Prospective Elimination Of Distal Coronary Sinus-Left Atrial Connections for Atrial Fibrillation Ablation Trial
Phase: NA
Conditions: Atrial Fibrillation, Arrhythmias, Cardiac
Sponsor: University of Pennsylvania

 
PROSPECTIVE ELIMINATION OF DISTAL CORONARY SINUS-
LEFT ATRIAL CONNECTIONS FOR ATRIAL FIBRILLATION 
ABLATION TRIAL: A RANDOMIZED, SINGLE BLIND, SINGLE 
CENTER STUDY 
Principal Investigator (1) 
Saman, Nazarian, M.D., PhD 
Hospital of the University of Pennsylvania 
Cardiac Electrophysiology, 9 Founders Pavilion 
3400 Spruce Street, Philadelphia, PA 19104 
Phone: (215) 615-5220 
Email: Saman.Nazarian@uphs.upenn.edu 
Principal Investigator (2) 
[PI at additional sites, etc. as 
applicable] 
N/A 
Regulatory Sponsor [If 
applicable] 
N/A 
NIH Grant Number                     
 
N/A 
 
Investigational Product: 
 
N/A  
Protocol Number: 
 
 
IRB Number: 
N/A 
  
IND/ IDE Number: 
 
N/A 
 
 
 
ClinicalTrials.gov Number       
 
 
 
Pending 
 
 
Initial version 
4-9-2018-v-0.1 
Amended 
N/A 
Amended 
N/A 
 
 

CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
Table of Contents 
 
Contents 
LIST OF ABBREVIATIONS.......................................................................................................................... V 
STUDY SUMMARY ...................................................................................................................................... 1 
BACKGROUND AND STUDY RATIONALE ................................................................................................ 3 
INTRODUCTION ............................................................................................................................................ 3 
1.1 
BACKGROUND AND RELEVANT LITERATURE ..................................................................................... 3 
1.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT .......................................................... 3 
THE REFERENCE THERAPY IS PULMONARY VEIN ISOLATION AND ELIMINATION OF NON-PV TRIGGERS. THE 
INVESTIGATIONAL ARM WILL INCLUDE PULMONARY VEIN ISOLATION AND NON-PV TRIGGER ELIMINATION, IN 
ADDITION TO DISTAL CORONARY SINUS ISOLATION. IN THE INVESTIGATIONAL GROUP, DISTAL CORONARY SINUS 
PACING WILL BE UTILIZED TO LOCALIZE THE EARLIEST CONNECTION (ASIDE FROM SEPTAL) FROM THE CORONARY 
SINUS TO THE LEFT ATRIAL MUSCULATURE. ONCE LOCALIZED FOCAL RADIOFREQUENCY LESIONS WILL BE APPLIED 
AT THE DISCRETION OF THE INVESTIGATOR UNTIL CENTRAL (SEPTAL) ACTIVATION OF THE LEFT ATRIUM IS NOTED 
DURING DISTAL CORONARY SINUS PACING. .................................................................................................... 3 
1.2.1 
Nonclinical Data....................................................................................................................... 3 
1.2.2 
Clinical Data to Date ................................................................................................................ 3 
1.2.3 
Clinical Studies in Children ...................................................................................................... 4 
1.3 
DOSE RATIONALE (IF APPLICABLE) .................................................................................................. 4 
2 
STUDY OBJECTIVES ......................................................................................................................... 4 
2.1 
PRIMARY OBJECTIVE ...................................................................................................................... 4 
3 
INVESTIGATIONAL PLAN .................................................................................................................. 4 
3.1 
GENERAL DESIGN .......................................................................................................................... 4 
3.1.1 
Screening Phase ..................................................................................................................... 4 
3.1.2 
Study Intervention Phase ........................................................................................................ 4 
3.1.3 
Follow Up Phase ..................................................................................................................... 5 
3.1.4 
Allocation to Interventional Group ........................................................................................... 5 
3.2 
STUDY ENDPOINTS......................................................................................................................... 5 
3.2.1 
Primary Study Endpoints ......................................................................................................... 5 
3.2.2 
Secondary Study Endpoints .................................................................................................... 5 
3.2.3 
Primary Safety Endpoints [if applicable] .................................................................................. 5 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ........................................................ 5 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 5 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 5 
4.3 
SUBJECT RECRUITMENT ................................................................................................................. 5 
4.4 
DURATION OF STUDY PARTICIPATION .............................................................................................. 6 
4.5 
TOTAL NUMBER OF SUBJECTS AND SITES........................................................................................ 6 
4.6 
VULNERABLE POPULATIONS: .......................................................................................................... 6 
5 
STUDY INTERVENTION ..................................................................................................................... 6 
5.1 
DESCRIPTION ................................................................................................................................. 6 
5.2 
INTERVENTION REGIMEN ................................................................................................................ 6 
5.3 
RECEIPT ........................................................................................................................................ 6 
5.4 
STORAGE ...................................................................................................................................... 6 
5.5 
PREPARATION AND PACKAGING ...................................................................................................... 6 
5.6 
BLINDING ....................................................................................................................................... 6 
5.7 
ADMINISTRATION AND ACCOUNTABILITY .......................................................................................... 6 
5.7.1 
Return or Destruction of Investigational Product ..................................................................... 6 
6 
STUDY PROCEDURES ....................................................................................................................... 6 
TABLE 1: SCHEDULE OF STUDY PROCEDURES ................................................................................... 7 
6.1 
STUDY INTERVENTION PHASE ......................................................................................................... 8 

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6.1.1 
Baseline visit ............................................................................................................................ 8 
6.2 
FOLLOW UP PHASE OF THE STUDY ................................................................................................. 8 
6.2.1 
Visit 1 (6 weeks) ...................................................................................................................... 8 
6.2.2 
Visit 2 – End of Study Visit (6 months) .................................................................................... 8 
6.3 
UNSCHEDULED VISITS .................................................................................................................... 8 
6.4 
SUBJECT WITHDRAWAL .................................................................................................................. 8 
7 
STUDY EVALUATIONS AND MEASUREMENTS .............................................................................. 8 
7.1 
MEDICAL RECORD REVIEW ............................................................................................................. 8 
7.2 
PHYSICAL EXAMINATION ................................................................................................................. 9 
7.3 
VITAL SIGNS .................................................................................................................................. 9 
7.4 
LABORATORY EVALUATIONS ........................................................................................................... 9 
7.5 
EFFICACY EVALUATIONS ................................................................................................................. 9 
7.6 
SAFETY EVALUATIONS .................................................................................................................... 9 
8 
STATISTICAL PLAN ........................................................................................................................... 9 
8.1 
PRIMARY ENDPOINT ....................................................................................................................... 9 
8.2 
SECONDARY ENDPOINTS ................................................................................................................ 9 
8.3 
SAMPLE SIZE AND POWER DETERMINATION ..................................................................................... 9 
8.4 
STATISTICAL METHODS .................................................................................................................. 9 
8.4.1 
Baseline Data ........................................................................................................................ 10 
8.4.2 
Efficacy Analysis.................................................................................................................... 10 
8.4.3 
Safety Analysis ...................................................................................................................... 10 
8.5 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 10 
9 
SAFETY AND ADVERSE EVENTS ................................................................................................... 10 
9.1 
DEFINITIONS ................................................................................................................................ 10 
9.1.1 
Adverse Event ....................................................................................................................... 10 
9.1.2 
Serious Adverse Event .......................................................................................................... 10 
9.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 10 
9.3 
RELATIONSHIP OF AE TO STUDY ................................................................................................... 11 
9.4 
REPORTING OF ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND UNANTICIPATED PROBLEMS ..... 11 
9.4.1 
Follow-up report..................................................................................................................... 11 
9.4.2 
INVESTIGATOR REPORTING: NOTIFYING THE PENN IRB .................................................................. 11 
9.5 
UNBLINDING PROCEDURES ........................................................................................................... 11 
9.6 
STOPPING RULES ......................................................................................................................... 11 
9.7 
MEDICAL MONITORING ................................................................................................................. 11 
9.7.1 
Data and Safety Monitoring Plan........................................................................................... 12 
10 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .................................... 12 
10.1 
CONFIDENTIALITY ......................................................................................................................... 12 
10.2 
DATA COLLECTION AND MANAGEMENT .......................................................................................... 12 
11 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 12 
11.1 
STUDY MONITORING PLAN ............................................................................................................ 12 
11.2 
AUDITING AND INSPECTING ........................................................................................................... 12 
12 
ETHICAL CONSIDERATIONS .......................................................................................................... 12 
12.1 
RISKS .......................................................................................................................................... 13 
12.2 
BENEFITS .................................................................................................................................... 13 
12.3 
RISK BENEFIT ASSESSMENT ......................................................................................................... 13 
12.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION .............................................................. 13 
13 
STUDY FINANCES ............................................................................................................................ 13 
13.1 
FUNDING SOURCE ........................................................................................................................ 13 
13.2 
CONFLICT OF INTEREST ................................................................................................................ 13 
13.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 13 
14 
PUBLICATION PLAN ........................................................................................................................ 13 
15 
REFERENCES ................................................................................................................................... 14 
BIBLIOGRAPHY ......................................................................................................................................... 14 

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List of Abbreviations 
 
 
 
ACC: American College of Cardiology 
AE: Adverse event 
DMC: Data Monitoring Committee 
DM: Diabetes Mellitus 
ECG: Electrocardiogram 
AF: Atrial Fibrillation 
CS: Coronary Sinus 
LA: Left atrial 
 
 
 
 
 

PRECAF Trial 
 
page 1 
Version 0.2 
Study Summary 
Title 
Prospective Elimination Of Distal Coronary Sinus-Left Atrial 
Connections for Atrial Fibrillation Ablation Trial 
Short Title 
PRECAF Trial 
IRB Number 
 
Protocol Number 
 
Phase 
Pilot Study. 
Methodology 
Randomized; Single blind. 
Study Duration 
2 years 
Study Center(s) 
Single-center 
Objectives 
To examine the efficacy of targeting connections between coronary sinus 
and left atrium during an ablation procedure in addition to pulmonary 
vein (PV) isolation and non-PV triggers in Atrial fibrillation patients. 
Number of Subjects 
100 subjects are expected to be enrolled. An interim analysis will be 
performed after enrollment of 50 patients. 
Main Inclusion and 
Exclusion Criteria 
Inclusion criteria are: 
 Patients with paroxysmal or persistent atrial fibrillation; AND 
 Undergoing first AF ablation; AND 
 Age ≥ 18 years. 
Patients are not eligible if they have any of the following exclusion 
criteria: 
 Previous left atrial ablation;  
 Women currently pregnant; 
 Mental or physical inability to take part in the study; 
 Known terminally ill patients. 

CONFIDENTIAL 
 
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Investigational 
Product (drug, 
biologic, device, etc.) 
For Device include 
the planned use 
For Drug, food, 
cosmetic, etc. 
include the dose, 
route of 
administration and 
dose regiment 
N/A 
N/A  
Duration of 
administration (if 
applicable) 
N/A 
Reference therapy 
The reference therapy is pulmonary vein isolation and elimination of non-PV 
triggers. The investigational arm will include pulmonary vein isolation and 
non-PV trigger elimination, in addition to distal coronary sinus isolation. 
Statistical 
Methodology 
The primary efficacy analysis will be performed among the intent-to-
treat study groups using Cox-regressions and Kaplan-Meier curves to 
compare time to the initial occurrence of AF after the blanking period 
following AF ablation.  
Safety Evaluations  
Occurrence of one or more of the following events during the 30 day 
period following the ablation procedure:  
1. stroke, 
2. myocardial infarction, 
3. esophageal injury, 
4. pulmonary vein stenosis, 
5. bleeding, 
6. heart failure, and 
7. death. 
Data and Safety 
Monitoring Plan  
 
Clinical data will be entered and securely stored 
The principal investigator will be responsible for monitoring the data quality 
and the ongoing safety of subjects.  

CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
BACKGROUND AND STUDY RATIONALE 
 
This study will be conducted in full accordance all applicable University of Pennsylvania Research Policies 
and Procedures and all applicable Federal and state laws and regulations including Consolidated 
Guidelines approved by the International Conference on Harmonisation (ICH). All episodes of 
noncompliance will be documented. 
Introduction 
1.1 
Background and Relevant Literature  
Atrial fibrillation (AF) is the most common cardiac arrhythmia affecting millions of people in the US and 
around the world. Over the last 20 years, the catheter based AF ablation procedure has been widely 
adopted. However, the long-term success in paroxysmal AF is 50% and as low as 20% in persistent 
AF. To achieve temporary arrhythmia suppression, repeated ablation procedures may be needed. 
The cost of AF ablation among Medicare patients followed for a year after ablation was found to be 
US$16,049±$12,536 if ablation was successful versus US$19,997±$13,958 for failed ablation.1 
Previous literature indicates that most people have distal connections between coronary sinus 
musculature and the left atrium and that these connections may provide a substrate for single or 
multiple reentry beats as a trigger for atrial fibrillation.2,3 In this proposal we wish to examine the 
efficacy of elimination of distal connection(s) between coronary sinus and left atrial musculature for 
suppression of recurrent atrial arrhythmias. 
1.2 
Name and Description of the Investigational Product  
The reference therapy is pulmonary vein isolation and elimination of non-PV triggers. The 
investigational arm will include pulmonary vein isolation and non-PV trigger elimination, in addition 
to distal coronary sinus isolation. In the investigational group, distal coronary sinus pacing will be utilized 
to localize the earliest connection (aside from septal) from the coronary sinus to the left atrial musculature. 
Once localized focal radiofrequency lesions will be applied at the discretion of the investigator until central 
(septal) activation of the left atrium is noted during distal coronary sinus pacing. 
1.2.1 
Nonclinical Data 
In canine hearts, the coronary sinus musculature is electrically connected to the right atrium (RA) and the 
left atrium (LA) which forms an RA-LA connection.4  
 
1.2.2 
Clinical Data to Date 
In prior work, we sought to describe the prevalence and variability of coronary sinus (CS) and left atrial (LA) 
myocardium connections, their susceptibility to rate-dependent conduction block, and association with atrial 
fibrillation (AF) and flutter induction. The study cohort included 30 consecutive AF patients (age 63.3±10.5 
years, 63% male). Multipolar catheters were positioned in the CS, high right atrium (HRA), and LA parallel 
to and near the CS. Trains of 10 pacing stimuli were delivered during sinus rhythm from each of the following 
sites: CS proximal (CSp), CS distal (CSd), LA septum (LAs), lateral LA (LAl), and HRA, at the following 
cycle lengths: 1000, 500, 400, 300, and 250 ms, while recording from the other catheters. With the CS 9 to 
10 bipole just inside the CS ostium, CS-LA connections were observed in 100% at CS 9 to 10, 30% at CS 
7 to 8, 23% at CS 5 to 6, 23% at CS 3 to 4, and 97% at CS 1 to 2. Eighteen patients (60%) had AF/atrial 
flutter induced. Rate-dependent conduction block of a CS-LA connection at cycle length of ≥250 ms was 
present in 17 (94%) of those with versus none of those without AF/atrial flutter induction (P<0.001). We 
concluded that rate-dependent eccentric CS-LA conduction block is associated with AF/atrial flutter 
induction in patients with drug-refractory AF undergoing ablation. The presence of dual muscular CS-LA 
connections, coupled with unidirectional block in one limb, seems to serve as a substrate for single or 
multiple reentry beats, and arrhythmia induction. (Huang, D. et al. Association of Rate-Dependent 

CONFIDENTIAL 
 
This material is the property of the University of Pennsylvania.   
 
Conduction Block Between Eccentric Coronary Sinus to Left Atrial Connections With Inducible Atrial 
Fibrillation and Flutter. Circ Arrhythm Electrophysiol. 2017 Jan;10(1)).  
 
Importantly, 4 patients in the above study cohort, with AF/AFL induction after rate-dependent CS–LA 
conduction block, the connection site was targeted from the endocardial LA surface. These were distal CS 
to lateral LA connections. The CS–LA connection was successfully and safely ablated in all 4 cases. 
Repeating the identical pacing protocol after ablation failed to induce any arrhythmia in these cases (Circ 
Arrhythm Electrophysiol. 2017 Jan;10(1)). 
1.2.2.1 
Human Pharmacokinetics  
N/A 
1.2.2.2 
Clinical Studies in Adults  
The study will enroll only adults patients aged > 18 years. 
1.2.3 
Clinical Studies in Children  
No children will be enrolled in this study. 
1.3 
Dose Rationale (if applicable)  
N/A 
2 
Study Objectives 
 
2.1 
Primary Objective 
To examine the efficacy of targeting connections between coronary sinus and left atrium during an ablation 
procedure in addition to standard pulmonary vein (PV) isolation and non-PV triggers elimination.  
3 
Investigational Plan  
3.1 
General Design 
The study is designed as a randomized, single-blind, small scale pilot study. Expected duration of subject 
participation is six months. A 30-day event monitor will be used for the first month after ablation. Then, 
regular clinic visits at 6 weeks and 6 months will arranged after ablation with 12 lead electrocardiogram 
check-up. In the last month, a 30-day event monitor will be set to detect the recurrence of atrial arrhythmias. 
 
3.1.1 
Screening Phase 
Participants with be recruited in the cardiology clinic at the Hospital of the University of Pennsylvania or 
satellite sites. The protocol will be explained to those who are indicated for atrial fibrillation ablation. Eligible 
participants will be identified according to the inclusion/exclusion criteria section of the protocol. Written 
consent will be obtained before the ablation procedure .        
3.1.2 
Study Intervention Phase  
Participants will be randomized in a 1:1 fashion to 2 groups. Group 1 participants will undergo the current 
standard of care ablation with pulmonary vein isolation and non-pulmonary vein triggers elimination; group 
2 participants will undergo coronary sinus-left atrium connection ablation, in addition to pulmonary vein 
isolation and non-pulmonary vein triggers. The distal coronary sinus electrode pair will be paced at an 
output not higher than 10mA. During pacing, the earliest activation time in the left atrium at 20 plus 
milliseconds after the pacing spike will be localized and targeted for ablation. Lesions will be delivered at 
40 watt or less, for 30 seconds or less and titrated down using standard criteria at the discretion of the 
proceduralist. Stimulation for induction of AF with pacing cycle length from 250 to 180 ms or 2:1 capture 

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will be performed from proximal coronary sinus and distal coronary sinus and at the site of left atrial to CS 
connection before and after ablation.  
3.1.3 
Follow Up Phase 
A 30-day event monitor will be used for the first month after ablation. Then, regular clinic visits at 6 weeks 
and 6 months will arranged after ablation with 12 lead electrocardiogram check-up. In the last month, a 30-
day event monitor will be set to detect the recurrence of atrial arrhythmias. An adjudication committee 
consisting of two electrophysiologists that are blinded to the randomization scheme will review AF events. 
Time to first AF episode will be recorded as the primary outcome. 
 
3.1.4 
Allocation to Interventional Group  
Study randomization will be performed in a 1:1 fashion using the Urn Randomization program 
(https://health.uconn.edu/community-medicine/programs/health-services-research-unit/project-match/urn-
randomization/) while balancing sex and AF type (paroxysmal and non-paroxysmal). The master list of 
study assignments will be kept by the study coordinator in a password protected and encrypted computer.  
3.2 
 Study Endpoints  
3.2.1 
Primary Study Endpoints 
The primary endpoint of the study is the recurrence of atrial arrhythmia post-ablation. The primary 
endpoint is defined as a non-self-terminating bout of atrial fibrillation, atrial flutter, or atrial tachycardia  >30 
seconds in duration following the 90-day post-ablation blanking period.  
 
3.2.2 
Secondary Study Endpoints 
AF burden will be compared among study groups as a secondary outcome variable. AF burden will be 
measured from the 30 day monitors. 
3.2.3 
Primary Safety Endpoints [if applicable] 
The primary safety composite outcome is defined by occurrence of one or more of the following 
events during the 30-day period following the ablation procedure: stroke, myocardial infarction, 
esophageal damage, pulmonary vein stenosis, bleeding, heart failure and death.  
 
4 
Study Population and Duration of Participation  
4.1 Inclusion Criteria 
 
Patients with paroxysmal or persistent atrial fibrillation; AND 
 
Undergoing first AF ablation; AND  
 
Age ≥ 18 years. 
4.2 
Exclusion Criteria 
 
Previous AF ablation 
 
Women currently pregnant; 
 
Mental or physical inability to take part in the study; 
 
Known terminally ill patients. 
4.3 
Subject Recruitment  
Participants with be recruited from investigator clinical practices in the University of Pennsylvania Health 
System.  
 

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4.4 
Duration of Study Participation 
Participants will be part of the study for 6 months after ablation.   
4.5 
Total Number of Subjects and Sites  
           Recruitment will end when 100 participants are enrolled at Penn.  
 
4.6 
Vulnerable Populations:  
  Vulnerable populations will not be targeted. 
5 
Study Intervention  
5.1 
Description 
The reference therapy is pulmonary vein isolation and elimination of non-PV triggers. The investigational 
arm will include pulmonary vein isolation and non-PV trigger elimination, in addition to distal coronary sinus 
isolation.  
5.2 
Intervention Regimen 
In the investigational group, distal coronary sinus pacing will be utilized to localize the earliest connection 
(aside from septal) from the coronary sinus to the left atrial musculature. Once localized focal 
radiofrequency lesions will be applied at the discretion of the investigator until central (septal) activation of 
the left atrium is noted during distal coronary sinus pacing. 
5.3 
Receipt  
N/A. 
5.4 
Storage 
N/A 
5.5 
Preparation and Packaging 
N/A. 
5.6 
Blinding 
 
The unblinded research coordinator will keep a master file of participant assignments. Once a participant 
is randomized, the investigator/clinician for the patient will be notified of the participant assignment. The 
remainder of the research team and the participant will be blinded to participant assignment. 
5.7 
Administration and Accountability    
N/A. 
5.7.1 
Return or Destruction of Investigational Product 
N/A. 
 
 
6 
Study Procedures 
 

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TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Screening 
Intervention: 
Ablation 
Visit Number 
 
 
Visit 1 
Visit 2  
Study Days 
 
0 
6 weeks  
6 months 
Informed Consent/Assent 
X 
 
 
 
Review Inclusion/Exclusion 
Criteria 
X 
 
 
 
Demographics/Medical History 
X 
 
 
 
Physical Examination 
X 
 
X 
X 
Vital Signs: BP, HR, RR 
X 
X 
X 
X 
Height and Weight 
X 
X 
 
 
Randomization  
 
X 
 
 
Adverse Event / Unanticipated 
Problems Assessment 
 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
30-day Monitor 
 
X 
 
X 
 
 
 
Figure 1. Study flowchart 
 

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6.1 
Study Intervention Phase 
6.1.1 
Baseline visit  
 
Physical Exam 
 
Vital Signs 
 
Height and Weight  
 
Medical Records Review  
 
Review Inclusion/Exclusion Criteria 
 
Informed consent 
 
6.2 
Follow Up Phase of the Study  
6.2.1 
Visit 1 (6 weeks)  
 
Physical Exam 
 
Vital Signs 
 
Medical Records Review 
 
Assess possible adverse events 
 
Consider stopping anti-arrhythmic drug if continued post procedure 
 
12 lead ECG 
6.2.2 
Visit 2 – End of Study Visit (6 months) 
 
Physical Exam 
 
Vital Signs 
 
Medical Records Review  
 
Assess possible adverse events 
 
30 day monitor 
 
12 lead ECG 
6.3 
Unscheduled Visits 
Subjects may experience unanticipated problems, complications or intolerable symptoms such as 
palpitations, dyspnea after ablation, unscheduled visits may occur. Physical examination, 12-lead ECG, 
medical treatment, and complication management may be applied for the study subjects. If subjects have 
severe condition, admission will be arranged.  
6.4 
Subject Withdrawal  
Participants may be withdrawn if failure to adhere to protocol requirements is noted, or if the participant 
wishes to and consents to withdrawal.  
7 
Study Evaluations and Measurements   
7.1 
Medical Record Review 
The following variables will be abstracted from the medical chart:  
 
Date of birth 
 
Height 
 
Weight 

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 
History of co-morbidities related to AF including obstructive sleep apnea, hypertension, and 
thyroid disroders. 
 
Any history of prior cardiovascular disease 
 
Cardiovascular imaging details including echocardiography, CT angiography, or cardiovascular 
MR imaging  
7.2 
Physical Examination 
Standard cardiovascular physical examinations will be performed at study enrollment, on the date of 
ablation and during the 2 follow-up visits. 
7.3 
Vital Signs 
Standard vital signs at clinic visits ill be recorded. No study related changes to routine measurements will 
be made. 
7.4 
Laboratory Evaluations 
N/A 
 
7.5 
Efficacy Evaluations 
12 lead ECGs obtained at clinic visits, and as prompted by symptoms, as well 30 day monitors immediately 
following AF ablation and at 6 months will be utilized for efficacy assessment. Two electrophysiologists that 
will be blinded to study assignments will adjudicate the AF ECG data. Time to first AF episode (following 
ablation) and AF burden (following ablation) will be ascertained. 
 
7.6 
Safety Evaluations 
Comparing study adverse outcomes between the two study groups will be utilized to assess the safety of 
the additional ablation lesions in the investigational arm. 
8 
Statistical Plan 
8.1 
Primary Endpoint 
The primary endpoint is the recurrence of atrial arrhythmia post-ablation. The primary endpoint is defined as 
a non-self-terminating (>30 seconds) episode of atrial fibrillation, atrial flutter, or atrial tachycardia demonstrated 
by ECG or 30 day monitors after the 90-day post-ablation blanking period.  
8.2 
Secondary Endpoints  
The secondary endpoint will be AF burden on the immediate post ablation and 6-month 30-day monitors. 
8.3 
Sample Size and Power Determination 
Assuming alpha 0.05, power 0.80, and 1:1 randomization of 100 participants, and 0.7 probability of AF 
freedom in the control group, we will resolve a 2-sided minimum experimental arm hazard ratio of 0.2 with 
implementation of the log-rank test.  
8.4 
Statistical Methods 
Descriptive summaries of baseline clinical and demographic characteristics will be provided by randomized 
treatment assignment for each analysis population. Cumulative incidence curves for the first atrial arrhythmia 
recurrence will be constructed by randomization group and compared via log rank and proportional hazard models. 
 

CONFIDENTIAL 
 
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8.4.1 
Baseline Data 
Baseline and demographic continuous variables will be summarized as mean+standard deviation (SD). 
Categorical variables will be expressed as standard percentages. 
8.4.2 
Efficacy Analysis  
Cumulative incidence curves for the first atrial arrhythmia recurrence and for death will be constructed by 
randomization group and compared using log rank and proportional hazard methods. 
8.4.3 
Safety Analysis  
All subjects entered into the study and randomized at the baseline visit will have detailed information 
collected on adverse events for the overall study safety analysis 
8.5 
Subject Population(s) for Analysis 
Data from all participants that are randomized into the study will be analyzed as long as the participants 
does not withdraw from the study. 
9 
Safety and Adverse Events 
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study. Intercurrent illnesses or injuries will be regarded as adverse events.  
Abnormal results of study procedures will be considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Additionally, any untoward medical occurrence associated with ablation near the coronary sinus will be 
considered an adverse effect.  
9.1.2 
Serious Adverse Event 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  
 
All adverse events that do not meet any of the criteria for serious will be regarded as non-serious adverse 
events.  
9.2 
Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 

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form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results will be 
recorded in the source document, but grouped under one diagnosis. 
 
All adverse events occurring during the study period will be recorded.  The clinical course of each event  
will be followed until resolution, stabilization, or until it has been determined that the study intervention or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
will be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study intervention or study participation will be 
recorded and reported immediately. 
9.3 
Relationship of AE to Study  
The principal investigator will characterize the relationship of each adverse event to the study procedures 
as definitely related, probably related, possibly related, unlikely or unrelated. 
9.4 
Reporting of Adverse Events, Adverse Device Effects and Unanticipated Problems 
Investigators will conform to the adverse event reporting timelines, formats and requirements of the various 
entities to which they are responsible. The minimum necessary information to be provided at the time of 
the initial report includes: 
 
Study identifier 
 
Study Center 
 
Subject number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study intervention was discontinued 
 
The reason why the event is classified as serious 
 
Investigator assessment of the association 
between the event and study intervention 
 
 
Additionally all other events (unanticipated problems, adverse reactions, unanticipated adverse device 
effects and subject complaints will be recorded and reported with respect to institutional and federal policies 
as described in the Penn Manual and below.  
9.4.1 
Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes the  
investigator’s assessment of the event, a follow-up report including all relevant new or reassessed  
information (e.g., concomitant medication, medical history) will be submitted to the IRB. The investigator  
is responsible for ensuring that all SAE are followed until either resolved or stable.  
9.4.2 
Investigator Reporting: Notifying the Penn IRB  
Any adverse events will immediately be reported to the Penn IRB using forms and guidelines at 
https://irb.upenn.edu/reportable-event.  
9.5 
Unblinding Procedures 
We do not anticipate any medically necessary situation for which the participant must be unblended 
regarding their randomization assignment.  
9.6 
Stopping Rules  
N/A 
9.7 
Medical Monitoring 
The Principal Investigator will oversee the safety of the study along with other co-investigators.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above.  

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9.7.1 
Data and Safety Monitoring Plan 
 
Principal Investigator monitoring  
  
10 Study Administration, Data Handling and Record Keeping 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect 
at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
10.2 Data Collection and Management  
Study data will be collected from the EMR and investigator clinic notes. Data will be de-identified prior to 
recording into the study database. 
 
– MS Excel will be used to maintain an ongoing database  
– The study coordinator will have access to PHI  
– Data containing PHI will be kept on a password protected computer in the PI research laboratory  
– Data will be stored for 1 year following study completion and publication 
 
11 Study Monitoring, Auditing, and Inspecting 
11.1 Study Monitoring Plan 
N/A 
11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB and University 
compliance and quality assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
12 Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study will be 

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made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  
12.1 Risks 
The risks for subjects are the same as standard ablation in atrial fibrillation with the exception of slightly 
prolonged mapping and ablation time by approximately 5-10%. Ablation of the region near the coronary 
sinus is also associated with higher risk of coronary injury. However, the risk of coronary injury is low given 
the investigators prior extensive experience ablating in this region for peri mitral flutters and accessory 
pathways. 
12.2 Benefits 
Subjects may benefit from the intervention with longer atrial arrhythmia free duration, the study also provide 
the potential beneficial ablation strategy in addition to standard ablation in atrial fibrillation.  
12.3 Risk Benefit Assessment 
The risks of participating in the study are likely outweighed by the potential benefits of participating in the 
study.  
12.4 Informed Consent Process / HIPAA Authorization  
The risks and benefits of the procedure will be delineated by investigators, and consent will be obtained 
before ablation either in clinic or in the Cardiology Recovery Unit.  
 The study PI or a co-investigator will obtain consent  
 Privacy will be assured by de-identification of all data in the study database. 
 Subjects will be permitted to provide consent at the time of the consent discussion  
 Investigators will explain the study associated risks and benefits and consent process in eight grade 
language to ensure that subjects comprehend the nature of the study 
 It will be made clear that study participation is not necessary 
 Written informed consent will be documented and informed consent documentation will be retained in 
the the PI laboratory 
 
13 Study Finances 
13.1 Funding Source 
N/A – pilot study 
13.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of 
Interest Related to Research.  
13.3 Subject Stipends or Payments 
N/A 
14 Publication Plan 
Study results will be presented in de-identified format at national meetings and published in peer reviewed 
journals. 
 

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15 References 
Bibliography 
[1] M. H. Kim, J. Lin, C. Kreilick, and S. H. Foltz Boklage. Total costs and atrial fibrillation ablation 
success or failure in Medicare-aged patients in the United States. Adv Ther, 27(9):600–12, 2010. 
[2] The Anatomic Basis of Connections Between the Coronary Sinus Musculature and the Left 
Atrium in Humans. Michel Chauvin et al. (Circulation. 2000;101:647-652.)  
[3] Association of Rate-Dependent Conduction Block Between Eccentric Coronary Sinus to Left 
Atrial Connections With Inducible Atrial Fibrillation and Flutter.  Dong Huang, et al. (Circ 
Arrhythm Electrophysiol. 2017;10:e004637. DOI: 10.1161/CIRCEP.116.004637.) 
 
[4] Electrical Conduction Between the Right Atrium and the Left Atrium via the Musculature 
of the Coronary Sinus.  Matthias Antz et al. (Circulation. 1998;98:1790-1795.)