reMARQable nMARQ™ Pulmonary Vein Isolation System for the Treatment of Paroxysmal Atrial Fibrillation
Phase: PHASE3
Conditions: Atrial Fibrillation
Sponsor: Biosense Webster, Inc.

 
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CONFIDENTIAL 
  
 
 
 
 
 
reMARQable 
 
nMARQ™ Pulmonary Vein Isolation System for the 
Treatment of  Paroxysmal Atrial Fibrillation 
 
 
 
 
Sponsor: 
BIOSENSE WEBSTER, INC. 
 
3333 Diamond Canyon Road 
 
Diamond Bar, CA 91765 
 
Version: 
5.2 
 
September 19, 2016 
 
 
 
 
 
 
 
 

 
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CONFIDENTIAL 
Protocol Agreement Form 
 
Study Title:  reMARQable, nMARQ™ PVI Ablation System IDE 
 
I, the undersigned, have read and understand this clinical study, including the appendices.  I will 
implement and conduct the clinical study in strict compliance with the study protocol and in 
accordance with good clinical practices (GCP) and all applicable laws and regulations. I will 
ensure that all persons assisting in this study are adequately informed about the protocol, study 
product(s), and their clinical study-related duties and functions. 
 
I agree to maintain all study related information supplied by Biosense Webster, Inc. in strictest 
confidence.  When information regarding this study is submitted to an institutional review board 
(IRB)/Independent Ethics Committee (IEC), it will be forwarded with a requirement that all 
study related material is to be held strictly confidential. 
 
 
 
 
_______________________    _______________________    _______________ 
 Principal Investigator  
   Signature 
 
 
     Date 
 Name (PRINT) 
 
 
 

 
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Contact Details 
 
SPONSOR:   
Biosense Webster, Inc. 
3333 Diamond Canyon Road 
Diamond Bar, CA 91765 
USA 
Tel: +1 909-839-8500 
Fax: +1 909-839-8804 
 
EMERGENCY SAFETY CONTACT: 
Biosense Webster, Inc. 
WW Clinical Operations  
 
 
3333 Diamond Canyon Road  
Diamond Bar, CA  91765 
Email: RA-BWIUS-NMARQCLIN@its.jnj.com 
Fax:  +1 909-839-8804  
 
 
 

 
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Table of Contents 
1.0 Protocol Summary .........................................................................................................10 
2.0 Abbreviations .................................................................................................................16 
3.0 Introduction ....................................................................................................................18 
3.1 
Background ............................................................................................................18 
3.1.1 
Clinical Outcomes and Published Guidelines .....................................................18 
3.1.2 
Overview of General and Vascular Risks Associated with Catheter Ablation ...19 
3.1.3 
Study Population .................................................................................................21 
3.2 
Study Rationale ......................................................................................................21 
3.3 
Previous Experience with nMARQ™ PVI Ablation System .............................22 
3.3.1 
Bench and Animal Studies ..................................................................................22 
3.3.2 
Circular Ablation Catheter and Crescent Ablation Catheter for the 
Radiofrequency Ablation of Atrial Fibrillation (AFCC-126) Feasibility Study .23 
3.3.3 
REVOLUTION clinical study ............................................................................23 
3.4 
Device Description .................................................................................................25 
3.4.1 
Description of Currently Marketed Devices .......................................................25 
4.0 Detailed Risk Analysis ...................................................................................................27 
4.1 
Description and Analysis of Risks ........................................................................27 
4.1.1 
Minimization of Risks.........................................................................................30 
5.0 Study Objectives.............................................................................................................32 
5.1 
Primary Study Objectives .....................................................................................32 
5.2 
Secondary Study Objective: Subpopulation Neurological Assessment (SNA) .32 
6.0 Study Design ...................................................................................................................33 
6.1 
Calibration Roll-in Phase: up to 250 Subjects ....................................................33 
6.2 
Main Study: up to 500 Subjects ............................................................................33 
6.3 
Subpopulation Neurological Assessment (SNA): 60 Subjects ............................35 
6.4 
Total Enrollment ....................................................................................................36 
6.5 
Study Duration, Completion, and Termination ..................................................36 
6.6 
Recruitment and Screening Procedures ..............................................................36 
6.7 
Informed Consent and Enrollment Procedures ..................................................37 
6.8 
Subject Selection ....................................................................................................37 
6.8.1 
Study Inclusion Criteria ......................................................................................37 
6.8.2 
Study Exclusion Criteria .....................................................................................37 
6.9 
Subject Status and Disposition Definitions ..........................................................38 

 
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6.10 
Subject Withdrawal ...............................................................................................39 
7.0 Definitions .......................................................................................................................40 
8.0 Study Endpoints .............................................................................................................41 
8.1 
Primary Safety Endpoint ......................................................................................41 
8.2 
Primary Effectiveness Endpoint ...........................................................................41 
8.3 
Secondary Endpoints .............................................................................................42 
9.0 Schedule of Procedures and Examinations (Description of Treatment)...................43 
9.1 
Patient Screening ...................................................................................................43 
9.2 
Randomization .......................................................................................................43 
9.3 
Study Medication ...................................................................................................43 
9.3.1 
Anticoagulation Medications ..............................................................................43 
9.3.2 
Antiarrhythmic Drug Management .....................................................................44 
9.3.3 
Use of Additional Medications ...........................................................................46 
9.4 
Pre-Procedure (Baseline) Assessments ................................................................46 
9.5 
Treatment Description...........................................................................................48 
9.5.1 
TEST - Required Devices ...................................................................................48 
9.5.2 
CONTROL – Required Devices .........................................................................50 
9.6 
General AF  Procedure Guidelines ......................................................................51 
9.6.1 
Electrophysiology study and pre-ablation procedures: .......................................51 
9.6.2 
TEST Group ........................................................................................................52 
9.6.3 
CONTROL Group ..............................................................................................53 
9.6.4 
Procedural data to be collected ...........................................................................54 
9.6.5 
Optional ablation procedure(s) based on clinical findings: ................................55 
9.7 
Post Procedure (pre-discharge) Assessment ........................................................55 
9.8 
Follow-up Visit Assessment ...................................................................................55 
9.9 
Summary of Subject Assessment ..........................................................................56 
9.10 
Descriptions of Procedures....................................................................................57 
9.11 
Unscheduled Visits .................................................................................................59 
9.12 
Repeat Ablation Procedures .................................................................................59 
9.13 
Core Laboratory for Evaluation Tests .................................................................60 
10.0 Adverse Events ...............................................................................................................61 
10.1 
Definitions / Classifications ...................................................................................61 
10.1.1 
Adverse Event (AE) ............................................................................................61 
10.1.2 
Serious Adverse Event (SAE) .............................................................................61 
10.1.3 
Primary Adverse Event .......................................................................................62 
10.1.4 
Adverse Device Effect / Serious Adverse Device Effect ....................................63 
10.1.5 
Anticipated Adverse Events ................................................................................63 

 
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10.1.6 
Unanticipated Adverse Device Effect .................................................................66 
10.1.7 
Non-Serious Adverse Events ..............................................................................66 
10.1.8 
Study Device Failure or Malfunction .................................................................66 
10.2 
Causality .................................................................................................................67 
10.3 
Intensity / Severity .................................................................................................67 
10.4 
Outcome ..................................................................................................................68 
10.5 
Adverse Event Reporting and Documentation Requirements...........................68 
10.5.1 
Adverse Event Reporting Requirements .............................................................68 
10.5.2 
Complaint Reporting ...........................................................................................69 
10.5.3 
Adverse Event Documentation ...........................................................................69 
10.6 
Global Safety Monitoring Committee ..................................................................70 
11.0 Statistical Analysis .........................................................................................................71 
11.1 
Overview of Study Design .....................................................................................71 
11.2 
General Considerations .........................................................................................71 
11.3 
Sample Size and Power Calculation .....................................................................72 
11.3.1 
Main Study ..........................................................................................................72 
11.3.2 
Adaptive Sample Size .........................................................................................72 
11.3.3 
SNA Population Sample Size .............................................................................73 
11.3.4 
Total Sample Size ...............................................................................................73 
11.4 
Analysis Populations ..............................................................................................73 
11.5 
Statistical Analyses for the Primary Endpoints ..................................................74 
11.5.1 
Primary Safety Endpoint .....................................................................................74 
11.5.2 
Primary Effectiveness Endpoint .........................................................................74 
11.5.3 
Site Heterogeneity ...............................................................................................75 
11.5.4 
Handling of Missing Data ...................................................................................76 
11.5.5 
Additional Analyses for Primary Effectiveness and Safety Endpoints ..............79 
11.6 
Adaptive Design Interim Analyses .......................................................................80 
11.6.1 
Adaptive Sample Size .........................................................................................80 
11.6.2 
Sample Size Interim Analyses ............................................................................80 
11.6.3 
Early Success Claim Interim Analyses ...............................................................80 
11.7 
Secondary Effectiveness Endpoints Analyses ......................................................81 
11.7.1 
Acute Effectiveness (PVI Confirmation) ............................................................81 
11.7.2 
One-Year Effectiveness ......................................................................................81 
11.7.3 
Long-Term Effectiveness....................................................................................81 
11.7.4 
Secondary Effectiveness Endpoint Analyses ......................................................82 
11.8 
Secondary Safety Endpoints Analyses .................................................................82 
11.8.1 
Incidence of AEs and SAEs during 12 Month Follow-up ..................................82 
11.8.2 
PV Stenosis at 3 Months Post Ablation ..............................................................82 
11.8.3 
Incidence of AEs and SAEs during 2nd and 3rd Year Follow-up ......................82 

 
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11.9 
Analyses for Additional Endpoints.......................................................................82 
12.0 Administrative Responsibilities ....................................................................................84 
12.1 
Institutional Review Board (IRB; or Equivalent) Review .................................84 
12.2 
Informed Consent ..................................................................................................84 
12.3 
Subject Confidentiality ..........................................................................................85 
12.4 
Data Monitoring .....................................................................................................85 
12.5 
Labeling ..................................................................................................................85 
12.6 
Management of Protocol Deviations ....................................................................86 
13.0 Study Management ........................................................................................................87 
13.1 
Study Timelines ......................................................................................................87 
13.2 
Study Advisory Committee (SAC) .......................................................................87 
13.3 
Interim Monitoring Committee ............................................................................87 
13.4 
Investigator Responsibilities .................................................................................88 
13.5 
Sponsor Responsibilities ........................................................................................89 
13.6 
Training ..................................................................................................................89 
13.7 
Sponsor Contact Information ...............................................................................90 
13.8 
Investigator Selection.............................................................................................90 
13.9 
Initiation of the Investigation ................................................................................90 
13.10 Data Reporting and Monitoring ...........................................................................90 
13.11 Termination of the Study ......................................................................................91 
13.12 Device Accountability ............................................................................................91 
13.13 Device Returns .......................................................................................................91 
13.14 Annual Requirements ............................................................................................92 
13.15 Electronic CRFs .....................................................................................................92 
13.16 Source Documentation...........................................................................................92 
13.17 Subject Confidentiality/Record ............................................................................93 
13.18 Records....................................................................................................................93 
13.19 Record Retention and Archiving ..........................................................................94 
13.20 Reports ....................................................................................................................94 
13.21 Investigator’s Annual and Final Report ..............................................................95 
13.22 Publication Policy...................................................................................................95 
13.23 Data Management ..................................................................................................95 

 
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14.0 Regulatory / Ethical Considerations ............................................................................96 
14.1 
Role of Sponsor ......................................................................................................96 
14.2 
General Duties (21 CFR 812. 40) ..........................................................................96 
14.3 
Selection of Investigators (21 CFR 812. 43) .........................................................96 
14.4 
Supplemental Applications (21 CFR 812. 335 [A] and [B]) ...............................96 
14.5 
Maintaining Records (21 CFR 812. 140 [B]) .......................................................96 
14.6 
Submitting Reports (21 CFR 812. 150 [B]) ..........................................................97 
15.0 References .......................................................................................................................98 
 
 
 
 

 
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List of Figures and Tables 
Table 2.0A: List of Acronyms/Abbreviations and Study Terms/Definitions ...................16 
Table 3.4.1A: Marketed Devices to be Used with the nMARQ™ PVI System ................26 
Figure 6.2A: Study Design ....................................................................................................34 
Table 7.0A: AF and Ablation Terms ....................................................................................40 
Table 9.3.2A: AAD Usage and Impact on Primary Effectiveness Classification .............46 
Table 9.4A: Baseline (Pre-Ablation) Evaluations and Completion Timeframe ...............47 
Table 9.5.1A: TEST (nMARQ) Required Investigational Study Devices.........................48 
Table 9.5.1B: TEST (nMARQ™) Required Non-Investigational Devices. ......................49 
Table 9.5.1C: nMARQ™ Circular and Crescent** Irrigated Catheter – Maximum 
Settings for RF Power, Temperature and Duration ...........................................................49 
Table 9.5.1D: NAVISTAR® THERMOCOOL® Catheter - Recommended RF Energy 
Delivery Parameters when connected to the nMARQ™ Generator AND used for 
Atrial Ablation .......................................................................................................................50 
Table 9.5.2A: CONTROL (THERMOCOOL® Navigational) Required Non-
Investigational Devices ..........................................................................................................51 
Table 9.9A: Summary of Subject Assessments ...................................................................56 
Table 10.1.3A: Primary Adverse Events..............................................................................62 
Table 10.1.5.A: Anticipated Adverse Events .......................................................................63 
Table 10.2A: Adverse Event Causality Classifications .......................................................67 
Table 10.3A: Adverse Event Intensity / Severity Definitions .............................................67 
Table 10.4A: Adverse Event Outcome Classifications .......................................................68 
Table 10.5.1A: AE Reporting Requirements .......................................................................69 
Table 13.20A: Responsibilities for Preparing and Submitting Reports ...........................94 
 
 

 
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CONFIDENTIAL 
1.0 Protocol Summary 
 
Title: 
reMARQable  
Design: 
The Main Study will consist of a prospective, multi-center, randomized 
(1:1 
concurrent 
nMARQ™ 
Catheter 
System 
[nMARQ] 
vs  
THERMOCOOL® Navigational Family of catheters [TC]), controlled, two-
arm, single-blind design. Embedded within the Main Study will be a 
Subpopulation Neurological Assessment (SNA) with a prospective, 
controlled design, with consecutive enrollment.   
 
Objective: 
The objective of this study will be to demonstrate safety and effectiveness 
of nMARQ compared to TC in treating subjects with drug-refractory 
symptomatic paroxysmal atrial fibrillation (PAF). 
 
The objective of the Subpopulation Neurological Assessment (SNA) is to 
evaluate the comparative incidence of symptomatic and asymptomatic 
cerebral emboli, and any associated neurological deficits, both pre- and 
post-ablation by treatment group, among a subset of Main Study subjects. 
 
 
 
Clinical Sites: 
Up to 50 sites in the United States (U.S.) and other regions may be 
included in the study. 
 
Subject Population: Subjects with symptomatic PAF who have had at least one AF episode 
documented within one (1) year prior to enrollment and who have failed at 
least one antiarrhythmic drug (AAD [class I or III, or AV nodal blocking 
agents such as beta blockers and calcium channel blockers] as evidenced 
by recurrent symptomatic AF, or intolerance to the AAD). 
 
Term 
Study Definition 
AF episode* 
AF documented by ECG monitoring and has a duration of at 
least 30 seconds or, if <30 seconds, is present continuously 
throughout the ECG monitoring tracing.  The presence of 
subsequent episodes of AF requires that sinus rhythm be 
document by ECG monitoring between AF episodes.  [Atrial 
fibrillation and atrial flutter (including atypical flutter) are 
considered episodes of AF.  Atrial flutter alone is not 
considered an episode of AF.] 
Paroxysmal 
AF* 
Recurrent AF (≥2 episodes that terminate spontaneously within 
7 days.  (Episodes of AF of ≤48h duration that are terminated 
with electrical or pharmacologic cardioversion should also be 
classified as paroxysmal AF episodes.) 

 
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Term 
Study Definition 
Persistent 
AF* 
Continuous AF that is sustained beyond 7 days. (Episodes of 
AF in which a decision is made to electrically or 
pharmacologically cardiovert the patient after ≥48 hours of AF, 
but prior to 7 days, should also be classified as persistent AF 
episodes.) 
Symptomatic 
AF 
AF where symptom(s) exhibited by the subject are concurrent 
with a documented episode by ILR, ECG, TTM, Holter 
monitor, or telemetry recording.  Symptoms may include but are 
not limited to: palpitations, irregular pulse (e.g., rapid, racing, 
pounding, fluttering, bradycardia), dizziness, weakness, chest 
discomfort, and breathlessness. 
Documented 
AF episode 
An AF episode documented by an electrocardiographic 
monitoring tool. This may include ILR, ECG, TTM, HM, or 
telemetry strip.  
Reporting of a symptomatic episode by a patient or in a referral 
letter is not considered a documented AF episode. 
* The HRS/EHRA/ECAS 2012 Consensus Statement recognizes that patients may have 
both paroxysmal and persistent AF episodes and that the AF classification should be 
defined as the most frequent type of AF experienced within  6 months of an ablation 
procedure. 
 
Inclusion Criteria: Candidates must meet ALL of the following criteria: 
1. 
Patients with symptomatic paroxysmal AF who have had at least one 
AF episode documented within one (1) year prior to enrollment. 
Documentation may include ECG, transtelephonic monitor (TTM), 
Holter monitor (HM), or telemetry strip. 
2. 
Patients who have failed at least one antiarrhythmic drug (AAD; 
class I or III, or AV nodal blocking agents such as beta blockers and 
calcium channel blockers) as evidenced by recurrent symptomatic 
AF, or intolerance to the AAD.   
3. 
Pre-procedure anticoagulation on warfarin, rivaroxaban, or apixaban. 
 
If receiving warfarin therapy, patients must agree to take 
warfarin for at least 4 weeks prior to the scheduled ablation 
procedure. 
4. 
Age 18 years or older. 
5. 
Signed Patient Informed Consent Form (ICF). 
6. 
Able and willing to comply with all pre-, post-, and follow-up testing 
and requirements. 
 
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 ablation for atrial fibrillation. 
3. 
Patients on amiodarone at any time during the past 3 months prior to 
enrollment. 

 
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CONFIDENTIAL 
4. 
AF episodes lasting > 7 days. 
5. 
Any cardiac surgery within the past 60 days (2 months).  
6. 
Any valvular cardiac surgical procedure (i.e., ventriculotomy, 
atriotomy, and valve repair or replacement and presence of a 
prosthetic valve). 
7. 
CABG procedure within the last 180 days (6 months). 
8. 
Awaiting cardiac transplantation or other cardiac surgery within the 
next 365 days (12 months). 
9. 
Documented left atrial thrombus on imaging. 
10. History of a documented thromboembolic event within the past one 
(1) year. 
11. Diagnosed atrial myxoma. 
12. Presence of implanted ICD. 
13. 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. 
14. Significant congenital anomaly or medical problem that in the 
opinion of the investigator would preclude enrollment in this study. 
15. Women who are pregnant (as evidenced by pregnancy test if subject 
is of child-bearing age and potential), breast feeding, or planning to 
become pregnant. 
16. Acute illness or active systemic infection or sepsis. 
17. Unstable angina. 
18. Myocardial infarction within the previous 60 days (2 months).   
19. Left ventricular ejection fraction <40%. 
20. History of blood clotting or bleeding abnormalities. 
21. Contraindication to anticoagulation (i.e., heparin, dabigatran, 
Vitamin K Antagonists such as warfarin). 
22. Life expectancy less than 365 days (12 months). 
23. Enrollment in an investigational study evaluating another device or 
drug. 
24. Uncontrolled heart Failure or NYHA Class III or IV heart failure. 
25. Presence of intramural thrombus, tumor or other abnormality that 
precludes catheter introduction or manipulation. 
26. Presence of a condition that precludes vascular access. 
27. Left atrial size >50 mm. 
 
 
Roll-in Phase: 
Roll-in nMARQ™ Catheter System:  The first 3 subjects  at each 
investigational site will be considered an nMARQ roll-in subject. An 
additional 1-2 (prospectively designated) roll-in subjects will be allowed 
per site to minimize the learning curve effect of using the new nMARQ 
system. Therefore, up to 5 roll-in subjects will be allowed per site. These 
subjects will be analyzed only as part of the Safety Population. For OUS 

 
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CONFIDENTIAL 
investigational sites with prior experience of at least 5 nMARQ cases, the 
minimum number of roll-in subjects will be 1.   
   
 
Main Study: 
Treatment Groups: Eligible subjects who sign the informed consent 
form (ICF) will be randomized into one of two study arms: 
 
 
nMARQ™ Catheter System* (Test) Group: up to 250 subjects will 
undergo catheter ablation with the nMARQ™ System. 
 
The nMARQ™ Catheter System consists of 2 investigational 
catheters (a circular and a crescent catheter; the crescent catheter 
was discontinued in January 2015) and an investigational multi-
channel RF generator.  Additionally, and as part of the system 
toolkit, a NAVISTAR® THERMOCOOL® Catheter may be utilized for 
necessary focal touch-up. 
  
 
TC (Control) Group: up to 250 subjects will undergo TC ablation. 
 
Primary Endpoints:  
 
 
 
Primary Safety:   
The primary safety endpoint will be the incidence of early-onset primary 
adverse events within 7 days of the AF ablation procedure (pulmonary 
vein stenosis and atrio-esophageal fistula that occur beyond one week (7 
Days) post-procedure shall be deemed primary AEs) in the as treated 
population. 
 
Primary Effectiveness:   
The primary effectiveness endpoint is freedom from documented, 
symptomatic atrial fibrillation (AF), atrial tachycardia (AT), or atrial 
flutter (AFL) episodes based on electrocardiographic data through the 
effectiveness evaluation period (3-12 months follow-up post ablation 
procedure) in the intention to treat (ITT) population as randomized.  
 
Sample Size and  
Power Calculation:  
Main Study:  
Trial simulation was carried out to evaluate the performance 
characteristics of the trial. Under the assumptions of equivalent 
effectiveness success rate at 55% and equivalent safety event rate at 8.6% 
in both groups, at an experiment-wise error rate of 0.05, an adaptive 
sample size of 250-500 (mean sample size of 417) will provide 80% 
power for trial success, meeting both effectiveness and safety endpoints, 
and 82.8 and 87.4% power for meeting effectiveness and safety endpoints 
respectively.  The probability of early trial success is 36.8%.  
 

 
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CONFIDENTIAL 
 
Total Sample Size:  
• 
Includes up to 5 nMARQ roll-in cases per investigational site for a 
total of up to 250 Roll-in cases. 
• 
An adaptive sample size of 250-500 subjects will be enrolled and 
randomized to nMARQ or TC in the Main Study.    
 
Subpopulation Neurological Assessment (SNA): 
The purpose of this neurological assessment is to evaluate the comparative 
incidence of symptomatic and asymptomatic cerebral emboli, with or 
without emboli-associated neurological deficits, at pre- and post-ablation 
time points and by treatment group.   
 
SNA Endpoint:  
The SNA primary endpoint is the comparative incidence of pre- and post-
ablation symptomatic and asymptomatic cerebral emboli, as determined 
by MRI evaluations. The presence of emboli-associated neurological 
deficits was also  evaluated, using the National Institute of Health Stroke 
Scale (NIHSS) and general neurological assessments. 
 
SNA Clinical Sites  
Up to 15 sites will be included in the assessment.   
 
Number of SNA Subjects:   
At least 60 subjects (30 from each treatment group in the Main 
Study) were selected for the SNA.  The Roll-in subjects at each 
participating site were not included in the SNA.  All other subjects 
consecutively enrolled in the Main Study at SNA sites were asked 
to also enroll in the SNA (until sufficient SNA subjects are 
accrued).  This approach helped to mitigate the confounding 
effects of an nMARQ system learning curve, which is associated 
with early experience using a new and complex ablation catheter 
system. 
 

 
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CONFIDENTIAL 
Summary of Subject Assessments 
Assessments 
BL 
D/C 
D7 
M1 
D7-42 
M3    
D70-110 
M6 
D150-210 
M9 
D235-315 
M12 
D316-405 
UNS 
Y2 
±45D 
Y3 
±45D 
Clinic visit 
  
 
 
 
 
 
 
 
 
 
 
  
Patient Information 
(Demographics) and 
Consent  
  
 
 
 
 
 
 
 
Medical history 
  
 
 
 
 
 
 
 
Pregnancy Test1  
  
 
 
 
 
 
 
 
TTE2 
  
  
 
 
 
 
 
 
Imaging for detection of 
LA thrombus (e.g., TEE, 
ICE, CT, MRI)3 
  
 
 
 
 
 
 
 
ECG4 
  
  
 
 
 
 
 
 
 
 
 
  
TTM5 
 
 
 
 
 
 
 
 
 
 
  
CT/MRA 
nMARQ GROUP 
ONLY 
 6 
 
 
 
 
 
 
 
 
Cardiac medication 
  
 
 
 
 
 
 
 
 
 
 
  
Adverse events 
 
  
 
7 
 
 
 
 
 
 
 
 
  
7 
AFL/AT/AF recurrence 
and repeat ablation 
 
 
 
 
 
 
 
 
 
 
 
  
7 
CCS-SAF Scale 
  
 
 
 
 
 
 
 
 
 
 
Cerebral MRI8 
 9 
 10 
 
 
11 
 
11 
 
11 
 
11 
 12 
Neurological Exam8 
 9 
 10 
 
 
11 
 
11 
 
11 
 
11 
 12 
NIH Stroke Scale8 
 9 
 10 
 
 
11 
 
11 
 
11 
 
11 
 12 
mRS 
 9 
 
 
 
MoCA 
 9 
  
 
 
 
 
11 
 
11 
 
11 
 12 
1. 
In all women of child-bearing age and potential. To be completed within 24 hours prior to ablation procedure. 
2. 
Completed within 30 days prior to ablation period. 
3. 
To be completed  the day before or the day of the ablation procedure. 
4. 
To be collected if completed as standard of care. 
5. 
Dispensation of TTM device at Month 3.  
6. 
 Within 30 days prior to ablation procedure. 
7. 
To be assessed via phone follow-up. 
8. 
Only for SNA subjects. 
9. 
To be performed within 72 hours prior to ablation procedure. 
10. 
To be completed within 72 hours post-ablation procedure. 
11. 
To be undertaken if neurologic symptoms and/or cerebral ischemic lesions identified in a prior evaluation. 
12. 
To be completed only if: (i) a previously mandated test was missed; or, (ii) subject reports neurologic difficulties 
between scheduled follow-up visits and unscheduled assessment per investigator approval.   
 

 
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2.0 Abbreviations 
Table 2.0A: List of Acronyms/Abbreviations and Study Terms/Definitions  
Acronym/ 
Abbreviation 
Expanded Term 
AAD 
Antiarrhythmic Drug 
ACC/AHA 
American College of Cardiology/American Heart Association 
ACL 
Advanced Catheter Location 
ACT 
Activated clotting time 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AMI 
Acute Myocardial Infarction 
ARB 
Angiotensin II Receptor Blockers 
AT 
Atrial Tachycardia 
CABG 
Coronary Artery Bypass Graft 
CHF 
Congestive Heart Failure 
CK 
Creatine Kinase 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CS 
Coronary sinus  
CT 
Computed tomography 
CVA 
Cerebrovascular Accident or Stroke 
DM 
Diabetes Mellitus 
EB 
Ethics Board  
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EHRA AF 
European Heart Rhythm Association Atrial Fibrillation 
EMEA 
Europe, Middle East and Africa 
EP 
Electrophysiology 
FAM  
Fast Anatomical Mapping  
FDA 
Food and Drug Administration 
Fr 
French 
FU 
Follow-Up 
GCP 
Good Clinical Practices 
GSMC 
Global Safety Monitoring Committee 
HM 
Holter Monitoring 
HRS/EHRA/ECAS 
Heart Rhythm Society / European Heart Rhythm Association / European 
Cardiac Arrhythmia Society 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFU 
Instruction For Use 
ILR 
Implantable Loop Recorder 
ITT 
Intention to treat 
LA 
Left Atrium 

 
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Acronym/ 
Abbreviation 
Expanded Term 
LV 
Left Ventricle 
LVEF 
Left Ventricular Ejection Fraction 
MI 
Myocardial Infarction 
NSR 
Normal Sinus Rhythm 
PAF 
Paroxysmal Atrial Fibrillation 
PFO 
Patent foramen ovale 
PI 
Principal Investigator 
PV 
Pulmonary Vein 
PVAC® 
Pulmonary Vein Ablation Catheter® 
PVI 
Pulmonary Vein Isolation 
QoL 
Quality Of Life 
RA 
Right Atrium 
RF  
Radiofrequency  
RFCA 
Radiofrequency Catheter Ablation 
RV 
Right Ventricle 
SAE 
Serious Adverse Event 
SDV 
Source Data Verification 
SNA 
Subpopulation Neurological Assessment 
TEE 
Transesophageal Echocardiography 
TIA 
Transient Ischemic Attack 
TS 
Transseptal 
TTE 
Transthoracic Echocardiography 
TTM 
Transtelephonic Monitoring 
UADE 
Unanticipated Adverse Device Effect 
 

 
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3.0 Introduction 
3.1 
Background 
3.1.1 Clinical Outcomes and Published Guidelines 
Atrial fibrillation (AF) is the most common cardiac arrhythmia in the developed world.1   Most 
recently published studies, which discuss prevalence of AF, continue to cite pivotal studies that 
were published prior to 2005.2-5  AF prevalence increases with age, ranging from 0.1% to 9%, in 
adults under 55 and over 80 years old, respectively.6  In fact, the ATRIA Study revealed that 
5.3% of adults over 60 had a diagnosis of nonvalvular AF, with rates higher in non-Hispanic 
whites than in other races and ethnicities.7  The number of Americans with AF has been 
estimated at 2.66 million and is expected to surpass 5.6 million by 2050. 6,8  An alternate estimate 
of US prevalence is even higher, based upon data from a Minnesota community, with 15.9 
million cases projected in 2050.9  Another recent community-based study noted that the 10-year 
risk of AF ranged from less than 1% to over 24% depending on risk strata.10   A European study 
reported lifetime risk of developing AF as 25%.11    
 
Prevalence and/or incidence studies of AF have also been conducted in other regions of the 
world including: Japan (overall annual prevalence rate of 9.3/1000 patient-years and overall 
prevalence rate of 4.4% for men and 2.2% for women ≥ age 80 ); France (prevalence estimated to 
be between 600,000-1 million people and incidence estimated to be between 110,000-230,000 
new cases per year); Brazil (age-adjusted prevalence of AF of 3.9% for men and 2.0% for 
women); and, China (age-adjusted prevalence of 0.65% for persons ≥30 years of age) 12-16. The 
percentage of AF patients with paroxysmal AF, at first detection, was 76% in the previously-
mentioned Minnesota community study and 53% in a French study that contained a higher 
proportion of patients with permanent AF. 9,17      
 
Atrial fibrillation is a supraventricular arrhythmia that is characterized by chaotic and 
uncoordinated contractions of the atria.  Episodes of AF are initiated by ectopic sites which 
derive from the pulmonary veins, in more than 90% of cases. One or several pulmonary veins 
may be implicated and often multiple initiation sites (foci) originate from a single vein. The foci 
originate in the muscular cardiac bundles that line the pulmonary veins.  These muscular 
extensions occupy various proportions within the vein perimeter, ranging from a single quadrant 
to the entire circumference.  AF is most often diagnosed from an electrocardiogram (ECG) when 
an irregular ventricular rate is present.  Characteristic ECG findings include the absence of P-
waves, which are replaced with irregular atrial complexes (fibrillatory waves) that vary in 
amplitude, shape, and timing.  In subjects with intact atrio-ventricular (AV) conduction, the R-R 
interval will almost always vary due to the irregular conduction of impulses from the atria to the 
ventricles.18   The frequency and duration of AF episodes varies, with current guidelines dividing 
the condition into paroxysmal, persistent, longstanding persistent, and permanent types.18   
 
Briefly, paroxysmal AF is defined as recurrent AF that terminates spontaneously within 7 days.  
Persistent AF is defined as AF sustained beyond 7 days, or lasting less than 7 days but 
necessitating pharmacologic or electrical cardioversion. Permanent AF is long-standing AF in 

 
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which cardioversion has failed or is no longer attempted. The most recently published 
HRS/EHRA/ECAS Consensus Statement included similar definitions for paroxysmal and  
persistent AF; current diagnostic terms now include ‘long standing  persistent AF’, which is 
defined as continuous AF of greater than 1 year duration.19   
 
Cardiopulmonary co-morbidities, such as heart failure (HF) and hypertension, have been 
associated with the occurrence of AF.18  Patients suffering from episodes of AF have an 
increased long-term risk of stroke, HF, and all cause mortality.20  This is especially true among 
women, where AF is an independent predictor of adverse cardiovascular events such as stroke 
and HF.20  The risk of ischemic stroke in AF patients is anywhere from 2 to 7 times greater than 
in individuals without AF, and exceeds a rate of 7% per year when pathological changes are 
detected by brain imaging.  In one study, the 3-year incidence of development of AF in patients 
with HF was 9%.18,21  AF also has been associated with a 40-90% increased mortality rate.3,22     
 
The impact of undesirable symptoms associated with AF cannot be underestimated.  Patients 
describe a considerably impaired quality of life that is independent of disease severity.23,24  
Improvement in patients’ quality of life following treatment of AF is directly correlated with the 
restoration and maintenance of normal sinus rhythm.23-26  The treatment of AF and its 
consequences make this disease a costly public health burden. Total annual US expenditure for 
the treatment of AF patients has been estimated at $6.65 billion, and approximately $15.7 billion 
USD in the European Union.18,27 
 
Radiofrequency (RF) catheter ablation has provided excellent results for treating many types of 
supraventricular arrhythmias.28-33  The prevalent use of catheter ablation techniques, targeting the 
isolation of the pulmonary veins (PVs), was reflected in the 2007 and 2012 HRS/EHRA/ECAS 
Consensus Statements, emphasizing that electrical isolation of the PVs from the left atrium is 
“the cornerstone for most AF ablation procedures” and is widely considered the best method to 
treat AF in the paroxysmal AF population.19,34  In the prevention of recurrent AF, recent clinical 
guidelines have evolved from a point of considering catheter ablation as a reasonable alternative 
to pharmacological therapy  to a recognition that it may be appropriate as a first-line therapy in 
rare clinical situations or for selected symptomatic patients with HF and/or reduced ejection 
fraction. 18,34,35  A key contributor to the current perspective is that, since the 2007 and 2012 
Consensus Statements, “a large body of literature, including multiple prospective randomized 
clinical trials, has confirmed the safety and efficacy of catheter ablation of AF”.19   
 
Systematic reviews and meta-analyses of multiple AF studies have demonstrated clear 
advantages of catheter ablation in preventing disease recurrence.37-39  There have been multiple 
randomized clinical trials that have measured outcomes of catheter ablation versus AAD alone, 
in patients with paroxysmal AF.  Among these trials, while the definitions of success varied, 
reported catheter ablation efficacy rates ranged from 66 to 89%.41 
 
3.1.2 Overview of General and Vascular Risks Associated with Catheter Ablation 
In general, rare but serious complications of catheter ablation occur in the range of 2-3% of 
cases, with approximately 1 in 1000 (0.1%) having a fatal outcome.39,40  A global survey, 
published in 2005, reported a 6% incidence of major complications among 8,745 AF ablation 

 
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procedures.  More than 1 procedure was performed on 27% of these patients.35   However, a 
more recent global survey, published in 2010, reported a post-ablation complication rate of 4.5%, 
from among more than 16,000 catheter ablation procedures.  These results reflected treatments of 
patients with paroxysmal, persistent and longstanding persistent AF, within which one would 
expect a much higher rate of complications in the latter two patient groups versus paroxysmal 
AF patients.41 
 
There are a variety of possible vascular complications, with a reported incidence of assorted 
events ranging from 0-13%.   More definitive occurrence rates, among 8,745 ablation 
procedures, have included 0.53% for pseudoaneurysm and 0.43% arteriovenous fistulae.35  Other 
critical vascular complications included intracerebral microembolic events, caused by air or 
thrombus, which manifest as stroke, TIA, or silent microemboli.  Intracerebral thromboembolism 
has been reported in electrophysiology literature for AF up to a 7% incidence and the majority of 
published studies report at least one cerebrovascular event.  Most embolic events occur within a 
24-hour period following an ablation procedure.  However, these data derive from varied 
measurement techniques, with inconsistencies in reporting cerebrovascular events.  As a result, 
catheter ablation for AF has yet to clearly demonstrate a reduced risk of stroke, an important 
consideration in the management of AF patients.42   
 
Post-ablation silent (asymptomatic) intracerebral microbembolic lesions have a major impact on 
therapeutic approaches to AF. Though general causes of microembolic lesions may be well 
understood, what remains unclear is the precise influence of individual and combined factors, 
such as patient health status, selected catheter ablation technology, overall patient management, 
control of RF energy during ablation, and peri- and intraprocedural anticoagulation regimens.  
To better understand some or all of these factors, in the context of using the nMARQ™ Circular- 
and nMARQ™ Crescent-shaped Irrigated RF ablation Catheters to achieve pulmonary vein 
isolation (PVI), when used in conjunction with the nMARQ™ Multi-channel RF Generator, this 
study will include an assessment of the frequency, size and anatomic location of post-ablation, 
intracerebral, microembolic lesions and any measurable, associated neurological deficits.  
 
 
Recent studies have included analyses of cerebral ischemia following AF ablation, using 
magnetic resonance imaging (MRI). MRI has been used to assess symptomatic cerebrovascular 
accidents after RF ablation  and is a very valuable tool in identifying post-ablation asymptomatic 
cerebral ischemia.43-50  Two non-randomized, comparative studies, using MRI analysis, found 
that new cerebral lesions were much more common among patients treated with a Pulmonary 
Vein Ablation Catheter (PVAC, Medtronic Ablation Frontiers), as compared to those patients 
treated with either a cryoballoon or a conventional irrigated RF ablation catheter.  Cerebral 
microembolic lesions for PVAC occurred in approximately 38% of patients.  There was a 6% 
combined incidence of cerebral microembolic lesions for cryoballoon and conventional RF 
ablation.  Though the number of subjects was small in each of the 3 published studies (N = 108, 
74, & 89, respectively), the marked differences of incidence of microembolic lesions, between 
PVAC and the other two devices, were statistically significant (p<0.001 on multivariate 
analysis45 and p = 0.003).45,46,48  In all 3 studies, no significant differences were found between 
cryoablation and conventional irrigated RF ablation for this endpoint.   
 
 

 
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A fourth publication also included MRI analyses for cerebral microemboli. Among PVAC, 
cryoballoon, and conventional RF ablation catheters, the authors reported a  high number of post-
ablation intracerebral ischemic events. 44  In post-ablation MRI analyses, asymptomatic cerebral 
lesions were found in 33/86 (38%) patients.  Of the 33 patients, 30 were ablated with phased RF 
(PVAC) technology.  Fourteen of the 33 patients underwent follow up MRI assessments for up to 
one year post-ablation.  MRI analyses identified 50 new lesions (average of 3-6/patient); 
however, none were associated with neurological symptoms.  The predominant anatomic 
locations of  microemboli were: left hemisphere (60%) or cerebellum (26%). Overall, half (52%) 
were ≤3 mm diameter, 42% were from 4-10 mm diameter, and 3 (6%) were more than 10 mm in 
diameter.  Only the 3 largest lesions were present beyond 3 months post-ablation.  Among all 
microembolic lesions identified, 94% resolved without residual scarring at follow-up >2 weeks 
to <1 year after ablation.  
 
3.1.3 Study Population 
Current practice guidelines reflect extensive expert reviews of published risks and benefits 
among various treatment modalities and patient populations. Calkins et al. have indicated that 
the highest ratio of benefits over risks (Class I) and the strongest level of clinical evidence (Level 
A) support the use of catheter ablation among symptomatic, paroxysmal AF patients, who are 
refractory or intolerant of at least one Class I or III antiarrhythmic medication.19  Other experts 
have recommended catheter ablation for symptomatic PAF in patients failing a single AAD 
either strongly or under certain conditions. 18,40,51,52  All key published guidelines agree that the 
primary clinical benefit of catheter ablation for PAF is an improvement in quality of life, 
following abatement of arrhythmia-related symptoms. 
  
According to the HRS/EHRA/ECAS 2012 Consensus Statement, stand alone catheter ablation, 
prior to the initiation of an antiarrhythmic drug, is a reasonable approach for symptomatic 
patients with paroxysmal AF. 19  In this circumstance, the benefits of catheter ablation outweigh 
the risks (Class IIa); however, the strength of evidence/data supporting this therapeutic modality 
(Level B) reflects a limited number of clinical studies. Not all expert bodies are in line with the 
aforementioned expert opinion.  In a 2010 publication, the ESC-published guidelines and 
recommendations for the management of AF recommended first-line use of ablation for patients 
with paroxysmal AF and minimal or no heart disease.51  The authors conceded that data 
comparing the use of AADs versus ablation are limited but add that ablation may be a reasonable 
first-line therapy for some patients with AF. As more robust and consistent clinical research data 
are made public, ablation as first-line therapy may well be widely supported among medical 
communities and regulatory authorities, in the future. 
3.2 
Study Rationale 
Catheter ablation has been used for over a decade to treat AF patients to achieve PVI. The 
primary intent of this study is to generate clear and sufficient safety and effectiveness data for 
PMA approval on the use of the nMARQ™ Circular-shaped Irrigated RF ablation Catheter, in 
achieving PVI, when used in conjunction with the nMARQ™ Multi-channel RF Generator.  
 

 
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The 2012 HRS/EHRA/ECAS Expert Consensus Statement points out that the “concordance of 
the clinical trial data revealing the superiority of ablation over drugs for symptomatic 
paroxysmal AF recurrences” and the difficulties of subject enrollment and study management in 
conducting drug versus ablation studies, have led to widespread support of more relevant study 
designs, which compare a “novel device” to one that is already approved for use.19  The design 
of this protocol, a comparison of the nMARQ™ Catheter System [nMARQ™] versus the already 
marketed THERMOCOOL® Navigational Family of catheters [TC], reflects the same approach as 
supported by global experts for industry-sponsored clinical trials that assess new technology for 
catheter ablation. 
 
Anticoagulation leading up to, during, and following ablation treatment, can influence subject 
outcomes, particularly stroke.  Therefore, this protocol will require a specific regimen for 
anticoagulation (Section 9.3.1) throughout the study period based on current recommendations 
and standards of practice.  These requirements will include (i) a warfarin, rivaroxaban, or 
apixaban treatment regimen; (ii) a need to keep the pre-ablation International Normalized Ratio 
(INR) ≥2.0 (for patients receiving warfarin treatment); (iii) appropriate use of heparin during the 
procedure to maintain an Activated Clotting Time (ACT) ≥325 seconds; (iv) giving heightened 
attention to continuous flushing of sheaths; and, (v) maintaining a vigilant awareness of risks of 
air embolism.      
       
Efforts to achieve PVI with current catheter designs may present technical challenges for some 
operators in creating long contiguous ablation lines. Currently available RF catheters are used to 
ablate single targets (areas of potential) at a time in patients with AF; however, long contiguous 
lesions, which are formed by making multiple, consecutive single lesions, are often required to 
achieve PVI. Placement of additional RF lesions in the left and right atria has been investigated 
by a number of research centers34, 31, 53, 54 (e.g., a line of block between the left inferior PV and 
the mitral annulus); however, there is no consensus on the necessity, quantity, or anatomical 
placement of these extra RF lesions.  Given that the nMARQ™ irrigated RF ablation catheters 
were designed specifically to create long continuous lesions, this trial will evaluate the relative 
ability of physicians to achieve PVI with confirmed entrance block.    
 
The primary purpose of this randomized, controlled study is to establish the overall safety and 
effectiveness of the nMARQ™ PVI System for the radiofrequency catheter ablation treatment of 
symptomatic, drug refractory, paroxysmal atrial fibrillation.  A key focus within the full safety 
assessment of the nMARQ™ System will be the frequency of occurrence, clinical sequelae, and 
duration of effect of cerebroembolic lesions associated with stroke, TIA, or silent microemboli. 
Other key measurements will address the duration and manner in which treated subjects remain 
asymptomatic. 
 
 
3.3 
Previous Experience with nMARQ™ PVI Ablation System 
3.3.1 Bench and Animal Studies 
Bench and animal testing has been performed using the  nMARQ™ Circular and Crescent 
Irrigated Catheters and the nMARQ™ Multi-channel RF Generator.  Please refer to the Report of 
Prior Investigations for detailed summaries of the test protocols and corresponding reports. 

 
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3.3.2 Circular Ablation Catheter and Crescent Ablation Catheter for the Radiofrequency 
Ablation of Atrial Fibrillation (AFCC-126) Feasibility Study 
A total of 9 subjects were enrolled in this study from December 2009 through July 2010.  One 
subject was excluded (after signing the informed consent form) for not meeting the inclusion 
criteria to have a documented AF episode in the 6 months prior to enrollment.  Therefore, 8 
subjects are considered evaluable, 5 PAF subjects (62.5%, 5/8) and 3 Persistent AF subjects 
(37.5%, 3/8).  The mean age at date of procedure was 59.9 ± 7.2 years and ranged from 26.7 to 
70.9.  Three (3) of the enrolled subjects (33.3%) were female and six (6) (66.7%) were male.    
 
Excluding the protocol-specific arrhythmias, the most prevalent medical condition reported at 
baseline was atrial flutter (55.6%) followed by hypertension (33.3%).  
 
No subject deaths, early-onset primary AEs, serious adverse events or device or procedure 
related adverse events were reported.  Four non-serious adverse events were reported; all were 
unrelated to the device or procedure. Two (2) subjects required a repeat ablation procedure, both 
>6 months post index ablation.   
 
No pulmonary vein stenosis (≥70% narrowing) was reported for any of the subjects treated with 
the investigational catheters. 
 
All investigators responded that the catheter/tissue contact interface was ‘excellent.’  On a scale 
of 1 to 5, the mean rating for effectiveness of mapping and ablation for both catheters was 4 or 
greater.  Acute success, defined as isolation of a targeted pulmonary vein using the nMARQ™ 
Circular or nMARQ™ Crescent Irrigated Catheter, was greater than 60% for each targeted vein 
(LIPV: 62.5%, LSPV: 75%, RIPV: 62.5%, RSPV: 75%). 
 
The Circular and Crescent Irrigated Catheters, when used with the RF Generator System for the 
treatment of paroxysmal and persistent atrial fibrillation, performed as expected.   
 
3.3.3 REVOLUTION clinical study 
The REVOLUTION study is a prospective, multi-center, non-randomized clinical evaluation of 
subjects undergoing RF catheter ablation for the treatment of drug refractory symptomatic PAF.  
Following a successful 20 subject Workflow phase, the study continued with Roll-in (the first 3 
enrolled) subjects at each site, followed by the enrollment of subjects into the Effectiveness 
Cohort. A total of 186 subjects were enrolled in this study across 8 sites in Europe.  Of these 186 
subjects, five (5) were excluded (4 nMARQ and 1 ThermoCool), leaving 181 subjects planned 
for ablation procedures.  Eighteen (18) of the 181 subjects underwent ablation with the 
THERMOCOOL® catheter while the remaining 163 subjects (Safety Cohort) were scheduled for 
ablation with the nMARQ™ System.  Three (3) nMARQ subjects were discontinued from the 
study since no RF energy was delivered with the nMARQ™ Catheter so the Evaluable Cohort 
consists of 160 subjects undergoing ablation with the nMARQ™ Catheter. Excluding the 
workflow and roll-in subjects, 118 subjects comprise the Effectiveness Cohort. 
 

 
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All except 2 of the subjects in the Evaluable Cohort completed the 12 month follow up of the 
study, representing a high compliance rate of 98.8% (158/160). Overall TTM compliance within 
the Effectiveness Cohort was 87.0%, demonstrating rigorous AF recurrence monitoring 
throughout the study follow up period. 
 
Of the 163 subjects in the Safety Cohort, 112 (68.7%) were male and 51 (31.3%) were female.  
The mean age for the 163 subjects was 58.7 ± 10.24 years, representative of PAF population.  
The most prevalent medical condition reported at baseline was hypertension (62/163, 38.0%), 
followed by atrial flutter (32/163; 19.6%) and dyslipidemia (20/163, 12.3%). Subjects suffered 
from symptomatic AF for an average of 5.5 years at baseline and the majority of subjects 
(64.8%) were classified as NYHA Class I. 
 
No subject deaths, strokes, MI, PV stenosis, esophageal fistula, thromboembolism or 
unanticipated adverse device effects were reported in the trial.  For the primary safety endpoint, 
9 (5.5%) subjects experienced an early-onset (≤ 7 days) primary AEs, with only 4 (2.5%) 
subjects assessed with some level of device-relatedness. The primary safety endpoint was met 
since the observed rate of primary adverse events at 5.5%, and the corresponding upper bound of 
the 95% CI at 10.2% were less than the pre-specified performance goal of 16%. 
 
Apart from the primary adverse events, there were no other subjects observed with device-related 
SAEs throughout the 12 month follow-up period.  However, 2 subjects exhibited SAEs deemed 
as possibly related to procedure for dyspnea and TIA. In both cases, the condition completely 
resolved. No pulmonary vein stenosis (> 70% narrowing), as evaluated by baseline and post 
ablation CT/MRA imaging, was observed in any of the study subjects. 
 
Acute effectiveness, defined as the confirmation of entrance block in the targeted PVs, was 
achieved in 100% (117/117; entrance block data not available for 1 subject) of Effectiveness 
Cohort subjects. The use of a focal catheter for PV isolation was based on investigator’s choice 
and preference. This leads to a wide variability of touch-up use between the different 
participating investigational centers and resulted into an average touch-up rate of 16.1% of the 
targeted PVs.  Three (3) of the 8 investigational centers did not use any touch up for any of the 
nMARQ subjects. This represents a low rate of touch up use that is acceptable for achieving PV 
isolation. 
 
The primary effectiveness endpoint was freedom from documented symptomatic AF through 8 
months (day 240) post-index ablation. The primary effectiveness endpoint was met with 71.6% 
(83/116) of subjects achieving freedom from documented symptomatic AF recurrence at 8 
months post ablation. At the 12 month follow-up visit, freedom from documented symptomatic 
AF in the Effectiveness Cohort was 60.3% (70/116), still exceeding the performance goal of 
49%. Further analysis demonstrated a positive association between investigator experience and 
freedom from recurrent AF. The predicted probability of success after approximately 15 
procedures was 70%. 
 
Since the initiation of the REVOLUTION Study, published literature has generated an increased 
awareness of post-ablation asymptomatic cerebral emboli (ACE).  Although there was no 
incidence of stroke or other thromboembolic events in REVOLUTION study subjects, to better 

 
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understand the performance of the nMARQ™ System in light of the recently published literature 
on ACE, Biosense Webster added an amendment to the REVOLUTION study protocol that 
included the Subpopulation Neurological Assessment (SNA).  The SNA focused on generating 
pre- and post-ablation cerebral MRI assessments to evaluate intracerebral microemboli and 
neurological assessments in a subset of the overall study population.   
 
The SNA Cohort consisted of 19 evaluable Test (nMARQ) and 17 evaluable Control 
(ThermoCool) subjects.  Among the 36 subjects part of the SNA Cohort, 5 (13.9%) subjects were 
observed with asymptomatic cerebral embolic (ACE) lesions post ablation. One subject (1/17; 
5.9%) was part of the 17 subjects in the control group and 4/19 (21.1%) occurred within the test 
group.  No new neurological deficits were observed in the 5 subjects with ACE. None of the 5 
subjects with ACE had pre- or post-ablation NIHSS Scores above zero.  None of the subjects 
exhibited any new neurological abnormalities post-ablation.  Of the 5 subjects that developed 
ACE 1 nMARQ subject exhibited ACE associated with suboptimal irrigation.  Except for this 
one subject, observations of ACE were isolated to one site in the study and detected in both arms 
of the SNA assessment. No incidence of ACE was observed in subjects exclusively treated with 
warfarin and INR≥2.0 at the time of ablation. 
 
As a conclusion, operational and procedural variables such as anticoagulation management may 
have influenced the development of ACE in the REVOLUTION study. The % of ACE reported 
in REVOLUTION may possibly be further reduced by strict anticoagulation management and 
optimal procedural operation. 
 
When combined with evidence of high acute procedural success, favorable procedural, quality of 
life, and secondary effectiveness measures, these results demonstrate an acceptable safety and 
effectiveness profile that supports the safe use of the nMARQ™ Catheters along with the RF 
generator for the treatment of PAF.  
3.4 
Device Description  
3.4.1 Description of Currently Marketed Devices 
Table 3.4.1A lists the marketed devices that are used in conjunction with the nMARQ™ PVI 
System.  
 
 

 
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Table 3.4.1A: Marketed Devices to be Used with the nMARQ™ PVI System 
 
Device 
Description 
NAVISTAR® THERMOCOOL® Catheter 
Marketed in the US, EMEA, and other 
regions.  
Catheter Interface Cable (various 
model #s) 
Marketed in the US, EMEA, and other regions.  
COOLFLOW® Irrigation Pump 
(CFP002) and Tubing Set (CFT001) 
The COOLFLOW Saline Irrigation Pump 
(CFP001) is marketed in EMEA but is 
investigational in the US.  The Tubing Set 
(CFT001) is marketed in the US, EMEA, and 
other regions. 
CARTO® 3 EP Navigation System 
(Various Versions other than V 2.5 or 
later approved C3 version) 
Marketed in the US, EMEA, and other 
regions 
 

 
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4.0 Detailed Risk Analysis 
The risks posed are expected to be comparable to those anticipated during routine use of catheter 
ablation systems for intracardiac radiofrequency (RF) ablation procedures and use of AAD 
therapy according to current AF management guidelines.1,18,34  Appropriate measures have been 
outlined in this protocol to minimize the risk to subjects, while still providing the possible 
benefits of the treatment options to be studied.   
 
RF catheter ablation has been used for nearly two decades, and the risks and complications are 
well understood.  The uses of non-irrigated and saline-irrigated ablation catheters are routine for 
many PAF ablation procedures.  Section 3.1.2 provides a summary of some general risks 
associated with RF catheter ablation.  When compared to the usual standards of practice and 
published literature few, if any, additional risks are anticipated for subjects enrolled in this study, 
during and following  RF ablation of symptomatic PAF.  A summary of risks associated with 
catheter ablation, including analysis of and plans to minimize these risks, is provided below: 
4.1 
Description and Analysis of Risks 
The most common complications associated with catheter ablation of AF include: cardiac 
tamponade, with a reported incidence of >1.0%, pulmonary vein stenosis, with a 2003 
publication reporting a 3.4% incidence of serious PV stenosis (21/608 procedures) and more 
recently reported occurrences, among 8,745 AF ablation procedures, of 0.32% acute PV stenosis 
and 1.3% persistent PV stenosis.35,55  Complication rates for esophageal injury are quite varied, 
depending upon energy source used, lesion location, or type of lesion found (erythema, necrotic 
ulceration, perforation, or fistula formation).  Phrenic nerve injury, related to the application of 
RF energy, has a <1% reported incidence.56,57  
 
A 2010-published global survey has provided a comprehensive understanding of complications 
associated with RF catheter ablation.  Reported serious complications, among more than 16,000 
procedures, included 25 procedure-related deaths (0.15%), 213 episodes of cardiac tamponade 
(1.31%), 115 transient ischemic attacks (0.71%) and, 37 strokes (0.23%). An overall mortality 
rate of 0.1% was reported, among 45,115 AF procedures (32/32,569 patients).  Among the most 
frequent causes of death were cardiac tamponade (25% of deaths), stroke (16%), atrio-
esophageal fistula (16%) and massive pneumonia (6%).39 
 
Radiofrequency current may cause occlusion of a coronary artery, either by direct thermal 
damage, spasm, or thrombus formation.  Experience at numerous centers suggests that the risk of 
coronary occlusion is less than 0.5%.49,50   Coronary arterial occlusion could produce myocardial 
infarction (MI), angina or death.  Should occlusion of a coronary artery occur for any reason, the 
investigator will attempt to restore coronary blood flow through pharmacological, catheter and/or 
surgical intervention as medically indicated.  
 
The application of radiofrequency 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.  

 
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As discussed in Section 3.1.2, thrombus generation during the procedure may pose a serious and 
even life-threatening risk to the patient.  Thrombus may form on the ablation electrode during the 
application of radiofrequency current with or without any change in impedance.  The thrombus 
might become dislodged and embolize to produce an ischemic stroke, MI, or other occlusive 
injury.  The risk of thromboembolism is reduced by quickly terminating the application of 
current after an impedance rise, which limits the size of the coagulum on the electrode.  The use 
of open irrigation catheters, such as the THERMOCOOL® Catheters, provide cooling of the 
electrode-tissue interface, allowing the use of higher power while reducing the risk of thrombus 
formation.  Probably the most important aspect of TC is the near absence or very low likelihood 
of thrombus formation during RF.58  In an analysis of 6 clinical studies utilizing the NAVISTAR® 
THERMOCOOL® Catheter there was no reported incidence of stroke or TIAs within 7 days 
postprocedure. 58  
 
Thrombus formation on the endocardium following ablation may produce an arterial or 
pulmonary embolus.  This risk may be reduced by the use of aspirin or anticoagulation therapy, 
at the discretion of the physician.  
 
Cardiac perforation may result from catheter manipulation or application of radiofrequency 
current.  Published risks of cardiac perforation range from  <1%to 2.4%.35,41,49,50  This potentially 
life-threatening injury may result in cardiac tamponade and may require percutaneous pericardial 
drainage or surgical repair.  In a recent study representing  early experience using the nMARQ™ 
PVI Ablation System, there were 2 (2/138, 1.4%) reported incidents of tamponade.  Significant 
hemodynamic compromise can result in neurologic injury or death.  An increased risk of cardiac 
perforation may be associated with the use of a saline-irrigated electrode catheter due to its 
ability to create a larger, deeper RF lesion.  This risk is greatest in a thin walled chamber (i.e., 
RA, LA, appendage, or RV); 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 levels above 35 or 40 
watts.  If the lesion is deeper, the risk of steam pop is higher at power levels above 35-40 watts.  
 
There is an incrementally small risk associated with use of a saline-irrigated electrode catheter 
rather than a standard electrode catheter.  The larger RF lesion size produced with an irrigated 
catheter may cause moderate intra-procedural pain associated with RF applications and also may 
slightly increase the risk of cardiac perforation33.  Pain can be managed with intravenous 
analgesics.  Additionally, use of the cooled electrode tip catheter may reduce procedural and 
fluoroscopy times and increase procedural success by increasing lesion depth and by minimizing 
coagulum formation, which necessitates removal and re-deployment of the ablation  catheter.  
While the ability to cool the electrode-tissue interface allows the use of higher power (up to 50 
watts) than a conventional 4 mm electrode, RF power in the range of 30-40 watts is often 
adequate.  For any given power setting, the power delivered to the tissue is similar to that used 
with a 4 mm electrode.  
 
Injury to a cardiac valve may result from catheter manipulation or the application of 
radiofrequency current (risk <1%).43,49,50  This may produce valvular insufficiency and possibly 
require valve replacement surgery.  
 

 
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The application of RF current along the posterior left atrium can result in thermal injury to the 
esophagus and the formation of an atrio-esophageal fistula.  This is a very rare (0.04%) but 
severe complication of RF ablation that may require surgical intervention and may result in 
permanent impairment or death.43  Reducing power at sites in close proximity to and/or avoiding 
sites directly over the esophagus may reduce the risk of thermal injury. Additionally, using 
esophageal monitoring techniques may minimize risk of injury19. Four cases of esophageal 
fistula associated with European commercial use of the product have been reported: two cases 
occurred soon after launch in 2013 and two occurred in early 2015. All four cases occurred 
outside of the reMARQable clinical study. 
 
Investigations have determined that workflow was a key contributing factor in all four events.  
Based on the investigation of the two cases in early 2015 it was concluded that the absence of 
esophageal protection coupled with extensive RF ablation on the left posterior atrial wall that 
included near-continuous ablation lasting up to 8 minutes. Mitigations for this risk are provided 
in sections 9.5.1 and 9.6.1. 
 
Injury to the phrenic nerve may occur as a result of RF application in the region of the right 
pulmonary veins.   The reported incidence of phrenic nerve injury varies from 0% to 0.48% 
when RF energy is used for catheter ablation.  Prior to ablation in the region of the RSPV, 
investigators are encouraged to perform precautionary measures such as evaluation of proximity 
to the phrenic nerve and pacing maneuvers. In a recent study representing  early experience using 
the nMARQ™ PVI Ablation System, there was 1 (1/138, 0.7%) reported incident of  
diaphragmatic paralysis. 
 
Radiation exposure during fluoroscopic imaging of 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%).52,54  
 
The risk of pulmonary AEs (e.g., pulmonary vein stenosis, thrombus and hypertension) 
associated with an AF ablation procedure targeting the pulmonary veins is <4%.42,59-65 
 
Other potential complications, which may result from catheter insertion and manipulation as part 
of a prerequisite electrophysiology study and mapping procedure, include: 
  
 
Allergic reaction to the local anesthetic, sedatives, x-ray dye, heparin, protamine, or other 
agents administered during the procedure (risk <1%).66-70  
 
Arterial or venous injury, including arterial dissection, thrombosis, occlusion, AV fistula, 
pseudoaneurysm, or hemorrhage at the catheter insertion sites or at other sites along the 
vessels (risk <1%).49,50  This may produce hemorrhage, hematoma or ischemic injury to an 
extremity or major organ. 
 
Hemorrhage as a result of anticoagulation (risk <0.5%), which may require transfusion.49,50 
 
Infection, either at the catheter insertion site or systemically, including endocarditis and 
septic emboli (risk <0.5%).43,49,50  This risk can be minimized by using standard aseptic 
technique and by the use of antibiotic agents when indicated.  
 

 
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Excessive heat generation during RF ablation is a known hazard for AF ablation procedures.  In 
addition to thermal risk associated with overlapping electrodes and suboptimal thermocouple 
contact to cardiac tissue, a new risk has been identified that was the main cause of a voluntary 
field action. This risk was due to improper solder joint(s) resulting in thermocouple malfunction 
and has been resolved through process improvements and validated testing. 
 
4.1.1 Minimization of Risks 
The criteria for subject selection, methods, personnel, facilities, and training that have been 
specified for this study are intended to minimize the risk to subjects undergoing this procedure.  
Subjects will be screened carefully prior to enrollment in the study to ensure compliance with the 
inclusion and exclusion criteria.  The exclusion criteria have been developed to eliminate 
confounding co-morbidities that might interfere with study interpretation; to furnish a more 
homogenous study population that allows a focused characterization of the nMARQ™ device for 
the treatment of PAF; and, to exclude subjects with a medical history or condition that increases 
their risk of adverse events. 
 
Subjects meeting any of the following three criteria must have a pre-procedure TEE to screen for 
the presence of LA thrombus: 
 
Subjects with history of AF sustained beyond 7 days, or lasting less than 7 days and requiring 
pharmacological or electrical cardioversion, who are in AF at the time of ablation.   
 
Subjects with known risk factors such as structural heart disease, presence of risk factors for 
stroke (i.e., CHADS2 score >1), and atrial enlargement. 
 
Subjects who have been in AF for 48 hours or longer or for an unknown duration unless 
systemic anticoagulation at a therapeutic level has been maintained for at least three weeks. 
All other subjects who do not meet the criteria above must either undergo TEE or one of the 
following methods to screen for LA thrombus on the day before or the day of the ablation 
procedure.  The imaging method used is at the discretion of the investigator based on the 
patient’s medical history and the investigator’s medical judgment: 
 
Computed Tomography (CT) 
 
Intracardiac Echocardiography (ICE) 
 
Magnetic Resonance Imaging (MRI) 
 
Participating investigators will be experienced and highly skilled in performing 
electrophysiology studies, intracardiac mapping and ablation of AF with the use of RF ablation 
catheters.  Each site’s Principal Investigator will have satisfied the established training criteria.  
Procedures will be performed in electrophysiology laboratories with the assistance of skilled 
nurses and technicians.  The laboratory will contain sufficient resuscitative equipment and 
facilities to manage any potential complication.  Immediate access to cardiac surgical facilities, 
as well as a qualified cardiovascular surgeon, will be available during the ablation procedure in 
the event that surgical intervention becomes necessary.  
 
Ablation procedures with TC will be performed according to the products’ Instructions for Use, 
including but not limited to instructions regarding indications and contraindications for using 

 
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these devices. 
 
The efforts to minimize the risk associated with the 3 identified excessive thermal hazards are 
described below.  Risk analyses were performed in conformance with BWI design control 
procedures and it was concluded that these mitigations reduced the risk to an acceptable level. 
 
The root cause analysis for the soldering issue has been identified and changes to manufacturing 
and validation process have been implemented to effectively address this issue.  Further, when 
catheter positioning results in overlapping electrodes or catheter positioning results in an 
electrode thermocouple not being in juxtaposition with the atrial wall, there is a risk of 
excessive heat generation if the scenario is not readily recognized by the investigator.  This 
protocol, investigator training, and Instructions for Use (IFU) have been revised to enhance 
investigator awareness.   
 
 
 

 
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5.0 Study Objectives 
5.1 
Primary Study Objectives 
 
To demonstrate the safety of the nMARQ (Test) Group compared to the TC (Control) 
Group based on difference in proportion of early-onset (within 7 days of ablation 
procedure) primary adverse events, using a non-inferiority margin of 8% for subjects 
with symptomatic PAF.   
 
 
To demonstrate the effectiveness of the nMARQ (Test) Group compared to the TC 
(Control) Group based on difference in proportion of freedom from documented, 
symptomatic AF/AT/AFL through 12 months post ablation follow-up using a non-
inferiority margin of 15% for subjects with symptomatic PAF. 
5.2 
Secondary Study Objective: Subpopulation Neurological Assessment (SNA)  
To evaluate, within a subset of the Main Study PAF population,  the comparative incidence of 
pre- and post-ablation symptomatic and asymptomatic cerebral emboli, as determined by MRI 
evaluations. The presence of emboli-associated neurological deficits will also be evaluated, using 
the National Institute of Health Stroke Scale (NIHSS), the Montreal Cognitive Assessment 
(MoCA), modified Rankin Scale (mRS), and general neurological assessments. 
 

 
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6.0 Study Design 
Following a Calibration Roll-In Phase of up to 5 nMARQ subjects per investigational site, the 
design of the Main Study will be carried out as a prospective, multi-center, randomized  (1:1 
concurrent nMARQ™ Catheter System  [nMARQ] vs THERMOCOOL® Navigational Family of 
catheters [TC]), controlled, two-arm, single-blind, clinical study.  
6.1 
Calibration Roll-in Phase: up to 250 Subjects  
One key purpose of this study will be to demonstrate the effectiveness of the nMARQ™ RF 
Catheter System in the absence of confounding evidence that reflects early stages of a complex 
medical device learning curve.  In addition to a requirement for nMARQ™ System training prior 
to each Principal Investigator’s participation in this study, additional experience of nMARQ™ 
use, in the context of this protocol, would serve to generate a clearer perspective of nMARQ™ 
System effectiveness in treating PAF patients.   Therefore, the first 3 subjects enrolled at each 
site will be assigned to the nMARQ group as a calibration roll-in subject. An additional 1-2 roll-
in subjects (prospectively designated) will be allowed at each site to minimize the learning curve 
effect of using the new nMARQ™ System. Up to 5 roll-in subjects will be allowed per site. A 
subject who is excluded  prior to insertion of the nMARQ™ catheter, will not count toward the 
roll-in subjects.  For OUS investigational sites with prior experience of at least 5 nMARQ cases, the 
minimum of roll-in subjects will be 1. All calibration roll-in subjects will be followed for 3 years 
post-ablation and be included in the Safety Population. 
6.2 
Main Study: up to 500 Subjects 
This will be a prospective, multi-center, randomized  (1:1 concurrent nMARQ™ Catheter 
System  [nMARQ] vs. THERMOCOOL® Navigational Family of catheters [TC]), controlled, two-
arm, single-blind, clinical study for subjects with symptomatic PAF who have had at least one 
AF episode documented within one (1) year prior to enrollment and who have failed at least one 
antiarrhythmic drug (AAD [class I or III, or AV nodal blocking agents such as beta blockers and 
calcium channel blockers]) as evidenced by recurrent symptomatic AF, or intolerance to the 
AAD. 
 
Eligible subjects who sign the study informed consent form and who satisfy all Inclusion and 
Exclusion Criteria will be randomized into one of two treatment groups: 
 
 
Test Group: subjects who undergo catheter ablation with the nMARQ™ System.  
 
Control Group: subjects who undergo catheter ablation with a device from the approved 
THERMOCOOL® Navigational Family of catheters. 
 
Randomized subjects will not be made aware of the treatment arm they have been assigned to 
throughout the effectiveness evaluation (through 12 months post-ablation). 
 

 
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The Test Group will be compared to the Control Group to assess non-inferiority with respect to 
the primary effectiveness and safety endpoints. An adaptive sample size of 250-500 subjects will 
be used for the Main Study. Planned statistical analyses of these endpoints are described in the 
Statistical Analysis section (Section 11.0) of this protocol. 
 
For this study, it is the Sponsor’s intention that the enrolled patient population be as 
representative as possible of the well-defined study population.  Investigators will be strongly 
encouraged to evaluate all consecutive eligible patients for participation in the study and, if 
inclusion and exclusion criteria are met, to approach all eligible patients.   Centers will be 
selected for participation in the study based on their capacity to screen and enroll a reasonable 
number of eligible patients and perform the required study procedures, according to this 
protocol.  Sponsor will attempt to include a diversified group of investigational sites engaging a 
variety of academic and private institutions geographically located throughout the US and other 
regions.  To ensure a widespread distribution of data and minimize site bias, no more than 20% 
of the total enrollment (including test and control) will be allowed at a single site. 
 
 
 
Figure 6.2A: Study Design 
 

 
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6.3 
Subpopulation Neurological Assessment (SNA): 60 Subjects 
A focused neuropathological evaluation was integrated within the Main Study.   Subjects were 
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). The SNA  addressed some recently published reports of silent 
(asymptomatic) cerebral emboli, as documented by MRI, immediately following RF ablation and 
among multiple ablation catheter systems. The reported frequencies of these occurrences vary 
considerably according to  the types of catheters used, study methods, and imaging methodology.  
Data from the SNA Final Analysis Report support the conclusion that the safety profile of the 
nMARQ irrigated catheter and its system is within acceptable limits based on previously 
reported data in literature where occurrence of ACE ranges from 6.8%48 to 21.4%.44  
 
An evaluation of at least 60 subjects (included in 250-500 total) were included in this assessment 
and were performed at up to 15 of the participating sites. To assure that the minimum numbers of 
Test and Control subjects participated in the SNA, enrollment continued until reaching at least 
30 Test and 30 Control subjects. The SNA was a prospective, controlled evaluation, with 
consecutive enrollment, comparing outcomes of Main Study Test and Control subjects treated 
with the nMARQ and TC, respectively.  The mandatory 3-5 Roll-in nMARQ subjects was NOT 
be eligible for the SNA. This approach minimized the confounding influence of a learning curve 
during early use of a complex medical device.  
 
Subjects who participated in the SNA were enrolled on a consecutive basis according to the 
randomization schedule.  Ablation therapy was according to the randomization that took place 
upon entering the Main Study with a maximum of 25% of the total SNA subjects at each site. 
The associated SNA ICF was a supplement to the current Main Study ICF. Subjects who, for any 
reason, did not qualify or consent to undergo the additional tests as part of the SNA were 
continued as enrolled subjects in the Main Study.   
At participating SNA sites and considering the above caveats, all remaining subjects (until SNA 
enrollment targets are met), who are enrolled in the Main Study and randomized to one of the 
two treatment groups, were sequentially considered for participation in the SNA, per specific 
eligibility requirements. 
1. If a subject satisfies any one of the 3 following conditions he/she was excluded from the 
SNA : 
 
Subject has a pacemaker, cardiac defibrillator, or tissue-embedded, iron-containing 
metal fragments. 
 
Subject has a contraindication to use of contrast agents for MRI such as advanced 
renal disease. 
 
Subject has an unresolved pre-existing neurological deficit. 
2. Subject provided written informed consent for MRI, National Institute of Health Stroke 
Scale (NIHSS), Montreal Cognitive Assessment (MoCA), Modified Rankin Scale (mRS), 
and general neurological assessments.  
 

 
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Special cautionary measures were taken for SNA subjects with claustrophobia or obesity. 
Subjects with claustrophobia or obesity were cautioned about the confining tubular space of an 
MRI machine and the length of time to complete brain imaging. Subjects with either problem 
risk severe emotional stress were provided a detailed explanation of the procedure and allowed to 
see an MRI machine prior to their signing an ICF for SNA. 
6.4 
Total Enrollment 
It is anticipated that 5% of potential subjects screened for eligibility will not participate in this 
study due to a failure to satisfy one or more inclusion/exclusion criteria; loss of contact by the 
study site;  or, early subject withdrawal before or after randomization.  To account for this 
attrition, between 414 (= 250 / 0.95 + 150 Roll-in) and 777 (= 500 / 0.95 + 250 Roll-in) subjects 
will need to be enrolled so that 250-500 subjects will participate in the Main Study. All subjects 
enrolled will be followed for 3 years following their index ablation procedure.  
6.5 
Study Duration, Completion, and Termination  
Duration:  The study duration is anticipated to be approximately 7.5 years; 4.5 years for 
enrollment phase (including the time in which enrollment was suspended), with an additional 3 
years to complete follow-up. 
 
Completion:  The study will be considered complete when the 3 year post-ablation follow-up 
phone calls are complete for all subjects.  At study completion, each site will undergo a 
monitoring visit to conclude any outstanding issues, collect all outstanding eCRF information, 
verify device accountability, and discuss any other items relevant to the conclusion of the study. 
 
Termination:  The study may be terminated prematurely at the discretion of the Sponsor or on 
statistical grounds (i.e., effectiveness or futility is determined).  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 IRB / EC / EB).  If early termination of the study is required due to safety concerns or the 
occurrence of unanticipated SAEs, 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. 
6.6 
Recruitment and Screening Procedures 
Patients with symptomatic PAF who have failed at least 1 AAD and are deemed eligible for RF 
ablation will be screened for this study.  Eligible subjects must have at least one documented AF 
episode within 1 year prior to enrollment. An electronic screening log will be  maintained by 
each study site and will be used to document patients considered for potential enrollment into the 
study.  The screening log will be part of the electronic CRF database and should be completed 
for any patient considered for study enrollment, regardless of selection outcome, as this will 
allow a better management of site specific study enrollment issues and rates. 

 
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6.7 
Informed Consent and Enrollment Procedures 
If deemed eligible for and willing to participate in the study, a patient or legal representative 
must sign the study’s informed consent form (ICF) prior to enrollment and collection of any 
study-related data.  The ICF and any revisions must have prior approval of the Sponsor and  
study site’s institutional review board (IRB), central IRB, or equivalent (e.g., ethics committee 
[EC] or ethics board [EB]).  The signed ICF must be kept in the subject’s files at the study site, 
with a signed copy of the ICF provided to each subject. 
6.8 
Subject Selection 
All patients considered for a RF ablation procedure for drug refractory recurrent symptomatic 
PAF should be screened by the investigator or designated member of the research team for study 
eligibility. 
   
6.8.1 Study Inclusion Criteria 
 
Candidates must meet ALL of the following criteria: 
1. Patients with symptomatic paroxysmal AF who have had at least one AF episode 
documented within one (1) year prior to enrollment. Documentation may include 
ECG, transtelephonic monitor (TTM), Holter monitor (HM), or telemetry strip.  See 
Section 7.0 of the protocol for specific definitions of documented AF, symptomatic 
AF, and paroxysmal AF. 
2. Patients who have failed at least one antiarrhythmic drug (AAD; class I or III, or AV 
nodal blocking agents such as beta blockers and calcium channel blockers) as 
evidenced by recurrent symptomatic AF, or intolerance to the AAD.   
3. Pre-procedure anticoagulation on warfarin, rivaroxaban, or apixaban. 
 
If receiving warfarin therapy, patients must agree to take warfarin for at least 
4 weeks prior to the scheduled ablation procedure. 
4. Age 18 years or older. 
5. Signed Patient Informed Consent Form (ICF). 
6. Able and willing to comply with all pre-, post-, and follow-up testing and 
requirements. 
 
6.8.2 Study 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 ablation for atrial fibrillation. 
3. Patients on amiodarone at any time during the past 3 months prior to enrollment. 
4. AF episodes lasting > 7 days. 
5. Any cardiac surgery within the past 60 days (2 months)  
6. Any valvular cardiac surgical procedure (i.e., ventriculotomy, atriotomy, and valve 
repair or replacement and presence of a prosthetic valve). 
7. CABG procedure within the last 180 days (6 months). 

 
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8. Awaiting cardiac transplantation or other cardiac surgery within the next 365 days (12 
months). 
9. Documented left atrial thrombus on imaging. 
10. History of a documented thromboembolic event within the past one (1) year. 
11. Diagnosed atrial myxoma. 
12. Presence of implanted ICD. 
13. 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. 
14. Significant congenital anomaly or medical problem that in the opinion of the 
investigator would preclude enrollment in this study. 
15. Women who are pregnant (as evidenced by pregnancy test if subject is of child-
bearing age and potential), breast feeding, or planning to become pregnant. 
16. Acute illness or active systemic infection or sepsis. 
17. Unstable angina. 
18. Myocardial infarction within the previous 60 days (2 months).   
19. Left ventricular ejection fraction <40%. 
20. History of blood clotting or bleeding abnormalities. 
21. Contraindication to anticoagulation (i.e., heparin, dabigatran, Vitamin K Antagonists 
such as warfarin). 
22. Life expectancy less than 365 days (12 months). 
23. Enrollment in an investigational study evaluating another device or drug. 
24. Uncontrolled heart Failure or NYHA Class III or IV heart failure. 
25. Presence of intramural thrombus, tumor or other abnormality that precludes catheter 
introduction or manipulation. 
26. Presence of a condition that precludes vascular access. 
27. Left atrial size >50 mm. 
6.9 
Subject Status and Disposition Definitions  
All criteria listed below apply to both the Test and Control Groups. 
Screen Failure: subjects that are screened, but do not meet eligibility criteria and have NOT 
signed an ICF.  Screen failures should be captured in the electronic database.  No data will be 
collected, only the date of screening and the reason for exclusion. 
 
Enrolled Subjects:  all subjects who sign the study ICF. 
 
• 
Excluded Subjects:  subjects who have signed the ICF, but are found to not meet the study 
eligibilities, PRIOR to insertion of the study catheter. Excluded subjects will not be included 
in either the effectiveness or safety analyses of the study catheters. 
 
• 
Evaluable Subjects:  all enrolled subjects who have the study catheter inserted. (Calibration 
Roll-in and randomized subjects.) 
 
Discontinued Subjects: evaluable subjects who have the study catheter inserted but do 
not undergo ablation (i.e., no RF energy is delivered with the study catheter).  Subjects 

 
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will be categorized as “discontinued” if ablation is not possible due to equipment failure 
or if their arrhythmia is determined at the time of electrophysiologic study to be a non-
study arrhythmia; e.g., AFL instead of PAF (required for subject enrollment per study 
inclusion criteria). Discontinued subjects will remain in follow-up for 30 days as part of 
the safety cohort.  If an SAE is reported for a discontinued subject, they will be followed 
until event resolution. 
 
Calibration Roll-in Subjects: enrolled subjects who have the study catheter inserted and 
RF delivered during the Calibration Roll-in Phase.  These subjects will be included as 
part of the analyses for secondary safety endpoints but not analyses for the primary 
endpoints.  Roll-in cases are not randomized and will be limited to not more than 5 
subjects enrolled and treated at each site. 
 
Lost to Follow-up Subjects:  subjects who are enrolled and evaluable, but contact is lost 
after most recent follow-up visit (despite 3 documented attempts to contact the subject). 
 
Withdrawn / Early Termination Subjects:  subjects who withdraw consent for study 
participation or are withdrawn by the investigator (as described in Section 6.10) or are 
terminated from the study prior to completion of all follow-up visits. 
 
Completed Subjects:  enrolled subjects who have not been excluded, discontinued, 
withdrawn, early terminated or lost-to-follow-up from the study prior to the final study 
visit. 
6.10 
  Subject Withdrawal 
Subjects may withdraw consent for study participation at any time without penalty or loss of 
benefits to which they may otherwise be entitled.  The investigator may also remove a subject  
from the study for any of the following reasons: no longer meets eligibility criteria, withdrawal is 
in the subject’s best interest, subject preference, concurrent illness, non-compliance, etc.  
Subjects 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.   
 
If a subject is removed 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.   
 

 
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7.0 Definitions 
Table 7.0A: AF and Ablation Terms 
Term 
Study Definition 
AF episode 
AF documented by ECG monitoring and has a duration of at least 30 seconds 
or, if <30 seconds, is present continuously throughout the ECG monitoring 
tracing.  The presence of subsequent episodes of AF requires that sinus 
rhythm be document by ECG monitoring between AF episodes.  [Atrial 
fibrillation and atrial flutter (including atypical flutter) are considered 
episodes of AF.  Atrial flutter alone is not considered an episode of AF.] 
Paroxysmal AF* 
Recurrent AF (≥2 episodes that terminate spontaneously within 7 days.  
(Episodes of AF of ≤48h duration that are terminated with electrical or 
pharmacologic cardioversion should also be classified as paroxysmal AF 
episodes.) 
Persistent AF* 
Continuous AF that is sustained beyond 7 days. (Episodes of AF in which a 
decision is made to electrically or pharmacologically cardiovert the patient 
after ≥48 hours of AF, but prior to 7 days, should also be classified as 
persistent AF episodes.) 
Symptomatic AF 
AF where symptom(s) exhibited by the subject are concurrent with a 
documented episode by ILR, ECG, TTM, Holter monitor, or telemetry 
recording.  Symptoms may include but are not limited to: palpitations, 
irregular pulse (e.g., rapid, racing, pounding, fluttering, bradycardia), 
dizziness, weakness, chest discomfort, and breathlessness. 
Documented AF episode 
An AF episode documented by an electrocardiographic monitoring tool. This 
may include ILR, ECG, TTM, HM, or telemetry strip.  
Reporting of a symptomatic episode by a patient or in a referral letter is not 
considered a documented AF episode. 
AF recurrence 
Recurrence of an AF episode as defined. 
Complete PVI  
Entrance block confirmed for all targeted PVs. 
Procedure time 
Time from the  introduction of the first catheter to withdrawal of last 
catheter. 
RF time 
Summation of RF delivery time during a procedure. 
Pulmonary vein stenosis  
(PV stenosis) 
PV stenosis is defined as a reduction of the diameter of a PV or PV branch. 
PV stenosis can be categorized as: 
None: 0-20% 
Mild: >20%-49%, 
Moderate: ≥50-69%,  
and Severe: ≥70%  
Severe PV stenosis is considered a primary adverse event for this study.  
* The HRS/EHRA/ECAS 2012 Consensus Statement recognizes that patients may have both paroxysmal and persistent 
AF episodes and that the AF classification should be defined as the most frequent type of AF experienced within 6 
months of an ablation procedure. 

 
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8.0 Study Endpoints   
8.1 
Primary Safety Endpoint 
The primary safety endpoint for this study is the incidence of early-onset (within 7 days of the 
ablation procedure) primary AEs. 
 
Death 
Myocardial infarction (MI) 
Pulmonary vein (PV) stenosis† 
Diaphragmatic paralysis 
Atrio-esophageal fistula† 
Transient Ischemic Attack (TIA) 
Stroke/Cerebrovascular accident (CVA) 
Thromboembolism 
Pericarditis requiring intervention (major) 
Cardiac Tamponade/Perforation 
Pneumothorax 
Vascular Access Complications 
Pulmonary edema    
Hospitalization (initial and prolonged)* 
Heart block 
*Excludes hospitalization (initial & prolonged) solely due to arrhythmia (AF/AFL/AT)  recurrence or due to non-
urgent cardioversion (pharmacological or electrical). Refer to Table 10.1.3A for definitions of the Primary AEs. 
†Pulmonary vein (PV) stenosis or atrio-esophageal fistula that occurs greater than one week (7 days) post-procedure 
shall be deemed a Primary AE. 
 
Refer to Table 10.1.6A for a comprehensive list of anticipated adverse events. 
8.2 
Primary Effectiveness Endpoint 
The primary effectiveness endpoint is defined as freedom from documented symptomatic 
AF/AT/AFL based on electrocardiographic data during the effectiveness evaluation period (Day 
91-365). Additionally if a subject meets any one of the following criteria, then the subject will be 
considered as chronic effectiveness failure. 
• 
Acute procedural failure (i.e., failure to confirm entrance block in all pulmonary veins post-
procedure). 
• 
A new AAD for AF during the effectiveness evaluation period (refer to Section 9.3.2 for 
details). 
• 
A repeat ablation for AF beyond the 90 day blanking period (refer to Section 9.12 for 
details). 
• 
A repeat ablation not conducted with the nMARQ system for Test Group subjects.  
• 
>2 repeat ablation procedures in the blanking period (Day 0-90). 
• 
A non-study ablation catheter (non nMARQ or TC) was used during the index ablation 
procedure. 
Note: For repeat ablation within the blanking period for nMARQ subjects, use the nMARQ™ 
System only (e.g., NAVISTAR® THERMOCOOL® catheter or nMARQ™ catheters). 

 
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8.3 
Secondary Endpoints 
The secondary endpoints supporting the study objective are: 
 
Acute Effectiveness: 
 
Acute effectiveness is defined as complete PVI confirmation as documented by confirmed 
entrance block (i.e., complete PVI with or without the use of the toolkit’s focal catheter). 
 
One-Year Effectiveness:  
 
Freedom from AF/AFL/AT off antiarrhythmic drug therapy as assessed from the end of the 
3-month blanking period to 12 months following the ablation procedure. 
 
Long-Term Effectiveness:  
 
Freedom from AF/AFL/AT off antiarrhythmic drug therapy as assessed from the end of the 
3-month blanking period to 2 year following the ablation procedure. 
 
Freedom from AF/AFL/AT off antiarrhythmic drug therapy as assessed from the end of the 
3-month blanking period to 3 year following the ablation procedure. 
 
Long Term Safety: 
 
Incidence of AEs and serious adverse events (SAEs) during the 12 month follow-up period 
post ablation procedure. 
 
Assessment of PV stenosis at 3 months post-ablation. 
 
Incidence of AEs and serious adverse events (SAEs) during the 2nd and 3rd year follow-up 
period post ablation procedure. 
 
Additional Endpoints:  
 
% PV isolation by study devices, by subject and by PV 
 
Repeat ablation rate (For AF/AFL/AT) 
 
Cardiac specific hospitalization rate  
 
Total fluoroscopy time 
 
Overall procedure time 
 
Ablation procedure related parameters 
 
Device use per targeted PV 
 
Subpopulation Neurological Assessment (SNA) (subset of patients):  
 
Comparative incidence of symptomatic and asymptomatic cerebral emboli pre- and post-
ablation.  
 
Frequency, anatomic location, and size (diameter and volume) of cerebral emboli by MRI 
testing at baseline, post-ablation and during follow-up (if lesions observed). 
 
Incidence of new or worsening neurologic deficits, post-ablation and during follow-up. 
 
Change from baseline in NIHSS score post-ablation and during follow-up (2 point change in 
either direction constitutes significant change). Change in baseline compared to post-ablation 
for Montreal Cognitive Assessment and modified Rankin scale.  
 

 
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9.0 Schedule of Procedures and Examinations (Description of 
Treatment) 
9.1 
Patient Screening 
An electronic screening log that is maintained at the clinical site will be used to document all 
patients reviewed for potential inclusion into the study. 
 
Patients who sign the patient informed consent form will be considered enrolled in the study.  No 
patient should undergo any study-specific tests or exams that fall outside the standard of care 
without first signing the patient informed consent document for this study. 
 
An informed consent document must be obtained for a patient that is a potential study candidate 
prior to collection of any study specific data collection or exams (excludes standard of care 
treatments).   
9.2 
Randomization 
Following completion of the Calibration Roll-in Phase (up to 5 subjects) at each site, eligible 
subjects who have signed a Main Study Informed Consent Form will be randomized 1:1 to either 
the nMARQ™ Catheter system (Test) treatment arm or the TC (Control) treatment 
arm.  Dynamic randomization will be defined and executed to balance the two treatment groups 
by site and gender via the Medidata Balance interactive web-based randomization system 
(IWRS).  The designated personnel at each site will be required to access the electronic 
randomization system to obtain the randomization assignment after entering stratification 
factors. The randomization treatment assignment and related information (e.g., randomization 
date and stratification factors) will be passed on to the electronic data capture system and 
integrated with the subject’s clinical study data. 
9.3 
Study Medication  
During this study, current AF management guidelines and the Investigator’s routine clinical 
practices  are to be followed as closely as possible. 1,18,34   These include the use of anticoagulants 
and AADs.  AADs are defined as class I or class III, or AV nodal blocking agents such as beta 
blockers (BB) and calcium channel blockers (CCB).  Previously ineffective AADs can be 
administered.  A new AAD can be administered, however, if continued past Day 90 (blanking 
period) this will be considered a primary effectiveness failure.  The choice of rate control versus 
rhythm control therapy and the specific drugs used will be left to the Investigator’s discretion. 
 
9.3.1 Anticoagulation Medications 
The following anticoagulation regimen is required for all study subjects, Test and Control.    
 

 
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Pre-Ablation Regimen  
Based on recommendations from the 2012 HRS/EHRA/ECAS expert consensus statement on 
catheter and surgical ablation of atrial fibrillation pre-ablation anticoagulation (warfarin, 
rivaroxaban, or apixaban) therapy is REQUIRED for this study. 
 
If receiving warfarin therapy, subject must be maintained on warfarin for 4 weeks prior to the 
scheduled ablation procedure and weekly INR measurement recorded in the medical 
records. These periodic INR measurements should be documented in the medical records as 
source documentation. Do NOT discontinue warfarin prior to the procedure. 
o Subject INR should be recorded 4-5 days prior to the procedure, 1-2 days before 
the procedure, and on the day of the procedure.  
o INR MUST be ≥ 2.0 on the day of the ablation procedure.  This must be 
documented in the medical records as source documentation. 
 
If receiving rivaroxaban or apixaban therapy, continuation of therapy throughout the 
procedure is recommended.73,74   
  
During Ablation Procedure  
 
Administer a heparin bolus prior to transseptal puncture.  Prior to commencing ablation, 
ensure that an activated clotting time (ACT) of ≥325 is achieved.  Maintain an activated 
clotting time (ACT) of ≥325, targeting 350 seconds throughout the ablation procedure.  
 
 ACT levels MUST be checked every 15-30 minutes during the procedure to ensure ACT 
≥325 seconds.  All recordings must be documented in the medical records as source 
documentation. 
 
Flush the sheath continuously with heparinized saline. 
   
Following Ablation Procedure  
 
If on warfarin, subjects MUST be maintained on warfarin anticoagulant for 2 months post-
procedure.  (Reinitiate warfarin within 4-6 hours post procedure.) 
o INR must be maintained at 2.0-3.0. 
 
If receiving  rivaroxaban or apixaban therapy,  continuation of therapy throughout the 
procedure is recommended with discontinuation at 2 months post-procedure depending on 
clinical judgment at the time.   
 
After 2 months post-procedure, decisions regarding continuation of systemic  anti-
coagulation agents should be based on subject’s risk factors.  It is recommended that 
physicians follow the relevant recommendations from the 2012 HRS/EHRA/ECAS Expert 
Consensus Statement on Catheter and Surgical Ablation of AF. 
 
9.3.2 Antiarrhythmic Drug Management 
Definitions: 
Antiarrhythmic drugs (AADs) - The study protocol will classify and analyze the 
following: 
 
Class I drugs (e.g., flecainide, propafenone, disopyramide, etc.) 
 
Class III drugs (e.g., amiodarone, dronedarone, dofetilide, etc.) 

 
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 
AV nodal blocking agents (such as beta blocking agents [BBs] or calcium channel 
blockers [CCBs]; e.g., propanalol, Metoprolol, diltiazem, verapamil, etc.) 
 
Previously Failed AAD - Any AAD that a subject has ever taken for the treatment of 
his/her AF, prior to enrollment, is considered a “previously failed AAD” if it meets ALL 
of the following conditions: 
 
prior to enrollment, the AAD was ineffective  in controlling the subject’s AF or 
produced intolerable side effects leading to its discontinuation, 
 
the AAD is administered for the recurrence of AF, and 
 
the prescribed dose is equal to or lower than the highest ineffective historical dose. 
 
New AAD – ANY of the following are considered a “new AAD” if the drug is 
administered to treat AF post-enrollment: 
 
the AAD was never taken for the treatment of AF prior to enrollment,  
 
the prescribed dose of the previously failed AAD is greater than the highest 
ineffective historical dose. 
 
AAD Therapy in the Blanking Period (Day 0-90) 
 
Subjects may receive new or previously failed AADs without affecting their primary 
effectiveness classification.  New AADs, however, must be stopped by Day 90 or 
the subject will be deemed a primary effectiveness failure (refer to Table 9.3.2A). 
 
AAD Therapy in the Effectiveness Evaluation Period (Day 91-365) 
 
New AADs 
 
Prescribed after the blanking period OR continued beyond the blanking period for 
AF and taken in this period will be deemed as primary effectiveness failures.   
New AADs prescribed for AF taken during the blanking period must be stopped 
at or prior to Day 90 or the subject will be classified as a primary effectiveness 
failure, regardless of the subject’s 3-month follow-up visit date. 
 
Previously failed AADs 
 
Started in the post-blanking period OR continued from the blanking period will 
not result in subject being classified as primary effectiveness failure. 
 
Table 9.3.2A illustrates the corresponding classifications based on AAD therapy 
administered in the blanking and post-blanking periods. 
 

 
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Table 9.3.2A: AAD Usage and Impact on Primary Effectiveness Classification 
AAD Type 
Blanking Period 
Post-Blanking Period 
(Day 90-Study Completion) 
New AAD*  
Can be initiated; subject will not be 
classified as a primary effectiveness 
failure. 
Should not be initiated  in the absence of 
AF recurrence; subject will be classified as 
a primary effectiveness failure. 
Should not be continued past 90-days post-
ablation (if initiated in blanking).  Subject 
will be classified as a primary effectiveness 
failure. 
Previously 
failed AAD 
Can be initiated; subject will not be 
classified as a primary effectiveness 
failure. 
Can be continued (from prior to study 
enrollment); subject will not be 
classified as a primary effectiveness 
failure. 
Can be initiated; subject will not be 
classified as a primary effectiveness failure. 
Can be continued past 90-days post-
ablation (if initiated in blanking).  Subject 
will not be classified as a primary 
effectiveness failure. 
* As noted earlier in this section, includes a prescribed dose of a previously failed AAD that is greater than 
the highest ineffective historical dose 
9.3.3 Use of Additional Medications 
The use of additional medication during the study will be at the discretion of the Investigator for 
clinical indications. 
9.4 
Pre-Procedure (Baseline) Assessments 
An electronic screening log maintained at the clinical site will be used to document all patients 
who were reviewed for potential inclusion into the study. 
 
Patients who sign the Patient Informed Consent Form and are randomized will be considered 
part of the Main Study. No patient will be  randomized for study participation or treated  with 
the Study Device without having first signed the approved  Patient Informed Consent Form.   
 
At each study site committed to participate in the Subpopulation Neurological Assessments 
(SNA) and after completion of the Calibration Roll-In Phase, consecutively eligible subjects who 
satisfy SNA exclusion criteria and who sign a unique SNA Patient Informed Consent Form will 
undergo a cerebral MRI and a general neurological assessment (including the administration of 
the NIHSS, mRS, MoCA) conducted by a neurologist certified in the administration of the 
NIHSS and mRS.  All baseline neurological assessments must be completed within a 72-hour 
period leading up to ablation therapy.  Ablation therapy will be according to the Main Study 
randomization.  
 
Following enrollment, but prior to the EP procedure, information will be collected regarding the 
presenting illness, medical history, and current/past medical therapy. 
 
Pre-procedure assessments are required within the time specified in Table 9.4.A. 
 
 

 
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Table 9.4A: Baseline (Pre-Ablation) Evaluations and Completion Timeframe 
Baseline (Pre-Ablation) Assessment 
Completion Timeframe 
Transthoracic Echo (TTE) 
 
Assess LA size and EF% to confirm eligibility. 
Within 30 days PRIOR to 
Ablation Procedure 
CT/MRA 
• 
Assess baseline PV diameters to evaluate post-ablation PV narrowing or 
stenosis. 
Within 30 days PRIOR to 
Ablation Procedure 
Transesophageal Echocardiogram (TEE), Intracardiac Echocardiogram 
(ICE), Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) 
Imaging for detection of left atrial thrombus: 
 
Subjects meeting any of the following three criteria must have a pre-
procedure TEE to screen for the presence of LA thrombus: 
 
Subjects with history of AF sustained beyond 7 days or lasting less 
than 7 days and requiring pharmacological or electrical 
cardioversion who are in AF at the time of ablation.   
 
Subjects with known risk factors such as structural heart disease, 
presence of risk factors for stroke (i.e., CHADS2 score >1), and 
atrial enlargement. 
 
Subjects who have been in AF for 48 hours or longer or for an 
unknown duration unless systemic anticoagulation at a therapeutic 
level has been maintained for at least three weeks. 
All other subjects who do not meet the criteria above must undergo one of 
the following alternative methods to screen for LA thrombus.  The imaging 
method used is at the discretion of the investigator based on the patient’s 
medical history, the investigator’s medical judgment, and institution 
standard practices: 
 
Transesophageal Echocardiogram (TEE) 
 
Intracardiac Echocardiography (ICE) 
 
Computed Tomography (CT) 
 
Magnetic Resonance Imaging (MRI) 
Day before procedure or 
day of Ablation 
Procedure 
Pregnancy test  
(For ALL women of child-bearing age and potential) 
Within 24 hours PRIOR 
to Ablation Procedure 
Subpopulation Neurological Assessment (SNA) 
Neurological Evaluation using the NIH Stroke Scale  (for SNA subjects 
only) 
Within 72 hours PRIOR 
to ablation procedure 
Modified Rankin Scale (mRS) (for SNA subjects only) 
Within 72 hours PRIOR 
to ablation procedure 
Montreal Cognitive Assessment (MoCA) (for SNA subjects only) 
Within 72 hours PRIOR 
to ablation procedure 
MRI Examination of the brain (for SNA subjects only) 
Within 72 hours PRIOR 
to ablation procedure 
 

 
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9.5 
Treatment Description   
9.5.1 TEST - Required Devices 
Each site will be supplied with the protocol-specified investigational devices (“Toolkit”) 
required for study participation (Table 9.5.1A/B). Investigational devices must be tracked 
according to the device accountability requirements in Section 13.11 and stored in a secure and 
locked facility.  These devices must be used to perform mapping and ablation procedures for 
subjects randomized to the TEST arm.  Device and equipment set-up must be completed 
according to the Instructions for Use. 
 
Table 9.5.1A: TEST (nMARQ) Required Investigational Study Devices 
Investigational Devices 
(“Toolkit”) 
Function 
nMARQ™ Circular Irrigated 
Catheter 
Used to map the targeted area of the heart and deliver RF energy to 
the targeted tissue 
nMARQ™ Crescent Irrigated 
Catheter (discontinued as of 
January 2015) 
Used to map the targeted area of the heart and deliver RF energy to 
the targeted tissue 
nMARQ™ Multi-channel 
RF Generator 
Transmits radiofrequency energy to the Circular and Crescent 
Mapping & Ablation Catheters 
nMARQ™ Interface Cable 
Provides a means to interface the Circular Ablation and Crescent 
Ablation Catheters to the Multi-Channel RF Generator 
CARTO™ 3 System Version 2.5 
or later 
Electroanatomical mapping system for mapping and visualization 
information 
COOLFLOW™ Irrigation Pump 
Delivers heparinized saline to the nMARQ™ Irrigated Catheters for 
cooling during the RF energy application. (up to 60 mL/min) 
NAVISTAR® THERMOCOOL®*
  
 
If a focal catheter is required for completion of PVI in the TEST arm, 
the  NAVISTAR® THERMOCOOL® Catheter is the only focal ablation 
catheter allowed for use with the nMARQ™ Multi-Channel RF 
Generator. 
The NAVISTAR® THERMOCOOL® Catheter must be used according to 
the  investigational instructions for use when interfacing with the 
nMARQ™ Multi-Channel RF Generator due to the specific ablation 
parameters required.  The catheter will not be subject to 
investigational device accountability tracking. 
*The use of the NAVISTAR® THERMOCOOL® is considered investigational when used with the 
nMARQ™ Multi-channel RF Generator.   
 
 

 
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Table 9.5.1B: TEST (nMARQ™) Required Non-Investigational Devices. 
Standard Equipment 
Function  
LASSO® Circular Mapping 
Catheter 
To be used in conjunction with the CARTO® 3 System to 
verify Entrance Block.  May also be used to obtain a 3-
Dimensional map of the Left Atrium (LA). 
Valley Lab adhesive electrical 
dispersive pads 
Component of the RF current return path 
EP lab recording equipment 
Records multiple intracardiac electrograms and signals from 
the RF generator (power, temperature, impedance) and for 
performs electrical stimulation. 
CARTO® System Junction Box 
(PIU) 
Provide the interface to the catheter, generator, and the 
CARTO® System. 
 
When used with the  nMARQ™ Circular Irrigated Catheters, the COOLFLOW®   Irrigation Pump 
will deliver a continuous infusion of room temperature heparinized saline (1 u heparin/1 mL 
saline), at a flow rate of 4 mL/minute, when not delivering radiofrequency current.  During 
ablation, the high flow setting must be used to deliver 60mL/minute or 42 mL/minute for the 
Circular and Crescent Catheters, respectively. 
 
The maximum settings for RF power, temperature and duration allowed for the nMARQ™ 
Circular and the Crescent Ablation Catheters are presented in Table 9.5.1C.  These settings for 
THERMOCOOL® catheters, used with the nMARQ™ System, are presented in Table 9.5.1D. 
 
Table 9.5.1C: nMARQ™ Circular and Crescent** Irrigated Catheter – Maximum Settings for 
RF Power, Temperature and Duration  
 
Unipolar Mode 
Bipolar Mode 
RF Power 
Maximum 
25 W 
15 W 
Temperature* 
Maximum 
45°C 
43°C 
Duration 
Maximum 
60 sec 
60 sec 
*The temperature displayed on the Multi-Channel RF Generator does not represent 
tissue temperature or electrode tissue interface temperature.  The maximum 
temperature per the IFU is 47°C, however this protocol limits the maximum 
temperatures to those listed above. 
**Discontinued as of January 2015. 
 
Recommended RF Power Settings and Titration 
 
The recommendations provided are based on data obtained from animal and clinical studies. Use 
clinical judgment and consider individual patient anatomy and conditions when selecting settings 
for RF power, temperature and duration.  During ablation, monitor commonly used parameters 
such as intracardiac signal reduction, temperature response and impedance changes to guide 
therapy.  Do not allow ablation electrodes to overlap during application of RF energy.  If the 
overlap of ablation electrodes cannot be avoided during application of RF energy, stop ablation 

 
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and reduce the power setting for one of the electrodes to 1W before proceeding.  Refer to the 
catheter IFU for the full list of warnings, precautions, directions for use, and recommendations.  
 
Reduce the RF power setting to 20W or less if the temperature of an electrode rises during 
ablation but does not reach the selected temperature limit.  
 
When ablating near adjacent anatomical structures, take precautions to minimize collateral 
damage to the adjacent structures. 
 
When ablating near the esophagus (along the posterior wall of the left atrium), take precautions 
to avoid injuring the esophagus.  These may include beginning ablation with reduced RF power, 
reducing application time, increasing the time between subsequent ablations, esophageal 
visualization and/or intraluminal esophageal temperature monitoring.  
 
 
Table 9.5.1D: NAVISTAR® THERMOCOOL® Catheter - Recommended RF Energy Delivery 
Parameters when connected to the nMARQ™ Generator AND used for Atrial Ablation 
Parameter 
Setting 
Idle Flow Rate 
2 mL/min 
Power Setting 
≤ 27 W 
Temperature Setting 
< 50 ° C* 
Irrigation Flow Rate During RF 
Application 
For power levels up to 27 watts, a flow rate of 17 mL/min 
should be used.  
At power levels between 28-45 watts, a high flow rate of 
30 mL/min should be used 
Application Time 
(max per application) 
≤ 120 seconds 
*The temperature displayed on the Multi-Channel RF Generator does not represent tissue temperature or 
electrode tissue interface temperature.   
 
9.5.2 CONTROL – Required Devices 
For treatment within the CONTROL arm, non-investigational THERMOCOOL® Navigational  
catheters widely available to all sites will be required for study participation (Table 9.5.2A). 
These devices must be used to perform mapping and ablation procedures for subjects 
randomized to the CONTROL arm.  Device and Equipment set-up must be completed according 
to the Instructions for Use. 
 

 
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Table 9.5.2A: CONTROL (THERMOCOOL® Navigational) Required Non-Investigational 
Devices 
Standard Equipment 
Function  
THERMOCOOL®  Navigational Family of 
catheters 
A commercially available THERMOCOOL®  Navigational 
catheter (NAVISTAR® THERMOCOOL® Catheter, 
THERMOCOOL® SF Catheter.) 
Delivers radiofrequency energy to the target tissue.  
Stockert RF Generator 
Transmits radiofrequency energy to RF ablation catheters. 
LASSO® Circular Mapping Catheter 
To be used in conjunction with the CARTO™ 3 System to 
verify Entrance Block.  May also be used to obtain a 3-
Dimensional map of the Left Atrium (LA). 
Adhesive electrical dispersive pads 
Component of the RF current return path 
EP lab recording equipment 
Records multiple intracardiac electrograms and signals from 
the RF generator (power, temperature, impedance) and for 
performs electrical stimulation. 
CARTO® 3 System Junction Box (PIU) 
Provide the interface to the catheter, generator, and the 
CARTO® System. 
9.6 
General AF  Procedure Guidelines 
Processes required as part of the study are indicated in BOLD.  All devices must be used 
according to the accompanying IFU and package labeling. 
9.6.1 Electrophysiology study and pre-ablation procedures: 
 
Anesthesia should be delivered per the standard EP lab procedures. 
 
REQUIRED: An appropriate strategy to minimize risk of esophageal injury MUST be 
used to ensure the physician has accurate information about the location of the esophagus 
relative to intended sites of ablation.  The method used to localize the esophagus will be 
collected in the CRFs. 
 
At least one of the following methods MUST be used for esophageal localization: 
 Use of an esophageal temperature probe 
 Esophageal visualization with CartoSound and/or ICE 
 Esophageal visualization using barium swallow 
 
Placement of Diagnostic Catheters: 
 
CS catheter in the coronary sinus (CS) for pacing purposes. 
 
LASSO® Catheter for diagnostic purposes. 
 
Other catheters may be placed at the discretion of the investigator. 
 
A standard electrophysiology (EP) study may be performed at the discretion of the 
investigator and per standard EP lab protocol if not already performed.   
 
A single or double transseptal (TS) puncture should be performed per standard EP Lab 
procedures.  A patent foramen ovale (PFO) may be used, if applicable. 

 
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 
One of the following compatible sheaths are REQUIRED to be used with the TEST 
Catheters to access the LA: 
 
8.5F or 9.5F Agilis™ NxT Steerable Introducers Dual-Reach™ Sheath 
 
9.0F Bard® Channel™ Steerable Sheath 
 
8.5F Heartspan Fixed Curve Braided Transseptal Sheath 
 
8.5F Zurpaz Steerable Sheath 
 
10.0F Bard® DiRex Steerable Sheath 
 
 
Systematic anticoagulation with heparin should be administered with activated clotting 
time (ACTs) checked at least every 30 minutes to maintain target ACT of > 325 
seconds. 
 
Use of CARTOMERGE™ is recommended, utilizing the subject’s baseline CT.   MRA or 
rotational angiography (PV venograms or intracardiac echocardiography [ICE]) may be 
performed, at the discretion of the investigator, per standard EP lab protocol to verify 
location, morphology, and dimensions of each PV. 
 
Prior to ablation in the region of the RSPV, precautionary measures to evaluate proximity 
to the phrenic nerve, such as pacing maneuvers, are REQUIRED. 
 
If the subject is in AF, cardioversion may be performed at the discretion of the 
investigator prior to the ablation procedure. 
9.6.2 TEST Group 
9.6.2.1 Mapping and Ablation procedure 
 
Use of the CARTO® 3 System is REQUIRED for mapping of Left Atrium (LA), 
pulmonary veins, and to acquire RF lesions tags. 
 
Mapping may be completed using the FAM / MEM functionality with the Test 
(nMARQ™) catheter or with a standard mapping catheter (THERMOCOOL® or LASSO®). 
o If available, the ConfiDENSE module should not be used with the nMARQ 
system. 
 
Once the PVs ostia have been defined, position the TEST catheter near the ostium of the 
targeted PV and find the optimal position of the catheter to maximize the contact with all 
or most of the electrodes. 
o If available, the Visitag module should not be used during ablation with the 
nMARQ system. 
 
When the position is satisfactory, commence energy delivery with the Test Catheter, 
observing the irrigation rate recommendations.  The RF energy can be delivered either in 
bipolar or unipolar configuration per application, at the physician’s discretion. 
 
Ablation of the PVs should be performed at least peri-ostial to isolate the left and right-
sided PVs and to ensure RF is not delivered beyond the PV ostia into the vein.  
 
During the ablation procedure, the investigator will assess the fluid status of the subject 
and determine if diuresis is necessary, and treat accordingly. 

 
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 
All subjects will undergo PV ablation until PVI is achieved and confirmed by entrance 
block. 
 
If necessary and at the physician’s discretion, a commercially available NAVISTAR® 
THERMOCOOL® Catheter  may be inserted to complete PVI or ablate other identified 
targets as described in section 9.6.5. 
NOTE:  Only a NAVISTAR® THERMOCOOL® Catheter may be used for touch-up with the 
nMARQ™ Multi-channel RF generator.  The THERMOCOOL® SF Catheter can NOT be used 
for this purpose. 
NOTE:  CARTO® 3 mapping of the anatomical location of the PV’s and RF lesions is 
REQUIRED.  At the completion of the procedure, two back-up copies should be made: one 
to keep on file in the onsite Study Subject File and one to provide to the Sponsor for the 
Master Study Files. 
 
9.6.2.2 Verification of ablation procedure(s) 
 
Verification of isolation of the targeted PVs by demonstrating entrance block into 
each targeted PV is REQUIRED.   
 
A 30 minute waiting period is REQUIRED from the last RF application at a PV 
target before verification may be confirmed.  The time of the last RF application in 
a PV target and the time of entrance block verification MUST be documented in the 
medical record as source documentation. If reconduction is noted, additional RF 
applications should be applied and a second 30 minute waiting period will be required 
to recheck for entrance block. If reconduction is still noted, additional RF applications 
should be applied but a third 30 minute waiting period is not required prior to recheck 
for entrance block. 
 
To verify entrance block, analyze electrograms in sinus and/or atrial paced rhythm to 
confirm that no PV potentials are present. 
 
Administering adenosine (ATP) and/or isoproterenol for induction prior to 
verification of entrance block is REQUIRED 
 
Demonstration of entrance block MUST be confirmed and documented by both the Test 
Catheter (if it can be accessed into the PV) and the LASSO® Circular Mapping Catheter.  
 
First:  confirmed and documented by the Test (nMARQ™ Circular Catheter).   
 
Second: confirmed and documented by the LASSO® Circular Mapping Catheter. 
 
Exit block, in addition to entrance block, may be demonstrated but is not required. 
 
The ablation procedure is considered complete when confirmation of entrance block in 
targeted PVs is confirmed. 
9.6.3 CONTROL Group 
9.6.3.1 Mapping and ablation procedure 
 
Use of the CARTO® 3 System is REQUIRED for mapping of Left Atrium (LA), 
pulmonary veins, and to acquire RF lesions tags.  
 
The mapping and ablation procedure in the Control Arm should follow standard PVI 
process. 

 
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o If available, the ConfiDENSE module should not be used in the CONTROL 
arm of the study. 
o If available, the Visitag module should not be used in the CONTROL arm of 
the study. 
 
When the THERMOCOOL®  Navigational catheter position is satisfactory, commence 
energy delivery observing the irrigation rate recommendations.   
 
Ablation of the PVs should be performed at least 1-2 cm outside the PV ostia to isolate 
the left and right-sided PVs and to ensure the lesions are not inside the PV ostia.  
 
During the ablation procedure, the investigator will assess the fluid status of the subject 
and determine if diuresis is necessary, and treat accordingly. 
 
All subjects will undergo PV ablation until entrance block is confirmed. 
 
9.6.3.2 Verification procedure 
 
Verification of isolation of the targeted PVs by demonstrating entrance block into each 
targeted PV is REQUIRED.   
 
A 30 minute waiting period is required from the last RF application at a PV target 
before verification may be confirmed.  The time of the last RF application in a PV 
target and the time of entrance block verification MUST be documented in the 
medical record as source documentation. If reconduction is noted, additional RF 
applications should be applied and a second 30 minute waiting period will be required 
to recheck for entrance block. If reconduction is still noted, additional RF applications 
should be applied but a third 30 minute waiting period is not required prior to recheck 
for entrance block. 
 
To verify entrance block, analyze electrograms in sinus and/or atrial paced rhythm to 
confirm that no PV potentials are present. 
 
Administering adenosine (ATP) and/or isoproterenol for induction prior to 
verification of entrance block is REQUIRED  
 
Demonstration of entrance block MUST be confirmed and documented using the LASSO® 
Circular Mapping Catheter.  
 
Exit block, in addition to entrance block, may be demonstrated but is not required. 
 
The ablation procedure is considered complete when confirmation of entrance block in 
targeted PVs is confirmed. 
9.6.4 Procedural data to be collected  
 
The following procedural information will be collected during each ablation procedure: 
 
RF Ablation parameters per application (power, temperature, flow rate, duration, 
impedance rise/fall, mode of RF delivery (bipolar or unipolar) 
 
Device(s) utilized for RF delivery (per targeted PV) 
 
Device(s) utilized for verification (per targeted PV) 
 
Duration of mapping time 
 
Duration of RF application time with study catheter (Test or Control) for AF targets 

 
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 
Duration of Fluoroscopy time during mapping 
 
Duration of Fluoroscopy time during ablation 
 
Total procedure time  
 
Fluid delivered by the Study Catheter 
 
For SNA subjects only, the number of catheters exchanged during each ablation 
procedure will be documented 
9.6.5 Optional ablation procedure(s) based on clinical findings: 
Additional RF lesions with the assigned catheter system may be performed in the left atrium at 
the investigator’s discretion based on treatment need.  When additional RF lesions are placed 
during an ablation procedure, these treatments must be clearly documented (location and 
justification) in the procedure notes and on the study case report forms.   
 
As noted in the 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical 
ablation of atrial fibrillation, optional ablation targets may include but are not limited to the 
following: 
 
If a focal trigger is identified outside a PV during the ablation procedure, ablation of that 
focal trigger should be considered. 
 
Ablation of the cavotricuspid isthmus is recommended in patients with a history of typical 
atrial flutter or inducible cavotricuspid isthmus dependent atrial flutter (using the 
ThermoCool catheter for roll-in subjects and those in the Test arm). 
NOTE: RF power should be reduced when creating lesions on the posterior wall near the 
esophagus. 
NOTE:  Catheters are for single use only as indicated in the Instructions for Use.  
9.7 
Post Procedure (pre-discharge) Assessment 
Prior to hospital discharge, the following assessments should be performed: 
• 
12 Lead ECG (if standard of care) 
• 
Transthoracic Echocardiogram (TTE) 
• 
For SNA subjects only 
 
MRI examination of the brain 
 
Neurological examination, including  NIH Stroke Scale 
9.8 
Follow-up Visit Assessment 
The subject will be required to complete follow up visits through 3 years post initial ablation 
procedure. The follow-up visits at 1 month, 3 months, 6 months, 9 months, and 12 months will 
consist of an office visit.   
 
Discharged subjects will receive a telephone call at 7 days post ablation procedure to assess any 
occurrence of Primary Adverse Events; otherwise, in-hospital surveillance will capture any 

 
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Primary Adverse Events.  Additionally subjects will be followed up at 2 years and 3 years post-
ablation by telephone to assess any late occurring adverse events and any patient reported 
recurrences of AF. 
 
Follow-up visits should be scheduled according to the following timeframes:  1 month -23/+12 
days (M-1, day 7-42), 3 month ± 20 days (M-3, day 70-110), 6 months ± 30 days, (M-6, day 
150-210), 9 month ± 40 days (M-9, day  235-315) and 12 month ± 45 days (M-12, day 316-405). 
Follow-up visit schedule will not reset if subject undergoes a repeat AF ablation procedure. 
 
The 2 and 3 year post-ablation telephone calls should occur within ± 45 days of their index 
ablation procedure anniversary.  
9.9 
Summary of Subject Assessment 
At each visit, the following assessments should be performed: 
 
Table 9.9A: Summary of Subject Assessments 
Assessments 
BL 
D/C 
D7 
M1 
D7-42 
M3    
D70-110 
M6 
D150-210 
M9 
D235-315 
M12 
D316-405 
UNS 
Y2 
±45D 
Y3 
±45D 
Clinic visit 
  
 
 
 
 
 
 
 
 
 
 
  
Patient Information 
(Demographics) and 
Consent  
  
 
 
 
 
 
 
 
Medical history 
  
 
 
 
 
 
 
 
Pregnancy Test1  
  
 
 
 
 
 
 
 
TTE2 
  
  
 
 
 
 
 
 
Imaging for detection of 
LA thrombus (e.g., TEE, 
ICE, CT, MRI)3 
  
 
 
 
 
 
 
 
ECG4 
  
  
 
 
 
 
 
 
 
 
 
  
TTM5 
 
 
 
 
 
 
 
 
 
 
  
CT/MRA 
nMARQ GROUP 
ONLY 
 6 
 
 
 
 
 
 
 
 
Cardiac medication 
  
 
 
 
 
 
 
 
 
 
 
  
Adverse events 
 
  
 
7 
 
 
 
 
 
 
 
 
  
7 
AFL/AT/AF recurrence 
and repeat ablation 
 
 
 
 
 
 
 
 
 
 
 
  
7 
CCS-SAF Scale 
  
 
 
 
 
 
 
 
 
 
 
Cerebral MRI8 
 9 
 10 
 
 
11 
 
11 
 
11 
 
11 
 12 
Neurological Exam8 
 9 
 10 
 
 
11 
 
11 
 
11 
 
11 
 12 
NIH Stroke Scale8 
 9 
 10 
 
 
11 
 
11 
 
11 
 
11 
 12 
mRS 
 9 
 
 
 
MoCA 
 9 
  
 
 
 
 
11 
 
11 
 
11 
 12 
1. 
In all women of child-bearing age and potential. To be completed within 24 hours prior to ablation procedure. 
2. 
Completed within 30 days prior to ablation period. 
3. 
To be completed  the day before or the day of the ablation procedure. 
4. 
To be collected if completed as standard of care. 

 
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5. 
Dispensation of TTM device at Month 3.  
6. 
Within 30 days prior to ablation procedure. 
7. 
To be assessed via phone follow-up. 
8. 
Only for SNA subjects. 
9. 
To be performed within 72 hours prior to ablation procedure. 
10. To be completed within 72 hours post-ablation procedure. 
11. To be undertaken if neurologic symptoms and/or cerebral ischemic lesions identified in a prior evaluation. 
12. To be completed only if: (i) a previously mandated test was missed; or, (ii) subject reports neurologic difficulties 
between scheduled follow-up visits and unscheduled assessment per investigator approval.   
 
9.10 
Descriptions of Procedures 
12-lead Electrocardiogram (ECG) – Standard of Care 
Data from 12-lead ECG recordings will be collected as described in Table 9.9A.  Data from 
unscheduled ECG’s between two consecutive follow-up visits will be collected and reported on 
the appropriate eCRF (i.e., unscheduled visit eCRF).  Copies of ECG reports should be filed in 
the subject’s medical chart with the participating investigator. 
 
Arrhythmia Monitoring - Standard of Care 
Additional arrhythmia monitoring data will be collected if standard of care (e.g., Holter 
monitoring). 
 
Cardiac Computed Tomography (CT) / Magnetic Resonance Angiogram (MRA) – nMARQ 
(TEST) GROUP ONLY 
A cardiac multi slice CT or MRA must be performed according to requirements in Table 9.9A.  
For each nMARQ subject, the same imaging technique (CT or MRA) should be used pre-
ablation and post-ablation, and the exam must follow the CT/MRA protocol supplied by the core 
lab.  Pre-ablation and post-ablation CT/MRAs will be analyzed by a core lab to evaluate PV 
Stenosis.   
 
Cardiac Medication 
All cardiac medications and the indication for which they are prescribed will be documented in 
subject charts and reported on the appropriate eCRF(s).  If an AE is related to intake of 
medications, details must be provided on the appropriate eCRF(s).  
 
CCS-SAF scale (Dorian et al., 2006) 
Subjects will be classified by the physicians (on the eCRF) according to the CCS-SAF scale pre-
ablation, and at the 3, 6, 9 and 12 month follow-up visits. 
 
Pregnancy Test 
A pregnancy test must be obtained within 24 hours prior to the ablation procedure for  ALL 
female patients of child-bearing age and potential.  
 

 
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Transtelephonic Monitoring (TTM)  
Each subject will be provided with a TTM device at the 3-month follow-up visit.  Transmissions 
will be required monthly beginning on Day 91 from their index ablation procedure per the 
following schedule: 
 
A minimum of 1 transmission per month will be required beginning Day 91 (following 
completion of the 3 month blanking period) through the 12-month follow-up visit.  
 
Additionally, any symptom-triggered episode that occurs from the end of the blanking period 
through the 12-month follow-up visit should be recorded and transmitted.  The core lab 
representative receiving the transmission will ask the subject to report arrhythmia-related 
symptoms experienced during each recording. 
 
Transesophageal Echocardiography (TEE) 
Transesophageal echocardiography may be completed according to the requirements in Table 
9.9A.  TEEs are performed to exclude atrial thrombus or other structural contraindications to an 
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. 
 
Transthoracic Echocardiography (TTE)  
Transthoracic echocardiograms must be performed according to requirements in Table 9.9A.  
TTE should be completed within 30 days prior to the study ablation procedure, and must be 
repeated before discharge to evaluate volume parameters, valve abnormalities, LA dimensions, 
and exclude presence of pericardial effusion.  Copies of TTE reports should be filed in the 
subject’s medical chart. 
 
Cerebral Magnetic Resonance Imaging (MRI; SNA subjects only) 
A cerebral MRI must be completed as described in Table 9.9A.  Pre-ablation and post-ablation 
cerebral MRIs will be analyzed (blinded) by a central core lab to determine the frequency, size, 
and anatomic location of cerebral micro-emboli, if any.  If there are findings noted on the post-
ablation cerebral MRI, a follow-up MRI will be required at each follow-up visit until resolution 
is observed.  
 
Montreal Cognitive Assessment (MoCA) (SNA subjects only) 
The SNA subjects will undergo a neurological assessment using the MoCA at baseline and 1M 
post-ablation.  Also, possibly at other follow-up visits, pending previous findings of 
microemboli/neurologic deficits.   
 
Modified Rankin Scale (mRS) (SNA subjects only) 
The SNA subjects will undergo a neurological assessment using the mRS at baseline and 3M 
post-ablation. This assessment will be performed by a neurologist certified in the administration 
of the mRS. 
 
Neurologic Exam (SNA subjects only) 
A medical staff member, who is not an investigator or part of the reMARQable study team, and 
who is a member of the neurology department, must perform neurologic exams at pre- and post-

 
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ablation 
and 
possibly 
at 
other 
follow-up 
visits, 
pending 
previous 
findings 
of 
microemboli/neurologic deficits.   
 
NIH Stroke Scale Assessment (SNA subjects only)  
The SNA subjects will undergo a neurological assessment using the NIH Stroke Scale at 
baseline, post-ablation, and possibly at other follow-up visits, pending previous findings of 
microemboli/neurologic deficits.  This assessment will be performed by a neurologist certified in 
the administration of the NIHSS  
 
Table 9.9A displays the required schedule for subject treatments and evaluations for the Test and 
Control Groups.  All subjects will be followed through 3 years post-ablation.  Subjects who 
undergo a repeat ablation procedure will continue follow-up according to the schedule of their 
index (first) ablation procedure.  Thus, subject visits will be counted from the index ablation 
procedure, not from the repeat ablation procedure.   
9.11 
 Unscheduled Visits 
If a subject returns for a visit outside of the protocol-defined visit schedule provided in Table 
9.9A, the visit will be considered “unscheduled” (UNS).  An Investigator may request an 
unscheduled visit in the presence of a new or worsened 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. 
9.12 
Repeat Ablation Procedures 
Repeat ablation(s) may be performed at the discretion of the investigator.  The devices used for 
any repeat ablation MUST be the same as the assigned catheter system during the blanking 
period.  A change to the assigned catheter system for repeat ablations during the blanking period 
will result in that subject being considered a chronic effectiveness failure.  All necessary eCRFs 
must be completed for all repeat ablation procedures.  Imaging for detection of LA thrombus 
should be completed pre-procedure and pre- and post-procedure TTEs for detection of 
pericardial effusion should also be completed for repeat procedures.  Additionally, for subjects 
receiving warfarin therapy, every effort should be made to keep the INR >2.0 pre-procedure for 
repeat procedures.  
 
Physicians should determine and document in eCRF if recurrence due to reconnection of target 
PVs or due to non-PV targets.  The follow up schedule will remain based on the initial ablation 
procedure.  If more than 2 repeat ablation procedures are required during the blanking period, 
this will be considered a chronic effectiveness failure.  Additionally, if a repeat ablation 
procedure is conducted, during the effectiveness evaluation period, it will be considered a 
chronic effectiveness failure.  An exception may be made for extenuating circumstances 
preventing the hospital from being able to schedule a repeat ablation within the blanking period.  
The occurrences will be evaluated by the Sponsor on an individual basis and documented 
approval must be granted. 

 
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9.13 
Core Laboratory for Evaluation Tests 
An independent central core laboratory or expert physiciana will conduct blinded/objective 
evaluations of TTM, CT/MRA, and cerebral MRI.  Initial evaluations may be performed by 
personnel trained in specific evaluation of these tests; ultimately, all tests will be reviewed by a 
physician expert who is certified/well qualified to make such assessments (e.g., cardiologist, 
experienced EP technician, neuroradiologistb, or neurologist).  AF episodes will be evaluated per 
the definitions provided in this protocol (refer to Study Definitions). 
                                                 
 
a For neurological assessments, including NIHSS Scoring, final assessments are to be done by a neurologist in the 
investigational site who remains unaware of the study device or treatment arm to which a subject has been 
randomized. 
b Protocol-based MRI assessments of subjects in the SNA or subjects who, post-ablation, have new onset 
neurological deficits will have 2 or up to 3 neuroradiologists assess submitted images per written Core Laboratory 
procedures. 

 
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10.0 Adverse Events   
10.1 
Definitions / Classifications 
10.1.1 Adverse Event (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 adverse events if the investigator determines they are clinically significant.    
 
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/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: 
• 
Minor pericarditis attributable to the ablation procedure defined as pleuritic chest discomfort 
with or without pericardial rub and ECG changes. 
• 
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. 
• 
Reablation for AF or pre-existing AFL/AT. 
10.1.2 Serious Adverse Event (SAE) 
A serious adverse event (SAE) is any event that meets one or more of the following criteria: 
 
Leads to a death 
 
Leads to a serious deterioration in the health of a subject that resulted in: 
 
a life-threatening illness or injury 
 
a permanent impairment of a body structure or a body function 
 
in-patient hospitalization or prolongation of an existing hospitalization* 
 
medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to body structure or a body function 
 Leads to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
*Planned hospitalization for a condition present prior to the participant’s enrollment in the study 
will not meet the definition of an SAE.  An AE would meet the criterion of “hospitalization” if 
the event necessitated an admission to a health care facility (e.g., an overnight stay).  Emergency 
room visits that do not result in admission to the hospital should be evaluated for one of the other 
serious outcomes. 
 

 
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10.1.3 Primary Adverse Event 
A Primary AEs is an event listed in Table 10.1.3A which occurs within the first week (7 days) 
following an ablation procedure.  Primary AEs are considered SAEs.   
 
Table 10.1.3A: Primary Adverse Events 
Primary Adverse Event 
Description/Criteria 
Death 
Adverse event resulting in patient death.   
Atrio-esophageal Fistula* 
Connection between the atrium and the lumen of the esophagus as 
evidenced by documentation of esophageal erosion combined with 
evidence of a fistulous connection to the atrium. 
Cardiac Tamponade/Perforation 
The development of a significant pericardial effusion during or within 
30 days of undergoing the index AF ablation procedure.  A significant 
pericardial effusion is one which results in hemodynamic compromise†, 
requires elective or urgent pericardiocentesis, or results in a 1 cm or 
more pericardial effusion as documented by echocardiography.   
 
Cardiac tamponade/perforation should also be classified as:  
 
Early – diagnosed prior to discharge 
 
Late – following initial discharge from the hospital (see Safety 
requirement below) 
Myocardial Infarction 
Presence of any one of the following criteria: 
 
Detection of ECG changes indicative of new ischemia (new ST-T 
changes or new LBBB) which persist for more than 1 hour 
 
Development of new pathological Q waves on ECG 
 
Imaging evidence of new loss of viable myocardium or new 
regional wall motion abnormality 
Stroke 
Stroke/CVA is an acute symptomatic episode of neurological 
dysfunction attributed to a vascular cause (ischemia or hemorrhage) in 
which symptoms last more than 24 hours, or if symptoms last less than 
24 hours, a brain imaging study demonstrates infarction. 
Cerebrovascular Accident 
(CVA) 
Thromboembolism 
Formation in a blood vessel of a clot (thrombus) that  results from the 
breaking loose of all or part of an existing thrombus, which is then 
carried by the blood to lodge in/occlude a more distal vascular site. 
Transient Ischemic Attack 
Acute episode of temporary (<24 hrs) and focal loss of cerebral 
function of vascular (occlusive) origin as determined by the consulting 
neurologist. 
Diaphragmatic Paralysis 
Change in baseline diaphragmatic functioning as evidenced by 
elevation of the diaphragm above the normal range but not due to a 
pulmonary process such as atelectasis. 
Pneumothorax 
Adverse event resulting in air introduction into the pleural cavity of the 
chest between the lung and the chest wall necessitating chest tube 
placement or surgical intervention. 
Heart Block 
Impairment of AV conduction requiring intervention due to 
inappropriate RF application. 
Pulmonary Vein Stenosis* 
≥70% diameter reduction of pulmonary vein from baseline CT/MRA 
scan. 
Pulmonary Edema 
(Respiratory Insufficiency) 
Respiratory insufficiency resulting in pulmonary complications 
necessitating intubation or other significant intervention (including 
diuretics administered specifically for treating pulmonary edema):  
 Pneumonia – infiltrate, fever and leukocytosis 
 ARDS 
 Pulmonary edema 

 
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Primary Adverse Event 
Description/Criteria 
Pericarditis 
Major: results in effusion which leads to hemodynamic compromise or 
requires pericardiocentesis, prolongs hospitalization by more than 48 
hours, requires hospitalization or persists for more than 30 days after 
ablation. 
Hospitalization 
 (initial and prolonged)  
Adverse event resulting in admission to the hospital or prolongation of 
expected hospital stay due to an AF ablation procedure or a study 
device-related cause.   
Excludes hospitalization solely due to arrhythmia recurrence or 
non-medically urgent cardioversion. 
Vascular Access Complication  
Vascular access complication (e.g., groin hematoma, AV fistula, 
pseudoaneurysm) requiring intervention (e.g., surgical repair, blood 
transfusion) or admission or prolonged hospitalization. 
* Atrio-esophageal fistula and pulmonary vein stenosis that occur greater than one week (7 days) post-procedure shall be deemed 
Primary AE. 
 
† Hemodynamic compromise or instability is defined as Systolic BP <80 mmHg. 
 
10.1.4 Adverse Device Effect / Serious Adverse Device Effect 
An adverse device effect is an adverse event related to the use of the investigational medical 
device. A serious adverse device effect (SADE) is an adverse device effect that has resulted in 
any of the consequences characteristic of an SAE.  
 
10.1.5 Anticipated Adverse Events 
An anticipated AE is an event that has been reported in previous studies of RF ablation/drug 
therapy, and can be anticipated in this current study per the risk analysis.  Table 10.1.5A 
provides a comprehensive list of anticipated AEs. 
 
Table 10.1.5.A: Anticipated Adverse Events 
Anticipated Adverse Events 
1. 
Acute Respiratory Distress Syndrome (ARDS) 
2. 
Air embolism 
3. 
Allergic reaction  
4. 
Anaphylactic shock 
5. 
Anemia 
6. 
Allergic reaction to Anesthesia (e.g., hair loss) 
7. 
Apnea - sedation induced 
8. 
Arrhythmia: bradycardia 
9. 
Arrhythmia: tachycardia 
10. 
Arrhythmia: pro-arrhythmias 
11. 
Arrhythmia: ventricular tachyarrhythmia / pro-arrhythmia 
12. 
Aspiration pneumonia 
13. 
Asthmatic attack 
14. 
Atelectasis 
15. 
Atrial fibrillation* 

 
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16. 
Exacerbation of pre-existing arrhythmia* 
17. 
Atrio-Esophageal fistula 
18. 
Atypical left atrial flutter 
19. 
AV fistula 
20. 
Bleeding complications 
21. 
Bleeding requiring transfusion 
22. 
Cardiac arrest 
23. 
Cardiac perforation  
24. 
Tamponade 
25. 
Cardiac thrombo-embolism 
26. 
Cerebro-vascular accident (CVA) / stroke 
27. 
Chest pain/discomfort 
28. 
Complete heart block, temporary or permanent 
29. 
Conduction block: ongoing / resolved 
30. 
Congestive Heart Failure 
31. 
Coronary artery dissection 
32. 
Coronary artery occlusion 
33. 
Coronary artery spasm 
34. 
Coronary artery Thrombosis 
35. 
Death 
36. 
Deep venous thrombosis 
37. 
Dislodgement of ICD (Implantable Cardioverter Defibrillator)  
38. 
Dislodgement of permanent pacing leads 
39. 
Disseminated Intravascular Coagulation 
40. 
Dyspnoea 
41. 
Endocarditis 
42. 
Epistaxis 
43. 
Expressive aphasia 
44. 
Fainting 
45. 
Fatigue 
46. 
Gastro-intestinal NOS 
47. 
Gastric reflux 
48. 
Nausea 
49. 
Gastrointestinal diverticulosis 
50. 
Heart Failure 
51. 
Hematoma (local) /ecchymosis 
52. 
Hemorrhage  
53. 
Hemothorax 
54. 
High / increased creatine phosphokinase (CPK) 
55. 
Hypotension 
56. 
Hypoxia 
57. 
Infection, localized  

 
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58. 
Infection, systemic 
59. 
Laceration 
60. 
Leakage of air or blood into the lungs or other organs due to perforation 
61. 
Liver toxicity 
62. 
Mobile strands in Inferior Vena Cava 
63. 
Myocardial Infarction 
64. 
Neurological disorders (tremor) 
65. 
Neurological disorders (poor coordination) 
66. 
Neurological disorders (headache) 
67. 
Obstruction to the vascular system 
68. 
Perforation to the vascular system 
69. 
Damage to the vascular system 
70. 
Pericardial effusion resulting in tamponade 
71. 
Pericardial effusion without tamponade 
72. 
Pericarditis 
73. 
Peripheral embolus 
74. 
Peripheral nerve injury 
75. 
Peripheral thromboembolism 
76. 
Phlebitis 
77. 
Phrenic nerve damage  
78. 
Diaphragmatic paralysis 
79. 
Pleural effusion 
80. 
Acute Respiratory Distress Syndrome (ARDS) 
81. 
Pneumothorax 
82. 
Pseudoaneurysm 
83. 
Pulmonary edema 
84. 
Heart failure 
85. 
Pulmonary embolism 
86. 
Pulmonary hypertension 
87. 
Pulmonary toxicity, like acute pulmonary syndrome 
88. 
Pulmonary vein dissection 
89. 
Pulmonary vein Stenosis 
90. 
Pulmonary vein thrombus 
91. 
Pump failure 
92. 
Renal failure 
93. 
Respiratory depression 
94. 
Respiratory failure 
95. 
Retroperitoneal hematoma 
96. 
Rhabdomyolysis, including produced by body position or propofol 
97. 
Sedation induced CO2 retention with lethargy and cholecystitis 
98. 
Seizure 
99. 
Sepsis 

 
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100. 
Skin burns (due to cardioversion, tape, etc) 
101. 
Skin discoloration 
102. 
Skin injury / muscle or connective tissue injury due to body position, electrical cardioversion 
103. 
Skin rash 
104. 
Thrombocytopenia 
105. 
Thromboembolism 
106. 
Thrombosis 
107. 
Thyroid disorders 
108. 
Transient extremity numbness 
109. 
Transient ischemic attack (TIA) 
110. 
Unintended complete or incomplete AV, Sinus node, or other heart block or damage 
111. 
Urinary retention 
112. 
Urinary tract infection 
113. 
Urinary tract injury or infection related to the urinary catheter 
114. 
Valvular damage/insufficiency 
115. 
Vasovagal reactions 
116. 
Vision change 
117. 
Volume overload 
118. 
Worsening obstructive, restrictive, or other form of pulmonary disease 
119. 
X-ray radiation injury of skin, muscle and/or organ 
*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. 
 
10.1.6 Unanticipated Adverse Device Effect 
An unanticipated adverse device effect (UADE) or unanticipated serious adverse device effect 
(USADE) is any serious adverse effect on health, safety, any life-threatening problem, or death 
caused by, or associated with a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or risk analysis 
report, or any other unanticipated serious problem associated with a device that relates to rights, 
safety, or welfare of subjects. 
  
10.1.7 Non-Serious Adverse Events 
A non-serious AE is any event that results in minimal transient impairment of a body function or 
damage to a body structure, and does not require any intervention listed under the criteria for 
“serious adverse event”.  
 
10.1.8 Study Device Failure or Malfunction 
A device has failed if it does not perform according to the Instructions for Use or fails to meet 
the expectations of the device and/or investigator (i.e., related to appearance of the device, 
performance, durability, safety, effectiveness, quality, reliability, labeling, etc.).   

 
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10.2 
Causality  
The causality of each AE must be assessed according to the following classifications: 
 
Table 10.2A: Adverse Event Causality Classifications 
Caused By 
Relation 
Definition of Relation 
Device 
Definitely 
The device directly caused or contributed to the AE. 
Possibly 
The device may have caused or contributed to the AE. 
Unrelated 
The AE is not associated with the device. 
Procedure 
Definitely 
The AE is an untoward medical occurrence directly associated by 
timing and/or pathophysiology with the standard electrophysiology or 
AF ablation procedure described in this protocol that would not have 
happened if the procedure had not been performed. 
Possibly 
The AE may be associated by timing and/or pathophysiologic with the 
standard electrophysiology procedure described in this protocol. 
Unrelated 
The AE is not associated with the standard electrophysiology or AF 
ablation procedure described in this protocol.  
 
10.3 
Intensity / Severity  
The intensity or severity of each AE must be assessed according to the following classifications: 
 
Table 10.3A: Adverse Event Intensity / Severity Definitions 
Mild 
Awareness of signs, symptoms, or events that are otherwise easily tolerated that may 
result in minimal transient impairment of a body function or damage to a body structure, 
but do not require intervention other than monitoring.  
Moderate 
Any event that results in moderate transient impairment of a body function or damage to 
a body structure that causes interference with usual activities, or that warrants possible 
intervention, such as the administration of medication, to prevent permanent impairment 
of a body function or damage to a body structure. 
Severe 
Any event that is incapacitating (an inability to do usual activities) or is life-threatening 
and results in permanent impairment of a body function or damage to a body structure, or 
requires intervention, such as major surgery, to prevent permanent impairment of a body 
function or damage to a body structure. 
 

 
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10.4 
Outcome  
The outcome of each AE must be assessed according to the following classifications: 
 
Table 10.4A: Adverse Event Outcome Classifications 
 
10.5 
Adverse Event Reporting and Documentation Requirements  
10.5.1 Adverse Event Reporting Requirements 
Each AE must be reported to the Sponsor regardless of classification, seriousness, intensity, 
outcome or causality.  Adverse events will be recorded on the electronic case report forms 
(eCRFs) 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.   
All serious AEs, UADE/SADE/USADE, and Study device failure/malfunction, whether or not 
they are related to the device or procedure, must be reported to the Sponsor, via eCRF, 
immediately upon awareness of the event by the study site personnel.   
Study Device Deficiencies (failure or malfunction) associated with an AE must be reported to the 
Sponsor immediately upon awareness of the event  by the study site personnel (both the device 
failure and AE), documented on the appropriate eCRF and the device returned according to the 
Sponsor’s instructions.  
Under no circumstances should UADEs be reported later than 10 business days. 
  
Biosense Webster will ensure that investigators are instructed to return devices suspected of 
causing an AE or SAE (i.e., definitely device-related or possibly device-related) in accordance 
with relevant regulations and current company procedures. 
 
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. 
 
Timing for reporting the different types of AEs is described in Table 10.5.1A. 
Classification 
Definition 
Resolved without 
sequelae 
Subject fully recovered with no observable residual effects 
Resolved with sequelae 
Subject recovered with observable residual effects 
Improved 
Subject’s condition improved, but residual effects remain 
Unchanged 
AE is ongoing 
Worsened 
Subject’s overall condition worsened 
Death 
Subject died as a result of the AE (whether or not the AE is related to the 
device or procedure) 

 
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Table 10.5.1A: AE Reporting Requirements 
Type of Adverse Event 
Reporting Requirements 
Serious Adverse Events 
(including Primary AEs) 
Report to sponsor immediately upon awareness  
UADE, USADE & SADE 
Report to sponsor immediately upon awareness  
Study device failure/malfunction 
associated with an AE 
Report both study device failure and AE to Sponsor immediately 
upon awareness  
All other Adverse Events 
Routine reporting via EDC     
 
10.5.2 Complaint Reporting 
Devices must be returned if suspected of malfunctioning or if suspected of causing an AE (as 
described in the AE Section of this protocol).  
 
Complaints related to non-Biosense Webster, Inc. products must be handled according to 
institutional policies, EC / EB (or equivalent) policies, and local regulations.   
 
All “device-related AEs AND BW device is used” AND/OR “Procedure-related AEs and BW 
device is used” need to be reported to Biosense Webster’s Complaints Management Department 
within 24 hours for SAEs and within 2 working days for any other AEs after site awareness date 
in accordance with current Biosense Webster procedures.  Institutional policies, EC / EB (or 
equivalent) policies, and local regulations must also be followed, as applicable.  General 
complaints and/or product malfunctions for Biosense Webster, Inc. products not affecting subject 
safety or welfare are to be reported according to current Biosense Webster procedures and other 
policies as necessary (i.e., institutional policies, EC / EB [or equivalent] policies, and local 
regulations). 
 
10.5.3 Adverse Event Documentation 
Each AE must be reported regardless of classification and 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 Adverse Events section of this protocol.  All AEs must be assessed by the study 
investigator and properly documented by completing the subject’s medical records (source 
documents) and appropriate eCRF.  All AEs must be monitored until they are adequately 
resolved or explained.  Additional 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 / IRB, 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. 

 
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10.6 
Global Safety Monitoring Committee 
All AEs will be monitored until they are resolved or explained.  Each AE will be reported 
regardless of severity, outcome, or causality. In order to minimize risks to subjects enrolled in 
the study, the Sponsor will convene a formal Global Safety Monitoring Committee (GSMC) at 
frequent intervals to review the safety data and recommend appropriate action(s) to ensure 
subject safety. 
 
In addition to review of the accumulated safety data, the committee will be tasked with 
independently adjudicating all SAEs reported by the investigators in the study.   The committee 
will be responsible for adjudicating severity and causality of the SAEs, and overall SAE event 
rates. 
 

 
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11.0 Statistical Analysis  
One objective of the Main Study is to demonstrate non-inferiority of the nMARQ (Test) Group 
compared to the TC (Control) Group based on the difference in the primary safety endpoint 
using a non-inferiority margin of 8% for subjects with symptomatic PAF.  
 
Another primary objective of  the Main Study is to demonstrate non-inferiority of the nMARQ 
(Test) Group compared to the TC (Control) Group based on the difference in the primary 
effectiveness endpoint using a non-inferiority margin of 15% for subjects with symptomatic 
PAF.  
 
The objective of the SNA is to evaluate, within a subset of the Main Study PAF population, the 
comparative incidence of symptomatic and asymptomatic post-ablation cerebral micro-emboli in 
the Test and Control groups and the presence or absence of emboli-related central nervous 
system (CNS) deficits for subjects with symptomatic PAF who are randomized and successfully 
complete the brain MRI and neurological assessments.  
11.1 
Overview of Study Design 
A Bayesian adaptive trial design is employed.  Several Bayesian aspects will be employed and 
crucial parameters of the trial will be determined by the accruing data using a completely 
prospective design.  The following is an overview of the design:   
 
1)  The sample size of the trial will be determined by Bayesian adaptive techniques.  At the 250, 
300, 350, 400, and 450 interim looks the trial may stop for expected success or for futility.  If the 
trial stopped for expected success then all subjects will be followed through to the final efficacy 
endpoint (12-months post procedure).  A cap of 500 subjects will be employed. 
 
2) An interim analysis will be conducted 16-weeks after enrollment ends for early success.  If the 
predictive probability of final success is greater than 99%, then trial success will be declared.  
All subjects will have complete safety data and all subjects will be followed through their trial 
completion. 
11.2 
General Considerations 
A comprehensive statistical analysis plan (SAP) will provide full detail on all planned analyses 
for this study.  Any changes (deviations) to the planned analysis methods and the justifications 
for making the changes will be reported in the final clinical study report. 
 
In general, descriptive statistics will summarize all primary, secondary, effectiveness, safety, and 
other endpoints as appropriate.  For continuous variables, number of subjects/events, mean, 
standard deviation, median, 25% percentile, 75% percentile, minimum, and maximum will be 
provided.  For categorical variables, frequency and percentage will be presented for each 
category.  
 

 
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Confidence intervals for binary variables, including the primary outcome variables, will be 
computed using the exact binomial distribution.  Categorical variables will be compared using 
Chi-square or Fisher’s exact test, with the Monte Carlo option used where computationally 
necessary.  Confidence intervals for continuous variables will be computed using the t-statistic.  
Continuous variables will be compared using ANOVA or Kruskal-Wallis test. 
 
Unless otherwise specified, the exact form of each statistical algorithm will be the default of 
SAS®. 
 
The data collected during the course of the trial will be presented in a listing format.  
11.3 
Sample Size and Power Calculation 
11.3.1 Main Study 
Trial simulation was carried out to evaluate the performance characteristics of the trial. For each 
scenario, 10,000 simulated trials were summarized to create the performance characteristics of 
that trial. Under the assumptions of equivalent effectiveness success rate at 55% and equivalent 
safety event rate at 8.6% in both groups, at an experiment-wise error rate of 0.05, an adaptive 
sample size of 250-500 (mean sample size of 417) will provide 80% power for trial success, 
meeting both effectiveness and safety endpoints, and 82.8% power and 87.4% power for meeting 
effectiveness and safety endpoints individually. The probability of early trial success is 36.8%. In 
the simulation, the non-inferiority margin is 15% for effectiveness and 8% for safety. The 
primary AE rate in the first 7-days is simulated as a Bernoulli random variable with a specified 
probability;  the occurrence of effectiveness failure and timing of the failure are based upon a 
three-piece exponential time-to-failure model. The detailed descriptions of the simulation 
assumptions as well as simulation under various scenarios are summarized in Appendix A. 
 
These trial simulations assume a primary AE rate of 8.6% for both Test and Control groups 
under the alternative hypothesis. Based on P030031/S011 data, the overall primary AE rate was 
10.8%. However, this primary AE rate included 3 study subjects deemed primary safety failures 
solely due to hospitalization for AF recurrence. The incidence of primary AEs excluding those 3 
subjects was 8.6%. Thus, an 8.6% primary AE rate is used for the purpose of trial simulations.  
 
These trial simulations assume an equivalent success rate of 55% for both Test and Control 
groups under the alternative hypothesis using the chronic definition of effectiveness failures as 
defined in Section 8.1. These assumptions are based upon review of data from recent pivotal 
P030031/S011 AF THERMOCOOL® Trial where the chronic success rate in the NAVISTAR® 
THERMOCOOL® Group at 1 year follow-up was 62.7% (64/102) for all sites and 43.3% (29/67) 
for US data only. Therefore, it is estimated that the chronic success rate for both the nMARQ™ 
System and THERMOCOOL® at 12 month follow-up will be around 55%. 
 
11.3.2 Adaptive Sample Size 
The sample size in the Main Study may vary from 250 to 500 due to the adaptations to the trial. 
Details regarding the adaptations are located in the Interim Analysis section of this protocol. 
 

 
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11.3.3  SNA Population Sample Size 
At least 60 subjects (≥30 Test subjects and ≥30 Control subjects) from the already enrolled and 
randomized subjects of the Main Study will be selected in sequence for the SNA.  The sample 
size is not intended for statistical comparisons by treatment group; however, 30 subjects in each 
arm will provide at least 91% probability of observing at least one event if the true event rate is 
at 8-14%. 
 
11.3.4 Total Sample Size 
Biosense Webster proposes the sample size for this IDE study to be up to 777 subjects 
(500/0.95+250), based upon the 250-500 subjects required for the effectiveness evaluation, up to 
250 Calibration Roll-in subjects and 5% potential subject attrition rate before randomization. Up 
to 250 roll-in subjects using the nMARQ™ System are expected in this study because up to 50 
sites will enroll up to 5 roll-in subjects each to reduce the influence of learning curve on  
effectiveness results.  It is also estimated that no more than 5% of enrolled patients will either not 
meet the inclusion/exclusion criteria or be lost to contact or withdrawn prior to the 
randomization.  The enrollment will be concluded when study outcomes meet the early stopping 
criteria or when 500 subjects have been randomized in the Main Study. 
11.4 
Analysis Populations 
The study contains two treatment arms with subjects receiving either nMARQ or TC ablation.  
The following analysis populations will be used to complete the analyses prespecified in this 
study:  
 
Intent-to-treat population (ITT): The ITT subject population will include all randomized 
patients who have the ablation catheter inserted.  They will be analyzed as randomized.  Lost-to-
follow-up and withdrawn / early termination subjects post randomization are included in the ITT 
population.  Calibration Roll-in cases will not be included.  
 
As-treated population (AT):  The AT subject population will include all randomized patients 
who have the ablation catheter inserted.  They will be categorized by the treatment received if 
this deviates from the treatment randomized. Calibration Roll-in cases will not be included.  
 
Per Protocol Population (PP):  The PP subject population will include randomized subjects 
who satisfy the following criteria.  Calibration Roll-in subjects will not be included. 
 
have undergone RF ablation,  
 
are treated with the study catheters as randomized (nMARQ or TC), 
 
are in compliance (no major protocol deviations) with the study protocol, and  
 
have been treated for the study-related arrhythmia. 
 
SNA Population (SNAP): The SNAP will include all subjects who are enrolled and randomized 
within the Main Study and who further satisfy specific inclusion and exclusion criteria and 
provide additional consent to participate in the SNA.   Eligible SNA subjects will have 
undergone RF delivery with the study ablation catheters and will have successfully completed 
pre- and post-ablation brain MRI examinations, NIHSS Questionnaires, and general neurological 

 
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assessments.   
 
Safety Population (SP): The SP will include all subjects who have undergone insertion of an 
ablation catheter.  The subjects will be analyzed according to the treatment they actually received 
regardless of the Group they are randomized to. The calibration roll-in cases will be included in 
the SP.  
11.5 
Statistical Analyses for the Primary Endpoints 
Formal statistical hypothesis are formulated for the primary statistical analyses as described 
below.  Inferential statistics for the primary safety and efficacy endpoints may be presented on 
the device label.  The study will be declared successful if the claim of non-inferiority is met for 
both the primary safety and primary efficacy endpoints. 
 
11.5.1 Primary Safety Endpoint  
The primary safety analysis is on the 7-day early onset event rate (except for PV stenosis and 
atrio-esophageal fistula).  The AT population is used as the analysis population.   
 
In order to have consistent mathematical notations for both effectiveness and safety endpoints, 
event-free rate is used for the safety hypothesis and analyses. The probability of a subject being 
event-free (success) in the experimental arm is α2 and in the control arm is α1.  The hypothesis of 
non-inferiority is  
 
2 1 S , 
 
where the non-inferiority δS value of 0.08 is used. 
 
The posterior distribution for the failure-free rate is determined using a non-informative prior 
distribution (Beta(1,1) priors independently for each arm). 
 
The claim of non-inferiority will be accepted if the posterior probability of non-inferiority is 
larger than 0.9675.  That is, if,  
 
Pr(𝛼2 > 𝛼1 − 𝛿𝑠|  Trial Results) ≥0.9675 
 
11.5.2 Primary Effectiveness Endpoint 
The primary effectiveness analysis is a non-inferiority test based on the 3 to 12 month failure-
free rate.  The ITT population is used as the analysis population based on the treatment group as 
randomized.  Any missing data will be imputed using Bayesian multiple imputation as described 
in the ‘Handling or Missing Data’ section in this protocol.   
 
The probability of a subject being failure-free (success) in the experimental arm is π2 and in the 
control arm is π1.  The hypothesis of non-inferiority is  
 

 
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2 1 E , 
 
where the non-inferiority δE value of 0.15 is used. 
 
The posterior distribution for the control failure-free rate calculated based on a non-informative 
prior distribution (Beta(1,1) priors independently for each arm). 
 
 
The claim of non-inferiority will be accepted if the posterior probability of non-inferiority is 
larger than 0.980.  That is, if,  
 
Pr(𝜋2 > 𝜋1 − 𝛿𝐸|  Trial Results) ≥0.980 
 
The critical values of 0.980 and 0.9675 for each of the two endpoints are used in order to control 
the experimentwise type I error for the trial given the adaptive design.  The type I error of the 
design is controlled at the 0.05 one-sided level.  The type I error control is demonstrated by the 
simulations in Appendix A.  
 
The primary effectiveness analyses will also be performed in the AT and PP populations as 
sensitivity analyses.  
 
If the primary effectiveness success rate is less than 40% for either the Test group or the Control 
group, then additional analyses will be conducted to examine the poor device performance as 
follows.  
 
1) The subject demographic and baseline characteristics will be compared between the 
current study and the P030031/S011 study where the chronic effectiveness endpoint 
was 62.1% (64/103) with a 95% confidence interval of 50.7% to 72.7% using the 
exact binomial method; If there is major difference in some of the covariates 
predicting the primary effectiveness endpoint, then covariates adjusted analyses will 
be performed for the primary effectiveness endpoint in the current study.  
2) Multivariate regression analyses will be performed to identify the characteristics 
predicting the low performance; 
3) Subgroup analyses will be performed to examine the impact of the characteristics that 
drive the low performance (e.g. by site, operators, regions, age, gender, ablation 
parameters, LA size etc.) 
 
11.5.3 Site Heterogeneity 
Each site should not enroll more than 20% of the total enrollment to minimize the possibility that 
the study results could be highly influenced by a few sites. We will combine sites with less than 
five randomized subjects according to the geographic regions. Using this pre-determined 
criterion, sites with less than five randomized subjects within the same geographic region will be 

 
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combined such that the combined center(s) would have five or more randomized subjects and no 
more than 5 sites combined.  
 
Although the primary endpoint analyses are based on a Bayesian framework, site heterogeneity 
will be investigated using a set of frequentist analyses. A Breslow-Day test will be conducted to 
examine the homogeneity across sites for the associations of the primary effectiveness and safety 
endpoints with treatment groups. A p-value less than 0.15 will be considered statistically 
significant for an assessment of homogeneity across the treatment sites.  A non-significant result, 
or a significant result that is only quantitative in nature, will support pooling of sites for the 
primary analyses.  If the sites are not poolable, the following additional sensitivity analyses will 
be performed: 
 
1. GEE models with the primary endpoints as the outcome and a fixed effect for treatment and a 
random effect for site will be used to estimate the treatment effect adjusting for site.   
 
2. Logistic regression models with the primary endpoints as the outcome and fixed effects for 
treatment and site will be used to estimate the treatment effect adjusting for site.   
 
If the sites are determined not to be poolable, then the overall treatment effect and its confidence 
interval will be estimated from the model in which sites are treated as random effects for the 
primary safety and effectiveness analysis. The claim of trial success will be based upon the 
totality of the data.  The sensitivity analyses treating sites as random effects examine the impact 
of site heterogeneity on the primary endpoints.  
 
11.5.4 Handling of Missing Data 
The primary effectiveness analysis will use the ITT population and as such there is potential for 
subjects to have missing data. Any missing data in this analysis will be imputed using Bayesian 
multiple imputation method. This approach will enable the primary effectiveness analysis to be 
done on the full ITT population.  The subjects who discontinued the study due to device related 
reasons will be treated as primary effectiveness failures in the ITT population.  
 
In the adaptive design interim analyses and at the trial completion, the following longitudinal 
model is used to handle incomplete and missing data.  The posterior distribution of the 
effectiveness success rate is updated using multiply imputed data from each subject with 
incomplete data71.  The model is a piecewise exponential model, with different parameters for 
each treatment arm.  The following model is used for the time-to-failure during the effectiveness 
observation phase (13-52 weeks after procedure).  
 
The time-to-failure in treatment arm t is assumed piecewise exponential with three distinct 
intervals (from (0,2], (2,8], and (8,39] weeks).  The probability of a failure during each interval is 
exponentially distributed, with a different hazard rate.  The model is: 
 
f texp th t

, 
where 

 
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h t
a,1
0 t 2
a,2
2 t 8
a,3
8 t 39






. 
 
The exponential parameter in each interval is a function of the interval and the treatment arm 
(a=1 is control; a=2 is experimental).  The prior distribution for each exponential parameter is 
based on the data from the THERMOCOOL® Pivotal trial, on the THERMOCOOL® arm.  The 
following priors, down weighted by a factor of 5 (meaning the data from each subject in the 
historical study is weighed as 1/5 of a subject).  This downweighting is used to insure the 
prospective trial data for each arm is weighed more heavily.  The independent priors are (in the 
scale of weeks) 
 
a,1

~ Gamma 26 / 5,160.8 / 5

 
 
a,2

~ Gamma 3/ 5,416.8 / 5

, 
 
and 
 
a,3

~ Gamma 7 / 5,1652.4 / 5

. 
 
 
In each piece of the exponential function, the prior distribution is updated using the observed 
number of events and total exposure time from the data. The predictive distribution of each 
subject, and each prospective new subject, is calculated using this longitudinal modeling. From 
the gamma posterior distribution, 10,000 hazard rates were sampled. Based upon the 10,000 
triplets of hazard rates for all of the three pieces, the probability of effectiveness success and 
event-free rate at 12 month follow-up time will be calculated. No baseline covariates were used 
in the imputation model.  
 
As a sensitivity analysis at each interim analysis, including the early success analysis, the results 
for an 11-piece exponential model will be presented.  This model is very flexible, and will 
provide robustness to the 3-piece model assumptions and the prior distributions used.  The 11-
piece exponential is: 
 
The time-to-failure in treatment arm t is assumed piecewise exponential with eleven distinct 
intervals.  The probability of a failure during each interval is exponentially distributed, with a 
different hazard rate per interval.  The model is: 
 
f texp th t

, 
 
where 

 
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h t
a,1
0 t 2
a,2
2 t 4
a,3
4 t 8
a,4
8 t 12
a,5
12 t 16
a,6
16 t 20
a,7
20 t 24
a,8
24 t 28
a,9
28 t 32
a,10
32 t 36
a,11
36 t 39



















. 
 
The exponential parameter in each interval is a function of the interval and the treatment arm 
(a=1 is control; a=2 is experimental).  The prior distribution for each exponential parameter is 
assumed to be very weak.  The independent priors are (in the scale of weeks)  
 
a,j

~ Gamma 0.001,0.001

     for a=1,2; j=1,…,11. 
 
For the safety outcome there is no interim information available on subjects and so there is no 
longitudinal aspect for safety.  In order to multiply impute final data for the adverse event rate 
we simulate the probability of a successful (no primary adverse event) using independent 
Beta(1,1) distributions. 
 
Additional frequentist sensitivity analyses will be used to test the robustness of the primary 
effectiveness results with regards to missing data. They include but not limited to the following: 
 
1. Kaplan-Meier analysis: this analysis will include all subjects in the ITT population and 
missing data will be censored at their last observations. The analyses will be stratified by the 
two treatment groups as randomized. Non-inferiority testing will be performed using the 
survival probabilities of the two treatment groups at 12 months follow-up.   
 
2. The success rate at 6, 9 and 12-month will be presented for subjects in the ITT population 
treating the endpoint as a binary variable.  The subjects who discontinued the study due to 
device related reasons will be treated as primary effectiveness failures in the ITT population. 
Other subjects with missing effectiveness outcomes will be excluded from the analyses. The 
point estimate for each treatment arm and the one-sided 95% confidence interval around the 
point estimate will be presented. The point estimate around the treatment difference 
(nMARQ-TC) and the one-sided 95% confidence interval around the difference will also be 
presented.   

 
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3. Tipping-point analysis: to examine the sensitivity of conclusions to missing data. 
 
Tipping-point analysis will also be used as sensitivity analysis for the primary safety endpoint. 
 
11.5.5 Additional Analyses for Primary Effectiveness and Safety Endpoints 
Logistic regression analyses:  Multivariate logistic regression analyses will be performed to 
examine the impact of potential demographic and baseline characteristics covariates (e.g., age, 
gender, ethnicity, LA size, AF duration, medical history, etc.) on the primary outcomes. The 
outcome variables (i.e., primary effectiveness and safety outcomes) will be the dependent 
variables and the covariates will be treated as independent variables with treatment group forced 
in the model. Model selection methods (e.g., forward selection, etc.) will be applied to identify 
the best set of predictors for the outcomes.  Significant interaction effects between the covariates 
and treatment groups will also be examined. The identification of relevant predictors provides 
additional characterization and interpretation of the primary effectiveness and safety outcomes. 
These analyses will be performed in the PP population as treated.  
 
Learning Curve Analyses: To further characterize if there is a learning curve for the nMARQ™ 
catheter system, subset analyses only including and excluding the first 3, 5, 7, etc. subjects 
randomized to nMARQ will be performed. Logistic regression analysis may be performed to 
examine the association of ablation experience with the predicted success rate. 
 
AT Analysis of the Primary Effectiveness Endpoint: The primary effectiveness analyses will 
be repeated with the AT population. We acknowledge that no formal statistical hypothesis will 
be formulated for the secondary effectiveness analyses.  
 
Per-Protocol Analysis of the Primary Endpoints: The primary effectiveness and safety 
analyses will be repeated with the PP population. We acknowledge that no formal statistical 
hypothesis will be formulated for the secondary effectiveness analyses.  
 
Sensitivity Analyses of the Primary Effectiveness Endpoint: Any subjects with repeat 
ablations post-blanking period will be treated as primary effectiveness failures to test for the 
impact of the exemptions for extenuating circumstances preventing the hospital from scheduling 
a repeat ablation within the blanking period.   
 
Subgroup Analyses: In order to examine the impact of potentially important confounders on the 
relationship between the treatment effect and the primary effectiveness and safety endpoints, the 
following subgroup analyses will be performed:  
 
Gender 
 
Catheter used, crescent or circular, in the nMARQ (Test) Group 
 
Generator used in the nMARQ (Test) Group 
 
Outperforming sites versus the remaining sites if the sites are determined to be not 
poolable 
 
Type of oral anticoagulant used 
 
Activation of Power Reduction Adjustment (PRA) algorithm (if used) 

 
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11.6 
Adaptive Design Interim Analyses 
11.6.1 Adaptive Sample Size 
A Bayesian adaptive approach to sample size selection is used.  A minimum total sample size of 
250 and a maximum of 500 are considered.  A sample size interim look is made when 250 
subjects have been accrued.  If trial success with the current 250 is highly likely accrual will be 
stopped for expected success and all subjects will be followed through their full follow-up and a 
final analysis done when all subjects have completed their primary follow-up at 12 months. If 
trial success at the maximum sample size of 500 is unlikely then the trial will stop for futility.  If 
accrual continues, another sample size look is made every 50 subjects accrued, until accrual is 
stopped or the maximum randomized sample size of 500 is reached.  Trial success is defined as 
meeting both the primary efficacy and safety thresholds for success. 
11.6.2 Sample Size Interim Analyses 
Interim looks are made before accrual is stopped.  At these looks predictive probabilities of trial 
success (both efficacy and safety) for the current sample size and the maximum sample size are 
calculated.  All interim results available are used to calculate the predictive probability of trial 
success for the currently accrued subjects.  A longitudinal model (as described in Section 11.5.4) 
is used for the prediction of subjects with incomplete efficacy data.  A decision is made whether 
to stop at the current sample size or to continue accrual.  These sample size looks are made at 
sample sizes of 250 enrolled, and then every 50 subjects enrolled until accrual stops or the 
maximum sample size of 500 is reached.  Let PPn be the predictive probability of trial success 
for a trial with the current sample size of n and PPmax the predictive probability of trial success 
if the trial is carried out to the maximum sample size (500).  The following rules are used to 
guide the sample size selection.  These predictive probabilities are probabilities of winning on 
both the efficacy and safety endpoints. 
 
If PPn > Sn  then the sample size is considered sufficient for non-inferiority, and accrual stops. If 
PPmax < 0.05 then accrual is stopped for futility.  The cut-offs for expected success are: 
 
n 
Sn 
250, 300 
0.95 
300, 350, 400, 450 
0.90 
 
 
11.6.3 Early Success Claim Interim Analyses 
An interim analysis will be conducted 16 weeks after enrollment ends for early success.  If the 
predictive probability of final success is greater than 99%, then trial success will be declared 
early.  All subjects will have complete safety data and all subjects will be followed through their 
trial completion. 
 

 
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Trial simulations are carried out in order to evaluate the performance (operating) characteristics 
of the trial.  The simulations mimic the design exactly as described above.  The same models are 
simulated as will be used in the design.  The timing of the trial is also mimicked.  The efficacy 
period is after a 12-week blanking period, and lasts 39 weeks.  The safety endpoint is assumed 
known for all subjects in the trial (in practice there will be a handful that do not have complete 
safety data).  Simulation details are attached in Appendix A. 
11.7 
Secondary Effectiveness Endpoints Analyses 
11.7.1 Acute Effectiveness (PVI Confirmation) 
Acute Effectiveness is defined as PVI documented by confirmation of entrance block (i.e., 
complete PVI [CPVI]).  The number and percentage of subjects with CPVI will be presented for 
each treatment group and compared between the two groups using Fisher’s exact test. Further 
analyses to characterize the CPVI will be included in the SAP.  
 
11.7.2 One-Year Effectiveness  
For the secondary effectiveness endpoint of freedom from AF/AFL/AT off antiarrhythmic drug 
therapy as assessed from the end of the 3-month blanking period to 12 month following the 
ablation procedure, the following analyses will be performed in the ITT population:  
 
The success rate at 6, 9 and 12-month will be presented for subjects in the ITT population 
treating the endpoint as a binary variable.  The subjects who discontinued the study due to 
device related reasons will be treated as primary effectiveness failures in the ITT population. 
Other subjects with missing effectiveness outcomes will be excluded from the analyses. The 
point estimate for each treatment arm and the one-sided 95% confidence interval around the 
point estimate will be presented.  The point estimate around the treatment difference 
(nMARQ-TC) and the one-sided 95% confidence interval around the difference will also be 
presented. 
 
Kaplan-Meier analysis: this analysis will include all subjects in the ITT population and 
missing data will be censored at their last observations. The analyses will be stratified by the 
two treatment groups as randomized. The confidence intervals around the difference in 
survival probabilities of the two groups (nMARQ-TC) at 12 months follow-up will be 
presented.  
 
11.7.3 Long-Term Effectiveness  
For the long-term effectiveness endpoint of freedom from AF/AFL/AT off antiarrhythmic drug 
therapy as assessed from the end of the 3-month blanking period to 2 and 3 year following the 
ablation procedure, the following analyses will be performed in the ITT population:  
 
The success rate at 2 and 3 year follow-up will be presented for subjects in the ITT 
population treating the endpoint as a binary variable.  The subjects who discontinued the 
study due to device related reasons will be treated as primary effectiveness failures in the ITT 
population. Other subjects with missing effectiveness outcomes will be excluded from the 
analyses. The point estimate for each treatment arm and the one-sided 95% confidence 
interval around the point estimate will be presented.  The point estimate around the treatment 

 
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difference (nMARQ-TC) and the one-sided 95% confidence interval around the difference 
will also be presented. 
 
Kaplan-Meier analysis: this analysis will include all subjects in the ITT population and 
missing data will be censored at their last observations. The analyses will be stratified by the 
two treatment groups as randomized. The confidence intervals around the difference in 
survival probabilities of the two groups (nMARQ-TC) at 2 and 3 year follow-up will be 
presented.  
11.7.4 Secondary Effectiveness Endpoint Analyses 
We acknowledge that no formal statistical hypotheses will be formulated for the secondary 
effectiveness endpoints. We will not present the inferential statistics for these endpoints in the final 
device labeling. 
 
The secondary effectiveness endpoints analyses will be conducted in ITT population.  
11.8 
 Secondary Safety Endpoints Analyses  
The secondary safety analysis will be conducted based on the SP population. The Roll-in 
subjects will only be included in the secondary safety analyses and will be analyzed separately 
from subjects included in the Main Study. 
 
11.8.1 Incidence of AEs and SAEs during 12 Month Follow-up 
Serious AEs will be reported by three timeframes (ablation to ≤7 days, >7 to 30 days post 
ablation and >30 days). AEs and serious AEs will be evaluated by causality and severity and 
treatment groups using descriptive statistics. 
 
11.8.2  PV Stenosis at 3 Months Post Ablation  
Incidence of PV stenosis (<50%, 50-70%, ≥70% diameter reduction in diameter of pulmonary 
vein from baseline CT/MRA scan) will be reported as the rate of incidence for Test subjects 
undergoing an RF ablation procedure.  This rate of incidence as well as the 95% confidence 
intervals will be presented descriptively for test group.  
 
11.8.3 Incidence of AEs and SAEs during 2nd and 3rd Year Follow-up  
The AEs and SAEs during the 2nd and 3rd year follow-up period will be summarized by AE 
categories, causality, severity and treatment groups using descriptive statistics. 
11.9 
Analyses for Additional Endpoints 
Procedural Data 
Procedural data such as procedure duration, fluoroscopy duration, power, fluid 
delivery, output and balance will be summarized with descriptive statistics in each treatment 
group. These analyses will be conducted in the ITT population.  
 
% PVI isolation with the study device(s) by subject and by PV 

 
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 
Repeat Ablation Rate (For AF or Atrial Tachycardia) 
 
Cardiac Specific Hospitalization Rate  
 
Total Fluoroscopy Time 
 
Overall Procedure Time 
 
RF Ablation parameters per application (power, temperature, flow rate, duration, 
impedance rise/fall, mode of RF delivery (bipolar or unipolar) 
 
Device(s) utilized (per targeted PV) 
 
Duration of mapping time 
 
Duration of RF application time 
 
SNA Endpoints (subset of patients) 
Changes from baseline in NIH Stroke Score (4 point change in either direction constitutes 
significant change72), MoCA, mRS, other neurological findings and MRI (lesion diameter and 
volume) during follow up will be summarized using descriptive statistics by treatment groups 
and also by type of oral anticoagulant used.  
 
Incidences of abnormal neurological findings and cerebral microemboli pre- and post- ablation 
identified on MRI evaluations will be reported by treatment groups and also by type of oral 
anticoagulant used. 
 
The lesion diameter and volume of each cerebral embolus will be summarized by treatment 
groups, type of anticoagulant used, and overall for each follow-up visit.  The relationship 
between change in NIH Stroke Scale score from baseline, and ablation parameters (e.g. ACT, 
INR, procedural time, ablation time, fluid delivered via study catheter, maximum power and 
maximum temperature, bipolar and unipolar use, TC use for touch-up, etc.) and the incidence of 
ACE and lesion size post-ablation may also be examined if appropriate.  

 
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12.0  Administrative Responsibilities  
12.1 
Institutional Review Board (IRB; or Equivalent) Review 
The investigator will obtain written and dated approval from the responsible IRB (or equivalent) 
for the study protocol (or amendment[s]) and informed consent before enrolling study subjects.  
Biosense Webster and the IRB (or equivalent) 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.  
 
A stamped copy of the IRB (or equivalent) approval letter and Informed Consent Form addressed 
to the investigator must be submitted to Biosense Webster certifying study approval prior to 
subject enrollment.  Investigators are responsible for submitting and obtaining initial and 
continuing review (per local requirements) of the study by their IRB (or equivalent). 
 
The investigator may implement a deviation from the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior IRB/IEC approval. If such deviation occurs, the 
implemented deviation and the reasons for it should be submitted to Biosense Webster, the 
IRB/IEC, and the regulatory authority(ies) (if applicable), as soon as possible.  
12.2 
Informed Consent 
Informed consent is mandatory and must be obtained from all subjects prior to their participation 
in this study.   
There are two Patient Informed Consent Forms (ICF); one for the Main Study and one for the 
SNA. Biosense Webster and the reviewing IRB (or equivalent) must approve any modifications 
to a Patient ICF prior to subject enrollment in the respective phase of the study.   A Patient ICF 
may be translated as appropriate.  A copy of an approved Patient ICF must be maintained by 
each investigator in a designated study administrative file.   
 
 
The investigator or designated member of the research team will obtain written informed consent 
from the subject.  
Prior to obtaining informed consent: 
 
The investigator or designee should provide information in both oral and written form in a 
language and at a level of complexity understandable to the patient  
 
The background of the proposed study and the potential benefits and risks of the study 
should be explained to the subject  
 
Patients or his/her legal representative must be given ample time and opportunity to inquire 
about details of the study and all questions about the study should be answered to the 
satisfaction of the patient or the representative 

 
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 
The study ICF should be signed and personally dated by the patient, or his/her legal 
representative, and by the person who conducted the informed consent discussion (investigator 
or designee)  
 
The patient or legal representative must sign the ICF prior to undergoing study-specific 
exams or tests that fall outside of the standard of care. 
Patients should not be coerced, persuaded, or unduly influenced to participate or continue to 
participate in the study.   
The original signed ICF must go in the patient file and a signed copy of the ICF must be given to 
each subject. 
12.3 
Subject Confidentiality 
All information and data sent to Biosense Webster concerning subjects or their participation in 
this study will be considered confidential.  Only authorized Biosense Webster personnel or 
representatives, local government authorities, or the FDA acting in their official capacities will 
have access to these confidential files.  All data used in the analysis and reporting of this 
evaluation will be without identifiable reference to the subject. 
12.4 
Data Monitoring 
Case Report Forms (CRFs) 
Electronic CRFs will be used to collect all subject data during the study. 
   
Data Reporting 
The Investigator, or a designated individual, is responsible for recording all data from the trial on 
the eCRFs supplied by Biosense Webster. The Investigator or a delegated 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 eCRFs will be reviewed and monitored 
at the investigational site by Biosense Webster personnel or designee at regular intervals 
throughout the trial. 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. 
 
Data Review 
All eCRFs will be tracked at Biosense Webster. Missing or unclear data will be requested 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. Biosense Webster will be responsible for auditing the database and 
confirming the overall integrity of the data. 
12.5 
Labeling 
The study device labels have been prepared and approved in accordance with all necessary 
regulations. 

 
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12.6 
Management of Protocol Deviations  
The Investigator will not deviate from the protocol without prior notification to and approval 
from Biosense Webster, Inc. except for isolated instances where minor changes are made that 
will not increase the subject’s risk or affect the scientific integrity of the study.  In medical 
emergencies, prior approval for protocol deviations will not be required, but Biosense Webster 
clinical operations personnel must be notified within 5 days of the deviation.  
 

 
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13.0 Study Management 
13.1 
Study Timelines 
Study Duration:  The study is expected to last 7.5 years including the enrollment phase.  The 
enrollment phase is expected to take 4.5 years from the enrollment of the first subject, including 
the time in which enrollment was suspended.  The primary safety and effectiveness study 
endpoint assessments will be completed after 12 months follow up and this data is intended to be 
submitted in support of the PMA.   
13.2 
Study Advisory Committee (SAC)  
A Study Advisory Committee will be assigned to this study.  The responsibilities of the SAC 
include: 
 
Consultation on study design, protocol development, and investigator training 
 
Ensure investigators’ compliance with the protocol 
 
Emergent Issues: 
 
Advising the Sponsor of any unforeseen medical issues identified during the clinical 
study 
 
Addressing patient medical concerns or conditions raised by investigators as related to 
the use of the investigational device or ablation procedure 
 
Review of evidence results (assist in data interpretation) 
 
Publication Committee (strategy and consultation) 
 
Supporting the Sponsor’s efforts in conducting meetings with the regulatory agencies, as 
appropriate. 
13.3 
Interim Monitoring Committee 
Biosense Webster has implemented an Interim Monitoring Committee (IMC) for this study.  The 
IMC is an independent expert advisory group commissioned to evaluate and suggest 
modifications to the adaptive design analysis plan for the study while eliminating operational 
bias of the Sponsor.  The IMC and a separate unblinded programming team will have access to 
aggregated, unblinded study information. The IMC is responsible for conducting the interim 
Bayesian analyses, verifying that the algorithms are performing correctly, ensuring that the trial 
adaptations are being conducted as planned, and making recommendations to the senior 
management of the Sponsor, who are blinded to the study data as specified in the IMC charter.  
In order to preserve the blind and integrity of the data, teams of blinded and unblinded personnel 
have been formed for the study and their roles are responsibilities are defined in a Biosense 
Webster internal procedure document.  This document outlines the procedures for the creation of 
the raw dataset, the protection of unblinded data and data analyses, the review and QC of data 
and analyses, and the dissemination of unblinded data and analyses for IMC Meetings.  The IMC 
is not responsible for the adjudication and review of adverse events, that remains the role of the 
Global Safety Monitoring Committee. 

 
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The IMC members will be independent of the Sponsor and will consist of two statisticians, at 
least one of whom had Bayesian adaptive trial expertise, and one medical doctor (not 
participating in the study execution). 
 
The IMC Charter for the reMARQable study provides details on the committee members and 
procedural workflow. 
13.4 
Investigator Responsibilities 
Investigators at each participating clinical site will have the following responsibilities: 
 
Compliance with the study protocol 
 
Providing the Sponsor with signed, dated Investigator Agreement 
 
Maintaining an accurate and current Delegation of Responsibility log which identifies all 
individuals authorized to perform work for the study and assuring compliance by all site 
personnel with the provisions of the protocol 
 
Completing the appropriate training on the device and the study protocol prior to enrolling 
and treating subjects 
 
Maintaining accurate and current logs for the study such as: Screening Log 
 
Subject log, Device Accountability Log 
 
Obtain initial IRB (or equivalent) approval and annual review/approval thereafter for the 
study protocol and informed consent 
 
Supply the Sponsor with a current curriculum vitae and Financial Disclosure for each 
Investigator and research staff member 
 
Supply the Sponsor with a current medical license for each study investigator 
 
Obtain informed consent form and enroll patients 
 
Perform medical procedures 
 
Order all tests required by the study protocol 
 
Follow subjects until the end of the study protocol 
 
Accurately complete and sign eCRFs in a timely manner 
 
Maintaining relevant source documentation and allow Sponsor direct access to perform 
monitoring or auditing duties  
 
Maintain records and provide reports according to prevailing regulatory requirements 
 
Share all relevant study-related information with delegated study staff 
 
Inform the appropriate entities (e.g., Sponsor, IRB) in a timely manner regarding the 
occurrence of any AEs and/or product malfunctions. 
 
Making sufficient effort to maintain contact with all treated subjects who fail to comply with 
the follow-up requirements 
 
Maintaining study records per applicable regulations 
 
Preparing periodic IRB updates and final report, as required 

 
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13.5 
Sponsor Responsibilities 
The Sponsor (Biosense Webster, Inc.) will be responsible for the following: 
 
Conduct of pre-study site assessment and approval 
 
Preparation and modification (if applicable) of study documents including but not limited to 
the protocol, CRFs and informed consent  
 
Selection of appropriately qualified and trained individuals, including monitors, to conduct 
the study  
 
Conduct protocol and device training for investigators and research personnel 
 
Select members for the Global Safety Monitoring Committee (GSMC) 
 
Obtain signed study contracts from  investigators/hospitals, CROs and other involved parties 
 
Ship investigational devices to each site 
 
Monitor sites for the duration of the study 
 
Maintain study database 
 
Inform investigator of his/her responsibilities  
 
Submit and obtain approval for study from applicable regulatory agencies (e.g. FDA) 
 
Prepare and distribute (e.g., FDA, Investigator) reports summarizing status of the study no 
less than annually 
 
Update Report of Priors, IFU, and Risk Analyses 
 
Update investigators on safety issues, if needed 
 
Prepare and submit final submissions to applicable regulatory agencies 
 
Report to study investigators and regulatory agencies, as required 
 
Have AEs reviewed by the GSMC, as required 
 
Report atrio-esophageal fistulas (regardless of outcome) and deaths associated with atrio-
esophageal fistulas to the FDA within 10 days of awareness. 
13.6 
Training 
Clinical site personnel training will be the responsibility of the Sponsor.  Prior to commencement 
of the study, appropriate protocol and device training will be provided to each site that 
participates in the study.  Investigators selected to participate in the study will have prior 
experience with the NAVISTAR® THERMOCOOL® catheters and CARTO™3 system and will 
undergo device training in accordance with the documented study training plan which will 
include pre-clinical bench data, human clinical study data, didactics, and biophysics.  The 
research sites will be able to order investigational product only after a participating study 
physician has completed the required BWI training.   
 
To ensure uniform data collection and protocol compliance, the Sponsor will conduct a training 
session that will include reviewing the protocol, eCRF and data collection process, 
randomization process and adverse event reporting process.   

 
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13.7 
Sponsor Contact Information 
Kendra McInnis 
Associate Director, Clinical Research Biosense Webster, Inc. 
3333 Diamond Canyon Road  
Diamond Bar, CA  91765   
909-839-7284 
13.8 
Investigator Selection  
In order to mitigate the effect of the learning curve, sites experienced with using the CARTO™ 3 
System or CARTO™ XP System and THERMOCOOL® family of catheters will be selected for the 
study.   
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 Investigational 
Plan.   
13.9 
Initiation of the Investigation 
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 Investigational 
Plan.  Each site that participates in the study will be provided with the appropriate training prior 
to commencement of the study. 
13.10 Data Reporting and Monitoring  
The Investigator, or a designated individual, is responsible for recording all data from the trial on 
the eCRFs supplied by Biosense Webster. The Investigator or a delegated individual is required 
to electronically sign the eCRF on the appropriate pages to verify that s/he has reviewed and 
attests to the correctness of the recorded data. The Investigator and institution must permit 
inspection of the trial files and subject eCRFs by such representatives and/or responsible 
government agencies. 
Biosense Webster personnel or designee will review and monitor completed eCRFs at regular 
intervals throughout the trial.  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  
 
Confirmation that randomization procedures are being followed  
 
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 Regulatory Binder 
 
Verification of accuracy of all study logs such as the Delegation of Responsibility Log, etc.  

 
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 
Compliance with applicable regulations 
 
Identification and action to resolve any issues or problems with the study. 
Missing or unclear data will be requested 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. 
13.11 Termination of the Study 
At the termination of the investigation, each site will undergo a monitoring visit to conclude any 
outstanding issues, resolve all data discrepancies and make sure any outstanding eCRFs are 
submitted, reconcile disposition of all investigational devices, discuss requirements for the final 
report with the Investigator, and discuss any other items relevant to the conclusion of the study.  
This termination visit will be documented by a written report. 
 
Any incidence of unanticipated serious adverse device effect may result in early termination or 
suspension of the clinical study.  All enrolled subjects will continue to be followed per the study 
protocol requirements.  
13.12 Device Accountability 
All Investigational Study Devices will be labeled as “Investigational Device” and are only to be 
used for subjects enrolled in this clinical study within the US. In regions where the nMARQ 
system is approved, equivalent, commercially-marketed devices will be used. 
 
The Sponsor will keep records of all investigational devices shipped to 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 that each device was used in the study 
and disposition information regarding disposal or return to the Sponsor.  
 
The Device Accountability Log shall record the following information: 
 
Date of receipt 
 
Person who received  the devices 
 
Quantity received 
 
Catalog number for catheters 
 
Serial/lot numbers 
 
Date device was used (if applicable) 
 
Subject ID on whom device was used (if applicable) 
 
Date of investigational device return 
13.13 Device Returns 
All Study Catheters will be labeled as “Investigational device” and are only to be used for 
subjects enrolled in this clinical study.  
 

 
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All shipped Study 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 case report form (eCRF). All returned devices must be properly 
decontaminated per hospital policy and properly labeled with the following: 
 
• 
Subject identification number 
• 
Date of event 
• 
Return type ( defective, non-defective, or adverse event)  
 
All  tracking information must be retained  in the event the package has been lost and requires 
tracking. All investigational devices should be returned to:  
 
ATTN: Analysis Lab 103 
Biosense Webster, Inc.  
15715 Arrow Highway 
Irwindale, CA 91706 
USA 
13.14 Annual Requirements 
 
Annual, or as required by local site and/or country requirements, reports to the IRB/EC from 
the Principal Investigator 
 
Annual, or as required by local site and/or country requirements, review and approval from 
the IRB/EC 
13.15 Electronic CRFs 
Electronic Case Report Forms (eCRFs) have been developed to capture the information outlined 
in this protocol.  Data from these eCRFs will be used for the analysis of study outcomes. 
 
Passwords will be issued to appropriate personnel to allow only certain levels of access to the 
computer system insuring confidentiality and protection of study data   For example, only the 
data entry personnel or the Data Manager may enter and/or verify data.  All other personnel may 
only read the data on-screen or print out subject listings. 
13.16 Source Documentation 
Data entered on to the eCRFs will be taken from source documentation, such as hospital 
procedure reports, admission and discharge summaries, and other hospital or investigator 
office/clinic documents.  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 the 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 must be 

 
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printed and added to the subject’s paper file.  A print-out of an eCRF cannot be used as source 
documentation.  
Regulations require that investigators 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. 
 
Medical history/physical condition of the study subject before involvement in the study 
sufficient to verify protocol selection criteria (if not already present). 
 
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 was obtained. 
 
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). 
 
Reports on AEs and their resolution, including supporting documents such as discharge 
summaries, EP lab reports, ECGs, lab results. 
 
Notes regarding protocol-required medication and prescription medications taken during the 
study (including start and stop dates). 
 
Notes on subject’s condition upon completion of or withdrawal from the study. 
13.17 Subject Confidentiality/Record 
Representatives of the Sponsor have undergone training for HIPAA regulations and appropriate 
conduct for compliance with HIPAA.  For the duration of this study, all representatives of the 
Sponsor will comply with all HIPAA regulations regarding contact with subjects, their medical 
record information, copying of information, protection of the subject identities, and all other 
aspects of HIPAA.  Authorization for access to Protected Health Information by Sponsor 
personnel should be obtained as part of subject informed consent. 
Where applicable, local subject confidentiality and data protection requirements will be 
followed. 
13.18 Records 
Records to be maintained by the investigator include: 
 
Study protocol/Investigational Plan and all amendments 
 
Signed clinical study agreement 
 
IRB/EC approval letter, including approved ICF document 
 
IRB/EC membership list 
 
Correspondence relating to the study 
 
CVs and medical licenses (as applicable) for all investigator(s) 
 
Financial Disclosures 
 
Delegation of Responsibility log 

 
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 
Clinical Monitor/Site Visit sign-in log 
 
Subject enrollment log 
 
Device accountability log 
 
Training logs/certificates 
 
Lab certification and lab test normal ranges (pregnancy test) 
 
Reports (e.g., annual reports, final reports from investigator and Sponsor) 
 
The following records must be maintained for each subject enrolled in the study: 
 
Signed Patient ICF 
 
All completed CRFs and supporting source documentation 
 
Supporting documentation of any AEs and/or death  
13.19 Record Retention and Archiving 
After the completion/termination of this study, records and reports will remain on file per the 
FDA requirement (for a minimum of two (2) years) or local regulations, whichever is more 
stringent.  After the completion or termination of this study, records and reports may be 
discarded upon notification by Biosense Webster to the study site.  The principal investigator 
must contact Biosense Webster prior to destruction of any study-related records or reports to 
ensure adherence to appropriate record retention process. 
 
If the principal investigator plans to leave the study site, Biosense Webster should be contacted 
immediately so that arrangements can be made for transfer of records and management of any 
active study subjects. 
13.20 Reports 
Investigators are required to prepare and submit accurate and timely reports on this study to the 
governing IRB/EC and Biosense Webster. Serious AEs, UADEs, and AEs are to be reported to 
IRBs/ECs per individual IRB/EC requirements (UADEs no later than 10 business days). 
 
Table 13.20A: Responsibilities for Preparing and Submitting Reports 
Type of Report 
Prepared by 
Investigator For 
Time of Notification 
Case Report Forms, eCRFs 
Biosense Webster 
 In a timely manner 
Subject death 
Biosense Webster, 
IRB/EC 
Immediately upon awareness 
Subject withdrawal 
Biosense Webster 
Within 5 working days 
Withdrawal of Institutional 
Review Board approval 
Biosense Webster 
Within 5 working days 

 
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Annual progress report 
Biosense Webster, 
IRB/EC 
Submitted annually within 60 days of the IRB 
annual review date. 
Informed consent not obtained 
from subject 
Biosense Webster, 
IRB/EC 
Within 5 working days 
Deviation to protect the life or 
physical well-being of subject 
in an emergency 
Biosense Webster, 
IRB/EC 
Within 5 working days 
13.21 Investigator’s Annual and Final Report 
Annually (or as required by local site and/or country requirements) and upon completion or 
termination of the Biosense Webster study, the principal investigator must submit a written 
report to Biosense Webster and the Investigational Review Board/Ethics Committee. The final 
report should be submitted within 3 months of completion or termination of the trial. 
The investigator’s annual and final report may include: 
 
IDE number  
 
Device name  
 
Indications for use  
 
Brief summary of study progress in relation to investigational plan  
 
Number of subjects enrolled  
 
Number of devices received, used, and, in the final report, the final disposition of unused 
devices  
 
Brief summary of results and, in the final report, conclusions  
 
Summary of anticipated and unanticipated adverse device effects  
 
Description of any deviations from investigational plan  
 
Reprints of any articles published by the investigator in relation to the study  
13.22 Publication Policy 
Publication of study results will be coordinated between Biosense Webster, Inc. and the study 
author(s).  Authorship will be determined prior to development of any manuscript.   
13.23 Data Management 
The Sponsor will be responsible for all data management activities.  These activities include 
development of a database and utilizing validated database software into which all study data 
will be entered.  The Sponsor will be responsible for auditing all data to ensure the overall 
integrity of the database. 
 

 
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14.0 Regulatory / Ethical Considerations 
14.1 
Role of Sponsor 
As the study Sponsor of this clinical 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.  In this study, Biosense Webster has certain direct 
responsibilities.  Biosense Webster will ensure adherence to the regulations as outlined in the 
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. 
14.2 
General Duties (21 CFR 812. 40) 
Sponsor’s general duties consist of: 
 Submitting the IDE application to FDA, obtaining FDA and IRB approvals prior to 
shipping the devices, selecting investigators, ensuring proper clinical site monitoring and 
ensuring subject informed consent is obtained. 
 Where applicable, submitting or supporting submission of the application to the local 
regulatory authorities, and obtaining EC and regulatory body approval(s).  
 
Sponsor is responsible for providing quality data that satisfy federal regulations and informing 
proper authorities of serious unanticipated adverse events and deviations from the protocol.  The 
Sponsor will prepare written progress reports, a final report and coordinate with the core 
laboratories. 
14.3 
Selection of Investigators (21 CFR 812. 43) 
Sponsor 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. 
14.4 
Supplemental Applications (21 CFR 812. 335 [A] and [B]) 
As appropriate, Biosense Webster will submit changes in the Investigational Plan to the 
investigators to obtain IRB/EC re-approval. 
14.5 
Maintaining Records (21 CFR 812. 140 [B]) 
Biosense Webster will maintain copies of correspondence, data, shipment of devices, adverse 
device effects and other records related to the clinical trial. Biosense Webster will maintain 
records related to the signed Investigator Agreements. 

 
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14.6 
Submitting Reports (21 CFR 812. 150 [B]) 
Biosense Webster will submit any required regulatory reports identified in this section of the 
regulation.  This includes unanticipated adverse device effects, withdrawal of IRB or FDA 
approval, current investigators list, annual progress reports, recall information, final reports and 
protocol deviations. 
 
Investigational sites will contact Biosense Webster immediately upon awareness of any 
unanticipated adverse device effects, and within 5 days of withdrawal of IRB or protocol 
violations.  Biosense Webster will also prepare an annual progress report and a final report for 
the study. 
 
This clinical study will be conducted under applicable regulatory requirements and good clinical 
practice (GCP) guidelines including but not limited to: 
 
ISO 14155: 2011 (Clinical Investigation of Medical Devices for Human Subjects) 
 
Declaration of Helsinki 
 
ICH E6 Good Clinical Practice 
 
Medical Device Directive 93/42/EC 
 
21 CFR 812 (Investigational Device Exemptions)  
 
21 CFR 803 (Medical Device Reporting)  

 
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15. Kawabata-Yoshihara LA, Bensenor IM, Kawabata VS, Menezes PR, Scazufca M, Lotufo PA. Prevalence 
of electrocardiographic findings in elderly individuals: the Sao Paulo aging & health study. Arq Bras 
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29. Jazayeri MR, Hempe SL, Sra JS, et al. Selective transcatheter ablation of the fast and slow pathways using 
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24, 2010. 

 
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43. Gaita F, Caponi D, Pianelli M, Scaglione M, Toso E, Cesarani F, et al. Radiofrequency catheter ablation of 
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51. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of 
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53. Jaïs P, Hocini M, Hsu L, Sanders P, Scavee C, et al. Technique and Results of Linear Ablation at the Mitral 
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54. Elayi CS, Tamer S. Fahmy TS, Wazni OM, Patel D, Saliba W, Natale A. Left superior vena cava isolation 
in patients undergoing pulmonary vein antrum isolation: Impact on atrial fibrillation recurrence. Heart 
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55. Saad EB, Rossillo A, Saad CP, et al. Pulmonary vein stenosis after radiofrequency ablation of atrial 
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56. Sacher F, Monahan KH, Thomas SP, et al. Phrenic nerve injury after atrial fibrillation catheter ablation: 
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