardiac multi slice CT/MRA image to evaluate the number, size and anatomy of the 
pulmonary veins and the left atrial anatomy within 30- days pre-procedure is mandatory.  
For each PV, the following measurements are to be done: 

Major axis (mm) 

Minor axis (mm) 

Average diameter (mm) 

Subjects with a PV with average diameter of ≥ 26mm will be excluded from the study. 

For subjects included in the neurological assessment subgroup, Cerebral MRI, 
Neurological Exam and Neurological Evaluation using the Montreal Cognitive 
Assessment (MoCA), NIH Stroke Scale and Modified Rankin Scale (mRS) are required to 
be performed within 72- hours pre-procedure to evaluate the neurological condition and 
presence of neurological deficits of the subjects before undergoing study ablation 
procedure. A certified/qualified neurologist  must perform neurologic exams at pre-and 
post-ablation and possibly at other follow-up visits, pending previous findings of micro-
emboli/neurologic deficits. Pre-and post-ablation cerebral MRIs will be analyzed by a 
central core lab to determine the frequency, size, and anatomical location of cerebral 
micro-emboli, if any.  

Imaging for detection of left atrial thrombus or other structural contraindications to an 
ablation procedure is mandatory the day before or the day of the ablation procedure. 
Presence of a thrombus will require postponement of the ablation procedure or may even 
lead to exclusion of the subject from further study involvement. The imaging method to 
be used for atrial thrombus detection is transesophageal echocardiography (TEE) or 
intracardiac Echocardiography (ICE)  

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- Confirmation of target ACT 350-400 PRIOR to insertion of the Balloon Catheter into 
the left atrium and maintain  throughout the procedure 
- Introduction of the RF Balloon Catheter  
- Introduction of the Multi-Electrode Circular Diagnostic Catheter (Frontera) 
- PV ablation with RF Balloon Catheter and confirmation of isolation by the Frontera 
- Confirmation of PV isolation in all targeted PVs using the Frontera 
- ROLL-IN SUBJECTS ONLY: Confirmation of PV isolation using Lasso®. Note that use of 
Lasso® is not allowed for non roll-in subjects. 
- ROLL-IN SUBJECTS ONLY: Voltage map creation 
- Isoproterenol/Adenosine challenge  
- Confirmation of entrance block in all targeted PVs  
 
 
8.2.2.3
Study Ablation Procedure Guidelines 
 
Electrophysiology Study, Mapping and Ablation Procedure 
 

Anesthesia or sedation should be delivered per standard EP lab procedure. 

Placement of diagnostic catheters: 

Coronary sinus catheter in the CS for pacing purposes 

Other catheters may be placed at the discretion of the investigator 

Mandatory use of a multi-electrode esophageal monitoring device to minimize 
risk of esophageal injury. 

(Optional: Introduce an Intracardiac Echo (ICE) probe to review LA anatomy and 
PVs) 

Administration of heparin bolus PRIOR to transseptal puncture.  

A single transseptal puncture should be performed per standard EP lab. Aim for 
an anterior, inferior puncture.  

Following successful transseptal puncture, a FAM map can be performed utilizing 
Lasso® or PentaRay® (at investigator discretion). 

Confirm target ACT 350-400 sec. Systematic anticoagulation with heparin should 
be administrated with ACT level checked every ± 15-30 minutes to target ACT of 
350-400 seconds throughout the procedure. 

Introduction of the 13.5 F sheath. Before inserting the sheath into the patient, 
flush the sheath with heparinized normal saline to remove air bubbles. In order to 
achieve a smooth introduction of the sheath a 10 or 11 F dilator to upsize the 
femoral vein access before introducing the sheath is recommended. 

Introduce the Balloon Catheter and Frontera Catheter as per instructions for use.  
To facilitate insertion, the Y-connector (Copilot, Abbot, 0.096 inch) should be 
used. The choice of loop diameter (15mm, 20mm and 25mm) of the Frontera 
Catheter is at investigator’s discretion. Prior to extending the balloon outside the 
sheath, advance the Frontera Catheter under fluoroscopy to access the vein  

Use the steerable sheath to drive the Frontera Catheter to the first target vein 
under fluoroscopy. 

Advance and position the Balloon Catheter at the pulmonary vein ostium.  

Start saline flow rate at 35 mL/min to fully expand balloon. 

Check for occlusion using Radiopaque Contrast (use contrast & saline mixture of 
50/50). 

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
Perform and record angiography to confirm occlusion of the PV (mandatory). 
Ensure that the catheter is not inside the pulmonary vein before starting ablation.  

Identify the posterior electrodes via the fluoroscopic markers (optional) and on 
the CARTO image, prior to each ablation.  

When position is satisfactory, commence energy delivery with the Balloon 
Catheter.  

Prior to ablation in the region of the right sided veins, precautionary measures to 
evaluate the proximity to the phrenic nerve are mandatory.   

Pace out of the superior vena cava (SVC) for phrenic nerve pacing. 

Assure diaphragmatic capture PRIOR to RF delivery. 

Stop RF delivery if phrenic nerve capturing is lost or attenuated. 

Ensure continuous monitoring of ablation parameters, PV recordings and 
esophageal temperature during RF energy delivery. 

Stop RF ablation posteriorly if esophageal temperature rises more than 2 
degrees from baseline temperature. 

Record time to Pulmonary Vein Isolation. Bonus lesions are not permitted 
once acute PVI has been confirmed  

Turn off RF energy delivery to posterior electrodes after maximum 20 
seconds 

All subjects will undergo PV ablation with the Balloon Catheter until PVI is 
achieved and isolation confirmed by Frontera Catheter 

Confirmation of entrance block of all targeted PV by Frontera Catheter 

Additionally, in case of roll-in subjects, confirm entrance block of all targeted PV 
with Lasso® and perform voltage mapping 

Administer adenosine or isoproterenol for each targeted PV to rule out dormant 
conduction.  

(If necessary and at the investigator’s discretion, a commercially available 
ThermoCool® family catheter may be inserted to complete PVI or other identified 
targets.) 

Confirmation of entrance block of all targeted PVs  
 
 
Ablation outside the PV Ostia 
 

Prophylactic ablation outside the PV or CTI region, empirical sites and CFAE ablation 
is not allowed per protocol.  

If an arrhythmia requiring ablation outside the PV or CTI region (investigator 
discretion) is identified, the subject will be excluded from the study before any of 
the study catheters (Balloon or Frontera) has been inserted.   

If linear lesions for CTI AFL are placed, bidirectional block should be confirmed as 
demonstrated by mapping and/or pacing maneuvers.  
 
Verification of ablation procedure 
 

Verification of isolation of the targeted PVs by demonstrating entrance block into 
each targeted PV is required.  

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
To verify entrance block, analyze electrograms in sinus and/or atrial paced rhythm to 
confirm that no PV potentials are present.  

Administration of adenosine (ATP) and/or isoproterenol for each targeted PV prior to 
verification of entrance block is required. 

Demonstration of entrance block MUST be confirmed and documented by the 
Frontera Catheter. (Followed by Lasso® validation for roll-in subjects) 

The ablation procedure is considered complete when confirmation of entrance block 
in targeted PVs is confirmed. 
 
 
8.2.3
Collection of Ablation Procedure data for post-analysis 
 
At the completion of the study ablation procedure, two back-up copies of the CARTO® and 
generator log files will be made. One copy should be kept at the site within the investigator 
site or patient binders, and one fully anonymized copy will provided to/ collected by  the 
Sponsor. 
A copy of the fully anonymized angiography images (preferable with contrast), confirming 
position of the balloon and occlusion of the PVs will be  provided to / collected by  the Sponsor.  
 
 
8.2.3.1
Data collection during study ablation procedure                         
 
The following information will be collected during the procedure: 
RF ablation parameters per PV 

Number of RF application(s) per target PV 

Number of RF application(s) required with a focal catheter 

Total RF duration per target PV 

Total time of RF application with the balloon catheter until PV isolation of targeted 
vein was achieved (TTI = time to isolate) 

Total time of RF application with the focal catheter (if applicable) 

PVI confirmed with Frontera Catheter 

PVI confirmed with Lasso® (roll-in subjects only) 

PV acute reconnection yes/no 
RF ablation parameters per application 

Targeted veins (location) 

Ablation number of the generator 

Total Duration of RF energy per application 

Balloon Inflation Index prior to target PV application 

Identification of posterior pacing electrodes 

Ablation parameters (impedance, temperature, power, number of active electrodes 
per application, total duration of RF application, RF duration of posterior/anterior 
electrode, etc.) will be collected during the ablation procedure via the generator log 
files.  

Ablation lesion information will be collected in the CARTO3 system.  
Ablation parameters, including but not limited to 

Percentage of targeted PV isolated on first shot 

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
Percentage of targeted PV with acute reconnections 
Procedural parameters, including but not limited to 

Duration of time in mapping (LA and PVs) 

Total RF duration (consecutive time of RF energy delivered by multi-electrode RF 
balloon catheter and focal catheter (if applicable) 

Total PVI time with balloon catheter (Duration of time from 1st PV application to final 
PV application)  

Total PVI time with focal catheter (if applicable) 

Total procedure time (from first femoral puncture to catheter removal) 

Total fluoroscopy time and dose 

Total Balloon dwell time (from first RF balloon insertion until RF balloon removal) 

ECG data  

Total fluid delivered via ablation catheter 

Total fluid delivered via intravenous line (if captured) 

Fluid output (if captured) 

Net Fluid input 

ACT level and timepoint of heparin administration 

Strategy to evaluate the proximity to the phrenic nerve 

Strategy used to minimize risk of esophageal injury 

Type of temperature probe, cut-off temperature and any abnormal increases in 
temperature observed. 
 
8.2.4
Pre-Discharge Assessments 
 
Prior to hospital discharge, the following assessments should be performed: 

Cardiac and Anti-Coagulation Medication Regimen. 

TTE 

Adverse Events 

ECG in case standard of care 

For subjects in the neurological assessment subgroup: Cerebral MRI, Neurological 
exam and Neurological Evaluation using the NIH stroke Scale within 48- hours post 
procedure, prior to discharge.  A certified/qualified neurologist  must perform 
neurologic exams at pre-and post-ablation and possibly at other follow-up visits, 
pending previous findings of micro-emboli/neurologic deficits. 
 
8.2.5
Repeat Ablation Procedures 
Repeat procedures may be performed at the discretion of the investigator. Repeat 
procedures during follow up may be managed per investigator discretion using an 
commercially available ablation catheter. The follow-up schedule will remain based on the 
initial ablation procedure. 
 
 
 
 
 

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8.3 Post-Ablation Follow-up Schedule 
 
The subject will be required to complete follow-up visits through 12 months post initial 
ablation procedure. Follow-up will be done at 7 days (phone call or clinic visit), 1, 3, 6 and 12 
months (clinic visit).   
 
Discharged subjects will receive a telephone call or have a clinic visit at 7 days (7D, day 6-8) 
post ablation procedure to assess any occurrence of Primary Adverse Events; otherwise, in-
hospital surveillance will capture any Primary Adverse Events.   
 
Follow-up visits should be scheduled according to the following timeframes:  1 month (1M, 
day 23-37), 3 month (3M, day 76-104), 6 month (6M, day 150 - 210) and 12 month (12M, day 
315-405). Follow-up visit schedule should be based on the date of the index study ablation 
procedure and will not reset if subject undergoes a repeat AF ablation procedure. 
 
 
At 1, 3, 6 and, 12month follow-up visits, the following assessments will be performed: 
 

Adverse events (1M through 12M) 

Cardiac and Anti-coagulation medication regimen (1M through 12M) 

Atypical (left side) AFL/AT/AF recurrences and repeat ablations (1M through 12M) 

NYHA Functional Class Scale (3M) 

12 Lead-ECG (if completed per standard of care) 

Quality of Life questionnaire AFEQT (3, 6 and 12M) 

Cardiac CT/MRA (3M):  3M follow-up CT/MRA should be performed for subjects 
presenting with symptoms on PV stenosis, using the same imaging technique as pre-
ablation. Pre-ablation and post-ablation CT/MRAs of symptomatic subjects will be 
analyzed by a core lab to evaluate the level of PV stenosis.  

Transtelephonic monitoring (TTM) (1M through 12M) 
Subjects will be provided with a TTM device at the 1M follow-up visit and asked to 
record and transmit a minimum of 1 transmission (60 seconds) every week through 
the end of month 5 of follow-up. Starting at month 6 of follow-up, subjects will be 
asked to record and transmit a minimum of 1 transmission (60 seconds) every month 
until the effectiveness evaluation period is completed (12 months post index 
procedure). Subjects will also be asked to transmit any symptom-triggered episode 
that occurs from the time they receive the TTM device through the 12M follow-up 
visit. A core lab will be used to evaluate and assess the TTM tracings. 
 
TTM monitoring will be conducted as follows:  
x
Distribution and start TTM monitoring by Month 1  
x
<6M: Weekly transmission of at least 1 scheduled TTM recording  
x
≥6M: Monthly transmission of at least 1 scheduled TTM recording 
x
Conduct and transmit TTM recording whenever symptoms are present  
 
-
24 Hour Holter (6M and 12M) 
Holter monitor will be used at 6M and 12M follow-up visit to monitor the subjects’ 
heart rhythm for 24 hours continuously. Following the 24h Holter, subjects will be 

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contacted by the site to verify if symptoms are experienced during 24h Holter. A core 
lab will be utilized to evaluate and assess the 24-hour Holter recordings. 
 
 
For subjects in the NAE subgroup: 

Cerebral MRI, neurological exam and NIH Stroke Scale assessments will be performed 
at 1M, 3M, 6M and 12M visit in case observations were noted during previous 
assessments. 

MoCA and mRS assessments are mandatory at 1M visit.  Subjects with findings of 
micro-emboli/neurologic deficits will undergo additional MoCA/mRS through 12M 
follow-up 

A certified/qualified neurologist  must perform neurologic exams at pre-and post-
ablation and possibly at other follow-up visits, pending previous findings of micro-
emboli/neurologic deficits 
 
8.4 Early Termination Visit 
 
If early termination of the study is required due to safety concerns, each site will undergo a 
monitoring visit to conclude any outstanding issues, collect all outstanding CRF information, 
verify device accountability, and discuss any other items relevant to the conclusion of the 
study.  Any enrolled subjects will continue to be followed per the study protocol requirements. 
 
8.5 Unscheduled visit 
If a subject returns for a potential study related cardiovascular or neurological visit outside of 
the protocol-defined visit schedule provided in Table 8.7-A, the visit will be considered 
“unscheduled” (UNS).  An investigator may request an unscheduled visit in the presence of a 
new or worsened cardiovascular condition or neurological deficit. If the unscheduled visit is 
for a repeat ablation procedure, the protocol follow-up schedule is based on the index 
ablation procedure.  For all unscheduled visits, an unscheduled visit eCRF must be completed 
and the subject must also return for their next scheduled study visit per clinical investigational 
plan. 
 
8.6 Core Laboratory for Evaluation 
 Independent central core laboratories or expert physician(s) will conduct objective 
evaluations of TTM, Holter, Cerebral MRI and will evaluate PV stenosis of symptomatic 
subjects. 
 
 

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* Within 60 days prior to procedure 
 
** A certified/qualified neurologist  must perform neurologic exams at pre-and post-ablation and possibly at other 
follow-up visits, pending previous findings of micro-emboli/neurologic deficits. 
9 Assessment of Safety 
 
9.1 Specific Safety Parameters 
 
9.1.1
Definition of Adverse Events (AE) 
 
An AE is any untoward medical occurrence in a subject whether or not related to the 
investigational medical device. 
 
Specifically, an adverse event (AE) is any undesirable experience (sign, symptom, illness, 
abnormal laboratory value, or other medical event) occurring to a subject during the course 
of the study, whether or not it is related to the device or procedure.  Physical findings 
(including vital signs) observed at follow-up, or pre-existing physical findings that worsen 
compared to baseline are considered adverse events.    
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. Such conditions should be added to 
background medical history, if not previously reported. However, if the study participant’s 
condition deteriorates at any time during the study, it will be recorded as an AE.  
 
AF recurrence by itself is considered a recurrence of disease (pre-existing condition), and, 
therefore, does not meet the definition of an AE.  Recurrence of pre-existing AFL/ atrial 
tachycardia (AT) is also considered recurrence of disease, and does not meet the definition 
of an AE. 
 
The following clinical events will not be considered an adverse event for this clinical study: 
x
Minor pericarditis attributable to the ablation procedure defined as pleuritic 
chest discomfort with or without pericardial rub and ECG changes. 
x
AF/AFL/AT recurrence requiring pharmacological or synchronized electrical 
cardioversion during the hospitalization for the index ablation procedure, or 
throughout the duration of the study.  However, new onset of left atrial flutter 
occurring post-ablation is an AE. Re-ablation for AF or pre-existing AFL/AT itself is 
not an AE, however any procedural complication is considered an AE and shall be 
reported within the applicable timelines. 
 
9.1.2
Definition of Serious Adverse Event (SAE) 
 
A serious adverse event (SAE) is any event that meets one or more of the following criteria: 
x
Leads to a death 
x
Leads to a serious deterioration in the health of a subject that resulted in: 

A life-threatening illness or injury 

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Increase in frequency or duration of 
episodes of typical atrial flutter 
Increased phosphokinase level 
Infection, localized  
Infection, systemic 
Injury to skin, muscle, connective tissue due 
to body position, electrical cardioversion, 
etc. 
Laceration 
Leakage of air or blood into the lungs or 
other organs due to perforation 
Liver toxicity 
Local hematoma/ecchymosis 
Mobile strands in Inferior Vena Cava 
Myocardial Infarction 
Nausea 
Neurological disorders (headache) 
Neurological disorders (poor coordination) 
Neurological disorders (tremor) 
Obstruction to the vascular system 
Palpitations 
Perforation to the vascular system 
Pericardial effusion without tamponade 
Pericardial effusion resulting in tamponade 
Peripheral embolus 
Pericarditis 
Peripheral thromboembolism 
Peripheral nerve injury 
Phrenic nerve damage  
Phlebitis 
Pneumothorax 
Pleural effusion 
Pulmonary edema 
Pseudoaneurysm 
Pulmonary hypertension 
Pulmonary embolism 
Pulmonary vein dissection 
Pulmonary toxicity, like acute pulmonary 
syndrome 
Pulmonary vein thrombus 
Pulmonary vein Stenosis 
Renal failure 
Pump failure 
Respiratory failure 
Respiratory depression 
Rhabdomyolysis, including produced by 
body position or propofol 
Retroperitoneal hematoma 
Seizure 
Sedation induced CO2 retention with 
lethargy and cholecystitis 
Skin burns (due to cardioversion, tape, etc) 
Sepsis 
Skin injury / muscle or connective tissue 
injury due to body position, electrical 
cardioversion 
Skin discoloration 
Tamponade 
Skin rash 
Thrombocytopenia 
Temperature elevation 
Thrombosis 
Thromboembolism 
Transient extremity numbness 
Thyroid disorders 
Unintended complete or incomplete AV, 
Sinus node, or other heart block or damage 
Transient ischemic attack (TIA) 
Urinary tract injury or infection related to 
the urinary catheter 
Urinary retention 
Vasovagal reactions 
Valvular damage/insufficiency 
Volume overload 
Vision change 
X-ray radiation injury of skin, muscle and/or 
organ 
Worsening obstructive, restrictive, or other 
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*Atrial Fibrillation and exacerbation of an existing arrhythmia are anticipated adverse events.  
However, they will not be captured as such under this protocol, as they are considered 
recurrence of disease.] 
 
9.3 Time Period and Frequency for Event Assessment and Follow-up 
 
The investigator, or designated individual, will record all reportable events with start dates 
occurring any time after informed consent is obtained. At each study visit, the investigator will 
inquire about the occurrence of AE/SAEs since the last visit.  
 
All AEs need to be followed until the event is resolved (with or without sequelae). The medical 
monitor or designee of this clinical investigation will decide if more follow up information is 
needed in case the event is not resolved at study completion. All required treatments and 
outcomes of the SAE must be recorded in the eCRF. 
 
9.4 Reporting Procedures 
 
9.4.1
 Adverse Event Documentation and Reporting Requirements  
 
Subjects should be encouraged to report AEs spontaneously or in response to general, non-
directed questioning (e.g. “How was your health been since last visit?”). Anytime during the 
study, the subject may volunteer information that resembles an AE. 
 
Each AE must be reported to the sponsor regardless of classification, seriousness, intensity, 
outcome or causality. The investigator is responsible for ensuring that all AEs observed by the 
investigator, or reported by the subject, that occur from the time that the subject has signed 
the informed consent through the end of the study are properly assessed, recorded, and 
reported as defined and described in the AEs, Adverse Device Effects and Device Deficiencies 
section of this protocol. All adverse events must be documented by completing subject’s 
medical records (source documents) and appropriate eCRF by the investigator or study 
coordinator throughout the study and provided to the Sponsor.  All AEs will be monitored until 
they are adequately resolved or explained.   
 
Anonymized documentation pertaining to the AE (e.g. laboratory tests, consultation reports, 
post-mortem reports, new information relating to a previously reported AE, correspondence 
with the local EC, etc.) will be provided by the investigator to the sponsor or designee in a 
timely manner, when requested.  Follow-up reports relative to the subject’s subsequent 
course must be submitted to the sponsor or designee until the event has resolved or, in case 
of permanent impairment, until the condition stabilizes.  If the subject is withdrawn from the 
study because of the AE, the information must be included on the appropriate eCRFs. 
 
The sponsor is responsible for the classification of AEs and ongoing safety evaluation of the 
study and shall review the investigator’s assessment of all AEs. The sponsor will determine 
and document in writing their seriousness and relationship to the investigational device. In 

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In the case of serious device effects and device deficiencies that could have led to serious 
adverse device effects, the Sponsor will determine whether the risk analysis needs to be 
updated and whether corrective or preventative action is required. 
 
The sponsor will submit as per site specific requirements to all participating clinical 
investigators, an update of all SAEs and all device deficiencies that could have led to a SAE 
occurring to all participating sites. Event reporting to relevant regulatory authorities for non 
CE-marked devices per MEDDEV 2.7/3 Rev3 guidelines will occur by the sponsor and if 
indicated per local country requirements by the investigator. Pursuant to EN ISO 14155: 2011 
all SAEs will be fully recorded and reported by the sponsor to the regulating Ministry of Health 
(MOH) as well as the EC according to the deadlines in force. 
 
 
9.4.3
Unanticipated Device Effect Reporting 
 
All UADE/SADE/USADE must be reported to the Sponsor, via eCRF, immediately upon 
awareness of event but no later than 72 hours by the study site personnel.  An investigator 
shall submit to the reviewing EC a report of any unanticipated adverse device effect occurring 
during an investigation according to EC requirements. 
 
 
9.4.4
Events of Special Interest 
 
All study device failure/malfunction must be reported to the Sponsor, via eCRF, as soon as 
possible, within 72 hours by the study site personnel.  If a device failure is detected or 
suspected, it should be documented on the eCRF and the device returned according to the 
Sponsor’s instructions.  
 
The investigational device should be sent to appropriate R&D team or designated Quality 
engineer. Complaints related to non-investigational products manufactured and/or 
distributed by Biosense Webster, used during the procedure related to other devices (other 
than the study device under investigation), are to be reported according to current Biosense 
Webster procedures and other policies as necessary (i.e., institutional policies, EC policies, and 
local regulations), investigators are instructed to return devices in accordance with current 
company procedures and other relevant regulations.  
 
Event reporting to relevant competent authorities in accordance with the jurisdictional 
regulations will occur by the sponsor and/or by the investigator, depending upon the local 
requirements and will be done in EU per MEDDEV 2.12/1 guidelines for CE-marked devices 
manufactured by Biosense Webster and per MEDDEV 2.7/3 guidelines for non CE-marked 
devices manufactured by Biosense Webster.  
 
A device deficiency related to a medical device not manufactured by Biosense Webster should 
be reported by the investigator to their respective manufacturer as per relevant regulation. 
Complaints related to non-Biosense Webster, Inc. products must be handled according to 
institutional policies, EC policies, and local regulations. 
 

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9.5 Safety Oversight 
 
Safety oversight will be conducted as described in the safety management plan. Aggregate 
safety data will be reviewed during enrollment by the study safety lead in order to promptly 
identify new issues or trends which may have an impact on the conduct of the study and/or 
subject safety. Under the rules of an approved study-specific charter, safety events will be 
reviewed by an established committee which may recommend appropriate action(s) to 
ensure subject safety.  
 
 
10 Administrative Responsibilities 
10.1Ethics Committee and Competent Authority Application 
The study protocol (or amendment[s]), ICF, and other applicable study related documents 
must be approved by the Ethical Committee (EC) and Competent Authorities (CA) before 
enrollment of subjects. Any additional requirement imposed by the EC or regulatory authority 
shall be discussed, agreed upon, and followed. A signed copy of the EC and CA approval letters 
addressed to the investigator must be submitted to Biosense Webster certifying study 
approval prior to subject enrollment. Biosense Webster and the EC must approve, in writing, 
any changes to the protocol that affect the rights safety and/or welfare of the subjects, or may 
adversely affect the validity of the study. 
 
In addition, Biosense Webster, Inc. is responsible for notifying the relevant CA of the intention 
to perform a clinical investigation under this protocol and ensure to get the official response/ 
approval before starting the clinical investigation. 
 
 
10.2Audits and Inspections 
The sponsor and/or designee and/or Regulatory Authorities may contact the participating 
institution to inform the investigator of an upcoming audit/inspection. The investigator should 
immediately notify the sponsor of any Regulatory Authority audits/inspection at the study 
site. The audit/inspection can include the review of documents, facilities, records and any 
other resources deemed by the authorities to be related to study. 
 
11 Deviations from the Clinical Study Plan 
 
The investigator is responsible for ensuring that the clinical investigation is conducted in 
accordance with the procedures and evaluations described in this protocol. The study 
monitors shall verify that the conduct of the study is in compliance with the currently 
approved protocol and applicable regulations, and shall identify any issues of non-compliance 
with regulations or guidelines. 
 

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Issues of non-compliance include but are not limited to repeated protocol deviations; failure 
to obtain proper informed consent; non-conformance to EC requirements; failure to report 
Adverse Events, product malfunctions and other product issues; and other non-conformance 
to GCP. 
 
A protocol deviation is defined as an instance of failure to follow, intentionally or 
unintentionally, the requirements of the protocol (e.g. missed test or procedure, visit out of 
window, non-adherence to inclusion/exclusion criteria). Investigators are not allowed to 
deviate from the protocol. Protocol deviations will be monitored closely and will be reported 
per EC/CA requirement.  
 
Under emergency circumstances, deviations from the protocol to protect the rights, safety 
and well-being of a subject may proceed without prior approval of the sponsor and EC.  Such 
deviations shall be documented and reported to the sponsor and the EC as required. 
 
All instructions described in this study protocol are to be followed. If an amendment is 
required, it must be made in written form and receive approval from all persons and 
authorities who approved the original protocol. Administrative changes (do not affect 
subject’s benefits/risks ratio) may be inserted with abbreviated approval. All amendments will 
be distributed to all original protocol recipients. 
 
 
12 Investigational Product  
 
12.1Use of the Investigational Device and Investigator Experience 
In addition to the clinical protocol training (i.e. during the site initiation visit), all investigators 
who will be performing the ablation procedures for this study will be required to attend both 
a didactic session, which includes detailed reviews of the study catheter (specifications, 
parameters, etc.) and the results of the preclinical studies completed. Ablating physicians with 
no prior in human experience with multi-ablation catheter will also receive hands-on training 
using the Multi-electrode RF Balloon Catheter.  The combination of the didactic and hands-on 
(in-vitro and/or in-vivo) portions of the documented device training will provide the 
investigator with the experience necessary to perform the protocol specified procedures for 
the study. 
 
Investigators selected will be highly skilled in intracardiac mapping and AF ablation with RF 
ablation catheters.  
 
12.2Materials 
Biosense Webster, Inc., Irwindale, CA USA, has manufactured the catheters to be used in this 
study. The investigational devices were built in a clean room environment, and sterilized using 
EtO gas, in a manner similar to standard, commercially approved Biosense Webster products.  
 

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Complete manufacturing records of every lot of catheter manufactured for human use during 
this study are maintained at Biosense Webster, Inc. Each lot of catheters is released for human 
use under a Confirmation of Conformity from Regulatory Affairs that will certify that the 
investigational catheters conforms to the Essential Requirements for product release apart 
from those features, that are being investigated in this clinical investigation.  And that, with 
regard to these aspects, every precaution has been taken to protect the health and safety of 
the patient. 
 
12.3Device Acquisition and Accountability 
After obtaining a fully executed clinical trial agreement and appropriate competent authority 
(CA)/ethical committee (EC) approvals, the study site will receive the necessary amount of 
study-related materials prior to commencement. Study-related devices (investigational and 
non-investigational) will be shipped to the site upon completion of required documentation. 
Investigational Study Devices will be labeled as “Investigational Device” and are only to be 
used for subjects enrolled in this clinical study.  
 
The Sponsor will keep records of all investigational devices shipped to the site.  Investigational 
site personnel is responsible for appropriate logging of devices received, verification of 
packing slip information (i.e. lot numbers and quantity shipped) and date, and identifying that 
each device was used in the study and disposition information completed when returned to 
the Sponsor.  The Sponsor will label all investigational devices as “Investigational device” in a 
prominent location.  
 
The Investigational Device Accountability Log shall record the following information: 

Date of receipt 

Person in receipt of the devices 

Quantity received 

Catalog number  

Serial/lot numbers 

Expiry Date 

Date device was used 

Subject ID on whom device was used 

Date of return 
 
 
12.4Device Returns 
All investigational devices (used and unused) will be returned to the Sponsor’s attention at 
the below address. Any suspected malfunctioning device or device associated with an adverse 
event (device related or possibly device related) will undergo a thorough complaint analysis 
and must be properly documented on the electronic case report form (eCRF). All returned 
devices must be properly labeled with the subject identification number, date of issue, 
identified as a defective return, non-defective return, or adverse event (as applicable). All 
tracking information must be retained in the event the package has been lost and requires 
tracking. All investigational devices should be returned to:  
 

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ATTN: Complaints Lab 
Biosense Webster, Inc.  
15715 Arrow Highway 
Irwindale, CA 91706 USA 
 
 
13 Clinical Monitoring 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with applicable regulatory requirement(s). Each site 
will undergo periodic monitoring of the study, which involves a visit from a Sponsor 
representative, qualified to perform such visit.  Monitoring visits may include, but are not 
limited to, the following: 

Protocol adherence 

Source documentation verification and accuracy of the eCRFs  

Verification that informed consent is being obtained for all subjects participating in the 
study in accordance with requirements described in the study protocol 

Verification of completeness of the site file 

Verification of accuracy of all study logs such as the Delegation of Responsibility Log, etc.  

Compliance with applicable regulations 

Identification and action to resolve any issues or problems with the study. 
 
Data are to be submitted promptly via e-CRF after collection. Missing or unclear data will be 
corrected as necessary throughout the trial. Biosense Webster will request further 
documentation such as physician and/or cardiac EP lab procedure notes when complications 
or malfunctions are observed and reported. 
 
Further details on clinical monitoring are provided in the study specific monitoring plan. 
 
 
14 Statistical Methodology 
14.1Analysis Population 
14.1.1 Main-Study  
x
Modified Intent-To-Treat (mITT) Population: The Modified Intent-To-Treat (mITT) 
population consists of enrolled subjects who meet eligibility criteria and have the 
study catheter inserted.  
x
Safety Population (SP): The Safety Population will consist of all enrolled subjects who 
have undergone insertion of the study catheter. 
x
Per Protocol (PP) Population: The PP population is a subset of the mITT population 
and will include subjects who comply with the following criteria: 

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x Are enrolled and meet all eligibility criteria 
x Have undergone RF ablation with the study catheter 
x Have been treated for the study-related arrhythmia 
x
Neurological Assessment Evaluable (NAE) Population:  The NAE Population will 
include at least 40 subjects who are subset of the Per Protocol Population, consent 
and are eligible for the required neurological assessments, and have post-ablation 
MRI. Assessment of incidence of new lesions requires availability of pre-and post MRI. 
Assessment of incidence of new deficits requires availability of pre-and post-
neurological evaluation. Enrollment in the NAE population may be terminated prior to 
achieving the target number of subjects if study enrollment ends early after a planned 
interim look. 
 
14.1.2 Roll-In 
x
Roll-In Population: The Roll-In population will include all subjects from the roll-in 
phase of the ablating physician that have the study catheter inserted. All endpoints 
will be analyzed for the roll-in population separately. 
 
14.2Study Design 
This clinical investigation is a prospective, multicenter, single arm clinical evaluation utilizing 
the Biosense Webster multi-electrode radiofrequency balloon catheter and the Biosense 
Webster multi-electrode circular diagnostic catheter. The sample size for the study is primarily 
driven by the safety endpoint. An adaptive Bayesian design76 will be used to determine the 
sample size based on the safety endpoint alone. Sample size selection interim analyses will be 
performed when 80, 130, 180, and 230 evaluable subjects are enrolled in the main study (mITT 
Population). Safety outcome at 30 days will be used as a proxy for the primary safety endpoint 
at each interim. The final safety analysis will be based on complete follow-up for the primary 
safety endpoint for all evaluable patients in the main study. Predictive probabilities of success 
will be used to determine whether the sample size at each interim analysis will be sufficient 
or if the trial enrollment will continue. Sample size simulations were performed using 
performance goals of 15% and 80% respectively for the safety and effectiveness endpoint 
rates.  
At the time of each interim analysis, predictive probabilities of success will be estimated 
using the available data from all evaluable subjects in the mITT population, assuming a 
non-informative uniform prior distribution for the primary safety rate. Enrollment will be 
stopped if the predictive probability of trial success at any interim is greater than 90%, or 
if the predictive probability of trial success with the maximum sample size is less than a 
futility bound of 6.5%. Otherwise, enrollment will continue until the next interim or the 
final sample size. Analysis of the effectiveness endpoint will be performed at the final 
sample size determined for the safety endpoint. Power for the effectiveness endpoint 
assessment is >80% at all sample sizes ≥80 subjects. 
The primary safety and effectiveness endpoints will be evaluated using exact tests for binomial 
proportions at a one-sided 5% significance level. 

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In order to control for operational bias, the timing and results of the interim analyses will not 
be revealed to study investigators unless an interim analysis results in a decision to stop 
enrollment.  The interim analyses will be conducted seamlessly with no interruption to study 
enrollment unless indicated by an interim analysis.  An independent statistician will be 
responsible for conducting the interim analyses, and reviewing the results with the designated 
Data Monitoring Committee (DMC). The DMC charter will document the role and 
responsibilities of the committee and the independent statistician.  The predicted probability 
of study success or summary results which are calculated at the time of the interim analysis 
will not be disseminated by the statistician performing the interim analysis until the time of 
the final database lock for the CSR.  
 
14.3Treatment Assignment 
This is a single arm clinical study and all enrolled patients will be assigned to the study 
treatment.   
 
14.4Interval Windows 
Please refer to Table 8.7 A. 
 
14.5Primary Endpoints and Associated Hypothesis 
 
14.5.1 Analyses for Primary Effectiveness Endpoint 
The null and alternative hypotheses are: 
Hypothesis 
H0: PE < 0.80 
Ha: PE > 0.80 
PE: Proportion of patients with acute procedural success defined as confirmation of entrance 
block in treated PVs after adenosine and/or isoproterenol challenge (with or without the 
use of a focal catheter) 
Analysis Population: The per-protocol population will be used as the primary analysis 
population. Subjects with missing effectiveness endpoints data will be excluded in the primary 
analysis. Sensitivity analyses for missing data will be performed using the PP and population 
to assess the impact of missing data on the primary effectiveness outcome and are described 
in the Statistical Analysis Plan (SAP).  
 
14.5.2  Analyses for Primary Safety Endpoint 
The null and alternative hypotheses are: 
Hypothesis 
H0: PS > 0.15  
Ha: PS < 0.15 

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PS: The rate of early onset Primary Adverse Events  
Analysis Population:  
The Modified Intent-To-Treat (mITT)will be used as the primary analysis population. Subjects 
with missing primary safety data will be excluded in the primary analysis. Sensitivity analyses 
for missing data will be performed in the mITT population and are described in the Statistical 
Analysis Plan (SAP). 
 
14.6Levels of Significance 
A 1-sided alpha of 0.05 will be used for statistical testing and confidence intervals unless 
otherwise noted. The safety of this device was initially assessed in a feasibility study, and a 
safety event rate of 2.6% (1 in 39 patients) was observed. Given the available data on subjects 
from the feasibility study it was concluded that the proposed study could provide sufficient 
evidence for safety of the device using a type-I error of 5%, rather than requiring the 
conventional 2-sided 5%. 
 
 
14.7Sample Size Justification 
A Bayesian adaptive design will be utilized to select the final sample size of the trial.  Sample 
size selection interim analyses will be performed when the mITT Population reaches 80, 130, 
and 180 patients, and predictive probabilities for trial success will be used to determine 
whether the sample size at the time of the interim analysis will be sufficient or if the trial will 
continue to the full sample of 230. The final stopping sample size of 230 was determined by 
power calculations for the primary safety endpoint.  
 
 
It is assumed that the attrition rate for the study will be negligible. Study enrollment will 
continue during each interim analysis until a decision is reached to stop enrollment based on 
the interim results. Due to the continued enrollment during this time, we expect additional 
subjects to  be enrolled into the study. These additional subjects will be included in the 
primary analyses and should account for the potential subject attrition.  
 
14.7.1 Adaptive Sample Size Determination  
In this section, an incidence of any primary adverse events will be referred to as a failure 
for the primary safety endpoint. The methods described in Broglio et al.76 will be used for 
adaptive determination of the sample size.  
At the time of each interim analysis, predictive probabilities of success for safety will be 
calculated once using the current sample size and another time using the maximum sample 
size allowed. A uniform prior distribution will be assumed for the safety rate at the first interim 
analysis, and the distribution will be updated with the observed data at each subsequent 
interim analysis. The number of failures for the primary safety endpoint in subjects with 
incomplete information will be assumed to follow a beta-binomial distribution. The predicted 
number of failures for the primary safety endpoint will be estimated from these beta-binomial 

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distributions. The observed and predicted number of failures will provide estimates for the 
anticipated study outcomes with the sample size at the time of the interim analysis and the 
maximum sample size allowed. The Bayesian predictive probability of success for safety for 
each case will be calculated from these estimates. 
Enrollment will be stopped if the predictive probability of success for safety with the 
current sample size is greater than 90% or if the predictive probability of success for safety 
using the maximum sample size allowed is less than 6.5%. Otherwise, enrollment will 
continue until the 230th subject is recruited. The Statistical Analysis Plan contains details 
on the timing of the interim analysis and estimation of the predictive probability of success 
at the interim looks. Regardless of whether enrollment stops at one of the interim analyses 
or continues to a sample size of 230 subjects, the primary safety and efficacy analyses will 
be conducted after all subjects have completed their 3-month post-procedure evaluation.  
14.7.2 Power and Type-I Error Simulations 
 
Trial simulations were performed to estimate the Type-I error rate and the power for the 
success of the safety endpoint under a range of assumptions for the true safety rate and the 
assumed enrollment schedule. For accrual rates of 1.7, 3.4, 5.1, 8.5, 11.9, 17, 20.4, 23.8, 25.5, 
25.5, 25.5, 25.5, 25.5, 25.5, and 25.5 patients per month for months 1 to 15 respectively, and 
true safety rates of 0 to 9.0%, the power for showing success for the safety endpoint is 
estimated to be greater than or equal to 80.0%. For a safety rate of 9.5% this power decreases 
to approximately 73.0%. Based on the feasibility study results discussed in section 14.7, it is 
unlikely that the safety event rate is higher than 9.0%. The posterior probability of the safety 
rate being less than or equal to 9.0% is estimated to be 0.886. Therefore, we expect the study 
to be sufficiently powered for the primary safety endpoint. With a true effectiveness rate of 
96.0% and a performance goal of 80.0%, a minimum of 80 patients will provide 99.9% power 
for meeting the primary effectiveness endpoint. As a result, the power estimates for the 
primary safety endpoint closely estimate the overall power of the study.  
 
Since the primary analysis is performed at a 5.0% level Type-I error and the sample size is 
selected independent of the effectiveness endpoint, the Type-I error for the effectiveness 
hypothesis is controlled at 5.0%. To estimate the Type-I error for the primary safety endpoint, 
we considered the hypothetical scenario that the primary safety endpoint is on the decision 
boundary (i.e. equal to 15%). Based on 25,000 trial simulations, the estimated Type-I error for 
this scenario was 4.7%. As the primary safety rate moves away from the decision boundary 
under the null hypothesis, the Type-I error for the test decreases. Since our study success is 
defined as meeting both primary safety and effectiveness endpoints and because the Type-I 
error for each of these tests is controlled at 5.0%, the overall study Type-I error will be 
controlled at 5.0% (Please refer to the SAP for more details).  
 
 
Based on the simulation results, we concluded that the study is adequately powered to  
meet the primary safety and effectiveness endpoints and that the Type-I error for the overall 
trial success is controlled at 5%. 
 
 
 
 

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14.8Analyses to be Conducted 
 
14.8.1
General Conventions 
 
Standard descriptive summaries for continuous data include the number of observations 
with data, number of observations with missing data, mean, standard deviation, median, 
minimum, and maximum values. For categorical data, the count and percent will be 
provided. Percentages will be based on the number of subjects without missing data. 
 
 
14.8.2
Disposition of Study Subjects 
 
Subject disposition will be summarized for all enrolled subjects by summary tables, listings 
and flow diagrams. 
 
 
14.8.3
Demographic and Baseline Characteristics 
 
All demographic characteristics, procedural, and immediate post-operative details will be 
summarized overall in the safety and mITT populations. Descriptive statistics will also be 
presented for roll-in subjects.   
 
 
14.8.4
Analysis for Primary Effectiveness Endpoint 
The primary effectiveness endpoint will be evaluated using the exact test for a binomial 
proportion at a one-sided significance level of 5%. If the lower bound of the exact two-sided 
90% confidence interval of the primary effectiveness endpoint rate is greater than the 
performance goal of 80%, the study will be considered to have demonstrated effectiveness. 
 
14.8.5
 Analysis for Primary Safety Endpoint  
The primary safety endpoint will be evaluated using the exact test for a binomial proportion 
at a one-sided significance level of 5%. If the upper bound of the exact two-sided 90% 
confidence interval of the primary safety endpoint rate is less than the performance goal of 
15%, the study will be considered to have demonstrated safety. 
 
14.8.6
Analyses of Secondary and Additional Endpoints 
Percentage (%) of subjects with freedom from documented symptomatic atrial fibrillation 
(AF), atrial tachycardia (AT), or atypical (left side) atrial flutter (AFL) episodes will be 
estimated in the mITT population at 180 and 365 days with the corresponding one-sided  
95%  exact binomial  lower bound.  
 
Descriptive statistics will be presented for the remaining secondary endpoints in the Safety 
and mITT Populations overall and by roll-in cases. The neurological assessment related 
endpoints will be analyzed in the NAE population. No formal statistical hypotheses and 

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inferential statistics will be formulated and performed for the remaining effectiveness and 
safety endpoints. Details of analyses methods for secondary and additional endpoints will 
be provided in SAP. 
 
14.8.7
Handling of Missing Data 
Patients with missing effectiveness data will be excluded from the primary effectiveness 
analysis. Sensitivity analyses for missing data will be performed in the PP populations to 
assess the impact of missing values on the primary effectiveness outcome and are described 
in the SAP. Subjects with missing primary safety data will also be excluded from the primary 
safety analysis. Sensitivity analyses for missing data will be performed in SP and mITT 
populations and are described in the Statistical Analysis Plan (SAP)  
 
 
14.9Interim Monitoring  
An independent statistician will be responsible for conducting the interim analyses and 
reviewing the results with a designated Data Monitoring Committee (DMC). The DMC charter 
will document the role and responsibilities of the committee and the independent statistician.  
 
15 Ethics and Protection of Human Subjects 
15.1Ethical Standard 
As the Sponsor of this study, Biosense Webster has the overall responsibility for the conduct 
of the study, including assurance that the study meets the regulatory requirements of the 
Food and Drug Administration and the MDD 93/42/EC and the local government. The Sponsor 
will also maintain compliance with Good Clinical Practice (ICH version 4 du 1 May 1996), the 
European standard EN ISO 14155:2011 (Clinical Investigation of Medical Devices for Human 
Subjects), the Declaration of Helsinki (Ethical Principles for Medical Research Involving Human 
Subjects, Tokyo 2004), Sponsor general duties (21 CFR 812.40), selection of investigators (21 
CFR 812.43), monitoring (21 CFR 812.46), supplemental applications (21 CFR 812.35 [a] and 
[b]), maintaining records (21 CFR 812.140 [b]), and submitting reports (21 CFR 812.150 [b)]), 
and to local regulations where required. 
 
x
General Duties  
Biosense Webster’s general duties consist of submitting the clinical investigation 
application to appropriate regulatory agencies, assuring that sites have received EC 
approvals prior to shipping the devices, selecting investigators, ensuring proper 
clinical site monitoring and ensuring subject informed consent is obtained. 
 
x
Data Quality and Reporting 
Biosense Webster is responsible for providing quality data that satisfy federal 
regulations and informing proper authorities of serious unanticipated adverse events 
and deviations from the protocol.   
 

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x
Selection of Investigators 
All potential investigational sites will undergo an evaluation to ensure that the site 
has the appropriate facilities and personnel to conduct the study in compliance with 
the clinical investigational plan. Based on outcome of evaluation process, Biosense 
Webster will select qualified investigators, ship devices only to participating 
investigators, obtain a signed Investigator’s Agreement and provide the investigators 
with the information necessary to conduct the study. 
 
x
Supplemental Applications  
As appropriate, Biosense Webster will submit changes in the Clinical Investigational 
Plan to the investigators to obtain all applicable re-approvals. 
 
x
Maintaining Records  
Biosense Webster will maintain copies of correspondence, data, adverse device 
effects and other records related to the study. Biosense Webster will maintain records 
related to the signed Investigator Agreements. 
 
x
Submitting Reports  
Biosense Webster will submit any required regulatory reports identified in this section 
of the regulation.  This may include unanticipated adverse device effects, withdrawal 
of EC approval, current investigators list, annual progress reports, recall information, 
final reports and protocol deviations.  
 
15.2Informed Consent Process 
 
15.2.1 Informed Consent Procedure and Documentation 
 
Subjects informed consent must be obtained and documented according to the principles of 
informed consent in the latest version of the Declaration of Helsinki (Brazil, 2013), ISO 
14155:2011, and approved by the reviewing Regulatory Authority and EC 
 
Informed consent is mandatory and must be obtained from all subjects prior to their 
participation in the study. 
 
Prior to screening or performing any study related procedures that are solely for the purpose 
of determining eligibility for this study, any potential benefits and risks of the study must be 
explained to the subject. Subjects will be informed about aspects of the study that are relevant 
to the subject's decision to participate. Subjects should be made aware that by signing the 
Informed Consent Form (ICF), they are granting approval for study personnel to review their 
medical records and to collect/analyze personal medical information. Subjects should also be 
informed that study personnel will maintain confidentiality of the medical records at all times. 
 
The ICF will be written in a native, non-technical, language that is understandable to the 
subject and is to be approved by the applicable EC prior to enrolling subjects. The subject or 
designee will be provided with ample time to read and understand the ICF and to consider 
participation in the study. Informed consent will be requested prior to enrollment and must 

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be personally signed and dated by the subject, or subject’s legal representative, prior to 
performance of any study related activity or procedure. If a subject is unable to read or write, 
informed consent shall be obtained through the aid of an independent witness who will be 
present throughout the process. The written ICF and any other information shall be read aloud 
and explained to the prospective subject and, whenever possible, subject shall sign and date 
the ICF. The witness must also sign and date the ICF attesting that the information was 
accurately explained and that informed consent was freely given. The point of enrollment 
corresponds with the time that subjects signs the informed consent. 
 
The investigator and/or designee must also clearly document the process of obtaining 
informed consent in the subject’s source documents. The voluntary process of obtaining 
informed consent confirms the subject’s willingness to participate in the study. It’s the 
investigator’s responsibility to ensure that the informed consent process is performed in 
accordance with ICH-GCP and, where applicable, local and federal regulations. Subjects should 
not be coerced, persuaded, or unduly influenced to participate or continue to participate in 
the trial. Subjects or his/her legal representative must be given ample time and opportunity 
to inquire about details of the trial and all questions about the trial should be answered to the 
satisfaction of the patient or the representative. Failure to provide written informed consent 
renders the subject ineligible for the study. If new information becomes available that can 
significantly affect a subject’s future health and/or medical care, this information shall be 
provided to the subject(s) affected in written form. If relevant, all affected subjects shall be 
asked to confirm their continuing informed consent in writing by dating and signing the 
amended ICF. 
 
 
15.3Participant and Data Confidentiality 
During this clinical investigation, all representatives of the Sponsor will comply with all in-
country privacy laws and regulations regarding contact with subjects, their medical record 
information, copying of information, and protection of the subject identities. 
 
All information and data sent to Biosense Webster concerning subjects or their participation 
in this clinical investigation will be considered confidential. Only authorized Biosense Webster 
personnel or representatives (including contracted service providers, i.e. Core Lab, Clinical 
Research Associate, CRO, etc.), representatives of the FDA or Competent Authorities acting in 
their official capacities will have access to these confidential files upon request (including, but 
not limited to, laboratory test result reports, ECG reports, admissions/discharge summaries 
for hospital admission occurring during a patient’s study participation and autopsy reports for 
deaths occurring during the clinical investigation). Some of the countries to which the study 
subjects and investigators personal data may be transferred may not offer as comprehensive 
a level of protection of personal data as within the European Union but Sponsor will take all 
reasonable steps to ensure a sufficient level of data protection. All data used in the analysis 
and reporting of this evaluation will exclude identifiable reference to the subject. 
 
 
 
 

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15.3.1 Research use of Stored Data 
 
x
Intended Use: Data collected under this protocol may be used to study Atrial Fibrillation. 
x
Storage: Access to stored data will be limited. Data will be stored using codes assigned by 
the sponsor. Data will be kept in password-protected computers. Only investigators and 
the sponsor will have access to the data. 
 
 
16 Source Documents and Access to Source Data/Documents 
Data entered on to the eCRFs will be taken from source documentation, such as hospital 
procedure reports, admission and discharge summaries, other hospital or investigator 
office/clinic documents, and system data (CARTO, generator).  If unique study parameters are 
not documented on standard hospital or office reports, a worksheet may be developed to 
record this information.  The worksheet shall be signed by the PI or authorized designee and 
will serve as source document and as basis for monitoring the eCRFs.  Electronic subject 
records will be considered as source documents on the condition that the hospital’s database 
is a validated system.  If this is not the case, electronic records should be printed and added 
to the subject’s paper file.  A print-out of a completed eCRF cannot be used as source 
documentation.  
 
Investigators should maintain information in the subject’s medical records, which corroborate 
data collected on the eCRFs.  In order to comply with these regulatory requirements, at 
minimum, the following is a list of information that should be maintained. 
x
Medical history/physical condition of the study subject before involvement in the 
study sufficient to verify protocol selection criteria (if not already present). 
x
Dated and signed notes from the day of entry into the study including the study 
Sponsor (Biosense Webster), protocol number, clinical site, subject number assigned 
and a statement that consent to participate in the study was obtained. 
x
Dated and signed notes from each study visit with reference to the eCRFs for further 
information, if appropriate (for specific results of procedures and exams). 
x
Reports on AEs and their resolution, including supporting documents such as 
discharge summaries, EP lab reports, ECGs, lab results. 
x
Notes regarding protocol-required medication and prescription medications taken 
during the study (including start and stop dates). 
x
Notes on subject’s condition upon completion of or withdrawal from the study. 
 
Only authorized Biosense Webster personnel or representatives, authorized site personnel, 
local government authorities, or the FDA, acting in their official capacities, will have access to 
these confidential files. 
 
 
 
 
 
 

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17 Quality Assurance and Quality Control 
 
QC procedures will be implemented beginning with the data entry system and ongoing QC 
checks will be run on the database. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution.  
 
Following written SOPs, monitors will verify that the clinical trial is conducted and 
data are generated, documented, and reported in compliance with the protocol, GCP, 
and the applicable regulatory requirements. If noncompliance is identified, Sponsor 
is required by regulation to implement measures to secure compliance.  
 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, 
and inspection by local and regulatory authorities. 
 
 
18 Data Handling and Record Keeping 
 
18.1Data Collection and Management Responsibility 
 
The Sponsor will be responsible for all data management activities. These activities include 
development of an electronic data collection (EDC) system and utilizing a validated EDC 
system into which all study data will be entered. The Sponsor will be responsible for reviewing 
all data to ensure the overall integrity of the database. 
 
18.1.1 Data Collection 
Electronic Case Report Forms (eCRFs) will be used to collect all subject data during this clinical 
investigation. eCRFs have been developed to capture the information outlined in this clinical 
investigation Plan. Modification to the eCRF will only be made if deemed necessary by the 
sponsor. Data on these eCRFs will be monitored (source verified) and the monitor will ask the 
site representative to correct if necessary to match the source documents. All changes made 
to the data will be tracked in the electronic audit trail. The investigator will be required to sign 
designated eCRFs as verification that they have been reviewed and the data entered are 
correct. Data from these eCRFs will be used to provide analysis of this clinical investigation.  
 
18.1.2 Data Reporting 
The investigator, or a designated individual, is responsible for ensuring that clinical 
investigation data are timely and properly recorded on each subject’s eCRF and related 
documents. The investigator, or a designated individual, is required to electronically sign the 
eCRF on the appropriate pages to verify that he/she has reviewed and attests to the 
correctness of the recorded data. Completed eCRF will be reviewed and monitored by the 
sponsor personnel, or an appropriately qualified and trained designee, throughout the clinical 
investigation. To this end, the Investigator and institution must permit inspection of the trial 
files and subject eCRFs by such representatives and/or responsible government agencies. 

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writing, of transfer location, duration, and the procedure for accessing the study 
documentation. 
 
If the investigator retires, relocates, or withdraws from assuming primary responsibility for 
keeping the study records, custody transfer per written notice must be submitted to the 
sponsor indicating the name and address of the person accepting primary responsibility. The 
EC must be notified in writing of the name and address of the new custodian. Record retention 
dates must be provided to all parties by the sponsor’s corporation. 
 
 
 
19 Study Suspension or Termination 
 
This study may be temporarily suspended or prematurely terminated at the discretion of the 
Sponsor. The Sponsor may also terminate a site prior to study completion if the Sponsor 
believes the site is no longer capable of participating (e.g., cannot fulfill subject enrollment or 
protocol compliance goals, site suspension by EC). If the study is prematurely terminated or 
suspended, the PI will promptly inform the EC and will provide the reason(s) for the 
termination or suspension.  
 
If suspension or premature termination occurs, the terminating party shall justify its decision 
in writing and promptly inform the other parties with whom they are in direct communication. 
The principal investigator and sponsor shall keep each other informed of any communication 
received from either the EC or the regulatory authority. 
 
If early termination of the study is required due to safety concerns, each site will undergo a 
monitoring visit to conclude any outstanding issues, collect all outstanding CRF information, 
verify device accountability, and discuss any other items relevant to the conclusion of the 
study. Any enrolled subjects will continue to be followed per the study protocol requirements. 
 
If, for any reason, the sponsor suspends or prematurely terminates the study at an individual 
study site, the sponsor shall inform the responsible regulatory authority as appropriate and 
ensure that the EC is notified, either by the principal investigator or by the sponsor. If the 
suspension or premature termination was in the interest of safety, the sponsor shall inform 
all other principal investigators. 
  
Circumstances that may warrant termination or suspension include, but are not limited to:  
•
Determination of unexpected, significant, or unacceptable risk to participants  
•
Demonstration of efficacy that would warrant stopping  
•
Insufficient compliance to protocol requirements  
•
Data that are not sufficiently complete and/or evaluable  
•
Determination of futility  
 
Study may resume once concerns about safety, protocol compliance, data quality is addressed 
and satisfy the sponsor, EC and regulatory agency. 
 

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20 Data and Publication Policy 
Publications and/or presentation of clinical investigation results will be coordinated between 
Biosense Webster, Inc. and the clinical investigation author(s). Authorship will be determined 
prior to development of any manuscript. All information concerning the study, investigational 
medical device, sponsor operations, patent application, manufacturing processes, and basic 
scientific data supplied by the sponsor to the investigator and not previously published, are 
considered confidential and remain the sole property of the sponsor.  
 
 
 
21 Document Filing 
A copy of all approved versions of the Investigation Protocol will be kept, by the site, in the 
Investigator Site File and in the Sponsor Trial Master File. 
 
22 Scientific References 
 
1. Cain ME. Atrial fibrillation--rhythm or rate control. The New England journal of medicine 
2002;347(23):1822-3. 
2. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JJC, Conti JB, Ellinor PT, Ezekowitz 
MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW. 2014 
AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive 
SummaryA Report of the American College of Cardiology/American Heart Association Task Force 
on Practice Guidelines and the Heart Rhythm Society. Journal of the American College of 
Cardiology 2014;64(21):2246-2280. 
3. Calkins H, Hindricks G, Cappato R, Kim YH, Saad EB, Aguinaga L, Akar JG, Badhwar V, Brugada J, 
Camm J, Chen PS, Chen SA, Chung MK, Nielsen JC, Curtis AB, Davies DW, Day JD, d'Avila A, Natasja 
de Groot NMS, Di Biase L, Duytschaever M, Edgerton JR, Ellenbogen KA, Ellinor PT, Ernst S, Fenelon 
G, Gerstenfeld EP, Haines DE, Haissaguerre M, Helm RH, Hylek E, Jackman WM, Jalife J, Kalman 
JM, Kautzner J, Kottkamp H, Kuck KH, Kumagai K, Lee R, Lewalter T, Lindsay BD, Macle L, Mansour 
M, Marchlinski FE, Michaud GF, Nakagawa H, Natale A, Nattel S, Okumura K, Packer D, Pokushalov 
E, Reynolds MR, Sanders P, Scanavacca M, Schilling R, Tondo C, Tsao HM, Verma A, Wilber DJ, 
Yamane T. TEMPORARY REMOVAL: 2017 HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus 
Statement on Catheter and Surgical Ablation of Atrial Fibrillation. Heart rhythm 2017. 
4. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel 
H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P, 
Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca A, De Caterina R, 
Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B, Guenoun M, Hohnloser 
SH, Kolh P, Lip GY, Manolis A, McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, 
Sharma S, Suwalski P, Tamargo JL, Taylor CJ, Van Gelder IC, Voors AA, Windecker S, Zamorano JL, 
Zeppenfeld K. 2016 ESC Guidelines for the management of atrial fibrillation developed in 
collaboration with EACTS. European heart journal 2016;37(38):2893-2962. 
5. Jackman WM, Wang XZ, Friday KJ, Roman CA, Moulton KP, Beckman KJ, McClelland JH, Twidale N, 
Hazlitt HA, Prior MI, et al. Catheter ablation of accessory atrioventricular pathways (Wolff-

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Parkinson-White syndrome) by radiofrequency current. The New England journal of medicine 
1991;324(23):1605-11. 
6. Jazayeri MR, Hempe SL, Sra JS, Dhala AA, Blanck Z, Deshpande SS, Avitall B, Krum DP, Gilbert CJ, 
Akhtar M. Selective transcatheter ablation of the fast and slow pathways using radiofrequency 
energy in patients with atrioventricular nodal reentrant tachycardia. Circulation 1992;85(4):1318-
28. 
7. Wilber DJ, Pappone C, Neuzil P, De Paola A, Marchlinski F, Natale A, Macle L, Daoud EG, Calkins H, 
Hall B, Reddy V, Augello G, Reynolds MR, Vinekar C, Liu CY, Berry SM, Berry DA, ThermoCool AFTI. 
Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with 
paroxysmal atrial fibrillation: a randomized controlled trial. Jama 2010;303(4):333-40. 
8. Marrouche NF, Dresing T, Cole C, Bash D, Saad E, Balaban K, Pavia SV, Schweikert R, Saliba W, 
Abdul-Karim A, Pisano E, Fanelli R, Tchou P, Natale A. Circular mapping and ablation of the 
pulmonary vein for treatment of atrial fibrillation: impact of different catheter technologies. J Am 
Coll Cardiol 2002;40(3):464-74. 
9. Oral H, Knight BP, Tada H, Ozaydin M, Chugh A, Hassan S, Scharf C, Lai SW, Greenstein R, Pelosi F, 
Jr., Strickberger SA, Morady F. Pulmonary vein isolation for paroxysmal and persistent atrial 
fibrillation. Circulation 2002;105(9):1077-81. 
10. Pappone C, Oreto G, Rosanio S, Vicedomini G, Tocchi M, Gugliotta F, Salvati A, Dicandia C, Calabro 
MP, Mazzone P, Ficarra E, Di Gioia C, Gulletta S, Nardi S, Santinelli V, Benussi S, Alfieri O. Atrial 
electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: 
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