Conditions: Atrial Fibrillation
Keywords: Atrial Fibrillation Arrhythmias, Cardiac Heart Diseases Cardiovascular Diseases Pathologic Processes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 255
Healthy volunteers: no

Brief summary:
The objective of this study is to determine whether early radiofrequency (RF) ablation treatment, using the CARTO® 3 or CARTO® XP System, and THERMOCOOL® Catheter Family (including THERMOCOOL® SF or THERMOCOOL® SMARTTOUCH™) in subjects with paroxysmal atrial fibrillation (PAF), delays progression of atrial fibrillation (AF) compared with drug therapy (either rate or rhythm control) using current AF management guidelines.

Detailed description:
Eligible PAF subjects with recurrent AF for 2 years who have failed no more than 2 prescribed drugs (with either anti-arrhythmic or rate control drug) are randomized into one of two study arms (catheter ablation or drug therapy).

Arms:
arm 1: Radiofrequency catheter ablation treatment in subjects with Paroxysmal Atrial Fibrillation (PAF) arm 2: Drug therapy (either rate or rhythm control) using current AF management guidelines

Interventions: intervention 1: Catheter Ablation intervention 2: Drug Treatment
Intervention descriptions: intervention 1: Treat subjects with Paroxysmal Atrial Fibrillation (PAF) intervention 2: Drug therapy (either rate or rhythm control): Class I or class III, or AV nodal blocking agents such as beta blockers and calcium channel blockers in accordance with current atrial fibrillation management guidelines.

Protocol document:
Prot_001.pdf: 
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ATrial FibrillaTion ProgrESsion Trial 
(ATTEST Trial) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: 
BIOSENSE WEBSTER, INC. 
 
3333 Diamond Canyon Road 
 
Diamond Bar, CA 91765 
 
Version: 
3.0, April 9th 2013 
 
Protocol number: 
144 
 
 
 
 


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1.0 Protocol Agreement Form 
 
 
Study Title:  Atrial Fibrillation Progression Trial (ATTEST) 
 
I, the undersigned, have read and understand this clinical study, including the appendices.  I 
will conduct the clinical study in strict compliance with the protocol and in accordance with 
appropriate in-country ethical and regulatory considerations.  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 information supplied by Biosense Webster, Inc. in confidence and 
when information regarding this study is presented to an institutional review board (or 
equivalent; e.g., ethics committee [EC] or ethics board [EB]), it will include information 
regarding the confidential nature of all study-related material.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
Name (Print) 
 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 


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2.0 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 
Whereas, the Clinical Study is sponsored by Biosense Webster Inc., Johnson and Johnson 
Medical NV/SA with registered offices at Diegem, has been duly appointed by the Sponsor to 
conduct the Clinical Study on its behalf. 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Emergency Safety Contact: 
 
 
 
Johnson & Johnson Medical N.V. 
Biosense Webster 
Leonardo Da Vincilaan 15 
1831 Diegem 
Belgium 
Tel +32 (0) 2 746 3434 
Fax +32 (0) 2 746 3404 
clinical@its.jnj.com 
attest@its.jnj.com 
 
 
 
 
 


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Table of Contents 
 
1.0 Protocol Agreement Form ............................................................................................. 2 
2.0 Contact Details ................................................................................................................ 3 
3.0 Protocol Summary .......................................................................................................... 7 
Study Inclusion Criteria .................................................................................................................... 8 
Study Exclusion Criteria ................................................................................................................... 8 
Schedule of Examinations ................................................................................................................. 9 
4.0 List of Acronyms/Abbreviations and Study Terms/Definitions ............................... 10 
5.0 Introduction................................................................................................................... 11 
5.1 
Background ........................................................................................................................ 11 
5.2 
Rationale ............................................................................................................................ 13 
5.3 
Device Description ............................................................................................................. 14 
5.4 
Risk Analysis ...................................................................................................................... 15 
6.0 Study Hypothesis .......................................................................................................... 15 
7.0 Objective ........................................................................................................................ 15 
8.0 Investigational Plan ...................................................................................................... 16 
8.1 
Study Design ...................................................................................................................... 16 
8.2 
Treatment Groups ............................................................................................................. 16 
8.3 
Number of Centers ............................................................................................................ 16 
8.4 
Study Duration, Completion, and Termination .............................................................. 16 
9.0 Subject Selection and Disposition ................................................................................ 17 
9.1 
Recruitment and Screening Procedures .......................................................................... 17 
9.2 
Informed Consent and Enrolment Procedures ............................................................... 17 
9.3 
Study Inclusion Criteria .................................................................................................... 17 
9.4 
Study Exclusion Criteria ................................................................................................... 18 
9.5 
Subject Disposition ............................................................................................................ 19 
9.6 
Subject Withdrawal .......................................................................................................... 19 
10.0 Study Endpoints ............................................................................................................ 20 
10.1 
Primary Endpoint .............................................................................................................. 20 
10.2 
Secondary Endpoints ........................................................................................................ 20 
10.3 
Definition of Effectiveness Success ................................................................................... 21 
11.0 Treatment Description ................................................................................................. 21 
11.1 
Ablation Procedure and Medication Management Guidelines ..................................... 21 
11.2 
Schedule of Examinations ................................................................................................. 21 
11.2.1 
Study Visits and Phone Follow-up ............................................................................. 21 
11.2.2 
Unscheduled Visits .................................................................................................... 23 
11.3 
Medication Management .................................................................................................. 24 
11.4 
Management of Arrhythmia Recurrence During Follow-up ......................................... 24 


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11.4.1 
Arrhythmia Recurrence:  Test Group ......................................................................... 24 
11.4.2 
Arrhythmia Recurrence:  Control Group ................................................................... 24 
11.4.3 
Cardioversion for Arrhythmia Recurrence ................................................................. 25 
11.4.4 
Cardioversion as part of a (re-)ablation procedure ..................................................... 25 
11.5 
Core Laboratory for Evaluation Tests ............................................................................ 25 
12.0 Adverse Events .............................................................................................................. 26 
12.1 
Definitions / Classifications ............................................................................................... 26 
12.1.1 
Medical Devices ........................................................................................................ 26 
12.1.2 
Medicines ................................................................................................................... 27 
12.2 
Event categorization: ........................................................................................................ 28 
12.3 
Causality ............................................................................................................................. 28 
12.4 
Intensity / Severity ............................................................................................................. 29 
12.5 
Outcome ............................................................................................................................. 30 
12.6 
Adverse Event Reporting and Documentation Requirements ....................................... 30 
12.6.1 
Adverse Event Reporting Requirements .................................................................... 30 
12.6.2 
Adverse Event Documentation .................................................................................. 32 
12.6.3 
Serious Adverse Event Documentation ..................................................................... 32 
13.0 Statistical Analysis ........................................................................................................ 33 
13.1 
Clinical Study Objective ................................................................................................... 33 
13.2 
Primary Endpoint .............................................................................................................. 33 
13.3 
Overview of Statistical Methodology ............................................................................... 33 
13.4 
Sample Size and Power Calculation ................................................................................. 33 
13.5 
Randomization ................................................................................................................... 34 
13.6 
Analysis Populations ......................................................................................................... 34 
13.7 
Subject Disposition and Protocol Deviations .................................................................. 35 
13.8 
Demographic and Baseline Characteristics ..................................................................... 35 
13.9 
Primary Statistical Analyses ............................................................................................. 35 
13.9.1 
Primary Effectiveness Analysis ................................................................................. 35 
13.9.2 
Interim Analyses ........................................................................................................ 36 
13.10 
Handling of Missing Data ................................................................................................. 38 
13.11 
Secondary Statistical Analyses of Primary Effectiveness Endpoint .............................. 38 
13.11.1 
Per-Protocol Analysis ................................................................................................ 38 
13.11.2 
Subgroup Analyses .................................................................................................... 38 
13.12 
Secondary Effectiveness Endpoints Analyses ................................................................. 39 
13.12.1 
Rate and Time to Persistent AF/AT at 1 year, 2 and 3 years follow-up by number of 
ablations 
39 
13.12.2 
Number of Repeat Ablations and New AAD Drugs .................................................. 39 
13.12.3 
Rhythm Throughout 3 Years Follow-up .................................................................... 39 
13.12.4 
Factors Associated with AF Disease Progression ...................................................... 40 
13.13 
Secondary Safety Endpoints Analysis .............................................................................. 40 
13.14 
Secondary Health Economic Endpoint Analyses ............................................................ 41 
13.14.1 
Health Care Utilization .............................................................................................. 41 
13.14.2 
Quality of Life ........................................................................................................... 41 
13.15 
Site Heterogeneity .............................................................................................................. 41 
13.16 
Summary of Secondary Endpoints .................................................................................. 41 


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14.0 Administrative Responsibilities ................................................................................... 42 
14.1 
Ethics Committee (EC) / Ethics Board (EB) Information ............................................. 42 
14.2 
Informed Consent .............................................................................................................. 43 
14.3 
Subject Confidentiality ..................................................................................................... 43 
14.4 
Monitoring the Study ........................................................................................................ 44 
14.5 
Management of Protocol Amendments ........................................................................... 44 
14.6 
Management of Protocol Deviations ................................................................................ 44 
14.7 
Data Management ............................................................................................................. 44 
14.7.1 
Data Collection .......................................................................................................... 45 
14.7.2 
Data Reporting ........................................................................................................... 45 
14.7.3 
Source Documentation ............................................................................................... 45 
14.7.4 
Data Verification and Review .................................................................................... 45 
14.7.5 
Final Data Analyses ................................................................................................... 46 
14.7.6 
Confidentiality and Protection of Study Files ............................................................ 46 
14.8 
Publication Policy .............................................................................................................. 46 
15.0 Study Management ....................................................................................................... 46 
15.1 
Investigator Selection ........................................................................................................ 46 
15.2 
Investigator Training ........................................................................................................ 46 
15.3 
Investigator Responsibilities ............................................................................................. 46 
15.4 
Sponsor Responsibilities ................................................................................................... 47 
15.5 
Clinical Endpoint Committee (CEC) ............................................................................... 47 
15.6 
Data Safety Monitoring Committee (DSMC) .................................................................. 47 
16.0 Regulatory / Ethical Considerations ........................................................................... 47 
16.1 
Basic Principles and Standards ........................................................................................ 47 
16.2 
Record Retention and Archiving ...................................................................................... 48 
17.0 References ...................................................................................................................... 49 
Appendices ............................................................................................................................. 55 
Appendix A: Description and Analysis of Risks ........................................................................... 55 
Appendix B: Guidelines and Restrictions for the ATTEST Protocol Regarding Cross-over 
from the Drug (Control) Group ..................................................................................................... 58 
Appendix C: Justification for AF Disease Progression Rate Estimates ...................................... 60 
Appendix D: Safety Provisions - Drug Regulations ...................................................................... 62 
Appendix E: Informed Consent Form Template .......................................................................... 64 
 
 
 


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3.0 
Protocol Summary 
 
Title: 
 
 
Atrial Fibrillation Progression Trial (ATTEST) 
 
Design: 
This is a prospective, multi-center, randomized (1:1), controlled, two-arm, 
open-label, clinical study. 
 
Objective: 
The objective of this study is to determine whether in subjects with 
Paroxysmal AF (PAF), early RF ablation treatment using the 
THERMOCOOL® Catheter Family in conjunction with the CARTO® 3, 
CARTO® XP or CARTO® RMT System,  delays progression of AF compared 
with drug therapy (either rate or rhythm control) using current AF 
management guidelines.1-4 
 
Enrollment: 
Up to 330 subjects will be enrolled in this study. 
 
Clinical Sites: 
Up to 50 sites primarily in Europe, and/or Asia and/or North America. 
 
Subject Population: 
PAF patients with recurrent AF for at least 2 years who have failed at least 1 
but no more than 2 prescribed drugs (either anti-arrhythmic or rate control 
drug) 
 
Eligible subjects who sign the study informed consent form will be 
randomized into one of two study arms: 
 
PVI (Test) Group:  
RF ablation to achieve pulmonary vein isolation (PVI) using the 
THERMOCOOL® Catheter Family in conjunction with the CARTO
 ® 3, 
CARTO® XP or CARTO® RMT System  
Drug Therapy  
(Control) Group:   
AAD therapy (either rate or rhythm control) using current AF management 
guidelines1-4 
Primary Endpoint: 
Time to persistent AF/AT (excluding isthmus-dependent atrial flutter) at 3 
years. Persistent AF/AT is defined as AF/AT lasting longer than 7 
consecutive days or requiring termination by cardioversion after 48 hours.a 
 
Secondary Endpoints: 
Rate to persistent AF/AT; Number of repeat ablations and new AAD drugs; 
Rhythm (% subjects in SR, % subjects with recurrent AF); Pre-existing or 
new onset/worsening condition(s) that may be associated with AF 
progression; Catheter-related complications (ablation), adverse drug 
reactions (AAD); Health care utilization and Quality of Life. 
 
Study Duration: 
4.5 years (18 months enrollment period and 3 years follow-up per subject) 
                                                    
a  Unnecessary Cardioversion < 7 days should be discouraged, but within ethical bounds.  If the 
investigator believes the subject’s AF symptoms are sufficiently severe to warrant cardioversion, 
he/she should proceed, regardless of timing.  AF symptoms sufficiently severe to warrant 
cardioversion are angina, shortness of breath and/or systolic blood pressure < 90 mmHg related to 
AF. 
 


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Study Inclusion Criteria 
1. 
Patients with recurrent paroxysmal AF for at least 2 years, with ≥ 2 episodes over the last 
6 months;  
2. 
HATCH Score of at least ≥1 and ≤ 4.b 
3. 
Eligible for catheter ablation and for anti-arrhythmic or rate control medications, after 
having failed at least 1 but no more than 2 prescribed drugs (either anti-arrhythmic or rate 
control drug). 
4. 
Age 60 years or older.  
5. 
LA diameter ≤ 55mm by TTE. 
6. 
LV ejection fraction ≥ 50% when in sinus rhythm or LV ejection fraction ≥ 35% when in 
AF. 
NOTE: For patients entering the study in AF with an ejection fraction ≥ 35% and < 50%; the 
ejection fraction should be re-checked when in sinus rhythm. In case the ejection fraction is  
> 50% the subject can continue in the study. 
7. 
Patient signed the Informed Consent Form and is able and willing to comply with 
protocol requirements, including all baseline and follow- up testing. 
 
Study Exclusion Criteria 
1. 
Patients awaiting cardiac transplantation or other cardiac surgery. 
2. 
Acute illness (ongoing) or active systemic infection or sepsis which in the opinion of the 
investigator, may adversely affect the safety and/or effectiveness of the participant of the 
study. 
3. 
Reversible causes of AF, e.g. but not limited to thyroid disorders, acute alcohol 
intoxication, recent major surgical procedures or trauma,… 
4. 
Recent cardiac events including MI, PCI, or valve or bypass surgery in the preceding 3 
months. 
5. 
Heart failure decompensation. 
6. 
Previously diagnosed with persistent/permanent AF/AT 
7. 
Previously required cardioversion >48 hours after onset of AF/AT  
8. 
Subject having previous TIA or stroke (cerebrovascular accident) one year prior to patient 
enrolment and/or no sufficient recovery. 
9. 
Pulmonary embolism or recent atrial embolism/thrombosis. 
10. Hypertrophic obstructive cardiomyopathy. 
11. Class IV angina or Class IV CHF (including past or planned heart transplantation). 
12. Mandated anti-arrhythmic drug therapy for disease conditions other than AF. 
13. Heritable arrhythmias or increased risk for torsade de pointes with class I or III Drugs. 
14. Prior LA catheter ablation with the intention of treating AF; prior surgical interventions 
for AF such as the MAZE procedure. 
15. Prior AV nodal ablation. 
16. Patients presenting contra-indications for the study catheter(s), as indicated in the 
                                                    
b  Hypertension (+1); Age >75 years (+1); previous TIA or Stroke (+2); COPD (+1); Heart failure - 
including systolic or diastolic heart failure (+2). 
 


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respective Instructions For Use. 
17. Contraindication to warfarin, other anticoagulation therapy, or all anti-platelet 
medications. 
18. Medical conditions limiting expected survival to < 3 years. 
19. Concurrent participation in any other clinical study. 
20. Prior history of non-adherence to prescribed drug regimens. 
21. Women of child bearing potential whom are pregnant, lactating, or planning to become 
pregnant during the course of the trial 
 
NOTE: Prior ablation of the cavo-tricuspid isthmus is not a reason to exclude, if the patient 
develops subsequent recurrent atrial fibrillation. 
 
NOTE: For patients randomized to the PVI group (Test Group), a Transesophageal 
Echocardiography (TEE) should be performed (as per standard of care), within 48 hours pre-
procedure, to exclude atrial thrombus or other structural contraindications for an ablation 
procedure. 
 
Schedule of Examinations 
 
Table 1.  Summary of Subject Assessments:   
Assessments 
BL 
D08 
M3 
D76-
104 
M6 
D166-
210 
M9 
D240
-300 
Y1 
D330
-420 
M18 
D480
-600 
Y2 
D630
-809 
M30 
D810-
989 
Y3 
D990-
1170 
UNS 
Clinic visit 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Phone follow-up1 
 
 
 
X 
 
X 
 
X 
 
 
Patient Information and 
Consent  
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
HATCH score 
X 
X 
X 
 
X 
 
X 
 
X 
X 
ECG2 
X 
X 
X 
 
X 
 
X 
 
X 
X 
TTM3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TEE4 
X 
 
 
 
 
 
 
 
 
 
TTE5 
X 
 
 
 
X 
 
X 
 
X 
 
QoL (EQ-5D, AFEQT)6 
X 
X 
X 
 
X 
 
X 
 
X 
 
Health status7 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Cardiac medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardioversion / re-
ablation documented 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1. Phone follow-up calls include check for AEs, changes in cardiac medication and TTM. 
2. To be collected if completed as standard of care. 
3. Dispensation of TTM device at Month 3.  Additional details/instructions regarding TTM monitoring are 
provided below. 
4. Only for patients randomized to PVI, within 48 hours pre-procedure. 
5. TTE to be performed within 30 days pre-treatment. For the Test Group, TTE must be repeated prior to discharge 
6. AFEQT questionnaire is only to be completed by a subpopulation due to limited validated translations 
7. LA Size, blood pressure, NYHA Functional Classification of heart disease, Diabetes, lipid profile, renal function 
and dementia. 
8. Day 0 Test Group (PVI)= Index ablation procedure and Day 0 Control Group (AAD) = Randomization 
 
 
 
 
 
 


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4.0 
List of Acronyms/Abbreviations and Study Terms/Definitions 
 
Acronym / Abbreviation 
Expanded Term 
AAD 
Antiarrhythmic Drug 
ACC/AHA/ESC 
American College of Cardiology/American Heart 
Association/European Society of Cardiology 
ADE 
Adverse Device Effect 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AFEQT 
Atrial Fibrillation Effect on QualiTy-of-life 
ARDS 
Acute Respiratory Distress Syndrome 
AT 
Atrial Tachycardia 
BB 
Beta Blocker 
CCB 
Calcium Channel Blocker 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
COPD 
Chronic Obstructive Pulmonary Disease 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Form  
CVA 
Cerebrovascular Accident or Stroke 
EB 
Ethics Board  
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMEA 
Europe, Middle East and Africa 
EP 
Electrophysiology 
FDA 
Food and Drug Administration 
Fr 
French 
GCP 
Good Clinical Practices 
HM 
Holter Monitoring 
ICD 
Implantable Cardioverter Defibrillator 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFU 
Instruction For Use 
ILR 
Implantable Loop Recorder 
ISO 
International Organization for Standardization 
LA 
Left Atrium 
LV 
Left Ventricle 
MDR 
Medical Device Reporting 
MDV 
Medical Device Vigilance 
MI 
Myocardial Infarction 
PAF 
Paroxysmal Atrial Fibrillation 
PCI 
Percutaneous Coronary Intervention 
PI 
Principal Investigator 
PV 
Pulmonary Vein 
PVI  
Pulmonary Vein Isolation 
QoL 
Quality Of Life 
RA 
Right Atrium 
RF  
Radiofrequency  
RSPV 
Right Superior Pulmonary Vein 
RV 
Right Ventricle 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SR 
Sinus Rhythm 
TEE 
Transesophageal Echocardiography 
TIA 
Transient Ischemic Attack 
TTE 
Transthoracic Echocardiography 
TTM 
Transtelephonic Monitoring 
UADE 
Unanticipated Adverse Device Effect 
 


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Term 
Study Definition 
Symptomatic AF 
 
Symptom(s) that is/are exhibited by the subject, which make 
him/her seek medical attention, and are concurrent with a 
documented episode (i.e., by ILR [implantable loop recorder], 
ECG [electrocardiogram], TTM [transtelephonic monitoring], 
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. 
Paroxysmal AF 
Recurrent AF that terminates spontaneously within 7 days. 
Persistent AF/AT 
AF/AT which is sustained beyond seven days; or, lasting 
more than 48 hours and less than seven days but necessitating 
pharmacologic or electrical cardioversion. 
Long-standing persistent AF/AT 
Continuous AF of greater than one-year duration. 
AF episode 
An episode of AF > 30 seconds.  Atrial fibrillation and atrial 
flutter (including atypical flutter) are considered episodes of 
AF.  Atrial flutter alone is not considered an episode of AF. 
Complete PVI 
Entrance block confirmed with or without the use of a focal 
catheter. 
Procedure time 
Time from introduction of first catheter to withdrawal of last 
catheter (minutes). 
 
5.0 Introduction 
 
5.1 
Background  
 
Atrial fibrillation is the most common cardiac arrhythmia, with prevalence ranging from 0.1% 
in adults under 55 to 9% in adults over 80 years old.5-7  Patients with atrial fibrillation (AF) are 
at increased risk of stroke, cardiac dysfunction, and death, and may also experience an 
impaired quality of life due to AF symptoms.8-10  Frequency and duration of AF episodes vary, 
with ACC/AHA/ESC guidelines dividing the condition into paroxysmal, persistent, and 
permanent types.1  Transition from one form to another occurs, with episodes generally 
increasing in frequency and eventually failing to respond to attempts to restore sinus rhythm.  
Rates of disease progression are not well established, especially in regard to updated 
classification schemes and in the context of current AF management.11  
 
Rates of progression (from paroxysmal AF to more frequent and intractable forms) of up to 
30% at 5 years have been reported, with annual risk estimates generally 3-6%.12-15 In the first 
year of observation, rates of progression of 8-15% have been reported for paroxysmal AF.14, 
16, 17  Two studies with follow-up of 8 and 14 years12,13 reported well over half of all 
paroxysmal AF patients eventually progressing to persistent or permanent AF.  In contrast, a 
Mayo Clinic study of lone AF (no hypertension or structural heart disease, diagnosed before 
age 60) found only 31% of patients progressing over 25 years of follow-up, with mortality 
rates similar to age- and gender- matched population controls.18  
 
Variation in reported rates of AF progression is certainly due in part to the varying definitions 
used and in the baseline populations studied.  The most common definitions in recent 
published studies are consistent with recommended terminology of paroxysmal, persistent, 
and permanent AF from ACC/AHA/ESC guidelines.1  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 which cardioversion has failed 
or is no longer attempted. More recently, the HRS/EHRA/ECAS Consensus Statement 
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AF defined as “continuous AF of greater than 1 year duration”.  Additionally, terms such as 
"intermittent," "constant," "long-lasting," "sustained" and "chronic" have also been used, 
particularly in studies conducted prior to 2000.19-21  Progression of paroxysmal AF from 
baseline is often captured as development of either persistent or permanent AF.  These 
patients are not always described as moving from paroxysmal to persistent then to permanent 
AF.  In several studies, progression to permanent AF is reported as an endpoint for patients 
experiencing paroxysmal AF at baseline.22-25  Despite use of standard AF definitions, there is 
some element of subjectivity related to treatment decisions impacting the assigned "type" of 
AF.  For permanent AF in particular, a key component of most definitions is no further 
attempts to restore sinus rhythm, a treatment decision that is clearly subject to influence by 
practice patterns, individual physician and patient preferences, and even health care system 
factors.  A community-based study in Spain illustrates this problem.26  The authors defined 
patients as having "permanent AF" if their general practitioner managed them for rate control 
only.  The mean age of the patients in this study was 75 years, and high rates of both 
permanent AF at baseline (59% of 798 patients), and of progression (6.6% in the first 7 
months of follow-up) were observed.  Likewise, in the RECORDAF registry, very high rates 
of progression to permanent AF were reported in patients being treated with a rate control 
strategy (vs. rhythm control).27  The authors note that this distinction is "partly semantic", and 
related to a perception on the part of physicians that choosing a rate control strategy means 
accepting arrhythmia, contributing to the categorization of these patients as having 
"permanent" AF. 
 
Variables such as patient age and the presence of comorbidites must also be considered when 
determining rates of AF progression.  Age is the most well-studied and consistently 
significant factor associated with AF progression.  Two studies quantifying the increased risk 
of AF progression for each decade of age found 40% and 82% increases in risk, 
respectively.14, 28 Left atrial (LA) size/volume and hypertension have been frequently studied, 
with LA volume somewhat more likely to be significant in univariate analyses but not 
significant in predictive multivariate models.  A study from Japan focused on LA wall 
thickness as a marker of structural remodeling; the authors suggested it to be a stronger 
predictor of AF progression than LA volume in their cohort of patients.29  Valvular disease 
and heart failure were each reported as significant in 4 studies using multivariate models.  
Valvular disease13,14, 16, 23, 30, 31 (univariate or multivariate analyses) and heart failure11, 14, 16, 19, 
32 have also been reported as linked to AF progression.  In one study, a composite score 
(HATCH score), which incorporates hypertension (1 point), age >75 years (1 point), 
stroke/TIA (2 points), COPD (1 point), and heart failure (2 points), was found to be strongly 
predictive of AF progression; patients with a moderate to high HATCH score (2-7 points) 
faced a 25-40% annual risk of AF progression, as compared to below 10% for patients 
scoring 0 or 1.16 
In another AF study,  the HATCH score was not found to be predictive of AF progression 
among patients treated by catheter ablation.33 
 
The predictive power of patient age seems sensible in the context of AF as a self-perpetuating 
arrhythmia with interdependent mechanisms.34  Animal studies of atrial remodeling have 
proposed that "AF begets AF."  Experimental induction of sustained AF in dogs and in goats 
support this model.35, 36  Changes to atrial architecture (fibrotic disorganization and increased 
atrial size) have also been documented in these animal models.37  With animal models 
supporting the concept that “AF begets AF”, similar progression, though not well-studied, is 
thought to occur in humans, which may warrant treatment (either with AADs or catheter 
ablation) to delay or prevent such progression and/or changes.    
 
Though catheter-based PVI has been developed as a treatment for patients with AF, whether 
this procedure prevents or delays progression towards permanent AF has not been well-


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studied in patients with PAF.  Comparative data on AF progression after catheter ablation vs. 
no ablation are limited.   
 
Three randomized trials of AADs versus catheter ablation, by Santinelli, et al Wazni, et al 
and Pappone, et al, reported disease progression,38-40 however, disease progression was not a 
primary or secondary endpoint in these studies.  In the Santinelli study, AF rates were low 
and disease progression did not differ significantly between assigned treatment groups.  In the 
Wazni study, 3 patients in the AAD group developed chronic AF, and there was no mention 
of AF progression in the RFA group.  The definition of chronic AF and the timing of these 
events was not clear (during or at some unspecified time after the 1-year study follow-
up).  Rates of AF progression were not analyzed between groups; therefore, no level of 
significance is reported.  In the Pappone study, the primary endpoint was freedom from AF 
and atrial tachycardia (AT), irrespective of crossover, 4 years after randomization; however, 
rates of AF progression were also reported for both groups.  Among AADs patients, 19 
progressed to persistent AF before crossover, after a median follow-up of 32 months (min-
max, 25-47).  Among RFA patients, persistent AF developed just in one patient with previous 
myocardial infarction, hypertension, diabetes mellitus and left atrial enlargement (59 mm), 
which, at the time of progression, further increased to 65 mm.  Evidence regarding rates of 
disease progression from high-quality sources (randomized, controlled trials) is limited. 
Available data suggests radiofrequency catheter ablation may delay or possibly prevent AF 
progression, compared to medical therapy; but, no definitive studies have been conducted to 
date. 
 
Though observational in nature, some studies provide comparisons of AF progression in 
ablation-treated versus non-ablation treated subsets.11, 16, 32  The raw percentages of patients 
experiencing AF progression in these studies tended to favor catheter ablation; however, the 
number of patients undergoing ablation was relatively small, and no multivariate analyses 
were reported, attempting to adjust for other variables. 
 
The impact of catheter ablation in progression of PAF among RCT and observational studies 
(comparing the percent of progression for ablation versus no ablation) ranges from 0-6% per 
year for ablation groups to 2-53% per year for non-ablation groups.11, 16, 32, 38, 39  In single-arm 
studies, rates ranging from 0-11% were reported.22, 33, 41-46  In appraising this evidence, it is 
important to note that some studies limit the patient population to only those with successful 
ablation or available long-term follow-up and, in doing so are likely to create bias by avoiding 
the sicker patients.  Thus, rates estimated from these studies may be lower than those seen in 
prospective studies which follow patients from intention to treat forward.  For example, 2010 
studies by Bertaglia22 and Fichtner41 limited analysis to patients free of recurrence at 12 
months.  In the Fichtner study, this subgroup comprised less than half of the patients initially 
undergoing ablation (150/356); AF progression was not reported for the remaining 206 
patients with recurrence in the first year, as the focus of the study was on late recurrence.   
 
To better understand the progression of AF following catheter ablation in humans, a well-
controlled study should be conducted, in which AF terminology is defined according to 
current AF management guidelines, factors associated with AF progression are evaluated, an 
appropriate comparison group is included, and long-term follow-up is planned. 
 
5.2 
Rationale  
 
Disease progression, as an outcome in AF, has been studied less commonly than other long 
term outcomes such as AF recurrence in general (in catheter ablation studies) and 
cardiovascular events / mortality (in trials of anti-thrombotic and anti-arrhythmic drug 
therapy).  There are no published randomized trials, comparing ablation to medical treatment, 
that include this outcome as a primary endpoint; although, Veasey, et al47 conducted a 




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5.4 
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.1-4  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.   
 
The risks and complications of the different AAD medications are listed in their respective 
Package Inserts/Summaries of Product Characteristics. The use of AAD is routine treatment 
for many patients with Atrial Fibrillation, no additional risks are anticipated for subjects 
enrolled in this study compared to subjects undergoing AAD treatment outside of the study as 
per the current AF Management Guidelines1-4.  
 
RF catheter ablation has been used for nearly two decades, and the risks and complications 
are well understood.  The use of non-irrigated and saline-irrigated ablation catheters is routine 
for many PAF ablation procedures.  No additional risks are anticipated for subjects enrolled in 
this study compared to subjects undergoing ablation for symptomatic PAF outside of the 
study.  A summary of risks associated with catheter ablation, including analysis of and plans 
to minimize these risks is provided in Appendix A. 
 
6.0 Study Hypothesis 
 
For subjects undergoing early RF ablation for recurrent, symptomatic PAF, it is hypothesized 
that, compared to the Drug Therapy (control) Group, the PVI (test) Group will demonstrate 
superior effectiveness as evidenced by a longer time needed to progress to persistent AF/AT 
during follow-up through 3 years. 
 
7.0 
Objective 
 
The objective of this study is to determine whether in subjects with Paroxysmal AF (PAF), early 
RF ablation treatment using the THERMOCOOL® Catheter Family in conjunction with the CARTO® 3, 
CARTO
 ® XP or CARTO® RMT System  delays progression of AF compared with drug therapy 
(either rate or rhythm control) using current AF management guidelines.1-4 
 
 
 
 
 
 


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8.0 
Investigational Plan 
 
8.1 
Study Design 
 
This is a prospective, multi-center, randomized (1:1), controlled, two-arm, open-label, 
clinical study, which will evaluate the effectiveness of early RF ablation intervention in 
delaying progression of PAF to persistent AF/AT, compared with drug therapy (either rate or 
rhythm control).  Patients with recurrent, symptomatic PAF who meet the inclusion criteria 
will be considered for study participation and may be enrolled if no exclusion criteria apply.  
 
8.2 
Treatment Groups 
 
Eligible subjects who sign the study informed consent form will be randomized into one of 
two treatment groups: 
 
 
PVI (Test) Group: RF ablation to achieve PVI using the THERMOCOOL® Catheter 
Family in conjunction with the CARTO® 3, CARTO
 ® XP or CARTO
 ® RMT System. 
 
 
Drug Therapy (Control) Group: AAD therapy in accordance with current AF 
management guidelines1-4 
  
The Test Group will be compared to the Control Group to determine differences with respect 
to various effectiveness and safety endpoints.  Planned statistical analyses of endpoints and 
outcomes are described in Section 14 (Statistical Analysis) of this protocol. 
 
8.3 
Number of Centers 
 
Up to 50 sites in Europe and/or the Asia Pacific, North-America region will participate in this 
study.  Previous studies have reported cross-over rate ranges from 42% to 59% during the 1-
year follow-up time; Santinelli et al study (2009)37 reports 87.9% cross-over rate during the 
four years follow-up time. To mitigate high cross-over rates and minimize the unilateral and 
random efflux from the Control Group, sites with the potential to minimize potential cross-
over will be selected for study participation (refer to Section 9.2, Informed Consent and 
Enrolment Procedures, for additional detail).  Total enrolment among all sites of up to 330 
subjects is expected, with an approximately equal distribution between Test and Control 
Groups.  
 
8.4 
Study Duration, Completion, and Termination  
 
Duration:  The study duration is anticipated to be 4-5 years; 1-2 years to complete 
screening/enrollment, and 3 years to complete follow-up for all subjects.   
 
 
Completion:  The planned time of study completion is after all subjects have completed 
the required 3-year follow-up visits with the following exceptions: (a) subjects who 
withdraw from the study or who terminate early per protocol or investigator decision; 
and, (b) premature study stoppage for futility (see Termination). 
 
 
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 fulfil subject enrolment goals, site suspension by EC 
/ EB). 
 


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9.0 Subject Selection and Disposition   
 
9.1 
Recruitment and Screening Procedures 
 
Patients who have failed at least 1 but no more than 2 prescribed drugs for AF (either anti-
arrhythmic or rate control drug) will be screened for this study if eligible for both (i) RF 
ablation for treatment of recurrent, symptomatic PAF and (ii) medication management with 
either anti-arrhythmic or rate control drug. A screening log, maintained at each study site, will 
be used to document the subjects reviewed for potential enrolment into the study. The 
screening log should be completed for any patient considered for study inclusion, regardless 
of whether the patient is selected or not, as this will allow better management of the study 
enrolment rate.  
 
9.2 
Informed Consent and Enrolment Procedures 
 
For this study, it is important to minimize the number of Control Group subjects who undergo 
RF ablation for AF, after cross-over, and thus confound the treatment group analyses.  
Because high cross-over rates from the drug treatment group to the ablation treatment group 
have been reported in studies similar to this one, the following measures will be implemented 
at each study site to minimize subject cross-over (refer to Appendix B for additional detail): 
 
 
Avoid recruiting/enrolling patients who are initially referred specifically for RF ablation. 
 
Select sites with: 
o 
Significant experience with RF ablation; and that also with a large AF patient 
population on medication management alone. 
o 
Commitment to enrolling subjects who do not show an obvious bias toward one 
treatment arm over another and who will agree to accept the treatment to which they 
are randomized. 
 
The informed consent process will include a thorough discussion of the importance of 
minimizing cross-over in the Control Group (refer to Appendix B).  Patients who exhibit a 
clear understanding of this and who are deemed eligible for and willing to participate in the 
study must sign (or have their legal representative sign on their behalf) the study’s informed 
consent form (ICF), prior to enrolment and collection of any study-related data.  The ICF and 
any revisions must have prior approval of the study site’s ethics committee (EC) / ethics 
board (EB).  The signed ICF will be kept in the subject’s files.   
 
 
9.3 
Study Inclusion Criteria 
 
1. 
Patients with recurrent paroxysmal AF for at least 2 years, with ≥ 2 episodes over the last 
6 months;  
2. 
HATCH Score of at least ≥1 and ≤ 4.c 
3. 
Eligible for catheter ablation and for anti-arrhythmic or rate control medications, after 
having failed at least 1 but no more than 2 prescribed drugs (either anti-arrhythmic or rate 
control drug). 
4. 
Age 60 years or older.  
                                                    
c  Hypertension (+1); Age >75 years (+1); previous TIA or Stroke (+2); COPD (+1); Heart failure - 
including systolic or diastolic heart failure (+2). 
 


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5. 
LA diameter ≤ 55mm by TTE. 
6. 
LV ejection fraction ≥ 50% when in sinus rhythm or LV ejection fraction ≥ 35% when in 
AF. 
NOTE: For patients entering the study in AF with an ejection fraction ≥ 35% and < 50%; the 
ejection fraction should be re-checked when in sinus rhythm. In case the ejection fraction is  
> 50% the subject can continue in the study. 
7. 
Patient signed the Informed Consent Form and is able and willing to comply with 
protocol requirements, including all baseline and follow- up testing. 
 
9.4 
Study Exclusion Criteria 
 
1. 
Patients awaiting cardiac transplantation or other cardiac surgery. 
2. 
Acute illness (ongoing) or active systemic infection or sepsis which in the opinion of the 
investigator, may adversely affect the safety and/or effectiveness of the participant of the 
study. 
3. 
Reversible causes of AF, e.g. but not limited to thyroid disorders, acute alcohol 
intoxication, recent major surgical procedures or trauma,… 
4. 
Recent cardiac events including MI, PCI, or valve or bypass surgery in the preceding 3 
months. 
5. 
Heart failure decompensation. 
6. 
Previously diagnosed with persistent/permanent AF/AT 
7. 
Previously required cardioversion >48 hours after onset of AF/AT  
8. 
Subject having previous TIA or stroke (cerebrovascular accident) one year prior to patient 
enrolment and/or no sufficient recovery. 
9. 
Pulmonary embolism or recent atrial embolism/thrombosis. 
10. Hypertrophic obstructive cardiomyopathy. 
11. Class IV angina or Class IV CHF (including past or planned heart transplantation). 
12. Mandated anti-arrhythmic drug therapy for disease conditions other than AF. 
13. Heritable arrhythmias or increased risk for torsade de pointes with class I or III Drugs. 
14. Prior LA catheter ablation with the intention of treating AF; prior surgical interventions 
for AF such as the MAZE procedure. 
15. Prior AV nodal ablation. 
16. Patients presenting contra-indications for the study catheter(s), as indicated in the 
respective Instructions For Use. 
17. Contraindication to warfarin, other anticoagulation therapy, or all anti-platelet 
medications. 
18. Medical conditions limiting expected survival to < 3 years. 
19. Concurrent participation in any other clinical study. 
20. Prior history of non-adherence to prescribed drug regimens. 
21. Women of child bearing potential whom are pregnant, lactating, or planning to become 
pregnant during the course of the trial 
 
NOTE: Prior ablation of the cavo-tricuspid isthmus is not a reason to exclude, if the patient 
develops subsequent recurrent atrial fibrillation. 
 
NOTE: For patients randomized to the PVI group (Test Group), a Transesophageal 
Echocardiography (TEE) should be performed (as per standard of care), within 48 hours pre-
procedure, to exclude atrial thrombus or other structural contraindications for an ablation 
procedure. 
 


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9.5 
Subject Disposition 
 
 
Enrolled Subjects:  subjects who sign the study informed consent form and are 
randomized. 
 
 
Excluded Subjects:   
o Test Group: subjects who are enrolled and randomized to ablation therapy but never 
undergo insertion of the THERMOCOOL ablation catheter. 
o Control Group: subjects who are enrolled and randomized to medication management 
(AAD) but never begin taking investigator-prescribed AAD and are ineligible for 
ablation therapy. 
 
 
Discontinued Subjects:   
 Test Group: subjects who are enrolled and randomized to ablation therapy, undergo 
insertion of the THERMOCOOL ablation catheter, but do not undergo further ablation 
therapy (i.e., no RF energy is delivered). These subjects will be categorized as 
‘discontinued’ if therapy 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. 
atrial flutter, instead of PAF under investigation. 
 Control Group: subjects who are enrolled and randomized to medication management 
and have started an investigator-prescribed AAD, but do not complete the dose-loading 
period (~ 2 weeks), for reasons other than a safety failure or if their arrhythmia is 
determined to be a non-study arrhythmia, e.g. atrial flutter. 
 
 
Lost to Follow-up Subjects:  All subjects should be encouraged to return for protocol 
required office, clinic visit for evaluation during the study follow-up period. If a subject is 
unable to return for an office or clinic visit or unable to be contacted by telephone, 3 
separate telephone calls should be made to obtain subject related safety information. All 
attempts should be documented in the source documents. If the subject does not respond 
to the 3 telephone calls, then the investigator must send a certified letter to the subject. If 
the subject does not respond to the letter, then the subject will be considered “lost to 
follow-up” for the current study visit.  Subject contact must be attempted at each follow-
up time point and if unable to contact the subject after 3 phone calls, the subject should 
once again be sent a certified letter.  Only after failing to contact the subject at the final 
follow-up visit, the subject will be considered lost to follow-up and the study 
termination/end form will be completed in the individual case report form. 
 
 
Withdrawn / Early Termination Subjects:  investigator termination of a subject for 
reasons stated below in Section 9.6; or, subjects who withdraw consent for study 
participation and are terminated from the study prior to completion of all follow-up visits. 
 
 
Completed Subjects:  enrolled subjects who have not been discontinued, withdrawn or 
lost-to-follow-up from the study, prior to the final 3-year study visit. 
 
9.6 
Subject Withdrawal 
 
The investigator may 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, noncompliance, or any other situation the investigator deems a 
compromise to the integrity of the study.  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 
his or her future medical care by the physician or the institution.  The Sponsor also has the 
right to withdraw a subject from the study at any time and for any reason. 
 


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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 must comply with all 
reporting requirements and must follow the subject until the AE/SAE has resolved or 
stabilized.   
 
10.0 Study Endpoints 
 
10.1 Primary Endpoint 
 
Time to persistent AF/AT (excluding isthmus-dependent atrial flutter) at 3 years.  Persistent 
AF/AT is defined as AF/AT lasting longer than 7 consecutive days or requiring termination 
by cardioversion after 48 hours. 
 
10.2 Secondary Endpoints 
 
The secondary endpoints supporting the study objective are: 
 
Effectiveness: 
 
Rate and time to persistent AF/AT at 1 year and 2 years, rate of persistent AF/AT by 
number of ablations at 3 years. 
 
Number of repeat ablations and new AAD drugs per subject throughout 3 years follow-
up. 
 
Rhythm (% subjects in SR, % subjects with recurrent AF) throughout 3 years follow-up. 
 
Subject’s pre-existing or new onset/worsened condition(s), that may be associated with 
AF progression, will be collected at baseline and at each follow up visit throughout the 3-
year study period; parameters include subject’s age and gender and the following 
assessments of non-AF health status: LA size; HATCH Score; blood pressure; NYHA 
Functional Classification of heart disease; diabetes; lipid profile; renal function and, 
dementia.d 
 
Safety: 
 
Catheter-related complications (ablation); adverse drug reactions (AAD). 
 
Health Economics (HE) Outcomes: 
 
Health care utilization (number and length of hospitalizations and unscheduled 
cardiovascular-related visits). 
 
Quality of Life (QoL) at 3 months, 6 months, 1 year, 2 years and 3 years by EQ-5D and 
AFEQT Questionnaire and change from baseline. 
Note: AFEQT Questionnaire will only be used in validated languages and therefore, only 
distributed to a subgroup of the study population. The AFEQT questionnaire is validated 
in following languages: 
French, German, Italian, Spanish (Spain), Spanish (US), Polish, Czech, Simplified Chinese 
(China), Traditional Chinese (Taiwan), Dutch, Korean, Norwegian, Swedish. 
 
 
 
                                                    
d Baseline presence of dementia would preclude subject enrolment in this study; however, new onset 
dementia could occur during the course of the study.  If the dementia became sufficiently serious to 
preclude continued adherence to protocol requirements (Section 9.6), an Investigator may decide to 
terminate this subject from the study. 


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10.3 Definition of Effectiveness Success  
 
Subjects will be considered an effectiveness success if they do not progress to persistent AF 
through the 3-year follow-up period.   
 
11.0 Treatment Description   
 
11.1 Ablation Procedure and Medication Management Guidelines 
 
For Test Group Subjects, physicians are to perform procedures (i.e., EP study, ablation, 
verification of ablation, and post-ablation assessments) per institutional Standards of Care 
(“SOC”, which is defined as the clinical work flow that the physicians follow in their practice, 
without any mandated protocol requirements) and processes required by their institution.  For 
Control Group Subjects, physicians are to manage medication in accordance with published, 
current AF Management Guidelines1-4, the recommended approaches found in Appendix B, 
and with the SOC and procedures required by their institution.  
 
11.2 Schedule of Examinations 
 
11.2.1 Study Visits and Phone Follow-up 
 
Table 1 displays the required schedule for subject treatments and evaluations for Test and 
Control Groups.  Sites participating in this study have been selected upon their capabilities to 
successfully carry out those assessments. Subjects will need to return to the hospital for a 
follow-up clinical visit at 3 months, 6 months, 1 year, 2 years and 3 years. Follow-up by 
phone will be conducted for all subjects at 9 months, 18 months and 30 months.  Arrhythmia 
monitoring assessments, as described in Table 1, will be discontinued once subjects have 
progressed to persistent AF/AT.  
 
All subjects will be followed through 3-years. Subjects who reach the primary endpoint 
(progress to persistent AF/AT) will only have to return for the final visit at 3 years; however, 
they will be followed for safety through the 3-years study period by their hospital and all 
adverse events are to be reported by the investigator as per protocol requirements. Subjects in 
the Test Group 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 time of the index ablation procedure and not from the date of the repeat ablation 
procedure. Subjects in the Control Group who undergo an ablation procedure (cross-over), 
will continue follow-up according to their initial schedule. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1.  Summary of Subject Assessments:   
Assessments 
BL 
D08 
M3 
D76-
104 
M6 
D166-
210 
M9 
D240
-300 
Y1 
D330
-420 
M18 
D480
-600 
Y2 
D630
-809 
M30 
D810-
989 
Y3 
D990-
1170 
UNS 
Clinic visit 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Phone follow-up1 
 
 
 
X 
 
X 
 
X 
 
 
Patient Information and 
Consent  
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
HATCH score 
X 
X 
X 
 
X 
 
X 
 
X 
X 
ECG2 
X 
X 
X 
 
X 
 
X 
 
X 
X 
TTM3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TEE4 
X 
 
 
 
 
 
 
 
 
 
TTE5 
X 
 
 
 
X 
 
X 
 
X 
 
QoL (EQ-5D, AFEQT)6 
X 
X 
X 
 
X 
 
X 
 
X 
 
Health status7 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Cardiac medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardioversion / re-
ablation documented 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1.  Phone follow-up calls include check for AEs, changes in cardiac medication and TTM. 
2. To be collected if completed as standard of care. 
3. Dispensation of TTM device at Month 3.  Additional details/instructions regarding TTM monitoring are 
provided below. 
4. Only for patients randomized to PVI, within 48 hours pre-procedure. 
5. TTE to be performed within 30 days pre-treatment. For the Test Group, TTE must be repeated prior to discharge 
6. AFEQT questionnaire is only to be completed by a subpopulation due to limited validated translations 
7. LA Size, blood pressure, NYHA Functional Classification of heart disease, Diabetes, lipid profile, renal function 
and dementia. 
8. Day 0 Test Group (PVI = Index ablation procedure and Day 0 Control Group (AAD) = Randomization 
 
Transtelephonic monitoring (TTM) 
All subjects (test and control) will be provided with a TTM device to enable transmission of 
scheduled and symptom-triggered ECG recordings per the schedule described in Table 1.  
Both symptomatic and asymptomatic recordings will be analyzed by a Core Lab. Subjects 
will be trained by the study site personnel on the use of the TTM device and transmission of 
the recordings. A study specific Core Lab instruction manual, including procedures to be 
followed, will be made available. 
 
TTM monitoring (both groups) will be conducted as follows: 
 
 
Start TTM monitoring at Day 104 
 
Daily TTM monitoring if symptoms present (to capture symptomatic episodes). 
 
Weekly TTM monitoring as from Day 104 until Day 300 (to capture some 
asymptomatic episodes) 
 
Monthly TTM monitoring as from Day 300 until last study visit (3 Year) (to capture 
some asymptomatic episodes). 
 
 If AF is present, the subject will be contacted to begin daily monitoring for 7 consecutive 
days.  
 Discontinue TTM monitoring when AF is present for 7 consecutive days or requires 
termination by cardioversion after 48 hours (primary endpoint reached). 
 
Copies of TTM reports are to be filed in the subject’s medical chart. 


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12-lead Electrocardiogram (ECG) – standard of care 
Data from 12-lead ECG recordings will be collected as described in Table 1.  Data from 
unscheduled ECG’s between two consecutive follow-up visits will be collected and reported 
on the appropriate eCRF.  Copies of ECG reports should be filed in the subject’s medical 
chart with the participating investigator. 
 
Transthoracic Echocardiography (TTE) – standard of care 
Transthoracic echocardiograms must be performed according to requirements in Table 1.  
TTE is to be performed within 30 days pre-treatment start. For the Test Group, TTE must be 
repeated before discharge to evaluate volume parameters, valve abnormalities, and exclude 
presence of pericardial effusion.  Copies of TTE reports should be filed in the subject’s 
medical chart with the participating investigator. 
 
Transesophageal Echocardiography (TEE) – standard of care 
Transesophageal echocardiography must be performed for the Test Group within a 48-hour 
period immediately prior to the ablation procedure, 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.  Copies of TEE reports should be filed in the subject’s medical 
chart with the participating investigator. 
 
Quality of Life questionnaires 
The EQ-5D and AFEQT instruments must be completed at specified follow-up visits 
according to Table 1.  
Note: AFEQT Questionnaire will only be used in validated languages and therefore, only 
distributed to a subgroup of the study population. The AFEQT questionnaire is validated in 
following languages: French, German, Italian, Spanish (Spain), Spanish (US), Polish, Czech, 
Simplified Chinese (China), Traditional Chinese (Taiwan), Dutch, Korean, Norwegian, 
Swedish. 
 
Factors Associated with AF Progression 
Subject’s pre-existing or new onset/worsened condition(s), that may be associated with 
disease progression, will be collected at baseline and at specified follow-up visits, according 
to Table 1.  At each follow up visit, subjects will be assessed for recent onset or worsening of 
a comorbidity. Follow up visit assessments will focus upon increased LA size (per TTE), 
hypertension, diabetes, hyperlipidemia/dyslipidemia, renal insufficiency or dementia.  No 
additional diagnostic tests will be required per protocol. 
 
Adverse Events (AEs) 
Any untoward medical occurrence in a subject whether or not there is a relationship between 
the AE and the device under investigation and/or the drug therapy administered will be 
documented and reported to the Sponsor as outlined in Section 12 (Adverse Events) of this 
protocol. 
 
Cardiac Medication 
All cardiac medications will be documented in subject charts and reported on the appropriate 
eCRF(s).  In case an AE is related to intake of medications, details must be provided on the 
appropriate eCRF(s).  
 
11.2.2 Unscheduled Visits 
 
If a subject returns for a cardiovascular related visit outside of the protocol-defined visit 
schedule provided in Table 1, the visit will be considered “unscheduled” (UNS).  If the 


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unscheduled visit is for a repeat ablation procedure, the protocol follow-up schedule will be 
based on the index procedure.  For all cardiovascular related unscheduled visits, an 
unscheduled visit eCRF must be completed and the subject must also return for his/her next 
scheduled study visit. 
 
 
11.3 Medication Management 
 
During this study, current AF management guidelines1-4 and the investigator’s Institution 
Standards of Care (SOC) are to be followed as closely as possible.  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 may be used and new AADs may be started during the study.  The choice 
of rate control versus rhythm control therapy and the specific drugs used will be left to the 
investigator’s discretion. 
 
At the time of study enrolment, if subjects who are randomized to the AAD Group have 
already been switched from a failed medication to a new AAD, they will continue with the 
latter drug after enrolment; otherwise, subjects will begin the study with a newly prescribed 
AAD medication. 
 
A subject in the AAD Group may complain to his/her Investigator about the prescribed 
medication and request a cross-over to receive ablation.  In evaluating this request, the 
Investigator may uncover evidence that the subject did not take his/her medications as 
prescribed and/or took concurrent incompatible medications for other chronic diseases.  In 
such a circumstance, a subject should undergo Medication Managemente and then return to 
the hospital 3 weeks later for re-evaluation.   
 
11.4 Management of Arrhythmia Recurrence During Follow-up 
 
11.4.1 Arrhythmia Recurrence:  Test Group 
 
Each investigator’s routine clinical practice is to be followed as closely as possible regarding 
management of arrhythmia recurrence.  If a subject undergoes re-ablation(s) for arrhythmia 
recurrence, the decision should be made in accordance with current AF management 
guidelines.1-4  All re-ablation procedure(s) must be fully documented.  If a determination is 
made that progression to persistent AF/AT has occurred, no further arrhythmia monitoring 
(TTM, ECG, etc) will be required. After reaching the study endpoint, test subjects do not need 
to return for interim follow-up visits. These subjects will only have to return for the final visit 
at 3 year. However, they will be followed through the 3 years for safety  by their hospital and 
all adverse events are to be reported by the investigator as per protocol requirements.  
 
11.4.2 Arrhythmia Recurrence:  Control Group 
 
The investigator’s routine clinical practice is to be followed as closely as possible regarding 
management of arrhythmia recurrence.  Changes in AAD treatment are allowed if needed; 
however, changes should be made in accordance with current AF management guidelines.1-4  
If an investigator determines that progression to persistent AF/AT has taken place regardless 
of AAD regimen no further arrhythmia monitoring (TTM, ECG, etc) will be required. After 
                                                    
e Medication management includes reviewing all medications taken and an attempt to identify drugs 
with possible incompatibility with AAD medication(s); review and manage drug taking routine:  timing 
- warning about taking drugs too close together or too far apart; warning about drug holidays and 
dangers; discuss taking with or without food, as prescribed; coach to use robust routines (taking pills 
same time each day); pill organizers; and/or recruitment of family to assist subject. 


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reaching the study endpoint, control subjects do not need to return for interim follow-up 
visits. These subjects will still be followed for safety until the 3-year follow-up visit has taken 
place. 
 
If Control Group subjects are to undergo RF ablation (crossover) while not having reached 
the primary endpoint, they will continue follow-up through 3 years (refer to Appendix B for 
details regarding crossover management).  If crossover subjects experience AF recurrence, the 
investigator will assess whether a change in AAD(s) treatment is required, if repeat ablation is 
appropriate, or if progression to persistent AF/AT has occurred.  If a determination is made 
that progression to persistent AF/AT has occurred, no further arrhythmia monitoring (TTM, 
ECG, etc) will be required. After reaching the study endpoint, crossover subjects do not need 
to return for interim follow-up visits.  These subjects will still be followed for safety until the 
3-year follow-up visit has taken place. 
 
11.4.3 Cardioversion for Arrhythmia Recurrence 
 
Unnecessary Cardioversion < 7 days should be discouraged, but within ethical bounds.  If the 
investigator believes the subject’s AF symptoms are sufficiently severe to warrant 
cardioversion, he/she should proceed, regardless of timing.  AF symptoms sufficiently severe 
to warrant cardioversion are angina, shortness of breath and/or systolic blood pressure < 90 
mmHg related to AF.  
 
Subjects who undergo a cardioversion within 48 hours of arrhythmia recurrence are not 
considered as being progressed to persistent AF/AT, and, therefore, will not have reached the 
primary endpoint. These subjects will continue follow-up according to the protocol visit 
schedule through 3 years. 
 
Subjects who undergo a cardioversion after 48 hours of arrhythmia recurrence are considered 
as being progressed to persistent AF/AT and, therefore, will have reached the primary 
endpoint. These subjects will continue to be followed continuously for safety and will be 
asked to return for a final assessment at the 3-year follow-up visit but not to participate in 
interim follow-up visits. All adverse events are to be reported by the investigator as per 
protocol requirements. 
 
11.4.4 Cardioversion as part of a (re-)ablation procedure 
 
Subjects who undergo a cardioversion solely as part of a (re-)ablation procedure are not 
considered as being progressed to persistent AF/AT, and, therefore, will not have reached the 
primary endpoint. These subjects will continue follow-up according to the protocol visit 
schedule through 3 years. 
 
11.5 Core Laboratory for Evaluation Tests 
 
A core lab shall be used for the objective evaluation of both symptomatic and asymptomatic 
arrhythmia recordings.  The core lab will be instructed to prioritize analysis of asymptomatic 
recordings in the event that progression to persistent AF/AT has occurred without the 
subject’s awareness.  Initial evaluation of TTM recordings will be performed by technical 
personnel trained in the evaluation of these recordings and will be reviewed by a cardiologist 
or an experienced EP technician.  If asymptomatic AF is present, the subject will be contacted 
immediately to start daily TTM recordings for 7 consecutive days.  AF/AT episodes will be 
evaluated per the definitions provided in this protocol (refer to Study Definitions). 
 
 


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12.0 Adverse Events  
 
12.1 Definitions / Classifications 
 
12.1.1 Medical Devices 
 
Adverse Event (AE) (ISO 14155) 
Any untoward medical occurrence, unintended disease or injury or any untoward clinical 
signs (including an abnormal laboratory finding) in subjects, users or other persons whether 
or not related to the medical device. 
This includes events related to the device used in the study and events related to procedures 
involved (any procedure in the clinical investigation plan). 
For users or other persons this is restricted to events related to the investigational medical 
device. 
 
NOTE: 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. 
NOTE: AF recurrence by itself is considered a recurrence of disease (pre-existing condition) 
and therefore does not meet the definition of an AE, unless it is a worsening compared to the 
pre-existing condition. 
 
Primary Adverse Event (AE): 
A primary AE includes any of the following outcomes that occur within 7 days of an AF 
ablation procedure : 
 
 Death 
 Myocardial infarction (MI) 
 Pulmonary vein (PV) stenosis* 
 Diaphragmatic paralysis 
 Atrio-esophageal fistula* 
 Transient Ischemic Attack (TIA) 
 Stroke / Cerebrovascular accident 
(CVA) 
 Thromboembolism 
 Bleeding (including haematoma) 
requiring blood transfusion 
 Pericarditis 
 Cardiac Tamponade 
 Pericardial effusion 
 Pneumothorax 
 Astudy perforation 
 Vascular Access Complications 
 Pulmonary edema    
 Hospitalization (initial and prolonged)† 
 Heart block 
 
* Pulmonary vein stenosis and atrio-esophageal fistula that occurs greater than one week (7 
days) post-procedure shall be deemed a primary AE. 
 
† Excludes hospitalization solely due to pre-existing arrhythmia recurrence. 
 
Serious Adverse Event (SAE) (ISO 14155) 
An adverse event that: 
a) led to a death, 
b) led to a serious deterioration in health that either: 
1) resulted in a life-threatening illness or injury, or 
2) resulted in a permanent impairment of a body structure or a body function, 
or 
3) required in-patient hospitalization or prolongation of existing 
hospitalization, or 
4) resulted in medical or surgical intervention to prevent life threatening 
illness or injury or permanent impairment to a body structure or a body 
function. 


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c) led to fetal distress, fetal death or a congenital abnormality or birth defect. 
Under this definition, a planned hospitalization for a pre-existing condition, or a procedure 
required by the protocol, without serious deterioration in health, is not considered a serious 
adverse device and/or procedure effect. 
 
NOTE: An AE would meet the criterion of “hospitalization”, if the event necessitates an 
admission to a health care facility (e.g., overnight stay).  Emergency room visits that do not 
result in admission to the hospital should be evaluated for one of the other serious outcomes. 
 
Adverse Device Effect (ISO 14155) 
An adverse device effect (ADE) is an adverse event related to the use of a medical device, 
including any event resulting from insufficiencies or inadequacies in the Instructions for Use 
or the deployment, implantation, the installation, the operation, or any malfunction of the 
medical device. This includes any event that is a result of a use error or intentional misuse. 
 
Serious Adverse Device Effect (ISO 14155)  
A serious adverse device effect (SADE) is an adverse device effect that has resulted in any of 
the consequences characteristic of a SAE. 
 
Unanticipated Serious Adverse Device Effect (ISO 14155) 
An unanticipated serious adverse device effect (USADE) is any serious adverse device effect 
which by its nature, incidence, severity or outcome has not been identified in the current 
version of risk analysis report . 
 
Device Deficiency (ISO 14155) 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, 
safety or performance. These include malfunction, misuse or use errors, and inadequate 
labelling.  
 
12.1.2 Medicines 
 
Adverse Event (AE) (Directive 2001/20/EC and CT-3) 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including abnormal laboratory finding), symptom or disease temporarily associated with the 
use of a medicinal product whether or not considered related to the medicinal product. 
 
Serious Adverse Event (SAE) (Directive 2001/20/EC and CT-3) 
Any untoward medical occurrence or effect that at any dose results in death, is life-
threatening, requires hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. 
 
Adverse (Drug) Reaction (ICH-E2A) 
Adverse (drug) reaction (A(D)R) is a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease 
or for modification of physiological function. 
 
NOTE: All drugs taken per protocol requirements (AAD’s), drugs taken according to AF 
management guidelines (i.e. anticoagulants) are considered for AE recording by the 
Investigator to Biosense Webster. 
 
 


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12.2 Event categorization: 
 
 
Adverse 
Events (AE) 
Non-related 
Device/Procedure related 
Drug related 
 
Non-serious 
 
Adverse 
Event (AE) 
 
Adverse device Effect (ADE) 
 
Adverse drug reaction (ADR) 
 
 
 
Serious 
 
 
 
Serious 
Adverse 
Event (SAE) 
Serious Adverse Device effect 
(SADE) 
Serious Adverse drug reaction 
Anticipated 
Unanticipated  
Expected 
Unexpected 
 
Anticipated 
Serious Adv-
erse Device 
Effect 
(ASADE) 
 
Unanticipated 
Serious Adverse 
Device Effect 
(USADE) 
 
Expected 
Serious 
Adverse Drug 
Reaction 
 
Suspected 
Unexpected 
Serious 
Adverse Drug 
Reaction 
(SUSAR) 
 
 
12.3 Causality  
Regarding the causality of each device-, procedure-, or drug-related AE, the investigator will 
assess and evaluate the causal relationship according to the following classifications: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2.  Adverse Event Causality Classifications 
Caused By 
Relation 
Definition of Relation 
Study Device 
Definitely 
The device directly caused or contributed 
to the AE 
Probably 
The device likely caused or contributed to 
the AE  
Possibly 
The device may have caused or contributed 
to the AE 
Not Related 
The AE is not associated with the device 
studied in this protocol 
Ablation Procedure 
Definitely 
The AE is directly associated by timing 
and/or pathophysiology with the standard 
electrophysiology or ablation procedure 
described in this protocol that would not 
have happened if the procedure had not 
been performed. 
Probably 
The procedure likely caused or contributed 
to the AE 
Possibly 
The AE may be associated by timing and/or 
pathophysiologic with the standard 
electrophysiology/ablation procedure 
described in this protocol 
Not Related 
The AE is not associated with the 
EP/ablation procedure described in this 
protocol 
Drug 
Definitely 
The drug directly caused or contributed to 
the AE 
Probably 
The drug likely caused or contributed to the 
AE  
Possibly 
The drug may have caused or contributed 
to the AE 
Not Related 
The AE is not associated with the drug(s) 
used during the study 
 
12.4 Intensity / Severity  
Regarding the intensity/severity of each AE, the investigator will assess and evaluate the 
relationship according to the following definitions: 
 
 
 
 
 
 
 


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Table 3.  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. 
 
12.5 Outcome  
Regarding the outcome of each AE, the investigator will assess and evaluate the outcome  
according to the following classifications: 
Table 4.  Adverse Event Outcome Classifications 
 
12.6 Adverse Event Reporting and Documentation Requirements  
 
12.6.1 Adverse Event Reporting Requirements 
 
Investigator responsibilities: 
Reporting by the Investigator to Biosense Webster: 
AE information will be collected throughout the study and will be recorded on the eCRFs by 
the study investigator and/or study coordinator.  Each AE must be reported regardless of 
classification, seriousness, intensity, outcome or causality.  All AEs will be monitored until 
they are adequately resolved or explained.  Timing for reporting various AEs is described in 
Table 5. 
 
 
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  


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Table 5.  AE Reporting Requirements and device return 
Type of Adverse Event* 
Reporting Requirements for new and follow up 
information 
Non-serious non related AE 
or non serious ADR 
Report to Biosense Webster as soon as possible 
Non-serious ADE*** 
Report to Biosense Webster as soon as possible 
SAE 
Report to Biosense Webster immediately but not later than 
24 hours of awareness 
USADE & SADE*** 
Report to Biosense Webster immediately but not later than 
24 hours of awareness 
Subject Death 
Report to Biosense Webster immediately but not later than 
24 hours of awareness 
Study Device Deficiencies 
(failure/malfunction) 
associated with an AE*** 
Report both study device failure and AE to Biosense 
Webster immediately but not later than 24 hours of 
awareness 
Study Device Deficiencies 
that might have led to a 
SAE**/*** 
Report study device failure to Biosense Webster 
immediately but not later than 24 hours of awareness 
Study Device Deficiencies 
not associated with an 
AE*** 
Report study device failure to Biosense Webster 
immediately but not later than 24 hours of awareness 
Other (concomitant) Device 
Deficiencies associated or 
not associated with an AE 
Report to Biosense Webster as soon as possible per regular 
complaint process 
*  Must be reported by eCRF (telephone, e-mail or fax transmission) to Biosense Webster by the study 
site personnel, whether or not it is deemed related to the study device, procedure, or drug. 
** Device deficiencies that could have led to serious adverse device effect if  
a) if either suitable action had not been taken, 
b) if intervention had not been made, or 
c) if circumstances had been less fortunate, 
*** Devices need to be returned per Biosense Webster return procedure. 
 
NOTE: Complaints related to products manufactured and/or distributed by Biosense Webster, 
used during the procedure related to other devices (other than the study device under 
investigation), are to be reported according to current Biosense Webster procedures and other 
policies as necessary (i.e., institutional policies, EC / EB [or equivalent] policies, and local 
regulations), investigators are instructed to return devices in accordance with current 
company procedures and other relevant regulations. 
 
NOTE: Complaints related to non-Biosense Webster, Inc. products must be handled 
according to institutional policies, EC / EB (or equivalent) policies, and local regulations. 
 
Reporting by Investigator to EC/national CA 
The Investigator will report events to the EC / EB (or equivalent) as well as to the appropriate 
authorities (e.g., competent authorities) according to the prevailing regulations per country 
and/or site.  
 
 
 
 


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Biosense Webster responsibilities: 
 
The sponsor shall keep detailed records of all adverse events relating to the study which are 
reported to him by the investigators. 
 
Expedited reporting 
General 
Biosense Webster shall report all reportable events occurred throughout the study to relevant 
participating CA’s. ECs / EBs will receive events only occurred in subjects, recruited in their own 
country, unless more stringent national regulations are applicable. 
 
Device/procedure related events and device deficiencies 
In accordance with 21 CFR 812 (Subpart C), 803, ISO 14155, MDD 93/93/42/EC, Meddev 
2.12/1,any malfunction or deterioration in the characteristics and/or performance of a device, 
as well as any inadequacy in the labeling or the instructions for use which, directly or 
indirectly, might have led to or might have led to the death of a patient, or user or of other 
persons or to a serious deterioration in their state of health, will be considered for reporting by 
Biosense Webster to the appropriate authorities (e.g., competent authorities) as well as to the 
ECs / EB (or equivalent) according to the prevailing regulations per country. For countries 
outside Europe, Biosense Webster adheres to Medical device vigilance requirements per 
national regulations. 
 
Annual reporting 
Biosense Webster shall perform annual safety reporting to the appropriate authorities (e.g., 
competent authorities), ECs / EBs (or equivalent) as well to Investigators according to the 
prevailing regulations per country.  
 
12.6.2 Adverse Event Documentation 
 
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.  Additional documentation may be requested by 
Biosense Webster, including but not limited to, a written subject narrative detailing the 
clinical course of the AE, a copy of any correspondence with the local EC, and extracts from 
medical records. 
 
12.6.3 Serious Adverse Event Documentation  
 
Subjects experiencing a SAE must be examined by a physician or qualified health care 
professional as soon as possible.  The physician in attendance will do whatever is medically 
needed for the safety and well-being of the subject.  The subject will remain under 
observation as long as medically indicated.  All SAEs will be followed until resolution or 
until the event stabilizes according to the medical judgment of the investigator.  
 
All efforts shall be put in place, by the investigator, to collect SAE-related documentation 
(e.g., eCRFs, subject’s discharge summary) as soon as possible after initial notification of the 
event to Biosense Webster. Additional information shall be reported immediately but no later 
than 24 hours to Biosense Webster. Follow-up reports relative to the subject’s subsequent 
course must be submitted to Biosense Webster or designee until the event has resolved or, in 
case of permanent impairment, until the condition stabilizes. 
Documentation related to the SAE (e.g., additional laboratory tests, consultation reports, post-
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by the investigator to Biosense Webster or designee in a timely manner, when requested.  If 
the subject is withdrawn from the study because of the SAE, the information must be included 
on the appropriate eCRFs. 
 
 
13.0 Statistical Analysis 
 
13.1 Clinical Study Objective 
 
The objective of this study is to determine whether early RF ablation treatment, using the 
CARTO ® 3, CARTO ® XP or CARTO ® RMT System and THERMOCOOL ® Catheter Family  in 
subjects with PAF, delays progression of AF compared with drug therapy (either rate or 
rhythm control) using current AF management guidelines.1-4 
 
13.2 Primary Endpoint 
 
Time to persistent AF/AT (excluding isthmus-dependent atrial flutter) at 3 years will be used 
to measure the primary endpoint.  Persistent AF/AT is defined as AF lasting longer than 7 
consecutive days or requiring termination by cardioversion after 48 hours. 
 
13.3 Overview of Statistical Methodology 
 
Adaptive group sequential survival design is used in this study to examine the primary 
endpoint. The primary endpoint will be analyzed using the Kaplan-Meier (KM) method and 
account for censored observations following the intent-to-treat principle.  Group sequential 
method, multiple interim examinations of the primary endpoint using alpha spending 
functions and conditional power, will be performed at regular time intervals during the course 
of the trial to determine whether the study will be stopped early for effectiveness or futility. In 
addition, sample size re-estimation will be used to provide a chance to increase the sample 
size close to the end of the enrollment if the study is still promising but underpowered due to 
uncertainties regarding the effect size and cross-over rate. 
 
13.4 
Sample Size and Power Calculation  
 
A total sample size of 322 (161:161) subjects will be required to ensure 85% power to detect 
the effect size measured by negative log of the hazard ratio equal to 1.154f (treatment group 
over control group).  This calculation assumes a 50% cross-over rate from the AAD group to 
the ablation group, a 10% drop-out rate in each group over the 3 year follow-up period, and 
1.5 years accrual time.  This calculation is based upon one-sided superiority testing with alpha 
equal to 0.025.  Using meta-analysis, the rates of disease progression at the end of follow-up 
are estimated to be 25% and 5% in the AAD and ablation group, respectively (see the point 
estimate justification document for details, Appendix C).  The sample size calculation is 
based upon the method developed by Rubinstein, Gail and Santner66 (RGS,1981) and also 
incorporates group sequential design with multiple interim looks.   
 
Adaptive Sample Size Re-estimation:  
Due to the uncertainties associated with the cross-over rate and the effect size, the sample size 
will be reestimated 1.5 years after the start of enrollment or at the end of the enrollment 
                                                    
f       (
 ̂ 
 ̂ )          
         )
 
)   
         )
 
))        
 


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whichever occurs earlier.  Conditional power (CP) will be calculated at that time to determine 
how promising the interim results are.  CP is defined as the conditional probability that the 
final result will exceed a critical value given the data observed thus far, and an assumption 
about the trend to be observed in the remainder of the study.67  If the CP is less than 0.3, then 
the study is considered not promising and the sample size will not be increased.  If the CP is 
greater than 0.9, then the study is deemed fully powered and the sample size will not be 
increased.  If the CP falls in the promising zone (0.3-0.9), the sample size will be reestimated 
based upon the observed effect size and the CHW (Cui, Hung and Wang). Adaptive Method 
will be used for statistical testing.68  
 
13.5 Randomization  
 
Subject randomization will be 1:1 between catheter ablation and AAD therapy.  The 
randomized block design, stratified by gender and site, will be used to ensure a gender 
balance by treatment group at each site.  Adaptive randomization will also be executed to 
further ensure the allocation balance of treatment groups by gender at each site. Subjects will 
be randomized in the order of their enrollment.  If a randomization assignment is 
inadvertently disclosed prior to use, the assignment will never be used. 
 
13.6 Analysis Populations 
 
The study contains two treatment arms with subjects receiving either catheter ablation, with 
or without AAD therapy; or, AAD therapy alone.  The following analysis populations will be 
used to complete the analyses of data:  
 
 
Intent to treat subject population (ITT): The ITT subject population will include all 
subjects randomized, where subjects will be classified by the group to which they are 
randomized, regardless of the treatment received.  For the ITT population, cross-over subjects 
will be included in the Control Group per randomization. Lost-to-follow-up and withdrawn / 
early termination subjects will also be included in the ITT population.   
 
Per protocol subject population (PP):  The PP subject population will include randomized 
subjects who satisfy the following criteria, according to the treatment actually received: 
 
 
Test Group: subjects who  
o 
have undergone RF ablation,  
o 
are treated with the study catheter (THERMOCOOL ® Catheter Family) 
o 
are in compliance (no major protocol deviations) with the study protocol, and  
o 
have been treated for the study-related arrhythmia. 
 
Control Group:  subjects who  
o 
have started an investigator-prescribed AAD and completed the dose-loading 
period (2 weeks), 
o 
have not undergone RF ablation, 
o 
are in compliance (no major protocol deviations) with the study protocol, and  
o 
have been treated for the study-related arrhythmia. 
 
The analyses conducted in the PP population will be as treated analyses.  Subjects who have 
undergone RF ablation will be included in the Test Group regardless of the original treatment 
assigned (original randomization).  Thus, cross-over subjects will be included in the Test 
Group for PP analyses.  
 
Safety Population (SP): The SP will include all subjects who have undergone insertion of an 
ablation catheter, either as Test Group or cross-over subjects; and, subjects who started an 


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investigator-prescribed AAD in the Control Group and did not initiate ablation therapy.  
Analysis of catheter-related complications will be limited to include only subjects who 
initiated ablation treatment (catheter insertion) - Test Group and cross-over subjects. Adverse 
drug reactions will be analysed overall for all the subjects who have taken investigator-
prescribed AAD and analyzed separately for cross-over subjects, those in the Test and 
Control Groups (excluding cross-over patients). 
 
The primary effectiveness analysis will be conducted in the ITT population.  Secondary 
effectiveness analyses will be performed in the PP population.  All safety data analyses will 
be performed in the SP.   
 
13.7 
Subject Disposition and Protocol Deviations 
 
The number of subjects included in each of the study populations (ITT, PP, SP) will be 
summarized overall, by treatment group as randomized, and by study site.  A listing sorted by 
treatment group and subject will be provided that will include the reasons for exclusion from 
any of the study populations.  The number of subjects enrolled, excluded, discontinued, 
prematurely withdrawing from the study, lost to follow-up, evaluable, completed and the 
reasons for classification will be summarized and listed by treatment group for all subjects in 
the ITT population.  Protocol deviations will also be summarized by treatment group and 
listed. 
 
13.8 
Demographic and Baseline Characteristics 
 
Subjects’ demographic and baseline characteristics include but are not limited to (1) age; (2) 
gender; (3) race; (4) ethnicity; (5) medical history conditions; and (6) AF history and will be 
summarized overall and by treatment group.  The descriptive statistics including number of 
subjects, mean, median, 25th and 75th percentiles, minimum, maximum and standard 
deviation will be presented for continuous variables.  Frequency and percentage will be 
presented for ordinal and categorical variables.  Fisher’s exact tests will be used to examine 
the categorical, demographic, and baseline characteristics between two groups, and Kruskal-
Wallis tests will be used for the continuous variables as appropriate.  
 
13.9 Primary Statistical Analyses 
 
13.9.1 Primary Effectiveness Analysis 
 
The primary effectiveness analysis will be a Kaplan-Meier (KM) analysis for all subjects in 
the ITT population and account for censored observations.  The primary effectiveness 
analysis will be performed in the ITT population where the subjects will be attributed to the 
treatment group as randomized, regardless of treatment cross-over or post-randomization 
medical care.  A log-rank test will be used to compare the hazard functions between the two 
groups at any observed event time.  The median time to persistent AF/AT as well as the 95% 
confidence intervals will be reported by treatment group.  The survival probability and rate of 
persistent AF/AT at 3 years follow-up as well as the 95% confidence intervals for both groups 
will be presented.  
 
The effect size is defined as the negative log of the hazard ratio (hazard rate of the Test Group 
over hazard rate of the Control Group):              
⁄
) 
 
This study is to test the following hypothesis using a one-sided test at alpha equal to 0.025:  
H0: δ ≤ 0  


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H1: δ > 0 
 
Null hypothesis: the hazard rate in the Test Group is greater than or equal to the hazard rate in 
the Control Group at observed event times during the follow-up period  
 
Alternative hypothesis: the hazard rate in the Test Group is less than the hazard rate in the 
Control group at observed event times during the follow-up period  
 
At any interim monitoring calendar time   , we compute the Z statistic at information fraction 
   using the standardized logrank score statistic:   
 
 (  )      )
√    ) 
    
where      ) is the observed logrank score statistic at calendar time   , and      ) is the variance 
of      ). 
 
The Z test statistic will be compared with the stopping boundaries to determine whether this 
study will be stopped for effectiveness in each of the interim analyses.  If the Z statistic 
crosses the stopping boundary, that is, Z is greater than the critical value at the interim look, 
then the study will be stopped for effectiveness.  If the sample size exceeds the pre-planned 
sample size, then the CHW (Down-Weight) adaptive method will be used for statistical 
testing.68  
 
Conditional power will be calculated after the 1st interim look to assist the determination of 
whether the study will be stopped for futility.   
 
13.9.2 Interim Analyses 
 
An interim examination of the primary endpoint data will be performed at regular time 
intervals during the course of the trial to determine whether the study will be stopped for 
effectiveness or futility.  The primary objective of this study is to determine whether early RF 
ablation treatment using the CARTO ® 3, CARTO
 ® XP or CARTO ® RMT System and 
THERMOCOOL ® Catheter Family  in the PAF population delays progression of AF compared 
with AAD therapy (either rate or rhythm control) using current AF management guidelines.1-4  
In addition, interim reporting will also involve a review of subject recruitment, compliance 
with the study protocol, status of data collection, safety endpoints and other factors that may 
affect the overall progress and integrity of the study.  The results of the interim analyses and 
status reports will be reviewed by the Data Safety Monitoring Committee (DSMC). 
 
The DSMC will review the accumulated data at 1 year following the study startg and then 
approximately every 6 months thereafter.  Prior to each review, Biosense Webster will 
conduct statistical analyses and prepare an interim summary report.  The progress of subject 
enrollment, the rates of compliance with therapy, the frequency of protocol violations and 
rates of safety endpoints will be reviewed.  The number (status) of eCRFs completed, the 
number of outstanding data queries, the number of data queries completed, and the number of 
eCRFs reviewed through on-site monitoring will also be reviewed.  Extracted data files and 
analysis programs for each interim report will be archived in the study files. 
 
                                                    
g Time-interval related statistical deliverables are subject to change depending on the evolution of the 
study (e.g. delay in start-up, enrolment delay, …). 
 


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Interim effectiveness reports introduce well-recognized statistical problems related to the 
multiplicity of statistical tests performed on an accumulating set of data.  To properly account 
for the repeated interim testing in this study, a group sequential method similar to that 
proposed by O'Brien and Fleming as a guide in interpreting interim analyses will be used.69  
This procedure requires large critical values early in the study, but relaxes (i.e., decreases) the 
critical value as the trial progresses.  Because of the conservatism early in the trial, the critical 
value at the final analysis is near the "nominal" critical value.  Hence the sample size 
requirements with this group sequential procedure remain essentially the same as the 
conventional fixed sample size estimate.  The actual method for the interim reporting that will 
be employed in this study is the “alpha-spending function” approach to group sequential 
testing developed by Lan and DeMets.70  The Lan-DeMets approach is flexible to 
accommodate unequal sized groups with the number of interim looks unspecified in advance.  
It only requires specification of the rate at which the Type I error (which in this trial will be 
α=0.025 for the primary endpoint) will be "spent".  This procedure allows "spending" a 
portion of α at each interim analysis in such a way that at the end of the study, the total Type I 
error does not exceed 0.025.  This spending function generates boundaries that are nearly 
identical to the O'Brien-Fleming boundaries.  
 
In survival trials, information time is calculated based upon number of events rather than 
number of subjects accrued.  In practice, interim analyses are often scheduled based upon 
specified calendar time rather than number of events.  To address the logistical 
inconvenience, Lan and DeMets extended their general group sequential approach for the 
maximum duration trial.71  That is, the conduct of a trial is expected to occur within some 
period of time [0, Tc], where Tc is the maximum calendar (or duration) time for completion.  
The stopping boundaries can be adjusted based on the actual number of events observed at the 
interim look, rather than information fraction.  This method allows flexibility in the 
monitoring process for accommodating any changes in terms of timing and spacing of the 
looks or additional examination of the data that is not pre-determined in response to the 
concerns from the DSMC that may arise during the course of the trial. 
 
The analytic approach that will be used for the interim analyses for assessing treatment 
differences will be the time-to-event analysis method.  The standardized logrank score 
statistic will be compared with the stopping boundaries at each interim look to draw statistical 
inference.  If the stopping boundary is crossed, then the study will stop for effectiveness.  
 
Judgment concerning the continuation or termination of the study will involve not only the 
degree of statistical significance observed at the interim analysis, but also the likelihood of 
achieving significance should enrollment continue to the originally projected sample size.  As 
an aid in this latter assessment, the group sequential analyses outlined above will be 
supplemented with calculations of conditional power.  After approximately 25% of the total 
number of events have occurred (1st interim look), conditional power (CP) for the primary 
treatment comparison will be computed and provided to the DSMC as a regular part of the 
interim study reports.  If the CP is less than 0.2, then the study will be stopped for futulity.  
 
For example, the anticipated start time for this study is December, 2012 and the expected end 
of subject enrollment in June, 2014.  With 3 years follow-up time, the study is expected to be 
completed in June, 2017.  Interim looks are planned for December 2013, June 2014, 
December 2014, June 2015, December 2015, June 2016, and December 2016, with a final 
look in June 2017.  The stopping boundaries for effectiveness for these scheduled looks are 
displayed in Table 6.  If the study start time or calendar time for interim looks changes, the 
operating characteristics will be recalculated based upon actual calendar time of the interim 
looks and the number of events observed at each look.  
 
 


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Table 6.  Operating Characteristics for Group Sequential Design*  
Look # 
Calendar 
Time 
Information 
Fraction 
Number of 
Events 
Bounds 
Incremental 
Alpha 
Cumulative 
Alpha 
1 
Dec. 2013 
0.22 
5 
4.6374 
0.00000 
0.00000 
2 
June 2014 
0.33 
9 
3.7332 
0.00009 
0.00010 
3 
Dec. 2014 
0.44 
11 
3.1913 
0.00063 
0.00073 
4 
June 2015 
0.56 
15 
2.8277 
0.00192 
0.00265 
5 
Dec. 2015 
0.67 
20 
2.5881 
0.00341 
0.00606 
6 
June 2016 
0.78 
22 
2.3477 
0.00499 
0.01105 
7 
Dec. 2016 
0.89 
26 
2.2183 
0.00639 
0.01744 
8 
June 2017 
1 
28 
2.0507 
0.00756 
0.02500 
* Note: Time-interval related statistical deliverables are subject to change depending on the evolution 
of the study (e.g. delay in start-up, enrolment delay, …). 
 
13.10 Handling of Missing Data  
  
The primary effectiveness endpoint (time to disease progression) will be conducted in the ITT 
population.  Subjects with missing data will be included in this primary analysis.  The 
following analyses will be used to test the robustness of the analyses results with regards to 
missing data:  
 
1) Missing data will be censored at their last observation. 
2) Missing data will be imputed using multiple imputation.  This approach will enable 
an analysis to be conducted based on the full ITT population.  The details of this 
approach will be provided in the statistical analysis plan.   
 
13.11 Secondary Statistical Analyses of Primary Effectiveness Endpoint 
 
13.11.1 Per-Protocol Analysis 
 
This analysis will be performed in the PP subject population.  Propensity score weighting 
methodology will be applied to adjust for the imbalance of subjects’ characteristics between 
these two groups.  Cross-over subjects will be added to the ablation group and the time-
dependent covariate will be used to account for the different timing of cross-over.  A 
propensity score weighted Cox proportional hazards model will be used to compare the 
hazard rate between the two groups at observed death times.  Diagnosis analyses will be 
performed to examine the assumption of proportional hazards.  If the proportional harzards 
assumption is not met, then the interaction effect of time by treatment group and other remedy 
analyses will be investigated.  The adjusted hazard ratio and its 95% confidence intervals will 
be reported for the two groups.  Missing primary effectiveness endpoint data and the 
associated covariates that will be included in the propensity score modeling will be imputed 
using the multiple imputation method.  
 
13.11.2 Subgroup Analyses  
The primary effectiveness analysis (KM analysis of time to persistent AF/AT) will be 
performed for the Test Group as randomized and for the Control Group as randomized 
(excluding cross-over subjects).  The cross-over subjects (i.e., continued on their current 


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AAD or taking a newly prescribed AAD and had an RF ablation procedure) will be analyzed 
separately as a third group. 
 
Test Group: randomized to RF ablation to achieve PVI using the CARTO® 3, CARTO® 
XP or CARTO® RMT System, and THERMOCOOL® Catheter Family  
 
Control Group: randomized to AAD therapy in accordance with current AF 
management guidelines1-4 
 
Cross-over Group:  Control Group subjects who undergo RF ablation to achieve PVI 
using the CARTO® 3, CARTO® XP or CARTO® System, and THERMOCOOL® Catheter 
Family  
 
The median time to persistent AF/AT as well as the 95% confidence intervals will be reported 
for the three groups.  The survival probability and rate of persistent AF/AT at 3 years follow-
up as well as the 95% confidence intervals for these three groups will be presented separately.  
 
13.12 Secondary Effectiveness Endpoints Analyses  
 
13.12.1 
Rate and Time to Persistent AF/AT at 1 year, 2 and 3 years follow-up by 
number of ablations 
 
For the secondary effectiveness endpoint, the rate and time to persistent AF/AT (excluding 
isthmus dependent atrial flutter) at 1 year and 2 years and the rate of persistent AF/AT at 3 
years by number of ablations, a KM analysis will be performed to examine the hazard 
function of persistent AF/AT (excluding isthmus dependent atrial flutter) for the two 
treatment groups at 1 year follow-up time and 2 year follow-up and 3 year follow-up in the 
Test Group by the number of ablations.  Data will be censored at 1 year and 2 year follow-up 
in two separate analyses.  The analysis will be performed in both the ITT and PP populations.  
A log-rank test will be used to compare the hazard functions between the two groups at any 
observed event time.  The median time to persistent AF/AT at 1 year and 2 year follow-up as 
well as the 95% confidence intervals will be reported by the two groups.  The survival 
probability and rate of persistent AF/AT at 1 year and 2 years follow-up as well as the 95% 
confidence intervals for the two groups will be presented.  
 
The median time to persistent AF/AT at 3 years follow-up as well as the 95% confidence 
intervals will be reported for the Test Group by the number of ablations. The survival 
probability and rate of persistent AF/AT at 3 years follow-up as well as the 95% confidence 
intervals for the Test Group will also be presented by the number of ablations.  The KM 
curves will be plotted and results will be listed as well. 
 
13.12.2 
Number of Repeat Ablations and New AAD Drugs  
 
To analyze this secondary effectiveness endpoint, number of repeat ablations and new AAD 
drugs per subject throughout 3 years follow-up and the number of repeat ablations will be 
summarized and listed for the subjects who have undergone at least one ablation.  In addition, 
new AAD use will be summarized and listed for the subjects in the two groups by drug 
category and specific drug.  The analyses will be performed in both ITT and PP populations.  
 
13.12.3 
Rhythm Throughout 3 Years Follow-up 
 
To analyze this secondary effectiveness endpoint, rhythm (% subjects in sinus rhythm, % 
subjects with recurrent AF) throughout 3 years follow-up, the number of subjects and 
percentage of subjects with sinus rhythm and the number of subjects and percentage of 
subjects with recurrent AF/AT during the 3 year follow-up time will be summarized and 
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13.12.4 
Factors Associated with AF Disease Progression  
 
To analyze this secondary endpoint, conditions that may be associated with disease 
progression will be assessed at baseline and throughout the 3-year follow-up period.  These 
targeted parameters include: LA size at baseline and subsequent increase above baseline size; 
age ≥ 60 years; HATCH score at baseline and subsequent increase above baseline score; 
hypertension; NYHA Functional Classification of heart disease; diabetes; 
hyperlipidemia/dyslipidemia; renal insufficiency; and, dementia.  A Cox proportional hazards 
model will be performed to examine the associations of time with disease progression.  To 
document pre-existing diseases, measurable baseline parameters will include age, gender, LA 
size, AF duration, NYHA Functional Classification of heart disease, HATCH score, blood 
pressure, lipid profile, renal function and the presence of diabetes and/or dementia. The Cox 
proportional hazards model will also be used to examine time-varying covariates, based upon 
each follow-up visit and either as a new onset disorder or a worsened diagnosis since a 
previous assessment. These analyses will include all follow-up assessments throughout the 3-
year study period and measurable parameters will include: LA size; HATCH Score; blood 
pressure; NYHA Functional Classification of heart disease; diabetes; lipid profile; renal 
function and, dementia. All analyses will control for treatment assignment.  Any significant 
interactions between treatment effect(s) and covariates will also be examined. 
 
Univariate analysis will be performed to screen for significant factors associated with disease 
progression at p-value <0.2.  Then multivariate analyses will be performed to identify any 
factors associated with disease progression at p-value <0.05.  Model selection methods (e.g., 
Akaike Information Criteria [AIC], stepwise) will be applied to identify the best set of factors 
linked to disease progression.  The identification of relevant associations provides additional 
characterization and interpretation of the primary effectiveness outcome.  These analyses will 
be performed in both the ITT and PP populations. 
 
Descriptive statistics will be used to summarize the baseline and follow-up values of LA size, 
HATCH score, blood pressure, NYHA Functional Classification of heart disease, diabetes, 
lipid profile, renal function, and dementia by treatment groups.  Change-from-baseline will 
also be summarized and listed. Paired-sample test will be used to test whether the change 
from baseline values differs from zero (e.g., paired t-test, McNeman’s test) within each 
treatment group.  A two-sample comparison of the two groups with respect to changes in 
these characteristics will be performed using general linear models, including the baseline 
value as a covariate and assessing treatment group differences.  
 
13.13 Secondary Safety Endpoints Analysis  
 
A key secondary safety endpoint, catheter-related complications (AEs), is limited to subjects 
who have initiated RF ablation and who are in the safety population. The number and 
percentage of catheter-related AEs will be summarized and listed overall by Test Group and 
cross-over patients in the SP and by number of repeat ablations. The number and percentage 
of catheter-related complications will also be summarized and listed by AE category, 
causality, anticipated or not, severity and outcome.  
 
Serious catheter-related AEs will be reported by 2 timeframes: acute phase AEs, ablation to ≤ 
7 days; and, sub-chronic AEs occurring >7 to 30 days post ablation.  Serious AEs will be 
evaluated by causality and severity, using descriptive statistics. 
 


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The number and percentage of adverse drug reactions will be summarized and listed overall, 
according to Test Group; cross-over; and, Control Group excluding cross-over patients. The 
number and percentage of adverse drug reactions will also be summarized and listed by drug 
category and AE category, causality, anticipated or not, severity and outcome.  
 
13.14 Secondary Health Economic Endpoint Analyses 
 
13.14.1 
Health Care Utilization  
 
For this secondary health economic endpoint, health care utilization (number and length of 
hospitalizations and unscheduled cardiovascular-related visits), the total number and length of 
hospitalizations and unscheduled cardiovascular-related visits will be summarized and listed 
by treatment groups in the PP population.  
 
13.14.2 
Quality of Life  
 
Quality of Life (QoL) status will be compared to baseline at 3 months, 6 months, 1 year, 2 
years and 3 years. QoL will be measured by the EQ-5D and AFEQT questionnaires.  
Descriptive statistics for the baseline and changes-from-baseline measurements of the 
summary scores of these two measurement scales at follow-up visits will be summarized and 
listed by treatment groups.  The analyses will be performed in the PP population.  Paired-
sample test will be used to test whether the change-from-baseline values differs from zero 
(e.g., paired t-test) within each treatment group.  A two-sample comparison of the two groups 
with respect to changes-from-baseline in QoL will be performed using general linear models, 
including the baseline value as a covariate and assessing treatment group differences.  
 
13.15 Site Heterogeneity 
 
A Breslow-Day test for homogeneity of odds ratios measuring treatment effect on disease 
progression across site will be conducted at the significance level of 0.15.  Sites with less than 
five subjects will be combined to one mega-site by geographical locations.  If the results of 
the test show evidence of a lack of heterogeneity then the following sensitivity analyses will 
be performed:  
 
1) The primary effectiveness analysis in the ITT population will be performed using the Cox 
proportional hazard adjusting for significant site effects.   
 
2) The analysis for the secondary effectiveness endpoint ((factors associated with disease 
progression at baseline and throughout the 3 years follow-up) will include significant site 
effects.  
 
3) In the subgroup analysis of the primary effectiveness endpoint (KM analysis of time to 
persistent AF/AT), the KM analysis will also be performed by site performance (high 
performing sites versus low performing sites).  
 
13.16  Summary of Secondary Endpoints 
 
Secondary Endpoints – Effectiveness 
 
Effectiveness endpoint 1:  Rate and time to persistent AF/AT at 1 year and 2 years, rate of 
persistent AF/AT at 3 years by number of ablations at 3 years. 
Analysis Population: ITT and PP 
Analysis Method: KM curve 


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Effectiveness endpoint 2:  Number of repeat ablations and new AAD drugs per subject 
throughout 3 years follow-up. 
Analysis Population: ITT and PP 
Analysis Method: Descriptive statistics 
 
Effectiveness endpoint 3:  Rhythm (% subjects in sinus rhythm, % subjects with recurrent AF) 
throughout 3 years follow-up. 
Analysis Population: ITT and PP  
Analysis Method: Descriptive statistics 
 
Effectiveness endpoint 4:  Subject age (≥ 60 years); gender; and comorbidities possibly 
associated with disease progression, at baseline and throughout the 3-year follow-up period: 
abnormally large LA; HATCH Score ≥ 1; hypertension; Class 1 – 4 inclusive of NYHA 
Functional Classification of heart disease; hyperlipidemia/dyslipidemia; diabetes; renal 
insufficiency; and, dementia. 
Analysis Population: ITT and PP 
Analysis Method: Univariate and multivariate Cox proportional hazards model 
 
Secondary Endpoints – Safety 
 
Safety endpoint 1:  Catheter-related complications (ablation), side effects (AAD). 
Analysis Population: Safety Population 
Analysis Method: Descriptive Statistics 
 
 
Secondary Endpoints – Health Economics (HE) 
 
HE endpoint 1: Health care utilization (number and length of hospitalizations and unscheduled 
cardiovascular-related visits). 
Analysis Population: PP population 
Analysis Method: Descriptive Statistics 
 
HE endpoint 2:  Quality of Life at 3 months, 6 months, 1 year, 2 years and 3 years by EQ-5D and 
AFEQT Questionnaire and change from baseline. 
Analysis Population: PP population 
Analysis Method: Descriptive Statistics 
 
14.0 Administrative Responsibilities 
 
14.1 Ethics Committee (EC) / Ethics Board (EB) Information 
 
The protocol and amendments, informed consent form and other applicable study-related 
documents must be submitted to the appropriate EC and written approval must be obtained 
and submitted to the Sponsor prior to enrolling any subjects. 
 


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Before initiating this study, the Sponsor will work with the investigator to obtain approval 
from the EC / EB and fulfill any local, applicable requirements for notification to or to obtain 
approval from competent authorities if necessary. The investigator will obtain written and 
dated approval from the responsible EC / EB for the study protocol (or amendment[s]) and 
informed consent before enrollment of subjects. Biosense Webster and the EC / EB 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 signed copy of the EC / EB Approval Form and a signed copy of the EC / EB approval 
letter 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 regulations) of the study by their EC / EB. 
 
14.2 Informed Consent 
 
The investigator will obtain written and dated approval from the responsible EC / EB for the 
study ICF.  A patient's informed consent must be obtained and documented per institutional, EC 
/ EB, and applicable regulatory requirements. 
 
 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the patient in both oral and written form by the investigator or 
designee.  Patients should not be coerced, persuaded, or unduly influenced to participate or 
continue to participate in the study.  Patients or their 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 their representative. 
 
Prior to participation in the study, the investigator or designated member of the research team 
will obtain written informed consent from the patient. The background of the proposed study 
and the potential benefits and risks of the study should be explained to the patient.  The 
patient or legal representative must sign the ICF (see Appendix E) prior to any study-specific 
exams or tests are provided to them that fall outside of the standard of care.  The study’s 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).  If the patient 
or his/her legal representative is unable to read the study’s ICF, a witness should be present 
during the entire informed consent discussion.  After the study’s ICF is read to the patient and 
signed by the patient or his/her legal representative, the witness should also sign it, attesting that 
informed consent was freely given by the patient or his/her legal representative. 
 
The patient or his/her legal representative must receive a copy of the signed and dated ICF.  A 
copy of the EC/EB -approved ICF for this study must be maintained by each investigator in a 
designated study administrative file. 
 
14.3 Subject Confidentiality 
 
All information and data sent to Biosense Webster concerning subjects or their participation 
in this study will be considered confidential.  During this study, all representatives of the 
Sponsor will comply with all in-country privacy laws and regulations regarding contact with 
subjects, their medical record information, copying of information, and protection of the 
subject identities.  Information and data collected and used in the analysis and reporting of 
this evaluation will be without identifiable reference to the subject.  No information that can 
be used to identify subjects will be collected.  Only authorized Biosense Webster personnel or 
an appropriately qualified and trained designee, local government authorities or federal 
agencies (e.g., the U.S. FDA) acting in their official capacities will have access to these 
confidential files.   


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14.4 Monitoring the Study 
 
Monitoring will be conducted throughout the course of this study according to the Monitoring 
Plan. 
 
Monitoring visits will be conducted to oversee the progress of the study and verification of 
the following: 
 
the rights and well being of the subjects are protected; 
 
the study is conducted according to Good Clinical Practices (GCP) and FDA 
regulations; 
 
the protocol and applicable amendments are followed;  
 
the recorded data are accurately represented.   
 
The Sponsor and/or designee will perform on-site monitoring visits as defined in the study 
Monitoring Plan. Each visit will encompass activities such as verification that all subjects 
have signed the study’s ICF, confirmation that randomization procedures are being followed, 
completion of appropriate source document verification, and identification of and action taken 
to resolve any issues or problems with the study. 
 
Biosense Webster may request further documentation such as investigator and/or EP lab 
procedure notes when complications or product malfunctions are observed.  To this end, the 
investigator and institution must permit inspection of the study files and subjects’ eCRFs by 
Sponsor personnel.  
 
14.5 Management of Protocol Amendments  
 
All instructions described in this study protocol are to be followed.  If an amendment is required, 
it must be made in written form and receive approval from all persons and authorities who 
approved the original protocol.  Administrative changes (do not effect subjects benefits/risks 
ratio) may be inserted with abbreviated approval.  All amendments will be distributed to all 
original protocol recipients. 
 
14.6 Management of Protocol Deviations  
 
The investigator may not deviate from the protocol without prior notification and approval 
from Biosense Webster, Inc. 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.  All protocol deviations will be documented and followed up 
according to the applicable Standard Operating Procedures (SOPs).  All protocol deviations 
will be monitored closely by the Sponsor or designee(s). Any evident pattern of non-
compliance with respect to applicable standards will be cause for the site to be put on 
probation.  If corrective actions are not subsequently undertaken, the site will be asked to 
withdraw. 
 
14.7 Data Management  
 
Steps taken to assure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate centers, review of the protocol with the investigator and 
associated personnel prior to the study start and periodic monitoring visits by Biosense 
Webster or an appropriately qualified and trained designee. 
 
 
 


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14.7.1 Data Collection 
 
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.  If modification of study eCRFs is required during the course of this study, 
Biosense Webster will inform all sites and provide updated information and materials needed 
for continued study conduct. 
 
14.7.2 Data Reporting 
 
The investigator, or a designated individual, is responsible for recording all data from the 
study on the eCRFs using source-documents, such as hospital charts.  The investigator 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. 
 
After completion of study visits, eCRFs should be thoroughly completed without unjustified 
delay.  For AE reporting requirements, refer to the AE Section of this study protocol.  
 
14.7.3 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 no standard hospital or office document exists to capture 
information that may be unique to this study, a worksheet may be developed to record this 
information, which shall be signed by the PI at the given site and serve as the source 
document for unique study data.  These worksheet source documents 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 printed and added to the subject’s paper file.  A print-out of an 
eCRF cannot be used as source documentation. It is the obligation of each investigator (or 
designee) to assure that the medical files and all other possible files, e.g. nursing files, are 
appropriately completed. The subject’s file of each enrolled subject should clearly reflect the 
status of the subject. The subject’s file also should clearly show that this subject is a study 
participant by entering the following details: study Sponsor (Biosense Webster), protocol 
number, clinical site, subject number assigned, date of enrolment and a statement that consent 
was obtained prior to any study specific procedure. The use of a label is allowed to cover this 
information. 
Each follow-up visit needs to be reported in source documents and should at least contain: all 
AEs, concomitant medication, information on study-related activities per follow-up visit and 
general status of the subject. 
 
 
14.7.4 Data Verification and Review 
 
All eCRFs will undergo automated and manual initial inspection for omitted data, gross data 
inconsistencies, and timeliness of reporting.  Periodic analysis of each data field (across 
cases) will be performed in order to examine the expected distributions of data, and to 
identify outliers for possible data entry errors. 
 
 
 
 
 


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14.7.5 Final Data Analyses 
 
All exported datasets for analyses will undergo a final data verification procedure.  Once all 
critical data are monitored and the database is locked, the analysis of study data will be 
performed. 
 
14.7.6 Confidentiality and Protection of Study Files 
 
Passwords will be issued to appropriate personnel to insure confidentiality and protection of 
the data by allowing variable levels of access to the computer system.  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. 
 
14.8 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.   
 
15.0 Study Management 
 
15.1  Investigator Selection 
 
In order to mitigate the effect of the learning curve, sites experienced with using the CARTO® 
3, CARTO
 ® XP or CARTO
 ® RMT System and THERMOCOOL® family of catheters will be 
selected for the study.  Sites will be reflective of real world practice in terms of volume and 
experience in using these technologies. 
 
Therefore site selection criteria may include but are not limited to: 
 
 
At least 100 RF ablation procedures for the treatment of AF performed with the CARTO® 
XP System, CARTO
 ® RMT or other 3D mapping techniques 
 
At least 25 RF ablation procedures for the treatment of AF performed with the  CARTO®  
3 System, CARTO
 ® XP or  CARTO
 ® RMT System, and THERMOCOOL® family of 
catheters 
 
AF ablation volume will be at least 75 AF ablation procedures performed in 2011 or 2012 
 
Availability of a study coordinator/fellow to support the logistics of the study 
 
No other study ongoing at the site that would compete for the same patient population, 
unless the number of AF ablation procedures justifies conduct of 2 concurrent AF studies 
and commitment to enrollment targets can be made 
 
15.2 Investigator Training 
 
Training of appropriate clinical site personnel will be the responsibility of the Sponsor.  To 
ensure uniform data collection and protocol compliance, Sponsor personnel will present a 
formal educational session to the study site personnel including but not limited to reviewing 
the applicable Good Clinical Practice (GCP) guidelines, the protocol, the eCRF and data 
collection process, randomization process, and the adverse event and complaint reporting 
processes. 
 
15.3 Investigator Responsibilities 
 
 
Obtain EC/ EB approval, if applicable  
 
Supply the Sponsor with a current curriculum vitae and that of any colleagues involved in 
the study 


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 
Obtain informed consent form and enroll patients 
 
Perform medical procedures 
 
Order all tests required by the study protocol 
 
Adhere to the study protocol 
 
Follow subjects until the end of the study protocol 
 
Complete eCRFs on time, completely and accurately 
 
Allow the Sponsor direct access to source documents to perform monitoring duties, and to 
perform audits  
 
Maintain records and provide reports according to the local legislation/regulations 
 
Share all relevant study-related information with colleagues involved in this study 
 
Inform the appropriate entities (e.g., Sponsor, Biosense Webster, Inc.’s Complaints 
Management Department, the EC / EB) in a timely manner regarding the occurrence of 
any AEs and/or product malfunctions. 
 
15.4 Sponsor Responsibilities 
 
 
 
Selection of the study investigators  
 
Selection of appropriately qualified and trained individuals, including monitors, to 
conduct the study 
 
Selection of members for the Clinical Endpoint Committee (CEC) and Data Safety 
Monitoring Committee (DSMC). 
 
Development and, if applicable, modifications of protocol and eCRFs 
 
Obtain study contracts with investigators/hospitals, CROs and other involved parties 
 
Development and/or approval of an adequate informed consent form 
 
Ensure that appropriate training/information is provided to the study investigators and 
staff 
 
Data monitoring 
 
Database input, management and maintenance 
 
Inform investigator of his/her responsibilities 
 
Ensure that all AEs are reported by the study investigators and where appropriate, are 
reported to the other investigators and relevant regulatory authorities 
 
15.5 Clinical Endpoint Committee (CEC) 
 
The Sponsor may consider to assign a Clinical Endpoint Committee (CEC) to adjudicate the 
primary event outcome. 
 
15.6 Data Safety Monitoring Committee (DSMC) 
 
An independent DSMC, consisting of 3 physicians, at least one of which must be expert in 
electrophysiology, will meet according to a defined schedule to review interim analyses of 
both safety and effectiveness parameters, and for purposes of advising the study sponsor as to 
whether the study should continue or be suspended/terminated.  Telephone conferences may 
be initiated outside the defined schedule to discuss serious study issues that may have arisen.  
 
16.0 Regulatory / Ethical Considerations 
 
16.1 Basic Principles and Standards 
 
This clinical study will be conducted under applicable regulatory requirements and good clinical 
practice (GCP) guidelines including but not limited to: 
 
 
ISO 14155: 2011(E) (Clinical Investigation of Medical Devices for Human Subjects – 
Good Clinical Practice) 


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 
Declaration of Helsinki 
 
ICH E6 Good Clinical Practice 
 
Medical Device Directive 93/42/EC 
 
MEDDEV 2.12-1 Guidelines on a Medical Devices Vigilance System 
 
Directive 2001/20/EC and CT-3 
 
Vaughan Williams Classification of Anti-arrhythmic drugs 
 
ICH-E2A 
 
www.medicins.org.uk 
 
16.2 Record Retention and Archiving 
 
Each site will be asked to maintain study records as instructed by local requirements.  The 
Sponsor will maintain study records according to the applicable Biosense Webster procedure.   
 
 
 
 
 
 


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17.0 References 
 
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observations of clinical outcomes with rhythm‐ and rate‐control therapies for atrial 


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fibrillation RECORDAF (Registry on Cardiac Rhythm Disorders Assessing the Control 
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the transition from intermittent to permanent atrial fibrillation. Am Heart J 2000; 
140(1):142‐5. 
 
29. Nakamura K, Funabashi N, Uehara M, Ueda M, Murayama T, Takaoka H, et al. Left 
atrial wall thickness in paroxysmal atrial fibrillation by multislice‐CT is initial marker of 
structural remodeling and predictor of transition from paroxysmal to chronic form. Int J 
Cardiol 2011; 148: 139‐47. 
 
30. Ruigomez A, Johansson S, Wallander MA, Garcia Rodriguez LA. Predictors and 
prognosis of paroxysmal atrial fibrillation in general practice in the UK. BMC Cardiovasc 
Disord 2005; 5:20. 
 
31. Tsang TS, Barnes ME, Miyasaka Y, Cha SS, Bailey KR, Verzosa GC, et al. Obesity as a 
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32. Dabrowski R, Borowiec A, Janas J, Firek B, Kowalik I, Smolis‐Bak E, et al. High 
concentrations of B‐type natriuretic peptide and left ventricular diastolic dysfunction in 
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68(8):893‐900. 
 
33. Jongnarangsin K, Suwanagool A, Chugh A, Crawford T, Good E, Pelosi F, et al. Effect of 
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Electrophysiol 2011; Epub ahead of print. 
 
34. Kirchhof P. Can we improve outcomes in AF patients by early therapy? BMC Med 2009; 
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35. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during 
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37. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing. Structural, 
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38. Santinelli V, Radinovic A, Vicedomini G. Early rhythm control strategy by catheter 
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2 study. American Heart Association 2009; 2542. 
 
39. Wazni OM, Marrouche NF, Martin DO, Verma A, Bhargava M, Saliba W, et al. 
Radiofrequency ablation vs antiarrhythmic drugs as first‐line treatment of symptomatic 
atrial fibrillation: a randomized trial. JAMA 2005; 293:2634‐40. 
 


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40. Pappone C, Vicedomini G, et. al. Radiofrequency Catheter Ablation and Antiarrhythmic 
Drug Therapy: A Prospective, Randomized 4-Year Follow-Up Trial - The APAF Study. 
Circulation 
2011; 
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10.1161/CIRCEP.111.966408 
 
41. Fichtner S, Czudnochowsky U, Hessling G, Reents T, Estner H, Wu J, et al. Very late 
relapse of atrial fibrillation after pulmonary vein isolation: Incidence and results of repeat 
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42. Medi C, Sparks PB, Morton JB, Kistler PM, Halloran K, Rosso R, et al. Pulmonary vein 
antral isolation for paroxysmal atrial fibrillation: Results from long‐term follow‐up. J 
Cardiovasc Electrophysiol 2011; 22:137‐41. 
 
43. Ouyang F, Tilz R, Chun J, Schmidt B, Wissner E, Zerm T, et al. Long‐term results of 
catheter ablation in paroxysmal atrial fibrillation: lessons from a 5‐year follow‐up. 
Circulation 2010; 122: 2368‐77.   
 
44. Rosso R, Sparks PB, Morton JB, Kistler PM, Vohra JK, Halloran K, et al. Vagal 
paroxysmal atrial fibrillation: prevalence and ablation outcome in patients without 
structural heart disease. J Cardiovasc Electrophysiol 2010; 21(5):489‐93. 
 
45. Sawhney N, Anousheh R, Chen WC, Narayan S, Feld GK. Five‐year outcomes after 
segmental pulmonary vein isolation for paroxysmal atrial fibrillation. Am J Cardiol 2009; 
104(3):366‐72. 
 
46. Weerasooriya R, Khairy P, Litalien J, Macle L, Hocini M, Sacher F, et al. Catheter 
ablation for atrial fibrillation: are results maintained at 5 years of follow‐up? J Am Coll 
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47. Veasey RA, Arya A, Silberbauer J, Sharma V, Lloyd GW, Patel NR, et al. The 
relationship between right ventricular pacing and atrial fibrillation burden and disease 
progression in patients with paroxysmal atrial fibrillation: The long‐ MinVPACE study. 
Europace 2011; Epub ahead of print. 
 
48. Huang SKS, Wilber DJ (eds): Radiofrequency Catheter Ablation of Cardiac Arrhythmias: 
Basic Concepts and Clinical Applications, 2nd ed. Grouponk, NY: Futura Publishing 
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Catheter Ablation 2000.  Pages 737-746. 
 
49. Scheinman MM, Huang S. The 1998 NASPE Prospective Catheter Ablation Registry. 
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50. Cappato R, Calkins H, et. al. Updated Worldwide Survey on the Methods, Efficacy, and 
Safety of Catheter Ablation for Human Atrial Fibrillation. Circulation 2010; 3; 32-38. 
 
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52. Nahass GT. Fluoroscopy and the Skin: Implications for Radiofrequency Catheter 
Ablation Am J Cardiol 1995; 6: 174-176. 
 


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During Radiofrequency Catheter Ablation of Accessory Atrioventricular Connection, 
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55. Pappone C, Oreto G, Rosanio S, Vicedomini G, Tocchi M, Gugliotta F, Salvati A, 
Dicandia C, Calabrò MP, Mazzone P, Eleonora F, Di Gioia C, Gulletta S, Nardi S, 
Santinelli V, Benussi S, Alfieri O. Atrial Electroanatomic Remodeling After 
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2539-2544. 
 
56. Oral H, Knight BP, Tada H, Özaydin M, Chugh A, Hassan S, Scharf C, Lai SWK, 
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57. Takahasi A, Lesaka Y, Takahasi Y, Takahasi R, Kobayashi K, Takagi K, Kuboyama O, 
Nishimori T, Takei H, Amemiya H, Fujiwara H, Hiraoka M. Electrical Connections 
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58. Yamane T, Shah DC, Jaïs P, Hocini M, Deisenhofer I, Choi K-J, Macle L, Clémenty J, 
Haïssaguerre M. Electrogram Polarity Reversal as an Additional Indicator of 
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59. Macle L, Jaïs P, Weerasooriya R, Hocini M, Shah DC, Choi K-J, Scavée C, Raybaud F, 
Clémenty J, Haïssaguerre M. Irrigated-Tip Catheter Ablation of Pulmonary Veins for 
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60. Deisenhofer I, Schneider MAE, Böhlen-Knauf M, Zrenner B, Ndrepepa G, Schmieder S, 
Weber S, Schreieck J, Weyerbrock S, Schmitt C. Circumferential Mapping and Electric 
Isolation of Pulmonary Veins in Patients With Atrial Fibrillation.  Am J Cardiol 2003;  
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66. Rubinstein, L. V., Gail, M. H. and Santner, T. J. ‘Planning the duration of a comparative 
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Statistics in Medicine 1989; 8:1191-1198. 
 
 
 
 
 
 
 
 


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Appendices 
 
Appendix A: Description and Analysis of Risks 
 
The incremental risk associated with use of a saline-irrigated electrode catheter rather than a 
standard electrode catheter is small.  The larger RF lesion size produced with this catheter 
may increase pain (during the procedure) associated with RF applications and may increase 
the risk of cardiac rupture.  Increased pain, however, can be managed with intravenous 
analgesics.  Additionally, use of the cooled electrode tip catheter may reduce procedural time, 
fluoroscopy time and increase procedural success by increasing lesion depth and by 
minimizing coagulum formation, which necessitates repeated removal and re-deployment of 
the ablation catheter.  While the ability to cool the electrode-tissue interface allows the use of 
higher power than with a conventional 4mm 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 4mm electrode. 
 
Radiofrequency current may cause occlusion of a coronary artery, either by direct thermal 
damage, spasm, or thrombosis.  Experience at numerous centers suggests that the risk of 
coronary occlusion is less than 0.5%.47, 48   Coronary artery 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.  
 
A thrombus may form on the ablation electrode during the application of radiofrequency 
current without any change in impedance.  The thrombus might become dislodged and 
embolize to produce a stroke, MI, or other ischemic injury.  The risk of an embolus is reduced 
by quickly terminating the application of current after an impedance rise, which limits the size 
of the coagulum on the electrode.  Probably the most important aspect of the THERMOCOOL® 
family of catheters is the near absence or very low likelihood of thrombus formation during 
RF.  
 
Thrombus formation on the endocardium following ablation may produce an arterial or 
pulmonary embolus.  This risk may be reduced by the use of aspirin (antithrombotic) and/or  
anticoagulation therapy, at the discretion of the investigator. 
 
Cardiac perforation may result from catheter manipulation or application of radiofrequency 
current (risk is <1%).47, 48  This may result in cardiac tamponade and may require 
percutaneous pericardial drainage or surgical repair.  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, 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 above 35 or 40 watts.  If the lesion is deeper, the 
risk of steam pop is higher above 35-40 watts.  
 
Injury to a cardiac valve may result from catheter manipulation or the application of 
radiofrequency current (risk <1%).47, 48, 49 This may produce valvular insufficiency and 
possibly necessitate 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 or result in 
permanent impairment.49  Reducing power at sites in close proximity to and/or avoiding sites 
directly over the esophagus may reduce the risk of thermal injury.  
 
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. 
 
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%).50-52  
 
The risk of pulmonary AEs (e.g., pulmonary vein stenosis, thrombus and hypertension), 
associated with an AF ablation procedure targeting the pulmonary veins, is considered small 
(<4%).49, 53-59 
 
Other potential complications, which may result from catheter insertion and manipulation as 
part of the 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%).60-64  
 
Arterial or venous injury, including arterial dissection, thrombosis, occlusion or 
hemorrhage at the catheter insertion sites or at other sites along the vessels  
(risk <1%).47, 48  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. 47, 48   
 
Infection, either at the catheter insertion site or systemically, including endocarditis and 
septic emboli (risk <0.5%).47, 48, 49  This risk can be minimized by using standard aseptic 
technique and by the use of antibiotic agents when indicated.  
 
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 confirm 
compliance with the study inclusion and exclusion criteria.   
 
Participating investigators will be experienced and skilled in performing electrophysiology 
studies, intracardiac mapping, and ablation of AF with the use of the RF ablation catheters.  
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.  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 the THERMOCOOL® family of catheters will be performed 
according to the product Instructions for Use, including but not limited to instructions 
regarding indications and contraindications for using these devices.  
 


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Precautions: 
 
Invasive electrophysiological evaluation and catheter ablation may impart some degree of risk 
to the patient.  The risk of serious complications is generally related to the severity of cardiac 
disease.  The degree of risk of the electrophysiological and catheter ablation procedures and 
the potential benefit of the treatment of symptomatic PAF should be determined by a 
qualified physician.  Failure to observe all contraindications, warnings, and precautions, as 
listed in the Instructions for Use may result in procedural complications.  Procedural 
complications include: cardiovascular injury or perforation with or without cardiac 
tamponade, pulmonary embolus, tricuspid regurgitation, MI, bleeding at the catheter insertion 
site, sepsis, and death. 
 
Potential Benefit: 
 
The direct benefit for patients undergoing radiofrequency catheter ablation is the potential 
elimination of AF episodes.  It is furthermore expected that quality of life will improve and 
less frequent hospitalization will be required.  The information gathered during the conduct of 
this study may be of benefit in the future for the treatment of patients with atrial fibrillation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix B: Guidelines and Restrictions for the ATTEST Protocol Regarding 
Cross-over from the Drug (Control) Group 
 
 
1. Guidelines and principles for cross-over are to be followed by the investigator as laid down in 
this document and in the protocol. 
 
2. It is the intent of the Sponsor and organizers of this study that cross-over be significantly 
reduced from published rates quoted in previous drug versus ablation trials.   
 
3. The crossing over from the drug group undermines the tenets of equipoise that are intended in: 
(a) the study’s collective inclusion/exclusion criteria for all subjects; (b) the eligibility of all 
subjects at study onset to be randomized to either treatment group; and, (c) the intended 
balance of AF severity, drug history, concurrent illnesses (HATCH score severity), 
demographics, and other characteristics, such that legitimate statements might be made in 
comparing the outcomes of medical management versus ablation therapy.  The nature and 
conditions for cross-over from the Control (AAD therapy) Group to the Test (PVI) Group, in a 
randomized controlled study, are not well understood and are multi-factorial.  Thus, any 
assumptions that subjects crossing over reflect the general demographics, disease severity, and 
extent of disease progression within either study group at randomization cannot be held with 
certainty. 
 
4. One could justifiably argue that those most likely to suffer severe side effect reactions from 
AAD therapy might be those who take their drugs sporadically, take drugs sometimes too 
close together (shortened inter-dose time interval), suffer rebound effects from resumption of 
drugs after a drug holiday, and who do not heed the warnings of physicians/pharmacists about 
mixing drugs for AF/AT with those for other chronic diseases.  One might further argue that 
those with heightened disease progression, as noted in published literature, would be among 
the oldest in their randomized study group and that their baseline HATCH scores are likely to 
be high as well, which is consistent with elderly patients.  If one or more of these assumptions 
are true, those most likely to seek cross-over from the drug group would be among the 
aforementioned, resulting in a relatively younger, healthier, and more compliant group of 
subjects remaining in the drug group over the whole 3 year study period. In this context, 
extensive cross-over certainly would erode equipoise. 
 
5. The recognized reasons for patients not doing well on drug therapy are as follows: 
 
a. 
Patients failing to take the medication as prescribed – called “non-adherence”: 
i. Missed days (drug holidays) – recurring disease symptoms or sudden drug-
related side effects, if drug rebound effect, after resuming medication. 
ii. Irregular timing, resulting in low concentrations of active drug at some 
points or too high concentrations of active drug when medication is taken at 
close intervals (may manifest as side effect problem). 
iii. Medication dropout – patient takes no drug but does not share this 
information with his/her physician – unexpected disease progression. 
b. Patient cannot tolerate medication, even if compliant with prescribed regimen (side 
effects): 
i. Sensitivity to the prescribed AAD. 
ii. Concurrent prescribed medications for other chronic diseases are 
contraindicated for the particular AAD prescribed. 
 
6. When a subject complains to his/her Investigator about the medication and requests a cross-
over to receive ablation, the Investigator will have little idea of the root cause of the subject’s 
medication-related problem. 
 


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A cross-over management algorithmh  could be used to help sort out disease progression issues 
from drug-related problems. 
 
7. The following guidelines should be addressed by each investigator, prior to making a decision 
on a subject: 
 
REASON TO INDUCE CROSS-OVER 
REASON TO AVOID CROSS-OVER 
1. Severe symptoms of AF in the absence of 
evidence that the subject was not taking 
the prescribed medication and consensus 
that 
further 
medication 
would 
be 
unsuccessful. 
2. Severe side effects or AF symptoms, 
evidence of adherence to the prescribed 
AAD regimen, and no other drug options 
to which to switch the subject. 
1. Evidence that the subject did not take 
the medications as prescribed and/or 
took 
concurrent 
incompatible 
medications for other chronic diseases 
– 
this 
subject 
should 
undergo 
Medication Managementi and then 
return to the hospital 3 weeks later for 
re-evaluation.   
2. Evidence not sufficiently strong to 
merit cross-over, in the minds of the 
Investigator..  
 
 
 
                                                    
h A copy of this algorithm will be available to investigators in this trial as a reference guide to 
managing subjects with difficulties with their prescribed AAD. 
i Medication management includes reviewing all medications taken and an attempt to identify drugs 
with possible incompatibility with AAD medication(s); review and manage drug taking routine:  timing 
- warning about taking drugs too close together or too far apart; warning about drug holidays and 
dangers; discuss taking with or without food, as prescribed; coach to use robust routines (taking pills 
same time each day); pill organizers; and/or recruitment of family to assist subject. 


 
 
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Appendix C: Justification for AF Disease Progression Rate Estimates 
 
1. Introduction 
The study of Atrial Fibrillation Progression Trial (ATTEST) is to determine whether early RF ablation 
intervention using the CARTO
 ® 3 System, CARTO ® XP or CARTO
 ® RMT System and THERMOCOOL
 ® 
Catheter family in the paroxysmal AF (PAF) population delays or prevents progression of AF 
compared with conventional drug therapy (either rate or rhythm control) using current AF management 
guidelines.  The rates of disease progression at the 3 year follow-up for the ablation group and drug 
group were estimated at 5% and 25% respectively.  This document is to justify these estimates using 
DerSimonian and Laird meta-analysis method.1  
 
2. Methodology 
The weighted noniterative DerSimonian and Laird random effects model was used to synthesize 
information from relevant literature studies.  In this approach, we assume that there is a distribution of 
treatment effects and utilize the observed effects from individual studies to estimate this distribution. 
This approach estimates the magnitude of the heterogeneity, and assigns a greater variability to the 
estimate of overall treatment effect to account for this heterogeneity.  The approach allows for 
treatment effects to vary across studies and provides an objective and more conservative method for 
weighting.  
 
3. Literature Search 
An independent research group (S2 Statistical Solutions) conducted a literature search on AF disease 
progression outcomes, according to a prospective work plan.  Published studies (1990-2011) were 
searched via PubMed, and unpublished studies were sought from abstracts and presentations at recent 
professional meetings.  Fifty studies meeting inclusion criteria were identified, of which 4 compared 
catheter ablation to medical treatment.  Details of these comparative studies are shown in Tables C1 
and C2. 
 
4. Meta-Analysis Results 
The four comparative studies have different follow-up time.  Their disease progression rates at 3 years 
follow-up are estimated assuming a linear increase of subjects with disease progression over time.  The 
study characteristics and disease progression rates for the ablation arm are summarized in Table C1. 
The weighted estimate for disease progression of ablation treatment at 3 years follow-up combining the 
four comparative studies, using non-iterative weighted DerSimonian and Laird random effects model,1  
is 5.6% with the 95% interval of 0.4% - 47.9%. 
 
Table C1.  Literature Studies for Ablation Arm 
 
Author 
Study 
Design 
AF Type at 
Baseline 
 
Follow-
up time 
(months) 
Disease 
Progression 
Rate at Study 
Follow-up 
Time 
Disease 
Progression 
Rate at 3 Year 
Follow-up 
Time 
95% CI 
Santinelli 
2009 (APAF) 
RCT 
Paroxysmal to 
persistent/ permanent 
48 
1% (1/99) 
1% (1/99) 
(0.0% –
5.5%) 
Dabrowski 
2010 
Comparative 
(non-RCT) 
Paroxysmal to 
persistent/ permanent 
12 
0% (0/6) 
0% (0/6) 
(0.0% - 
45.9%) 
De Vos 2010 
Comparative 
(non-RCT) 
Paroxysmal to 
persistent/ permanent 
12 
6.5% (4/61) 
19.7% (12/61) 
(10.6% - 
31.8%) 
Pappone 2008 
Comparative 
(non-RCT) 
Paroxysmal to 
persistent/ permanent 
60 
0% (0/11) 
0% (0/11) 
(0.0% - 
28.5%) 


 
 
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The four comparative studies have different follow-up time.  Their disease progression rates at 3 years 
follow-up are estimated assuming a linear increase of subjects with disease progression over time.  The 
study characteristics and disease progression rates for the drug arm are summarized in Table C2.  The 
weighted estimate for disease progression of drug therapy at 3 years follow-up combining the four 
comparative studies, using non-iterative weighted DerSimonian and Laird random effects model,1  is 
26.4% with the 95% interval of 14.8% - 42.6%.  
 
Table C2.  Literature Studies for Drug Therapy 
 
5. Conclusion 
Our point estimates using the DerSimonian and Laird random effects meta-analysis method1 for disease 
progression rates at 3 years follow-up in the ablation arm and drug arm are 5.6% and 26.4% 
respectively, which are consistent with the physicians’ estimates of 5% and 25% for ablation and drug 
therapy in the new study.  Therefore, the published literature and experience in AF disease progression 
support our estimates of disease progression rate at 3 years follow-up and fully support the study 
design of a randomized trial testing whether early ablation treatment delays or prevents disease 
progression from paroxysmal AF to persistent or permanent AF compared with drug therapy. 
    
Reference 
 
1. DerSimonian R and Laird N.  Meta-analysis in clinical trials. Controlled Clinical Trials 1986; 
7:177-188.  
Author 
Study 
Design 
AF Type at 
Baseline 
 
Follow-up 
time 
(months) 
Disease 
Progression 
at Study 
Follow-up 
Time 
Disease 
Progression 
at 3 Year 
Follow-up 
Time 
95% CI 
Santinelli 
2009  
(APAF) 
RCT 
Paroxysmal 
to persistent/ 
permanent 
48 
2% (2/99) 
1.5% 
(1.5/99) 
(0.0% - 
3.9%) 
Dabrowski 
2010 
Comparative 
(non-RCT) 
Paroxysmal 
to persistent/ 
permanent 
12 
10% (15/148) 
Subgroups: 
Parox to 
perm: 0% 
(0/79) 
Pers to perm:  
20% (15/75) 
30.4% 
(45/148) 
(23.1% - 
38.5%) 
De Vos 
2010 
Comparative 
(non-RCT) 
Paroxysmal 
to persistent/ 
permanent 
12 
15% 
(174/1158) 
45.1% 
(522/1158) 
(42.2% - 
48.0%) 
Pappone 
2008 
Comparative 
(non-RCT) 
Paroxysmal 
to persistent/ 
permanent 
60 
53% (24/45) 
25.5% 
(14/45) 
(14.7% - 
39.0%) 


 
 
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 Appendix D: Safety Provisions - Drug Regulations  
Countries for which the Attest study is subjected to national drug regulations (EudraCT 
number: 2012-002338-35, if applicable) the following provisions are applicable in addition to 
Section 12 of the protocol. 
 
Definitions: 
Suspected Unexpected Adverse Reaction  (Directive 2001/20/EC and CT-3):  
An suspected unexpected adverse reaction (SUAR) is an adverse reaction, the nature or 
severity of which is not consistent with the applicable product information (e.g. investigator's 
brochure for an unauthorised investigational product or summary of product characteristics 
for an authorized product). 
 
A SUSAR is defined as an event meeting the definition of a suspicion of SUAR and 
Seriousness definition (medicines). 
 
To determine if an Serious Adverse Reaction of an AAD is expected or unexpected, Biosense 
Webster will refer to a list of SmPc’s (e.g. www.medicines.org.uk). 
 
ATC 
Class* 
Name 
Control 
C07AA05 
II 
Propranolol 
Rate 
C07AA07 
III 
Sotalol  
Rate/Rhythm 
C07AB02 
II 
Metoprolol 
Rate 
C07AB03 
II 
Atenolol 
Rate 
C07AB04 
II 
Acebutolol 
Rate 
C07AG02 
II 
Carvedilol 
Rate 
C07AB12 
NA 
Nebivolol 
Rate 
C07AB07 
II 
Bisoprolol 
Rate 
C08DB01 
IV 
Diltiazem 
Rate 
C08DA01 
IV 
Verapamil 
Rate 
C01AA05 
V 
Digoxine 
Rate 
C01BA01 
Ia 
Quinidine 
Rhythm 
C01BC04 
Ic 
Flecainide 
Rhythm 
C01BD01 
III 
Amiodarone 
Rhythm 
C01BD07 
III 
Dronedarone 
Rhythm 
C01BC03 
Ic 
Propafenone 
Rhythm 
C01BD04 
III 
Dofetilide 
Rhythm 
C01BG07 
Ic 
Cibenzoline 
Rhythm 
 
* Vaughan Williams Classification of Anti-arrhythmic drugs 
 
 
Investigator responsibilities: 
AAD related SUSAR’s shall be reported by the Investigator to Biosense Webster immediately 
but not later than 24 hours of awareness. 
 
NOTE: Pharmacovigilance reporting of events coming forth from drugs which are authorized 
medicinal products, shall be reported to the marketing authorization holder, unless otherwise 
indicated by institutional policies, EC / EB (or equivalent) policies, and local regulations. 


 
 
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Biosense Webster responsibilities 
Drug related events 
Any SUSARs must be handled and reported by Biosense Webster to the appropriate 
authorities (e.g., competent authorities) as well to the ECs / EBs (or equivalent) according to 
the prevailing regulations per country.  
 
Biosense Webster shall perform standard expedited reporting to participating CAs, ECs / EBs 
and Investigators, unless otherwise indicated by national regulations: 
Event Type 
Timelines 
SUSAR fatal or life-threatening 
7 days (after the sponsor was first aware of the 
reaction) 
 
8 days (any relevant additional information 
shall be sent within 8 days of the report) 
SUSAR (other) 
15 days 
Biosense Webster shall not report adverse reactions related to other drugs than AAD’s ( non-
IMP) received by the subject and without interaction with the AAD (IMP). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix E: Informed Consent Form Template 
 
Master Template Informed Consent Form, subject to change on country and/or site level upon 
need/request of local regulations. Site- and/or country-specific Informed Consent Forms 
require review and approval from the applicable EC or EB prior to its use in the ATTEST 
study. 
 
 
PATIENT INFORMATION 
 
subject’s Name: 
 
subject’s Number: 
 
 
STUDY NAME: ATTEST 
 
STUDY TITLE: Atrial Fibrillation Progression Trial (ATTEST) 
 
INVITATION  
 
You are invited to take part in a research study because you suffer from Paroxysmal Atrial 
Fibrillation. Atrial fibrillation is an abnormal heart rhythm; the atria of the heart don’t contract 
normally, but rapidly and irregularly.  In general, the heart keeps its vital ability to pump the 
blood around because the ventricles are still working effectively, but irregularly. Paroxysmal 
AF means that episodes happen occasionally and self-terminate in less than 7 days without 
medical intervention. 
 
Before you decide to participate, it is important for you to understand why the research is 
conducted and what is expected from you. Please read the following information carefully and 
take time to decide whether or not you wish to participate. Your participation to this clinical 
study is completely voluntarily. You have the right to decline participation without 
providing further clarification. Your decision not to participate to the study has no 
impact on your further medical treatment.  
Do not hesitate to ask questions if there is anything that is not clear or if you would like more 
information.  
 
Principal Investigator’s name 
Hospital name 
Telephone number 
Fax number 
 
This research project is sponsored by Biosense Webster Inc, a Johnson & Johnson company. 
 
WHAT IS THE PURPOSE / OBJECTIVE OF THE STUDY? 
 
The goal of this study is to evaluate the progression toward persistent atrial fibrillation after 
undergoing radiofrequency (RF) ablation with a catheter from the THERMOCOOL® Catheter 
Family when used with the CARTO® 3, CARTO XP® or CARTO® RMT System (Biosense 
Webster, Inc.) compared to drug therapy. 
 
Persistent atrial fibrillation is a more chronic form of the illness, characterized by atrial 
fibrillation sustained beyond 7 days, or lasting less than 7 days but necessitating 
cardioversion (a medical procedure by which the cardiac arrhythmia is converted to a normal 
rhythm, using electricity or drugs).  
 
During an ablation, radiofrequency energy is used to destroy heart cells in order to treat an 
abnormality in the electrical conduction system of the heart. These abnormal electrical 
impulses can cause arrhythmia. 


 
 
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The aim of ablation is to restore and maintain normal heart rhythm, relieve symptoms 
associated with atrial fibrillation, and reduce the risk of stroke.  Stroke is a cerebrovascular 
accident or sudden interruption of the blood supply to a part of the brain by occlusion of a 
blood vessel by a blood clot.  These blood clots may be formed in the chambers of the heart 
during atrial fibrillation. 
 
Radiofrequency ablation is performed in the left upper chamber of the heart known as “left 
atrium”. Several studies have shown that electrical stimuli, that originate from the pulmonary 
veins (= blood vessels bringing blood from the lungs to the left atrium) trigger atrial fibrillation. 
Therefore, these veins have to be isolated electrically from the rest of the left atrium. This 
means that the electrical impulses that are generated in the pulmonary veins will be 
interrupted before they reach the heart, thereby eliminating the atrial fibrillation and related 
symptoms.  
 
Atrial fibrillation can also be treated with drugs. Your physician will discuss the different 
treatment strategies with you.  
 
STUDY TREATMENTS: 
 
During this trial, we will compare radiofrequency (RF) ablation with standard of care drug 
therapy. Standard of care drug therapy means the treatment you would most likely receive if 
you were not participating in this clinical trial and if you would not be eligible for catheter 
ablation.  
 
The ablation technology used is CARTO® 3, CARTO® XP or CARTO® RMT System-guided RF 
Ablation using a catheter from the THERMOCOOL ® Catheter Family.  
 
This technology uses a computer system to make a 3D image of your heart. Based on this 
image, your doctor will decide how to isolate the pulmonary veins. The THERMOCOOL® Family 
of Catheters use a single electrode to ablate, so only one lesion (destruction of tissue) will be 
created at a time. This electrode is cooled by the flow of saline solution coming through little 
holes at the tip of the catheter. During this ablation procedure your study doctor will assess 
the fluid status, determine if diuretics are necessary, and treat you accordingly. Diuretics are 
drugs used to increase the excretion of water from the body. If there is too much build up of 
fluid inside your body, diuretics will help to eliminate this via the urine. 
 
This study is a Prospective, Multi-center, Randomized (1:1), Controlled, Two-arm, Open-label 
Clinical Study.   
A Prospective study follows over time a group of individuals who have a similar medical 
condition. 
Multi-center: Approximately 330 patients in up to 50 hospitals in Europe, and/or Asia and/or 
North America will be enrolled in this study. 
Randomized (1:1) means that you will be assigned randomly (by chance like flipping a coin) 
to a treatment group (RF ablation or drug therapy). This will be done via a computerised 
system. You have an equal chance to be in the RF ablation group then in the drug therapy 
group.  
Two-arm: two types of treatment will be compared during this study. 
Open-label means that the researcher knows the full details of the treatment and so will you. 
 
ALTERNATIVE TREATMENTS: 
 
You do not have to participate in this study in order to be treated for your condition; your 
treatment will not differ much whether you decide to take part in the study or not. You may 
thus choose not to take part in the study and have the same treatment as the study 
treatments. By taking part in the study you help the medical community in better 
understanding the effect of both treatments for atrial fibrillation. 


 
 
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WHAT IS EXPECTED FROM ME WHEN PARTICIPATING IN THIS STUDY? 
 
If you agree to take part in the study, you are asked to strictly follow the instructions from your 
physician i.e. with respect to the planned visits and study procedures. For this study to be a 
success it is important that you remain in the treatment group that you have been assigned to 
during the entire duration of the study. Your physician might take a decision to treat you with a 
different treatment then the treatment you have been assigned to if clinically necessary.  
 
The duration of your participation in the study will be approximately 3 years. During this period 
you will have to visit the hospital at least 6 times. Your physician will also call you by 
telephone approximately 3 times during the study to check how you are doing and which 
medications you are taken. The entire study will take approximately 4.5 years to finalize. 
 
The following visits and study procedures are planned during this research study. All 
procedures performed during the study are done as standard of care. 
 
During the screening period (prior to the procedure/start drug therapy):  
 
Transesophageal Echocardiogram (TEE): an ultrasound device is passed into the 
esophagus (the swallowing tube) and is positioned directly behind the heart to 
provide more accurate pictures of your heart.  This test is standard and necessary to 
make sure there are no blood clots in your left atrium before the ablation procedure. 
This test will be performed within 48 hours before the procedure. This test will not be 
performed if you are randomized to the drug therapy group. 
 
Transthoracic Echocardiogram (TTE): An echocardiogram uses ultrasound waves to 
map a picture of the heart. A device is moved around your chest to obtain images of 
your beating heart. It's a simple and painless test that provides valuable information 
about a heart with an arrhythmia. 
 
Questionnaire(s): The physician may ask you to complete 1 or 2 questionnaires. 
These questionnaires ask some general questions about your quality of life and  
frequency and severity of symptoms related to your arrhythmia 
 
During the ablation procedure (only applicable if you are randomized to the RF 
ablation group): 
 
The first step of a radiofrequency ablation procedure is the placement, via the groin, 
of several types of catheters into your heart to record the electrical activity from areas 
that may be starting or maintaining the atrial fibrillation.  Fluoroscopy, which is a type 
of light x-ray, will be used to help guide the placement and movement of the 
catheters.  Your groin will be numbed to make the procedure more comfortable.  You 
may also be given medications to help you feel more relaxed, or asleep, depending 
upon the doctor’s choice.  Some of the catheters will need to be positioned into the 
left side of your heart.  To reach the left side, a small puncture is made in the area of 
the heart that separates the left from the right atrium, called the septum.  These 
catheters may also be used to pace (delivering pulses of electric current) your heart 
in different regions. 
 
Then energy will be applied to electrically isolate these pulmonary veins. These areas 
have recently been shown to trigger atrial fibrillation. This procedure may last several 
hours.   
 
At the end of the ablation procedure, your heart may once again be paced to verify 
that the areas in the heart that were targeted have been successfully ablated. After 
completing the ablation procedure, you will be monitored and remain in the hospital 
for a few days.  
 
After the procedure and before discharge another Transthoracic Echocardiogram 
(TTE) will be performed. 
 
Approximately 3 months after the procedure/enrolment to drug therapy you will visit your 


 
 
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clinic and you may be asked to complete the same questionnaire(s) as the one(s) completed 
before the procedure/dosing.  
 
As from this visit you will be asked to record your heart rhythm on a regular basis, and also 
when you are experiencing symptoms possibly related to your arrhythmia. You will receive a 
Transtelephonic monitoring (TTM) device. This is a small device that you will take home with 
you and keep with you all the time. You will put this device on your chest to measure your 
heart rhythm. This procedure is simple, painless and will only take a few minutes. After the 
recording, you will need to send your recording via a telephone.  Someone at the hospital 
will explain you how to do this. 
 
You will have to record your heart rhythm and send it via telephone during the entire study 
(3 years of follow-up). If you progress toward persistent atrial fibrillation, you will no longer 
need to record your heart rhythm 
6 months after the procedure/dosing you will visit your clinic and you may be asked again to 
complete the same questionnaire(s) about your quality of life and frequency and severity of 
symptoms related to your arrhythmia (the same questionnaire(s) as you completed before 
the procedure/dosing and at the 3-month follow-up visit). 
 
Approximately 9 months, 1.5 year and 2.5 years after the procedure/enrolment to drug 
treatment your physician will call you to check how you are doing, which medications you 
are taken and how the TTM transmission of your heart rhythm is going.  
 
Approximately 1 year, 2 years and 3 years after the procedure/enrolment to drug treatment 
you will visit your clinic to have the following assessments: 
 
1 or 2 questionnaire(s) (the same questionnaire(s) as you completed before). 
 
Transthoracic Echocardiogram (TTE): the same examination as at the start of the 
study will be performed. 
 
If you progress toward persistent AF before the end of the study, you will continue to be 
followed by your physician as per his standard of care but you will not have to attend all the 
last follow up visits of the study. You will only need to visit your clinic a last time for the 3 
year follow-up visit and have the assessments done as described above. 
 
During each follow-up visit / follow-up phone call, your medication and any adverse events 
you may have had will be recorded. There will also be some information collected on certain 
medical conditions during the study, for example diabetes, hyperlipidemia/dyslipidemia (too 
much cholesterol in your blood), kidney function and dementia. Other questions that will be 
addressed are about your adherence to the drug therapy - how well you take your 
medication as prescribed by the physician.  
 
 
WHAT ARE THE ANTICIPATED INCONVENIENCES, SIDE EFFECTS AND RISKS? 
 
There are risks associated with both ablation procedure and drug therapy. These risks do not 
differ as what you would experience outside the study since these treatments do not deviate 
from your doctor’s standard procedure. 
 
Previously identified risks with an ablation procedure are described below and are common to 
all catheter ablation procedures for atrial fibrillation.  
 
 
Catheters will be inserted into your blood vessels. The insertion of catheter(s) in the 
vein or the artery could cause different complications such as bleeding and infection. 
 
Catheters inserted in the left atrium could cause blood clots or air embolism (air 
bubbles) resulting in stroke, heart attacks or perforation of the wall of the heart. A 
perforation can possibly result in blood effusion (blood escaping) in the pericardium 
(the membrane enclosing the heart) and tamponade (accumulation of blood in the 


 
 
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pericardium, preventing the heart from expanding fully and finally causing the heart to 
stop pumping). 
 
Paralysis of the phrenic nerve, which could cause shortness of breath. 
 
Narrowing of the pulmonary veins. 
 
Atrio-esophageal fistula, a passage created between the heart and the esophagus, is 
a severe complication of AF ablation but is very rarely seen. 
 
During the ablation procedure, you may feel discomfort or a burning sensation in your 
chest. Sedation will be proposed and the known side effects associated with 
anesthesia will be explained to you. 
 
If any of the known or unforeseen risks occur, it is possible that other interventions may be 
necessary, such as angioplasty to open an obstructed coronary artery, surgery in case of a 
damaged heart valve or perforation of the heart, implantation of an artificial pacemaker, or 
other interventions not listed here. An angioplasty is a widening of narrowed arteries, by 
inserting a balloon in the narrow part and then inflating it. The balloon will be removed after 
the procedure. In some cases, a stent (tube) can be positioned in the artery to keep it open 
more effectively. 
 
Previously identified risks associated with drug therapy are listed below.  As per standard, 
risks identified with the drug treatment are described in the patient leaflet included in the pack 
of your medicine. If you have any questions about these leaflets, you should discuss this with 
your doctor, pharmacist or nurse. 
 
Risks of rate control drugs: Hypotension, heart block (disease in the electrical system 
of the heart), bradycardia (slow heart beat), asthma, heart failure (the inability of the 
heart to supply sufficient blood flow to meet the needs of the body), constipation. 
 
Risks of rhythm control drugs: photosensitivity (sensitivity of the skin to a light 
source), pulmonary toxicity, polyneuropathy (neurological disorder that occurs when 
many peripheral nerves throughout the body malfunction simultaneously), 
bradycardia, torsades de pointes (a specific, rare variety of ventricular tachycardia, a 
fast heart rhythm, that originates in one of the chambers of the heart), impaired liver 
function, thyroid dysfunction, eye complications, heart failure, glaucoma (an eye 
disorder in which the optic nerve suffers damage, permanently damaging vision in the 
affected eye(s)), urinary retention (the lack of ability to urinate), ventricular 
tachycardia (a fast heart rhythm, that originates in one of the chambers of the heart). 
 
Risks of anticoagulation: the most common side effects associated with anticoagulant 
therapy are itching, rashes, easy bruising, increased bleeding from injuries and 
purplish spots on the skin. Purplish skin spots are caused by small amounts of 
bleeding under the skin. Bruising tends to be more severe when taking 
anticoagulants, and bleeding from wounds can be difficult to stop. 
 
CAN I PARTICIPATE IN MULTIPLE STUDIES? 
Participation in multiple studies may be hazardous to you. If you are already participating in 
other studies please inform your physician fully.  
 
WHAT ARE THE POSSIBLE BENEFITS OF TAKING PART? 
The major benefit of undergoing radiofrequency catheter ablation and/or drug treatment for 
atrial fibrillation is the potential elimination of symptomatic AF episodes. It is furthermore 
expected that the quality of life will improve and less frequent hospitalization is needed. Also, 
your participation will allow us to gather information on the use of different technologies and 
treatments, which may be beneficial for the treatment of other patients with atrial fibrillation.  
 
DO I HAVE TO TAKE PART? 
Your participation is voluntary. It’s up to you to decide whether or not to take part in this study. 
No one can make the decision for you. You can withdraw from this study at any time and 
without giving a reason. A decision not to participate or to withdraw at any time during the 
study, will not affect the quality of the standard care you receive. It will not have any effect on 
your further treatment. You may thus choose not to take part in the study and still have the 


 
 
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same treatment for your arrhythmia as the study treatments (RF ablation or drug therapy) as 
both are part of daily practice. 
 
If you decide to withdraw, the information already collected may still be used. 
 
If you accept to participate in this study, you will receive this information form to keep and you 
will be asked to sign the last page for consent. 
 
The study doctor can stop your participation in this study at any time for one of the following 
reasons: 
 
You do not follow the instructions for participation in the study; 
 
Your further participation in the study appears to be harmful to you; 
 
At a later stage, it becomes clear that you do not meet the study criteria; 
 
The sponsor stops the study everywhere, or just in this hospital for reasons 
other than the ones listed above, and unknown at this moment. 
 
If the study is stopped prematurely, your physician will make sure you continue to have the 
best possible treatment.   
 
WHAT IF RELEVANT NEW INFORMATION BECOMES AVAILABLE? 
 
Sometimes, new information becomes available about the treatment that is being studied 
during the course of the study. If this happens, your doctor will inform you and will discuss 
whether you want to continue your participation in the study or not. If you decide not to carry 
on, your doctor will make sure you receive the best medical treatment available. If you decide 
to continue, you will be asked to sign an updated consent form.  
 
WHO SHOULD NOT TAKE PART IN THIS STUDY?  
 
Patients who do not fulfil the criteria to enter in the study should not participate. Your doctor 
will check if you are suitable to participate in this study.  
 
Pregnancy 
Pregnant women, lactating women or women planning to become pregnant during the study, 
are not allowed to participate. 
 
 
WHAT IN CASE OF STUDY RELATED PERSONAL INJURY - INSURANCE? 
 
If you incur damage which is connected to this study, this damage will be compensated by the 
sponsor of this study to you or your rightful claimants (family) in accordance with the 
[COUNTRY] law concerning experiments on the human person of [DATE].You do not have to 
prove someone’s fault.  
The sponsor has contracted an insurance policy with ACE European Group limited Policy n° 
[policy number] to cover the risk and the damage, which would follow from the study. You or 
your rightful claimants can sue the insurer [COUNTRY] directly. 
 
FINANCIAL COMPENSATION 
 
The sponsor, Biosense Webster Inc., pays your study doctor and/or hospital to carry out this 
study. There will be no financial benefit to you; you will not receive any money as payment or 
compensation for taking part in this trial.  
 
ANTICIPATED COSTS RELATED TO MY STUDY PARTICIPATION 
 
There will be no additional costs for you if you are taking part in this study. 
 
PROTECTION OF YOUR PRIVATE LIFE 


 
 
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Your identity and your participation to this study will be treated strictly confidential. You will 
not be identified by name or in any other identifying manner in files, results or publication 
concerning this study. The Investigator will encode your personal data to ensure that your 
identity shall remain secret at all times.  
 
According to the good clinical practice guidelines, your medical records will, insofar as this 
relates to the study, be examined by representatives of the sponsor or the subsidiaries of the 
sponsor and by the regulating authorities, in order to check the study data and study 
examinations and in order to assure that the information is accurate. Your identity remains 
secret since personal information will only be designated by a unique patient number 
(therefore coded). 
 
The sponsor might use your personal information for other research purposes. Only coded 
personal information will be used for this purpose.  
 
Your personal information might be transferred to regulation authorities (locally and/ or 
abroad), to the ethics committee and to other doctors and / or organizations which cooperate 
with the sponsor. Your personal information might also be transferred to other branches of the 
sponsor in this country and in other countries where the rules concerning data management 
might be different or less strictly followed. The sponsor will apply the same rules concerning 
data protection within the legal framework of the countries concerned.  
Your personal information will be processed and analysed electronically (in the computer) or 
manually in order to determine the results of this study. You have the right to ask the study 
doctor which data are collected about you in the context of the study and what the purpose of 
that collection is. You also have the right to request the study doctor to give you access to 
your personal information and to correct it if necessary. The protection of personal data is 
legally established in the Law of [DATE] concerning the protection of private life.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by US Law.  This Web site will not include information that can identify you.  At most, the Web 
site will include a summary of the results.  You can search this Web site at any time. 
 
If you consent to the participation in the study, this implies that you also consent to the use of 
your coded medical data for the abovementioned purposes and to the transfer of them to the 
abovementioned persons and/ or bodies.  
If your participation in the study is terminated early, your initial approval will allow for the data, 
relating to your inclusion in the study, to be used. 
 
ETHICS COMMITTEE and COMPETENT AUTHORITIES 
 
The hospital’s <local Ethics Committee> has given a favorable opinion to start this research 
project. The Competent Authority of your country has been notified, and where applicable, 
approval has been requested and obtained. 
 
 


 
 
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INFORMED CONSENT FORM 
 
 
 
 
 
I understand that my participation is voluntary and that I am free to withdraw at any 
time, without giving any reason and without my medical care being affected. 
  
 
I confirm that I have read and understood the information sheet. I have had the 
opportunity to consider the information, ask questions and have had these answered 
satisfactorily.   
 
 
I agree that relevant personal data will be used for the purpose of this clinical 
investigation.  
 
 
I understand that all documents belonging to my medical file will remain strictly 
confidential. I also understand that my medical notes may be looked at by:  
o 
The responsible individual from the Sponsor or a representative  
o 
Regulatory authorities 
o 
Members of the Ethics Committee 
 I give permission for these individuals to have access to my records. 
 
 
I agree/disagree that my general practitioner will be informed of my participation in 
this study (please circle ‘agree’ or ‘disagree’) 
 
 
I agree to take part in the above-mentioned study and will strictly comply with study 
procedures.  
 
 
I receive a copy of the patient information and signed informed consent form. 
 
 
 
 
 
 
 
 
Name patient 
 
Signature patient 
 
Date 
 
 
 
 
 
Name legal representative or 
witness (if applicable) 
 
Signature witness 
 
Date 
 
 
 
 
 
Name 
physician 
taking 
informed consent 
 
Signature physician 
 
Date 
 
 
 

SAP_000.pdf: 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
Atrial Fibrillation Progression Trial (ATTEST Trial) 
Protocol Number: 
144 Version 3.0 (9-Apr-2013) 
Device: 
CARTO® 3, CARTO® XP or CARTO® RMT System and 
THERMOCOOL® Catheter Family 
Phase: 
Post-marketing Study 
Sponsor: 
BIOSENSE WEBSTER, INC.  
3333 Diamond Canyon Road 
Diamond Bar, CA 91765 
USA 
SAP Author: 
SAP Version: 
FINAL Version 2.0  
SAP Date: 
  08-NOV-2018 
 
CONFIDENTIAL 


Protocol: ATTEST 
 
Page 2 of 45 
Statistical Analysis Plan FINAL Version 2.0 
 
 
CONFIDENTIAL 
 
08-NOV-2018 
 
 
STATISTICAL ANALYSIS PLAN DOCUMENT HISTORY 
 
Version 
Date 
Author 
Description 
Final 1.0 
12-JAN-2016 
 
Original 
Final 2.0 
08-NOV-2018 
 
SAP update after study was 
terminated early 
• 
Clarifications concerning 
primary endpoint analysis 
added 
• 
Sensitivity analysis for 
alternative definition of 
primary endpoint and first 
secondary endpoint added 
• 
Some of the analyses 
originally planned in the 
protocol removed 
• 
Minor updates based on 
shell development 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Statistical Analysis Plan FINAL Version 2.0 
 
 
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TABLE OF CONTENTS 
 
1. 
SYNOPSIS ................................................................................................. 9 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................... 9 
2.1 
Study Objective ............................................................................ 9 
2.2 
Efficacy, Safety and Health Economic Endpoints ....................... 9 
2.2.1 Efficacy Endpoints .............................................................. 9 
2.2.2 Safety Endpoints ............................................................... 10 
2.2.3 Health Economic and Quality of Life Endpoints .............. 10 
3. 
STUDY METHODS................................................................................ 10 
3.1 
Overall Study Design and Plan .................................................. 10 
3.2 
Selection of Study Population .................................................... 11 
3.3 
Method of Treatment Assignment and Randomization ............. 11 
3.4 
Treatment Masking (Blinding) .................................................. 11 
4. 
ANALYSES AND REPORTING .......................................................... 11 
4.1 
Interim Analyses ........................................................................ 11 
4.2 
Final Analyses ............................................................................ 12 
4.3 
SOPs ........................................................................................... 12 
5. 
CHANGES TO PLANNED ANALYSIS .............................................. 12 
5.1 
Changes for the final analysis .................................................... 12 
5.2 
Changes for the interim analyses ............................................... 13 
6. 
SAMPLE SIZE DETERMINATION .................................................... 13 
7. 
ANALYSIS POPULATIONS ................................................................ 14 
8. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ..................... 16 
8.1 
General Statistical Methodology................................................ 16 
8.2 
Handling of Missing Data .......................................................... 16 
8.3 
Derived Variables ...................................................................... 17 
9. 
STUDY SUBJECTS AND DEMOGRAPHICS.................................... 18 
9.1 
Disposition of Subjects and Withdrawals .................................. 18 
9.2 
Protocol Violations and Deviations ........................................... 19 
9.3 
Demographics and Other Baseline Characteristics .................... 19 
9.4 
Study Treatment ......................................................................... 20 
10. 
EFFICACY ANALYSIS ......................................................................... 21 
10.1 
Primary Efficacy Variable Analysis .......................................... 21 
10.2 
PP analysis ................................................................................. 22 
10.3 
Subgroup Analysis ..................................................................... 22 
10.4 
Interim Analysis ......................................................................... 23 
10.5 
Sensitivity Analysis for the Primary Efficacy Variable ............. 25 


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10.6 
Secondary Efficacy Variable Analysis ...................................... 25 
10.6.1 Rate and Time to Persistent AF/AT at 1 year and 2 years 
follow-up and at 3 years follow-up by number of 
ablations ............................................................................ 25 
10.6.2 Number of Repeat Ablations and New AAD Drugs ......... 26 
10.6.3 Rhythm throughout 3 Years Follow-up ............................ 27 
10.6.4 Factors Associated with AF Disease Progression ............. 27 
11. 
SAFETY AND TOLERABILITY ANALYSES ................................... 28 
11.1 
Adverse Events .......................................................................... 28 
11.2 
Catheter-related complications (AEs) ........................................ 29 
11.3 
Serious AEs ................................................................................ 29 
11.4 
Primary AEs ............................................................................... 29 
11.5 
Adverse Drug Reactions ............................................................ 29 
12. 
OTHER PLANNED ANALYSES ......................................................... 29 
12.1 
Quality of Life Analysis............................................................. 29 
12.2 
Health Economics Analysis ....................................................... 30 
13. 
REPORTING CONVENTIONS............................................................ 30 
13.1 
General Reporting Conventions ................................................. 30 
13.2 
Population Summary Conventions ............................................ 31 
14. 
REFERENCES ........................................................................................ 33 
15. 
TABLES, LISTINGS, AND FIGURES ................................................ 34 
15.1 
Planned Table Descriptions ....................................................... 34 
15.2 
Planned Listing Descriptions ..................................................... 43 
15.3 
Planned Figure Descriptions ...................................................... 45 
 


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ABBREVIATIONS 
 
ABBREVIATION DEFINITION OR DESCRIPTION 
AAD 
Antiarrhythmic Drug 
ADE 
Adverse Device Effect 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AFEQT 
Atrial Fibrillation Effect on Quality-of-life (AFEQT) 
Questionnaire 
ARDS 
Acute Respiratory Distress Syndrome 
AT 
Atrial Tachycardia 
ATC 
Anatomical Therapeutic Chemical 
BB 
Beta Blocker 
CABG 
Coronary Artery Bypass Graft 
CCB 
Calcium Channel Blocker 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
COPD 
Chronic Obstructive Pulmonary Disease 
CP 
Conditional Power 
CPMP 
Committee for Proprietary Medicinal Products 
CRF 
Case Report Form  
CSR 
Clinical Study Report 
CTP 
Clinical Trial Protocol 
CV 
Coefficient of Variation 
CVA 
Cerebrovascular Accident or Stroke 
GSMC 
Global Safety Monitoring Committee 
EB 
Ethics Board  
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMEA 
Europe, Middle East and Africa 
EP 
Electrophysiology 
EQ-5D 
EuroQoL 5 Dimensions 
FDA 
Food and Drug Administration 
Fr 
French 


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ABBREVIATION DEFINITION OR DESCRIPTION 
GCP 
Good Clinical Practices 
GEE 
Generalized Estimating Equations 
HM 
Holter Monitoring 
ICD 
Implantable Cardioverter Defibrillator 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFU 
Instruction For Use 
ILR 
Implantable Loop Recorder 
ISO 
International Organization for Standardization 
ITT 
Intent to Treat 
KM 
Kaplan-Meier 
LA 
Left Atrium 
LV 
Left Ventricle 
MDR 
Medical Device Reporting 
MDV 
Medical Device Vigilance 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
NYHA 
New York Heart Association 
PAF 
Paroxysmal Atrial Fibrillation 
PCI 
Percutaneous Coronary Intervention 
PI 
Principal Investigator 
PP 
Per Protocol 
PV 
Pulmonary Vein 
PVI  
Pulmonary Vein Isolation 
QoL 
Quality Of Life 
RA 
Right Atrium 
RF  
Radiofrequency  
RSPV 
Right Superior Pulmonary Vein 
RV 
Right Ventricle 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SR 
Sinus Rhythm 
TEE 
Transesophageal Echocardiography 


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ABBREVIATION DEFINITION OR DESCRIPTION 
TIA 
Transient Ischemic Attack 
TLG 
Table, Listing, Graph 
TTE 
Transthoracic Echocardiography 
TTM 
Transtelephonic Monitoring 
UADE 
Unanticipated Adverse Device Effect 
WHO 
World Health Organization 
VAS 
Visual Analogue Scale 
 
 
 


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1. SYNOPSIS 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for 
Biosense Webster ATTEST protocol “Atrial Fibrillation Progression Trial” dated 
9-Apr-2013 Version 3.0. 
This post-marketing trial is a prospective, multi-center, randomized, controlled, 
two-arm, open-label, clinical study to determine whether early radiofrequency (RF) 
ablation treatment, using the CARTO® 3, CARTO® XP or CARTO® RMT System, and 
THERMOCOOL ® Catheter Family in subjects with Paroxysmal atrial fibrillation (PAF), 
delays progression of atrial fibrillation (AF) compared with drug therapy (either rate 
or rhythm control) using current AF management guidelines. 
The planned analyses identified in this SAP may be included in clinical study reports 
(CSRs), regulatory submissions, or future manuscripts. Also, post-hoc exploratory 
analyses not necessarily identified in this SAP may be performed to further examine 
study data. Any post-hoc, or unplanned, exploratory analyses performed will be 
clearly identified as such in the final CSR. 
The following documents were reviewed in preparation of this SAP: 
• Clinical Research Protocol Number 144, Version 3.0 dated 9-Apr-2013 
• Case report forms (CRFs), Version 2.1 dated 01-Jul-2013 
The reader of this SAP is encouraged to also read the clinical protocol, and other 
identified documents, for details on the planned conduct of this study. Operational 
aspects related to collection and timing of planned clinical assessments are not 
repeated in this SAP unless relevant to the planned analyses. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objective 
The objective of this study is to determine whether in subjects with Paroxysmal AF 
(PAF), early RF ablation treatment using the THERMOCOOL® Catheter Family in 
conjunction with the CARTO® 3, CARTO® XP or CARTO® RMT System delays 
progression of AF compared with drug therapy (either rate or rhythm control) using 
current AF management guidelines. 
 
2.2 Efficacy, Safety and Health Economic Endpoints 
2.2.1 Efficacy Endpoints 
The primary efficacy endpoint is the time to persistent AF/AT (excluding isthmus-
dependent atrial flutter) at 3 years. According to the protocol, persistent AF/AT is 
defined as AF/AT lasting longer than 7 consecutive days or requiring termination by 
cardioversion after 48 hours.  
Secondary efficacy endpoints are: 
• Rate and time to persistent AF/AT at 1 year and 2 years, rate of persistent 
AF/AT by number of ablations at 3 years  
• Number of repeat ablations and new anti-arrhythmic drugs (AAD) per subject 
throughout 3 years follow-up 


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• Rhythm (% subjects in sinus rhythm (SR), % subjects with recurrent AF/AT) 
throughout 3 years follow-up 
• Factors associated with AF disease progression 
o Gender 
o Age 
o Left atrium (LA) size 
o HATCH score (score based on the five components: Hypertension, Age 
75 years or older, Previous transient ischemic attack or stroke, Chronic 
obstructive pulmonary disease, and Heart failure) 
o Blood pressure 
o NYHA functional classification of heart disease 
o Presence of diabetes 
o Presence of hyperlipidemia or dyslipidemia 
o Presence of renal insufficiency  
o Presence of dementia 
 
In addition, an alternative definition of the primary and the first secondary endpoint 
will be investigated based on the consensus statement of the HRS (Heart Rhythm 
Society, 2017). According to the HRS consensus statement 2017, persistent AF/AT is 
defined as continuous AF/AT that is sustained beyond 7 days.  
2.2.2 Safety Endpoints 
The key safety endpoints are:  
• Catheter-related complications (adverse events) 
• Drug related Adverse events-Adverse Drug Reactions (ADR) 
2.2.3 Health Economic and Quality of Life Endpoints  
The health economic endpoints are: 
• Health care utilization (number and length of hospitalizations and unscheduled 
cardiovascular-related visits) 
• Quality of Life (QoL) at 3 months, 6 months, 1 year, 2 years, and 3 years by 
change from baseline in  
o  EQ-5D Score 
o  AFEQT Score (collected in a subset of countries) 
3. STUDY METHODS 
3.1 
Overall Study Design and Plan  
ATTEST is a post-marketing, prospective, multi-center, randomized, controlled, 
two-arm, open-label, clinical study. For subjects randomized to the ablation group 
(Test), physicians are to perform procedures per institutional Standards of Care and 
processes required by their institution. For subjects randomized to the AAD group 
(Control), physicians are to manage medication in accordance with published, current 


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AF Management and with the Standard of Care and procedures required by their 
institution.  
All subjects will be followed through 3 years. A subject in the medication group may 
request a cross-over to receive ablation 
3.2 
Selection of Study Population 
This is a post-marketing study in subjects with Paroxysmal AF (PAF). Key inclusion 
criteria identified in the protocol are:  
• Subjects with recurrent paroxysmal AF for at least 2 years, with ≥ 2 episodes 
over the last 6 months 
• HATCH Score of at least ≥1 and ≤ 4 
• Eligible for catheter ablation and for anti-arrhythmic or rate control 
medications, after having failed at least one but no more than 2 prescribed drugs 
(either anti-arrhythmic or rate control drug) 
• Age 60 years or older  
• LA diameter ≤ 55 mm by Transthoracic Echocardiography (TTE) 
• Left ventricle (LV) ejection fraction ≥ 50% when in sinus rhythm or LV ejection 
fraction ≥ 35% when in AF 
• Subject signed the Informed Consent Form and is able and willing to comply 
with protocol requirements, including all baseline and follow- up testing. 
For the complete list of in- and exclusion criteria see the CTP, Sect. 9.3 and 9.4.  
3.3 
Method of Treatment Assignment and Randomization 
Subject randomization will be 1:1 between catheter ablation (Test) and AAD therapy 
(Control). The randomized block design, stratified by gender and site, will be used to 
ensure a gender balance by treatment group at each site. Adaptive randomization will 
also be executed to further ensure the allocation balance of treatment groups by 
gender at each site. Subjects will be randomized in the order of their enrollment. 
3.4 
Treatment Masking (Blinding)  
This is an open-label study. 
4. ANALYSES AND REPORTING 
4.1 
Interim Analyses 
An interim examination of the primary endpoint data will be performed at regular 
time intervals during the course of the trial to determine whether the study will be 
stopped for effectiveness or futility. Interim analyses will only be presented for the 
ITT and Safety Population. At the first interim analysis, sample size adjustment will 
be considered as specified in section 5. In addition, statistical interim reporting will 
also involve a review of adverse events. The results of the interim analyses will be 
reviewed by the Global Safety Monitoring Committee (GSMC) of Biosense Webster. 
 
The GSMC will review the accumulated data no earlier than 1 year following the 


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study start and then approximately every 6 months thereafter if enrollment was on 
target. Data for the primary effectiveness endpoint and adverse events will be 
reviewed. Extracted data files and analysis programs for each interim report will be 
archived in the study files. Further details on the planned interim analyses are given in 
section 10.4. Moreover, it is indicated in the table of contents (section 15) which 
subset of tables, listings and figures will also be produced for the interim analysis. 
4.2 
Final Analyses 
All final planned analyses identified in the protocol and in this SAP will be performed 
only after all relevant study data have been processed and the database has been 
locked. In addition, no database may be locked, random code unblinded, or analyses 
completed until this SAP has been approved. 
Key statistics and study results will be made available to Biosense Webster following 
database lock and prior to completion of the final CSR. 
Any post-hoc exploratory analyses completed to support planned study analyses, 
which were not identified in this SAP, will be documented and reported in appendices 
to the CSR. Any results from these unplanned analyses (post-hoc) will also be clearly 
identified in the text of the CSR. 
 
4.3 SOPs 
The following Premier statistics SOPs are applicable for this study: 
  
SOP Number  
SOP Title  
SOP-ST-45.01  
Statistical Analysis Plan  
SOP-ST-47.01  
Planning Execution and Delivery of Statistical Analyses  
SOP-ST-48.01  
Unblinding a Study for Statistical Analysis  
SOP-ST-46.01  
Development and Validation of SAS Programs  
 
 
5. CHANGES TO PLANNED ANALYSIS 
5.1 Changes for the final analysis 
As the study was terminated early, without having met primary effectiveness or 
futility criteria at the most recent interim analysis, it is not fully obvious which alpha 
level to use for the primary efficacy analysis. However as the number and time points 
of the interim analyses had not been fixed in advance, it was decided to spend all 
alpha remaining for the final analysis, in other words to spend what is left from the 
total alpha. Moreover, after further discussion, it has been decided to update the 
calculation of the primary endpoint to use procedure date as start date for time to 
event calculation rather than randomization date (see section 8.3). 
 
It also was decided to delete some of the analyses originally planned in the protocol:  


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• 
For secondary endpoint “factors associated with AF disease progression”, only 
the main analyses will be performed, and some of the supporting models were 
deleted 
• 
Analysis of site heterogeneity will not be performed 
 
Moreover, a sensitivity analysis for the primary endpoint and first secondary endpoint 
was added, using an alternative definition for the primary endpoint based on the 
consensus statement of the HRS (Heart Rhythm Society, 2017). 
 
5.2 Changes for the interim analyses 
 
Before the first interim analysis, some updates had been made to the orginally planned 
method for re-calculation of operating characteristics. Section 10.4 reflects those 
updates. 
6. SAMPLE SIZE DETERMINATION 
A total sample size of 322 (161:161) subjects will be required to ensure 85% power to 
detect the effect size measured by negative log of the hazard ratio equal to 1.1541 
(treatment group over control group).   
  -loge ቀ
λ෡t
λ෡cቁ= -loge((-
loge(0.95)
3
)/(-
loge(0.85)
3
)) = 1.1541 
This calculation assumes a 50% cross-over rate from the AAD group to the ablation 
group, a 10% drop-out rate in each group over the 3 year follow-up period, and 
1.5 years accrual time. This calculation is based upon one-sided superiority testing 
with alpha equal to 0.025. Using meta-analysis, the rates of disease progression at the 
end of follow-up are estimated to be 25% and 5% in the AAD and ablation group, 
respectively (see the point estimate justification document for details, Appendix C of 
the CTP). The cross-over to ablation is reflected in the use of the proportion 0.85 
instead of 0.75 in the formula above. The sample size calculation is based upon the 
method developed by Rubinstein, Gail and Santner4 (RGS, 1981) and also 
incorporates group sequential design with multiple interim looks.   
Adaptive Sample Size Re-estimation 
Due to the uncertainties associated with the cross-over rate and the effect size, the 
sample size will be reestimated at the time of the first interim analysis. Conditional 
power (CP) will be calculated at that time to determine how promising the interim 
results are. CP is defined as the conditional probability that the final result will exceed 
a critical value given the data observed thus far, and the assumption that the trend to 
be observed in the remainder of the study5will follow the expectation, which was used 
in the original sample size calculation. If the CP is less than 0.3, then the study is 
considered not promising, and the sample size will not be increased. If the CP is 
                                                 
 
 


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greater than 0.9, then the study is deemed fully powered and the sample size will not 
be increased. If the CP falls in the promising zone (0.3-0.9), the sample size will be 
re-estimated based upon the observed effect size. 
 In detail, the following formula will be applied to re-estimate the sample size:  
𝑀𝑀= 𝑁𝑁൬𝛿𝛿
∆൰
2
 
where M is the updated sample size per group, N is the initially planned sample size 
per group, δ is the expected effect size (1.1541) and ∆ is the effect size observed at 
the time of interim analysis: 
∆= −𝑙𝑙𝑙𝑙𝑙𝑙𝑒𝑒ቆ𝐷𝐷𝑡𝑡𝑇𝑇𝑡𝑡
⁄
𝐷𝐷𝑐𝑐𝑇𝑇𝑐𝑐
⁄
ቇ 
where Dt and Dc are the number of deaths observed in the treatment and control group 
and and Tt / Tc are the total times observed (up to the time of censoring) in the 
respective groups. 
In case the re-estimated sample size is unrealistic high, the sponsor will select one of 
the following 3 options: 
• Determine the maximum realistic sample size and continue the study to enroll 
the maximum number of patients 
• Continue study as planned to enroll original planned sample size 
• Stop the study for futility. 
In case the sample size will be increased, the CHW (Cui, Hung and Wang) adaptive 
method will be used for statistical testing.6   
The CHW weighting will be applied according to the following formula: 
 
𝑍𝑍= ඥ𝑡𝑡𝑎𝑎𝑎𝑎𝑎𝑎𝑍𝑍0;𝑎𝑎𝑎𝑎𝑎𝑎+ ට൫1 −𝑡𝑡𝑎𝑎𝑎𝑎𝑎𝑎൯𝑍𝑍𝑎𝑎𝑑𝑑𝑑𝑑;𝑚𝑚𝑚𝑚𝑚𝑚 
Where Z is the final test statistic, tadj is the (planned) information fraction at the time 
of sample size adjustment, Z0;adj is the test statistic derived from the data available at 
the time of sample size adjustment, and Zadj;max is the test statistic derived from data 
collected after the time of sample size adjustment, including a possibly increased 
sample. 
7. ANALYSIS POPULATIONS 
The following analysis populations will be used to complete the analyses of data.  
 
Cross-over subjects will be handled differently for each type of analysis population, 
as described subsequently. In general, subjects from the control group who have an 
ablation procedure after the primary endpoint is met will not be analyzed as cross-
over. 
 
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subjects randomized, where subjects will be classified by the group to which they are 
randomized, regardless of the treatment received. For the ITT population, cross-over 
subjects will be included in the Control Group per randomization. Lost-to-follow-up 
and withdrawn/early termination subjects will also be included in the ITT population.   
 
Per protocol (PP) population: The PP subject population will include randomized 
subjects who satisfy the following criteria, according to the treatment actually 
received: 
 
• Test Group: subjects who  
o 
have undergone RF ablation,  
o 
are treated with the study catheter (THERMOCOOL ® Catheter Family), 
o 
are in compliance (no major protocol deviations that has an impact on 
scientific value of the study) with the study protocol, and  
o 
have been treated for the study-related arrhythmia. 
• 
Control Group: subjects who  
o 
have started an investigator-prescribed AAD and completed the dose-
loading period (2 weeks), 
o 
have not undergone RF ablation, 
o 
are in compliance (no major protocol deviations that have an impact on 
scientific value of the study) with the study protocol, and  
o 
have been treated for the study-related arrhythmia. 
 
All analyses conducted in the PP population will be as treated analyses. For 
descriptive tables and simple inferential models with fixed treatment effectsubjects 
who have undergone RF ablation will be included in the Test Group regardless of the 
original treatment assigned (original randomization). Thus, cross-over subjects will be 
included in the Test Group for PP analyses. For more complicated inferential 
analyses, models will be applied where treatment itself is included as time-dependent 
covariate (see section 10.2 and 10.6.4). The approach described above applies for all 
tables which do not summarize data by visit (e.g. for time to event endpoints and 
other endpoints calculated overall per-patient). For summaries by visit and repeated 
measurement models, cross-over subjects will be completely excluded. 
Safety Population: The Safety Population will include all subjects who have 
undergone insertion of an ablation catheter, either as Test Group or cross-over 
subjects; and, subjects who started an investigator-prescribed AAD in the Control 
Group and did not initiate ablation therapy. Analysis of catheter-related complications 
will be limited to include only subjects who initiated ablation treatment (catheter 
insertion) either as Test Group and cross-over subjects.  
Adverse drug reactions will be analyzed overall for all the subjects who have taken 
investigator-prescribed AAD and analyzed separately for cross-over subjects, those in 
the Test and Control Groups (excluding cross-over subjects). 
 
 
 
 


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8. GENERAL ISSUES FOR STATISTICAL ANALYSIS 
8.1 
General Statistical Methodology 
Descriptive summaries will be provided where appropriate for each of the primary 
and secondary variables. Tables in the ITT population will summarize data by 
randomized treatment, tables in the PP and Safety populations will summarize data by 
treatment actually received if not otherwise specified. 
 
Primary and secondary effectiveness analysis will be conducted in the ITT and the 
PP populations. All safety data analyses will be performed in the Safety Population. 
Health economic and QoL tables will be completed for the ITT population unless 
otherwise specified. According to the protocol it was planned to use the PP population 
for health economic and QoL tables, but this was changed to ITT population to 
perform the analysis based on the randomized treatment groups. 
Continuous, quantitative, variable summaries will include the number of subjects (N) 
with non-missing values, mean, standard deviation (SD), median, minimum, 
maximum, and quartiles, unless otherwise specified.  
Categorical, qualitative, variable summaries will include the frequency and 
percentage (where applicable) of subjects who are in the particular category. In 
general, the denominator for the percentage calculation will be based upon the total 
number of subjects in the study population for the treatment groups unless otherwise 
specified.  
The baseline value will be defined as value entered to the screening/baseline page of 
the eCRF (terminology screening/baseline is not used consistently in eCRF, but there 
is only one screening/baseline assessment planned according to protocol).  
All analyses will be performed using SAS® Software version 9.1.3 or later. 
ADDPLAN® version 5.0.2 or later and East version 5.3 or later may also be used.  
For re-calculating of operating characteristics for the analyses of the primary 
endpoint, the software WinLD will be used. 
8.2 
Handling of Missing Data 
There will be no imputation for the primary efficacy analysis and no sensitivity 
analysis with multiple imputation for the ITT population as the log rank test accounts 
for censored (independent of the reason) observations, which is sufficient also for 
subjects who could not be followed up for the planned period. Other data except 
treatment group assignment are not required for this testing method. 
 
For the per protocol sensitivity analysis, the same applies to the time-to-event 
outcome (effectiveness endpoint) data. 
For the derivation of the variable ‘duration of AF’, incomplete dates will be imputed 
with the mid point of the possible interval (15th of a month if only the day is missing, 
1st of July if the month is missing as well). No further imputation is planned. 
 
 


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8.3 
Derived Variables 
Duration of AF [months] 
Time between the recorded date of first AF and the date of randomization. 
 
Time to persistent AF/AT 
According to protocol, persistent AF/AT is defined as AF/AT lasting longer than 
7 consecutive days or requiring termination by cardioversion after 48 hours.The 
primary endpoint is reached at the date of the first cardioversion after randomization 
(except cardioversion solely as part of a (re-)ablation procedure) or detection of 
persistent AF/AT by transtelephonic monitoring (TTM, performed between month 3 
and month 36). The sponsor will review and adjudicate all events (progressions to 
persistent AF/AT), which were reported by the Investigator. Adjudication will already 
be performed for the interim analyses. All events where the sponsor confirmed in their 
final assessment that the primary endpoint was reached will be taken into account for 
analysis. The date at which the primary endpoint was reached will be taken as 
adjudicated by the sponsor or as reported by the Investigator (if no sponsor 
adjudicated date is available).  
The protocol is not specific about the start date for time to event calculation. 
Originally according to SAP version 1.0 (which was applied for the interim analyses) 
time to event had been defined as the difference between randomization date and the 
date at which the endpoint was reached. However, after further discussion, it was 
decided to update the start date for time to event calculation for final analyis and to 
use date of procedure as start date for the test group, and date of randomization as 
start date for the control group.  
 
This approach seems to be more appropriate and more conservative, as visit windows 
are calculated from date of procedure for test group. Otherwise, if time to event was 
calculated from date of randomization, test group would have longer follow-up period 
and longer time to each follow-up visit as control group.  
 
 
If the primary endpoint is not observed during follow-up time, subjects will be 
regarded as censored at the completion visit/ last visit or at the last time TTM was 
recorded, whichever is later. 
 
 
Time to persistent AF (HRS 2017) 
 
According to the HRS consensus statement 2017, persistent AF is  defined as 
continuous AF that is sustained beyond 7 days. The sponsor will provide an additional 
adjudication using this alternative definition of time to persistent AF. Based on this 
additional adjudication, a sensitivity analysis for time to persistent AF based on 
HRS 2017 will be performed. 
 
AFEQT  
Several summary scores will be derived from the responses to questions 1 to 20 of 
section 2 of the AFEQT questionnaire, for each of which responses between 1 (most 
desirable outcome) and 7 (least desirable outcome) can be given. 


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Using the following statistics, the scores are defined below: 
• 
S(a,b) is the sum of responses for the range of questions between a and b (both a and b 
included) 
• 
N(a,b) is the number of responses given for the  range of questions between a and b (both a 
and b included) 
 
• 
AFEQT Overall Score = 100 – (((S(1,18) – N(1,18))*100) / (N(1,18)*6)) 
• 
AFEQT Symptoms Subscale Sore = 100 – (((S(1,4) – N(1,4))*100) / (N(1,4)*6)) 
• 
AFEQT Daily Activites Subscale Score = 
= 100 – (((S(5,12) – N(5,12))*100) / (N(5,12)*6)) 
• 
AFEQT Treatment Concern Subscale Score = 
= 100 – (((S(13,18) – N(13,18))*100) / (N(13,18)*6)) 
• 
AFEQT Treatment Satisfaction Subscale Score = 
= 100 – (((S(19,20) – N(19,20))*100) / (N(19,20)*6)) 
 
EQ-5D 
The EQ-5D questionnaire collects the EQ-5D visual analogue scale (VAS) score on a 
scale between 0 and 100 and five single items (mobility, self-care, activity, pain, and 
anxiety) with three response levels each (no problems, some problems, extreme 
problems). A summary score (EQ-5D health index) based on these five items will not 
be calculated, as this would require rather complex modelling using country-specific 
weights. 
 
9. STUDY SUBJECTS AND DEMOGRAPHICS 
9.1 
Disposition of Subjects and Withdrawals 
All subjects who provide informed consent will be accounted for in this study. 
Disposition and study population summaries will be presented for all enrolled subjects 
by randomized treatment groups. Enrolled subjects are defined according to study 
protocol section 9.5 as subjects who sign the study informed consent form and are 
randomized. Thus, the set of enrolled subjects corresponds to the ITT population.  
 Descriptive summaries of population data will include the following: 
• The number of subjects in each study population (ITT, PP, and Safety) will be 
summarized overall, by treatment group, and by study site. 
• A listing sorted by randomized treatment group and subject will be provided 
that will include the reasons for exclusion from any of the study populations 
and the treatment assignment for the PP and Safety Population analyses. 
• The number of subjects enrolled, excluded, discontinued, prematurely 
withdrawing from the study, lost to follow-up, died, not completed due to AE, 


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not completed due to other reasons, completed and the reasons for 
classification will be summarized. 
• A listing of disposition as described above, including further details if 
available, will be provided for subjects in the ITT population. 
A listing of screening failures (which are not randomized) with reason for screening 
failure will also be added. 
9.2 
Protocol Violations and Deviations 
Protocol deviations are captured in the CRF on a specific protocol deviation CRF 
page. 
Incidences of all protocol deviations reported in the CRF will be summarized by 
protocol deviation code. A listing of these protocol deviations will also be included. 
Each protocol deviation entered to the eCRF will be classified by the sponsor into 
major and minor from study conduct perspective. The sponsor assessment will be 
included in the data base extract. 
A major deviation will not automatically lead to exclusion of a subject from 
PP population. Generally, it is planned to exclude a subject only from PP population 
in case of a major protocol deviation related to inclusion or exclusion criteria. To 
make a final decision, the sponsor will review all cases with major deviations 
individually and decide which subjects to exlude from PP population. The sponsor 
will provide a list of subjects to be excluded from PP population The sponsor review 
will be completed before DB lock..  
 
9.3 
Demographics and Other Baseline Characteristics 
Descriptive summaries of the demographic and other baseline characteristics will be 
completed for the ITT population. Baseline summaries will be presented overall, by 
treatment group (as randomized) and for the two subgroups “AAD only within 
Control Group” amd “Cross-over within Control Group”. 
Descriptive summaries of demographic and other baseline conditions will include: 
• Demographics (Age, Gender) (ITT) 
Imbalances between treatment groups will be tested by a Wilcoxon rank 
sum test for age and a Fisher test for gender. 
• Cardiovascular Medical History (ITT Population) including 
o Lone AF 
o Reversible AF 
o Previously diagnosed with persistent/permanent AF/AT 
o Previously required cardioversion >48 hours after onset of 
AF/AT 
o Heart disease (including history of angina, congestive heart 
failure, hypertension, ischemic cardio-myopathy, non-ischemic 


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dilated cardio-myopathy, hypertrophic obstructive cardio-
myopathy, significant valve disease, valve 
replacement/surgery, congenital heart disease, left ventricular 
hypertrophy, myocardial infarction, Percutaneous Coronary 
Intervention (PCI), Coronary Artery Bypass Graft [CABG]), 
heart transplantation). 
o Micro-/Thromboembolisms (by type of micro-/ 
thromboembolism) 
o Other arrhythmia (by type of other arrhythmia) 
o Hemorrhagic Stroke 
• 
Other Medical History (significant pulmonary disease, obstructive lung 
disease, diabetes, hyperlipidemia/dyslipidemia, renal insufficiency, and 
dementia)  
• 
Prior Procedures  
• AF History (time since first experience of AF, number of episodes in the 
past 6 months and HATCH score)  
• Cardiovascular medication history (Previously failed therapeutic 
strategies by generic drug name, historical maximum dose by generic 
drug name converting all doses to the same unit (mg)) 
 
9.4 
Study Treatment 
The study treatments will be summarized according to the following features: 
 
• Number of subjects in Control group with crossover to a RF ablation  
• First ablation procedure (index ablation procedure in test group) 
o Anticoagulation strategy 
o Catheter used 
o Ablation catheter inserted (Y/N) 
o RF ablation performed (Y/N) 
o Heart rhythm at start 
o PV ablation (Y/N) 
o RF energy delivery time 
o Ablation outcome (complete PVI achieved: Y/N, entrance block 
confirmed: Y/N, sinus rhythm at the end of the procedure: Y/N, 
electrical cardioversion at the end of the procedure: Y/N, sinus rhythm 
post electrical cardioversion: Y/N) 
• Baseline Medication regimen (same as pre-study, new) (drug therapy group 
only) 
• Cardiovascular Medication (see below) 
 
Summaries of Cardiovascular Medication: Cardiovascular Medication will be coded 
using the WHO Drug Dictionary (September 2011 or newer). Incidences of 
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applicable, and by treatment group, unless otherwise specified. The following 
summaries of incidences will be prepared including test and control group:  
• 
Cardiovascular medication at baseline: All cardiovascular medication which 
was started before/at date of randomization and was not discontinued before/at 
date of randomization will be included in this summary. 
• 
Cardiovascular medication started after baseline: All cardiovascular 
medication which was started after date of randomization will be included in 
this summary. This may include dose changes after baseline if these are 
recorded as new medication entries. 
• 
Concomitant cardiovascular medication: All cardiovascular medication which 
was started at any time during study and was not discontinued before/at date 
of randomization will be included in this summary. 
  
In case start and/or end date are incomplete, a medication will be analyzed as 
concomitant medication as long as it cannot definitely be shown that the medication 
was discontinued before date of randomization. For concomitant medications, in case 
it cannot unequivocally be decided if the medication started before or after baseline, 
these will be analyzed as baseline medication, but excluded from medication started 
after baseline. 
Additionally to these general medication summaries, summaries of new AADs started 
after baseline will be prepared as described in section 10.6.2). 
 
10. EFFICACY ANALYSIS 
Formal planned analyses are described below. It may be necessary for additional 
exploratory analyses to be completed in this study after results from the planned 
analysis are completed. Full details of additional analyses will be given in the CSR. 
 
10.1 
Primary Efficacy Variable Analysis 
The primary analysis will be a Kaplan-Meier (KM) analysis for all subjects in the 
ITT population and account for censored observations. The primary effectiveness 
analysis will be performed in the ITT population, where the subjects will be attributed 
to the treatment group as randomized, regardless of treatment cross-over or post-
randomization medical care. A log-rank test will be used to compare the hazard 
functions between the two groups at any observed event time. If observed, the median 
time to persistent AF/AT as well as the 95% confidence intervals will be reported by 
treatment group based on Kaplan-Meier estimates. The rate of survival without 
persistent AF/AT and rate of persistent AF/AT at 3 years follow-up as well as the 
95% confidence intervals for both groups will be presented using the product limit 
estimate from the Kaplan Meier curve. Kaplan-Meier curves will be plotted. 
The effect size is defined as the negative log of the hazard ratio (hazard rate of the 
Test Group over hazard rate of the Control Group): δ = -loge(λt λc
ൗ
). 
This study is to test the following hypothesis using a one-sided test at alpha equal to 
0.025:  
 
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H1: δ > 0 
 
Null hypothesis: the hazard rate in the Test Group is greater than or equal to the 
hazard rate in the Control Group at observed event times during the follow-up period  
 
Alternative hypothesis: the hazard rate in the Test Group is less than the hazard rate in 
the Control group at observed event times during the follow-up period  
 
Subjects will be considered to have an effectiveness success if they do not progress to 
persistent AF/AT through the 3-year follow-up period.   
 
10.2 PP analysis 
 
The Kaplan-Meier analysis as described in section 10.1 will be repeated in the 
PP population (based on the as-treated principle).  
 
Moreover, an inferential analysis using a Cox proportional hazards model will be 
performed in the PP subject population. For the Cox proportional hazards model, 
treatment itself will be modelled as a time-dependent covariate, i.e:   
 
• for control group (without cross-over): treatment at time t is “control” at any 
time t 
• for ablation group (without cross-over): treatment at time t is “ablation” at any 
time t 
• for cross-over group: treatment at time t is control at any time t before cross-
over and ablation at any time t after cross-over 
 
The Cox proportional hazards model will be used to compare the hazard rate between 
the two treatment groups at observed event times.  
 
The hazard ratio and its 95% confidence interval will be reported. Missing primary 
effectiveness endpoint data will be censored at the time of the subject’s last 
visit/TTM.  
 
The same principles outlined for section 10.1also apply for section 10.2(PP analysis).  
 
10.3 Subgroup Analysis  
The primary effectiveness analysis (KM analysis of time to persistent AF/AT) will be 
performed for the Test Group as randomized and for the Control Group as 
randomized (excluding cross-over subjects). The cross-over subjects (i.e., continued 
on their current AAD or taking a newly prescribed AAD and had an RF ablation 
procedure) will be analyzed separately as a third group. 
• 
Test Group: randomized to RF ablation to achieve PVI using the CARTO® 3, 
CARTO ® XP or CARTO® RMT System, and THERMOCOOL® Catheter Family  


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• 
Control Group: randomized to AAD therapy in accordance with current AF 
management guidelines1-3 
• 
Cross-over Group: Control Group subjects who undergo RF ablation to achieve 
PVI using the CARTO® 3, CARTO ® XP or CARTO® RMT System, and 
THERMOCOOL® Catheter Family 
 
If observed, the median time to persistent AF/AT as well as the 95% confidence 
intervals will be reported for the three groups based on Kaplan-Meier estimates. 
Kaplan-Meier curves will be plotted. The product limit estimates of the rate of 
survival without persistent AF/AT and rate of persistent AF/AT at 3 years follow-up 
as well as the 95% confidence intervals for these three groups will be presented 
separately. 
10.4 Interim Analysis 
To properly account for the repeated interim testing in this study, a group sequential 
method similar to that proposed by O'Brien and Fleming as a guide in interpreting 
interim analyses will be used.7 This procedure requires large critical values early in 
the study, but relaxes (i.e., decreases) the critical value as the trial progresses. Because 
of the conservatism early in the trial, the critical value at the final analysis is near the 
"nominal" critical value. Hence, the sample size requirements with this group 
sequential procedure remain essentially the same as the conventional fixed sample 
size estimate. The actual method for the interim reporting that will be employed in 
this study is the “alpha-spending function” approach to group sequential testing 
developed by Lan and DeMets.8 The Lan-DeMets approach is flexible to 
accommodate unequal sized groups with the number of interim looks unspecified in 
advance. It only requires specification of the rate at which the Type I error (which in 
this trial will be α=0.025 for the primary endpoint) will be "spent". This procedure 
allows "spending" a portion of α at each interim analysis in such a way that at the end 
of the study, the total Type I error does not exceed 0.025. This spending function 
generates boundaries that are nearly identical to the O'Brien-Fleming boundaries.  
 
In survival trials, information time is calculated based upon number of events rather 
than number of subjects accrued. In practice, interim analyses are often scheduled 
based upon specified calendar time rather than number of events. To address the 
logistical inconvenience, Lan and DeMets extended their general group sequential 
approach for the maximum duration trial.9 That is, the conduct of a trial is expected to 
occur within some period of time [0, Tc], where Tc is the maximum calendar (or 
duration) time for completion. The stopping boundaries can be adjusted based on the 
actual number of events observed at the interim look, rather than information fraction. 
This method allows flexibility in the monitoring process for accommodating any 
changes in terms of timing and spacing of the looks or additional examination of the 
data that is not pre-determined in response to the concerns from the GSMC that may 
arise during the course of the trial. 
 
The analytic approach that will be used for the interim analyses for assessing 
treatment differences will be the time-to-event analysis method. The standardized log 
rank score statistic will be compared with the stopping boundaries at each interim 
look to draw statistical inference. If the stopping boundary is crossed, then the study 


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will stop for effectiveness.  
 
Judgment concerning the continuation or termination of the study will involve not 
only the degree of statistical significance observed at the interim analysis, but also the 
likelihood of achieving significance should enrollment continue to the originally 
projected sample size. As an aid in this latter assessment, the group sequential 
analyses outlined above will be supplemented with calculations of conditional power. 
Conditional power (CP) for the primary treatment comparison will be provided to the 
GSMC as a regular part of the interim study reports. If the CP is less than 0.3, then the 
study will be stopped for futility.  
 
The time points of the interim analyses and the number of interim analyses are not 
fixed in advance. The table below contains an example, based on initially estimated 
study times. The example assumes a first interim analysis after 12 months and then 
interim looks every half a year. For example, the anticipated start time for this study is 
December, 2012 and the expected end of subject enrollment is June, 2014. With 3 
years follow-up time, the study is expected to be completed in June, 2017. Interim 
looks are planned for December 2013, June 2014, December 2014, June 2015, 
December 2015, June 2016, and December 2016, with a final look in June 2017. The 
stopping boundaries for effectiveness for these scheduled looks are displayed in the 
table below. At the time point of each interim analysis, the operating characteristics 
will be recalculated based upon the actual information fractions for the interim 
analyses already conducted and proportionally adjusted information fractions for all 
future interim analyses following methods described by Proschan, Lan and Wittes 10.  
The software WinLD will be used. The approach implemented in the software WinLD 
takes into account calendar time as well as number of events. Calendar time scale will 
be used for the spending function. Number of events will be used to estimate 
covariance. At the time point of each interim analysis, boundaries will be re-estimated 
based on updated current calendar time estimate and actual number of events for all 
interim analyses up to the corresponding time point. The current calendar time 
estimate will be updated based on actual time point of current interim analysis, but 
using the maximum duration estimated at the time point of first interim analysis, thus 
previous estimates of calendar time will not change. 
 
 




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(excluding isthmus dependent atrial flutter) at 1 year and 2 years, a KM analysis will 
be performed to examine the hazard function of persistent AF/AT (excluding isthmus 
dependent atrial flutter) for the two treatment groups at 1 year follow-up time and 
2 year follow-up. Data will be censored at 1 year and 2 year follow-up (for subjects 
who are not censored earlier) in two separate analyses. The analyses will be 
performed on both the ITT and PP populations. Log-rank tests will be used to 
compare the hazard functions between the two groups at any observed event time. If 
observed, the median time to persistent AF/AT at 1 year and 2 year follow-up as well 
as the 95% confidence intervals will be reported by the two groups based on 
Kaplan-Meier estimates. The product limit estimates of the rate of survival without 
persistent AF/AT and the rate of persistent AF/AT at 1 year and 2 years follow-up as 
well as the 95% confidence intervals for the rates in the two groups will be presented.  
 
A KM analysis will also be performed to examine the hazard function of persistent 
AF/AT (excluding isthmus dependent atrial flutter) at 3 years by number of ablations 
for the Test group. Number of ablations will be categorized into 1, 2, ≥ 3 ablations if 
sample sizes allow (otherwise, only categories for 1 and ≥2 ablations will be used). 
The median time to persistent AF/AT at 3 years follow-up as well as the 95% 
confidence intervals will be reported for the Test Group by the number of ablations. 
The product limit estimates of the rate of survival without persistent AF/AT and the 
rate of persistent AF/AT at 3 years follow-up as well as the 95% confidence intervals 
for the Test Group will also be presented by the number of ablations. The KM curves 
will be plotted and results will be listed as well. 
 
These secondary efficacy variable analyses will also be repeated using the alternative 
definition of time to persistent AF (HRS 2017), as defined in section 8.3. 
 
10.6.2 
Number of Repeat Ablations and New AAD Drugs  
 
To analyze this secondary effectiveness endpoint (number of repeat ablations and new 
AAD drugs per subject throughout 3 years follow-up), the number of repeat ablations 
will be summarized and listed for the subjects who have undergone at least one 
ablation. In addition, new AAD use (number of new AAD drugs per subject) and the 
frequency of dose changes will be summarized and listed for all subjects by treatment 
group. A new AAD will be defined as an AAD (class I or class III, or AV nodal 
blocking agents such as beta blockers (BB) and calcium channel blockers (CCB), 
which was started after randomization and which was not administered at baseline (i.e 
there is no AAD entry with the same preferred term at baseline). The analyses will be 
performed on both ITT and PP populations. All medications will be coded by using 
the World Health Organization Drug Dictionary (September 2011 or newer) for this 
study. The number and percentage of subjects taking new AAD medications will be 
summarized by ATC level 2 and ATC level 4, overall and by treatment for the ITT 
and PP population. 


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10.6.3 
Rhythm throughout 3 Years Follow-up 
 
For this secondary endpoint, the following definition will be used: 
• 
% subjects in sinus rhythm at a specific visit: This variable will refer to the 
data captured at the visit. Details will be defined when preparing analysis 
programs. 
• 
% subjects with recurrent AF/AT at a specific visit: This variable will also 
refer to the time period after previous visit up the visit analyzed (including 
data captured at the visit analyzed). A subject has recurrent AF/AT if AF or 
AT is documented at any TTM, Holter or ECG within this timeframe 
(additional observations of any other rhythms at the same TTM; Holter or 
ECG are allowed). 
 
To analyze this secondary effectiveness endpoint, rhythm (% subjects in sinus 
rhythm, % subjects with recurrent AF/AT) throughout 3 years follow-up, the number 
of subjects and percentage of subjects in sinus rhythm and the number and percentage 
of subjects with recurrent AF/AT at each visit during the 3 year follow-up time will 
be summarized and listed by treatment group at each follow-up visit. The analyses 
will be performed in both ITT and PP populations. Cross-over subjects will be 
completely excluded in the PP population. 
 
10.6.4 
Factors Associated with AF Disease Progression  
 
To analyze this secondary endpoint, conditions that may be associated with disease 
progression will be assessed at baseline and throughout the 3-year follow-up period.   
 
Cox proportional hazards models will be used to examine the associations of baseline-
variables with time to disease progression. Time to disease progression is referring to 
time to persistent AF/AT (primary endpoint) in this section. The following baseline 
variables will be investigated: 
• 
gender 
• 
age (categories: <75 years, >=75 years) 
• 
LA size (Parasternal long axis view from transthoracic echocardiogram) (not 
large: <= 55mm/large: >55mm)  
• 
AF duration (continuous) 
• 
number of AF events in 6 months prior to trial 
• heart failure (yes vs. no) (as specified in HATCH score component) 
• 
hypertension (yes [past or present] vs. no) 
• 
hyperlipidemia/dyslipidemia (yes [past or present] vs. no) 
• 
renal insufficiency (yes [past or present] vs. no) 
• 
diabetes (yes vs. no) 
• 
dementia (yes vs. no) 
• 
previous TIA or stroke (yes vs. no) (as specified in HATCH score component) 
• 
previous COPD (yes vs. no)(as specified in HATCH score component) 
 
 
For the baseline variables, in a first step, single covariate Cox models including the 


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respective covariate, the treatment factor and the covariate*treatment interaction term 
will be fitted. In a second step, a multivariate Cox model will be fitted including the 
treatment factor and all covariates plus covariate*treatment interaction terms for 
which either the covariate or the interaction term had been associated with time to 
disease progression with a p-value < 0.2 in the single variate model. The Stepwise 
option of PROC PHREG will be used for model selection, setting the level for 
covariates to enter and to stay in the model to 0.05. 
 
 
These analyses will be performed in the ITT and PP populations (with fixed treatment 
effect in the PP population). 
 
Moreover, in the PP population the following analysis will be performed modelling 
the treatment effect as time-dependent covariate and additionally including baseline 
covariates: in a first step, single covariate Cox models including the respective 
covariate and the treatment factor (as time-dependent covariate) will be fitted. In a 
second step, a multivariate Cox model will be fitted including the treatment factor (as 
time-dependent covariate) and all covariates which had been associated with time to 
disease progression with a p-value < 0.2 in the single variate model. The Stepwise 
option of PROC PHREG will be used for model selection, setting the level for 
covariates to enter and to stay in the model to 0.05. 
 
 
11. SAFETY AND TOLERABILITY ANALYSES 
All safety end points will be presented by using the safety population. 
11.1 Adverse Events 
An overall summary of AEs will be presented and will include the number and 
percentages of subjects with 
• any adverse events 
• catheter-related adverse events  
• procedure related adverse events 
• study drug related adverse events 
• primary adverse events 
• serious adverse events 
• adverse events leading to withdrawal   
All adverse events will be coded using MedDRA coding dictionary. 
Summaries of incidence rates of individual AE (number and percentage of subjects) 
by MedDRA system organ class and preferred term will be prepared.  
Such summaries will be displayed for all AE, AE by maximum severity and AE by 
strongest causality to catheter, procedure or study drugs.  
In these summaries, each subject will be counted only once within each category. If a 
subject experiences more than one AE within a category, only the AE with the 
strongest causality or the maximum severity, as appropriate, will be included in the 
summaries by causality and severity.  


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11.2 Catheter-related complications (AEs) 
A key secondary safety endpoint, catheter-related complications (AEs), is limited to 
subjects who have initiated RF ablation and who are in the safety population. 
Catheter-related AEs are those AEs that are identified as possibly, probably or 
definitely related to the study device. The number and percentage of subjects with 
catheter-related AEs will be summarized by system organ class and perferred term for 
Test Group and cross-over subjects and overall in the safety population. Moreover, 
catheter-related complications will be summarized (overall, all types accumulated), in 
a further table containing the number and percentage of subjects with catheter-related 
complications by number of repeat ablations, by anticipated or not, by severity and by 
outcome.  
11.3 Serious AEs 
The number and percentage of subjects with SAEs will be summarized by system organ 
class and preferred term for both  treatment groups and overall and in a further table by 
causality and by severity. 
The summary by AE category will also be prepared for serious catheter-related AEs 
and serious catheter-related AEs by timeframe. Three timeframes will be included in 
this summary: acute phase AEs (ablation to ≤ 7 days) and sub-chronic AEs (>7 to 
30 days post ablation), and chronic AEs (occuring more than 30 days post ablation).  
11.4 Primary AEs 
Primary AEs are defined as specific AEs that occur within 7 days of ablation 
procedure (AE categories as defined in the study protocol). 
The number and percentage of subjects with primary AEs will be summarized by 
system organ class and preferred term, overall and by treatment group. 
11.5 Adverse Drug Reactions 
The number and percentage of subjects with adverse drug reactions defined as AE 
possibly, probably or definitely related to AAD will be summarized by system organ 
class and preferred term according to Test Group, cross-over group and Control 
Group (without cross-over subjects). The number and percentage of subjects with 
adverse drug reactions will also be summarized by causality, by anticipated or not, by 
severity and by outcome. 
 
12. OTHER PLANNED ANALYSES 
12.1 
Quality of Life Analysis 
Quality of Life (QoL) is assessed using the EQ-5D and AFEQT questionnaires. 
Quality of Life (QoL) status will be compared to baseline at 3 months, 6 months, 
1 year, 2 years and 3 years. Descriptive statistics for the baseline and absolute values 
as well as changes from baseline of the scores (AFEQT overall score, AFEQT 
symptoms score, AFEQT daily activity score, AFEQT treatment concern score, 
AFEQT treatment satisfaction score, EQ-5D VAS) )  at follow-up visits will be 
summarized by treatment groups. The analyses will be performed in the PP 
population. Cross-over subjects will be completely excluded for all QoL summaries. 


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Paired-sample t-tests will be used to test whether the change-from-baseline values 
differs from zero within each treatment group. A two-sample comparison of the two 
groups with respect to changes-from-baseline in QoL will be performed using a 
repeated measurement model, including the baseline value as a covariate and 
assessing treatment group differences.  EQ-5D single items will be summarized 
descriptively in a frequency table by treatment group for baseline and follow-up 
visits. Changes from baseline in EQ-5D single items will also be presented for each 
follow-up visit in a frequency table. It will then be tested if there is a difference 
between test and control group using Wilcoxon-Mann-Whitney test separately for 
each follow up visit. 
12.2 Health Economics Analysis  
For this secondary health economic endpoint, health care utilization (number and 
length of hospitalizations and unscheduled cardiovascular-related visits), the total 
number and length of hospitalizations will be summarized by treatment groups in the 
ITT population. 
 
13. REPORTING CONVENTIONS 
The following reporting conventions will be adopted for the presentation of study 
data. These conventions will enhance the review process and help to standardize 
presentation with common notations. 
 
13.1 General Reporting Conventions 
• All tables and data listings will be developed in Landscape Orientation, 
unless presented as part of the text in a CSR. 
• Figures will be presented in Landscape Orientation, unless presented as 
part of the text in a CSR. 
• Legends will be used for all figures with more than one variable or item 
displayed. 
• Figures will be in black and white, unless color figures have been 
identified as useful for discriminating presentation in the figure. Lines in 
figures should be wide enough to view the line after being photocopied.  
• Specialized text styles, such as bolding, italics, borders, shading, 
superscripted and subscripted text will not be used in tables, figures, and 
data listings unless they add significant value to the table, figure, or data 
listing.  
• Only standard keyboard characters should be used in tables and data 
listings. Special characters, such as non-printable control characters, 
printer specific, or font specific characters, will not be used on a table, 


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figure, or data listing. Hexadecimal character representations are allowed 
(e.g., µ, α, β). 
• All titles will be centered on a page. The ICH numbering convention is to 
be used for all TLGs. 
• All footnotes will be left justified and the bottom of a page. Footnotes 
must be present on the page where they are first referenced. Footnotes 
should be used sparingly and must add value to the table, figure, or data 
listing. If more than four footnote lines are planned then a cover page may 
be used to display footnotes. 
• Missing values for both numeric and character variables will be presented 
as blanks in a table or data listing. A zero (0) may be used if appropriate to 
identify when the frequency of a variable is not observed. 
• All date values will be presented as DDMMMYYYY (e.g., 29AUG2001) 
format. A four-digit year is preferred for all dates. 
• All observed time values will be presented using a 24-hour clock 
HH:MM:SS format (e.g., 01:35:45 or 11:26). Seconds should only be 
reported if they were measured as part of the study.  
• Time durations will be reported in HH:MM:SS notation. The use of 
decimal notation to present (display) time durations should be avoided 
(e.g. 0.083h = 5m) unless it is necessary to show the computation of time 
differences in a table, figure, or data listing, in which case both notations 
may be used to display the time duration.  
• All tables, figure, and data listings will have the name of the program, 
programmer, and a date stamp on the bottom of each output.  
13.2 Population Summary Conventions 
• Population(s) represented on the tables or data listings will be clearly 
identified in the last title of the Table as “Population: <name of 
population>” and will be identical in name to that identified in the protocol 
or SAP. 
• Consistent terminology will be used to define and identify a population.  
Common nomenclature may include (a) Full Analysis or ITT, (b) All 
Subjects, (c) PP or Per-Protocol, (d) Efficacy, (e) Safety, or (f) 
Pharmacokinetic. 
• Sub-population(s) or special population(s) descriptions will provide 
sufficient detail to ensure comprehension of the population (e.g., ITT 


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Females, Per-Protocol Males >60 years of age) used for analysis in a table 
or figure. 
• Population sizes may be presented for each treatment or dosing category as 
totals in the column header as (N=xxxx), where appropriate.  
• Population sizes shown with summary statistics are the samples sizes (n) 
of subjects with non-missing values.  
• All population summaries for continuous variables will include: N, mean, 
SD, minimum, and maximum. Other summaries (e.g. number missing, 
median, quartiles, 5%, 95% intervals, CV or %CV) may be used as 
appropriate. 
• All percentages are rounded and reported to a single decimal point 
(xx.x%).  
• Population summaries that include p-values will report the p-value to 
three decimal places with a leading zero (0.001). All p-values reported on 
default output from statistical software (i.e., SAS® Software) may be 
reported at the default level of precision. P-values <0.001 should be 
reported as <0.001 not 0.000. 
 
 


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14. REFERENCES 
1. US Federal Register. (1998) International Conference on Harmonization; 
Guidance on Statistical Principles for Clinical Trials. Department of Health 
and Human Services: Food and Drug Administration [Docket No. 97D-0174]. 
Federal Register Volume 63, Number 179, pages 49583-49598. September 16, 
1998. 
2. ASA. (1999) Ethical Guidelines for Statistical Practice. Prepared by the 
Committee on Professional Ethics, August 7, 1999.  
3. RSS. (1993) The Royal Statistical Society: Code of Conduct, August 1993.  
4. Rubinstein, L. V., Gail, M. H. and Santner, T. J. ‘Planning the duration of a 
comparative clinical trial with loss to follow-up and a period of continued 
observation’, Journal of Chronic Diseases, 34,469-479 (1981) 
5. Lachin JM. A review of methods for futility stopping based on conditional 
power. Statist Med 2005; 24:2747–2764. 
 
6. Cui L, Hung HJ, Wang SJ. Modification of sample size in group sequential 
clinical trials. Biometrics 1999; 55: 853-857. 
 
7. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. 
Biometrics 1979; 35(3):549-556.56. 
 
8. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. 
Biometrika 1983; 70:659-663. 
 
9. Lan KKG, DeMets DL. Group sequential procedures: calendar versus 
information time. Statistics in Medicine 1989; 8:1191-1198. 
 
10. Proschan MA, Lan KKG, Wittes, JT. Statistical Monitoring of Clincal Trials. 
Springer 2006. 87-89 
 
 


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15. TABLES, LISTINGS, AND FIGURES 
15.1 
Planned Table Descriptions 
The following are planned summary tables for protocol 144 (09-Apr-2013). Tables 
will be numbered according to the nomenclature used to support the clinical study 
report.  
Tables will be split according to population adding an additional table extension digit. 
It is indicated in the last column which tables will be also produced for interim 
analysis. All tables, where an interim analysis number is specified, will be included in 
the interim analysis. 
Table 
Number 
Population 
Table Title / Summary 
Sup- 
porting 
Listing  
Interim 
Analysis 
Number 
14.1 DEMOGRAPHIC DATA 
 
14.1.1.1.1 
ITT 
Study Subjects 
Analysis Populations 
16.2.1 
1.1 ITT 
and 
safety set 
only 
14.1.1.1.2 
ITT 
Study Subjects 
Distribution of Subjects by 
Site 
16.2.1 
 
14.1.1.2 
ITT 
Study Subjects 
Disposition  
16.2.3 
1.2 
14.1.1.3 
ITT 
Study Subjects 
Reasons for Withdrawals 
16.2.3 
 
14.1.1.4 
ITT 
Study Subjects 
Protocol Deviations 
Reported in CRF by 
Protocol Deviation Code  
16.2.4.2 
 
14.1.2 
ITT 
Demographics 
Age and Sex 
16.2.6 
 
14.1.3.1 
ITT 
Cardiovascular History 
Lone and Reversible AF, 
Previously Persistent/ 
Permanent AF/AT, 
16.2.7 
 


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Table 
Number 
Population 
Table Title / Summary 
Sup- 
porting 
Listing  
Interim 
Analysis 
Number 
Previously Required 
Cardioversion 
14.1.3.2 
ITT 
Cardiovascular History 
Heart Disease 
16.2.7 
 
14.1.3.3 
ITT 
Cardiovascular History 
Micro-/ Thromboembolism 
16.2.7 
 
14.1.3.4 
ITT 
Cardiovascular History 
Other Arrhythmia 
16.2.7 
 
14.1.3.5 
ITT 
Cardiovascular History 
Hemorrhagic Stroke 
16.2.7 
 
14.1.4.1 
ITT 
Other Medical History 
16.2.8 
 
14.1.4.2 
ITT 
Prior Procedures 
16.2.9 
 
14.1.5 
ITT 
AF History 
16.2.10 
 
14.1.6.1 
ITT 
Cardiovascular Medication 
History 
Previously failed 
therapeutic strategies 
16.2.11 
 
14.1.6.2 
ITT 
Cardiovascular Medication 
History 
Historical Maximum Dose 
by Generic Drug Name 
16.2.11 
 
14.1.7.1 
Safety 
Study Treatment Overview 
Number of subjects in 
Control group with 
crossover to a RF ablation  
16.2.1 
 
14.1.8.1 
Safety 
Study Treatment –Index 
Ablation Procedure 
Anticoagulation strategy 
16.2.15 
 
14.1.8.2 
Safety 
Study Treatment – Index 
Ablation Procedure 
16.2.15 
 


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Table 
Number 
Population 
Table Title / Summary 
Sup- 
porting 
Listing  
Interim 
Analysis 
Number 
Name of catheters used 
14.1.8.3.1 
Safety 
Study Treatment - Index 
Ablation Procedure 
Procedural data 
16.2.15 
 
14.1.8.3.2 
Safety 
Study Treatment - Index 
Ablation Procedure 
THERMOCOOL ® 
Catheter Specific Data 
16.2.15 
 
14.1.8.4 
Safety 
Study Treatment – Index 
Ablation Procedure 
Ablation outcome 
16.2.15 
 
14.1.9 
ITT 
Baseline Medication 
Regimen 
16.2.16 
 
14.1.10.1 
ITT 
Cardiovascular Medication 
at Baseline  
16.2.22 
 
14.1.10.2 
ITT 
Cardiovascular Medication 
started after Baseline 
16.2.22 
 
14.1.10.3 
ITT 
Concomitant 
Cardiovascular Medication  
16.2.22 
 
 
Table 
Number 
Populatio
n 
Table Title / Summary 
Sup- 
porting 
Listing  
Interim 
Analysis 
Number 
14.2 EFFICACY DATA  
14.2.1.1 
ITT 
Time to Persistent AF/AT 
(Primary Efficacy Analysis) 
Results of Kaplan-Meier 
analysis and log rank test 
16.2.17.1 2.1 (but 
without 
rates at 3 
years and 
incl. 
conditional 
power) 
14.2.1.2 
ITT 
Time to Persistent AF/AT 
(Primary Efficacy Variable) 
16.2.17.1 2.2 


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Table 
Number 
Populatio
n 
Table Title / Summary 
Sup- 
porting 
Listing  
Interim 
Analysis 
Number 
 
Recalculated Operating 
Characteristics for Group 
Sequential Design 
 
ITT 
Time to Persistent AF/AT 
(Primary Efficacy Variable) 
 
Sample Size Re-Estimation 
16.2.17.1 2.3 
Only 
required for 
first interim 
analysis; 
not 
required for 
final 
analysis 
14.2.1.3 
ITT 
Time to Persistent AF (HRS 
2017) 
Results of Kaplan-Meier 
analysis and log rank test 
16.2.17.1  
14.2.2.1 
PP 
Time to Persistent AF/AT  
 
Results of Kaplan-Meier 
analysis and log rank test 
16.2.17.1  
14.2.2.2 
PP 
Time to Persistent AF/AT 
 
Cox regression analysis 
including treatment as time-
dependent covariate  
16.2.17.1  
14.2.2.3 
PP 
Time to Persistent AF (HRS 
2017)  
 
Results of Kaplan-Meier 
analysis and log rank test 
16.2.17.1  
14.2.2.4 
PP 
Time to Persistent AF (HRS 
2017) 
 
Cox regression analysis 
including treatment as time-
dependent covariate  
16.2.17.1  
14.2.3.1 
ITT 
Time to Persistent AF/AT: 
Subgroup analyses 
 
Results of Kaplan-Meier 
16.2.17.1  


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Table 
Number 
Populatio
n 
Table Title / Summary 
Sup- 
porting 
Listing  
Interim 
Analysis 
Number 
analysis 
 
14.2.3.2 
ITT 
Time to Persistent AF (HRS 
2017): Subgroup analyses 
 
Results of Kaplan-Meier 
analysis 
16.2.17.1  
14.2.4.1 
ITT, PP 
Time to Persistent AF/AT 
by Number of Repeat 
ablations 
 
Results of Kaplan-Meier 
analysis 
 
16.2.17.1  
14.2.4.2 
ITT, PP 
Time to Persistent AF/AT at 
1 Year  
Results of Kaplan-Meier 
analysis and log rank test 
16.2.17.1  
14.2.4.3 
ITT, PP 
Time to Persistent AF/AT at 
2 Years  
Results of Kaplan-Meier 
analysis and log rank test 
16.2.17.1  
14.2.4.4 
ITT, PP 
Time to Persistent AF (HRS 
2017) by Number of Repeat 
ablations 
 
Results of Kaplan-Meier 
analysis 
16.2.17.1  
14.2.4.5 
ITT, PP 
Time to Persistent AF (HRS 
2017) at 1 Year  
Results of Kaplan-Meier 
analysis and log rank test 
16.2.17.1  
14.2.4.6 
ITT, PP 
Time to Persistent AF (HRS 
2017) at 2 Years  
Results of Kaplan-Meier 
analysis and log rank test 
16.2.17.1  
14.2.5 
ITT, PP 
Number of Repeat Ablations 16.2.17.3  


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Table 
Number 
Populatio
n 
Table Title / Summary 
Sup- 
porting 
Listing  
Interim 
Analysis 
Number 
14.2.6 
ITT, PP 
Number of New AAD Drugs 
per Subject 
16.2.17.3  
14.2.7 
ITT, PP 
Summary of Dose changes 
16.2.22 
 
14.2.8 
ITT, PP 
New AAD Drugs – ATC 
classes 
16.2.22 
 
14.2.9 
ITT, PP 
Heart Rhythm 
16.2.17.3  
14.2.10.1 
ITT, PP 
Factors Associated With 
Time to Persistent AF/AT  
Results of Cox models with 
single baseline covariates 
16.2.17.1  
14.2.10.2 
ITT, PP 
Factors Associated With 
Time to Persistent AF/AT  
Results of Cox model with 
multivariate baseline 
covariates 
16.2.17.1  
14.2.10.3 
PP 
Factors Associated With 
Time to Persistent AF/AT  
Results of Cox models with 
single baseline covariates 
and treatment as time-
dependent covariate 
16.2.17.1  
14.2.10.4 
PP 
Factors Associated With 
Time to Persistent AF/AT  
Results of Cox model with 
multivariate baseline 
covariates and treatment as 
time-dependent covariate 
16.2.17.1  
14.2.11.1 
PP 
Quality of Life – EQ5D 
Descriptive summary of 
VAS  
16.2.14 
 
14.2.112 
PP 
Quality of Life – EQ5D 
16.2.14 
 


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Table 
Number 
Populatio
n 
Table Title / Summary 
Sup- 
porting 
Listing  
Interim 
Analysis 
Number 
Descriptive summary of 
changes from baseline in 
VAS 
14.2.11.3 
PP 
Quality of Life – EQ5D 
Results of repeated 
measurement model for 
changes from baseline in 
VAS 
16.2.14 
 
14.2.11.4 
PP 
Quality of Life – EQ5D 
Frequency table for EQ-5D 
single items 
16.2.14 
 
14.2.11.5 
PP 
Quality of Life – EQ5D 
Frequency table for changes 
from baseline in EQ-5D 
single items and results of 
Wilcoxon-Mann-Whitney 
test 
16.2.14 
 
14.2.12.1 
PP 
Quality of Life – AFEQT 
Descriptive summary of 
derived scores 
16.2.13 
 
14.2.12.2 
PP 
Quality of Life – AFEQT 
Descriptive summary of 
changes from baseline 
16.2.13 
 
14.2.12.3 
PP 
Quality of Life – AFEQT 
Results of repeated 
measurement model 
16.2.13 
 
14.2.13.1 
ITT 
Health Economic Analysis 
Number of hospitalizations 
16.2.25 
 
14.2.13.2 
ITT 
Health Economic Analysis 
Length of hospitalizations 
16.2.25 
 
14.2.13.3 
ITT 
Health Economic Analysis 
16.2.25 
 


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Table 
Number 
Populatio
n 
Table Title / Summary 
Sup- 
porting 
Listing  
Interim 
Analysis 
Number 
Number of unscheduled 
cardiovascular-related visits 
14.3 SAFETY DATA 
 
14.3.1 
Safety 
Adverse Events 
Summary Table 
16.2.23 
 
14.3.2 
Safety 
Adverse Events by System 
Organ Class and Preferred 
Term 
16.2.23 
 
14.3.3.1 
Safety 
Adverse Events by System 
Organ Class and Preferred 
Term and Maximum 
Severity of Event 
16.2.23 
 
14.3.3.2 
Safety  
Adverse Events by System 
Organ Class and Preferred 
Term and Strongest 
Causality to Study Device 
16.2.23 
 
14.3.3.3 
Safety  
Adverse Events by System 
Organ Class and Preferred 
Term and Strongest 
Causality to Study 
Procedure 
16.2.23 
 
14.3.3.4 
Safety  
Adverse Events by System 
Organ Class and Preferred 
Term and Strongest 
Causality to Study Drugs 
16.2.23 
 
14.3.4.1 
Safety 
Catheter-Related Adverse 
Events by System Organ 
Class and Preferred Term 
16.2.23 
 
14.3.4.2 
Safety 
Catheter-Related Adverse 
Events by Number of Repeat 
Ablations, by Anticipated or 
not, by Severity and by 
Outcome 
16.2.23 
 


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Statistical Analysis Plan FINAL Version 2.0 
 
 
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08-NOV-2018 
 
 
Table 
Number 
Populatio
n 
Table Title / Summary 
Sup- 
porting 
Listing  
Interim 
Analysis 
Number 
14.3.4.3 
Safety 
Catheter Related Adverse 
Events – Listing of Cases 
16.2.23 
 
14.3.5.1 
Safety 
Serious Adverse Events by 
System Organ Class and 
Preferred Term 
16.2.23 
 
14.3.5.2 
Safety 
Serious Adverse Events by 
Causality and by Severity 
16.2.23 
 
14.3.5.3 
Safety 
Serious Catheter-Related 
Adverse Events by System 
Organ Class and Preferred 
Term 
16.2.23 
 
14.3.5.4 
Safety 
Serious Catheter-Related 
Adverse Events by System 
Organ Class and Preferred 
Term and Time Frame 
16.2.23 
 
14.3.5.5 
Safety 
Serious Adverse Events  
Listing of Cases 
16.2.23 
3.3 
14.3.6.1 
Safety 
Primary Adverse Events by 
System Organ Class and 
Preferred Term  
16.2.23 
 
14.3.6.2 
Safety 
Primary Adverse Events  
Listing of Cases 
16.2.23 
3.4 
14.3.7.1 
Safety 
Adverse Drug Reactions by 
System Organ Class and 
Preferred Term 
16.2.23 
 
14.3.7.2 
Safety 
Adverse Drug Reactions by 
Causality, by Anticipated or 
not, by Severity and by 
Outcome 
16.2.23 
 
14.3.7.3 
Safety 
Adverse Drug Reactions 
Listing of Cases 
16.2.23 
 
 
 


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Statistical Analysis Plan FINAL Version 2.0 
 
 
CONFIDENTIAL 
 
08-NOV-2018 
 
 
15.2 
Planned Listing Descriptions 
The following are planned data and subject listings for protocol 144 (09-Apr-2013). 
Listings will number according to the nomenclature used to support the clinical study 
report. Listings will be ordered by treatment group and subject and timepoint. In 
addition to the unique subject identification, the treatment group will be displayed on 
all listings. 
It is indicated in the last column which listings will also be produced for interim 
analysis. 
Listing 
Number 
Population 
Listing Title / Summary 
Interim 
Analysis 
16.2.1 
All Subjects 
Study Population Status for Each 
Subject 
 
16.2.2 
ITT 
Inclusion/Exclusion Criteria for 
Each Subject 
 
16.2.3 
ITT 
Study Completion Status and 
Discontinued Subjects 
 
16.2.4.1 
Screening 
Failures 
Reason for Screening Failures 
 
16.2.4.2 
ITT 
Protocol Deviations Reported in 
CRF 
 
16.2.4.3 
ITT 
Major Protocol Deviations and 
Exclusions from Analysis 
Populations 
 
16.2.5 
ITT 
Visit Dates Including Days since 
Randomization  
 
16.2.6 
ITT 
Subject Demographics  
 
16.2.7 
ITT 
Cardiovascular Medical History 
 
16.2.8 
ITT 
Other Relevant Medical History 
 
16.2.9 
ITT 
Prior Procedure History 
 
16.2.10 
ITT 
AF History 
 
16.2.11 
ITT 
Cardiovascular Medication History 
 
16.2.12 
ITT 
Screening Examination Done 
(Yes/No) 
 


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Statistical Analysis Plan FINAL Version 2.0 
 
 
CONFIDENTIAL 
 
08-NOV-2018 
 
 
Listing 
Number 
Population 
Listing Title / Summary 
Interim 
Analysis 
16.2.13 
ITT 
AFEQT Questionnaire 
 
16.2.14 
ITT 
EQ-5D Questionnaire 
 
16.2.15 
ITT 
Ablation Procedures 
 
16.2.16 
ITT 
Baseline Medication Optimization 
 
16.2.17.1 
ITT 
Primary Endpoint: Time to 
Persistent AF/AT 
3.1 
16.2.17.2 
ITT 
CEC Adjudication Form 
 
16.2.17.3 
ITT 
Secondary Endpoints - Number of 
repeat ablations and new anti-
arrhythmic drugs and heart rhythm 
 
16.2.18 
ITT 
Follow-Up Visits – Assessments 
Performed 
 
16.2.19 
ITT 
Blood Pressure 
 
16.2.20 
ITT 
NYHA Classification and 
Additional Diagnoses 
 
16.2.21 
ITT 
HATCH Score 
 
16.2.22 
ITT 
Cardiovascular Medication 
 
16.2.23 
ITT 
Adverse Events 
3.2 
16.2.24 
ITT 
Serious Adverse Events Form 
 
16.2.25 
ITT 
Unscheduled Cardiovascular 
Visit/Hospitalization 
 
16.2.26 
ITT 
12-Lead ECG 
 
16.2.27 
ITT 
Holter Monitoring 
 
16.2.28 
ITT 
Event Recorder 
 
16.2.29 
ITT 
Transesophageal Echocardiogram 
 
16.2.30 
ITT 
Transthoracic Echocardiogram 
 
16.2.31 
ITT 
Cardioversion 
 


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Statistical Analysis Plan FINAL Version 2.0 
 
 
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08-NOV-2018 
 
 
Listing 
Number 
Population 
Listing Title / Summary 
Interim 
Analysis 
16.2.32 
ITT 
Medication Management 
 
 
15.3 
Planned Figure Descriptions 
The following are planned summary figure for protocol 144 (09-Apr-2013). Figures 
will be numbered according to the nomenclature used to support the clinical study 
report.  
It is indicated in the last column which figures will be also produced for interim 
analysis. 
Figure 
Number 
Population 
Figure Title / Summary 
Supporting 
Listing 
Number 
Interim 
Analysis 
14.5.1 
ITT/PP 
Time to Persistent AF/AT 
(Primary Efficacy Analysis) 
Kaplan Meier Curves 
16.2.17.1 
 
14.5.2 
ITT 
Time to Persistent AF/AT - 
Subgroup Analysis 
Kaplan Meier Curves 
16.2.17.1 
 
14.5.3 
ITT/PP 
Time to Persistent AF/AT by 
Number of Ablations 
Kaplan Meier Curves 
16.2.17.1 
 
14.5.4 
ITT/PP 
Time to Persistent AF (HRS 
2017) 
Kaplan Meier Curves 
16.2.17.1 
 
14.5.5 
ITT 
Time to Persistent AF (HRS 
2017) - Subgroup Analysis 
Kaplan Meier Curves 
16.2.17.1 
 
14.5.6 
ITT/PP 
Time to Persistent AF (HRS 
2017) by Number of 
Ablations 
Kaplan Meier Curves 
16.2.17.1