Prospective Evaluation of Computed Tomography Guided Ablation of Cardiac Ganglionated Plexi in Patients With Atrial Fibrillation
Conditions: Atrial Fibrillation
Sponsor: University of Pennsylvania

 
CT Guided Ablation of Ganglionated Plexi 
 
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PROSPECTIVE EVALUATION OF COMPUTED TOMOGRAPHY GUIDED 
ABLATION OF CARDIAC GANGLIONATED PLEXI IN PATIENTS WITH 
ATRIAL FIBRILLATION  
 
 
 
 
Principal Investigator  
Saman Nazarian MD, PhD 
Department of Medicine, Division of Cardiology, Section for 
Cardiac Electrophysiology 
3400 Spruce Street, Founders 9124 
215-615-5219 
Saman.nazarian@pennmedicine.upenn.edu 
Co-Investigator 
 
Timothy Markman MD 
Department of Medicine, Division of Cardiology, Section for 
Cardiac Electrophysiology 
3400 Civic Center Blvd 
267-593-0103 
Timothy.markman@pennmedicine.upenn.edu 
 
Co-Investigator 
 
Pasquale Santangeli MD, PhD 
Department of Medicine, Division of Cardiology, Section for 
Cardiac Electrophysiology 
3400 Civic Center Blvd 
Pasquale.Santangeli@pennmedicine.upenn.edu 
 
NCT: 04642976 
Date: 6/24/21 
 
 

 
CT Guided Ablation of Ganglionated Plexi 
 
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Table of Contents 
 
1 
Study Summary .......................................................................................................... 6 
1.1 
Synopsis .................................................................................................................. 6 
1.3 Schema ......................................................................................................................... 8 
2 
Introduction and RationalE ...................................................................................... 9 
2.1 
Study Rationale ..................................................................................................... 9 
2.2 
Background ............................................................................................................ 9 
2.2.1 
Clinical Adverse Event Profile ..................................................................... 10 
2.3 
Risk/Benefit Assessment ..................................................................................... 11 
2.3.1 
Known Potential Risks .................................................................................. 11 
2.3.2 
Known Potential Benefits ............................................................................. 11 
2.3.3 
Assessment of Potential Risks and Benefits ................................................ 11 
3 
Study Objectives and Endpoints............................................................................. 12 
4 
Study Plan ................................................................................................................. 13 
4.1 
Study Design ........................................................................................................ 13 
4.2 
Scientific Rationale for Study Design ................................................................ 13 
4.3 
End of Study Definition ...................................................................................... 13 
Study Population ............................................................................................................. 14 
4.4 
Inclusion Criteria ................................................................................................ 14 
4.5 
Exclusion Criteria ............................................................................................... 14 
4.6 
Screen Failures .................................................................................................... 14 
4.7 
Strategies for Recruitment and Retention ........................................................ 14 
Study Intervention .......................................................................................................... 15 
4.8 
Study Intervention(s) Administration ............................................................... 15 
4.8.1 
Study Intervention Description .................................................................... 15 
4.9 
Measures to Minimize Bias: Randomization and Blinding Error! Bookmark not 
defined. 
4.10 
Study Intervention Compliance ......................................................................... 16 
5 
Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal ................................................................................... 17 
5.1 
Participant Discontinuation/Withdrawal from the Study ............................... 17 
5.2 
Lost To Follow-Up .............................................................................................. 17 
6 
Study Assessment and Procedures ......................................................................... 19 
6.1 
Efficacy Assessments ........................................................................................... 19 
6.2 
Safety and Other Assessments ........................................................................... 19 
6.3 
Adverse Events and Serious Adverse Events ................................................... 19 
6.3.1 
Definition of Adverse Events (AE) .............................................................. 19 
6.3.2 
Definition of Serious Adverse Events (SAE) ............................................... 19 
6.3.3 
Classification of an Adverse Event .............................................................. 20 
6.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ......... 22 
6.3.5 
Adverse Event Reporting ............................................................................. 23 
 

 
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6.3.6 
Serious Adverse Event Reporting ................................................................ 24 
6.4 
Unanticipated Problems ..................................................................................... 24 
6.4.1 
Definition of Unanticipated Problems (UP) ................................................ 24 
6.4.2 
Unanticipated Problem Reporting............................................................... 24 
7 
Statistical Considerations ........................................................................................ 26 
7.1 
Statistical Hypotheses ......................................................................................... 26 
7.2 
Sample Size Determination ..................................... Error! Bookmark not defined. 
7.3 
Statistical Analyses .............................................................................................. 26 
7.3.1 
General Approach ......................................................................................... 26 
7.3.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................ 26 
7.3.3 
Analysis of the Secondary Endpoint(s) ....................................................... 26 
7.3.4 
Safety Analyses .............................................................................................. 27 
7.3.5 
Baseline Descriptive Statistics ...................................................................... 27 
7.3.6 
Sub-Group Analyses ..................................................................................... 27 
7.3.7 
Tabulation of Individual Participant Data ................................................. 27 
8 
Supporting Documentation and Operational Considerations ............................. 28 
8.1 
Regulatory, Ethical, and Study Oversight Considerations ............................. 28 
8.1.1 
Informed Consent Process ............................................................................ 28 
8.1.2 
Study Discontinuation and Closure ............................................................. 29 
8.1.3 
Confidentiality and Privacy ......................................................................... 30 
8.1.4 
Future Use of Stored Specimens and Data ................................................. 30 
8.1.5 
Safety Oversight ............................................................................................ 31 
8.1.6 
Clinical Monitoring ....................................................................................... 31 
8.1.7 
Quality Assurance and Quality Control ..................................................... 31 
8.1.8 
Data Handling and Record Keeping ........................................................... 32 
8.1.9 
Protocol Deviations ....................................................................................... 32 
8.1.10 
Publication and Data Sharing Policy........................................................... 33 
8.1.11 
Conflict of Interest Policy ............................................................................. 34 
8.2 
Additional Considerations .................................................................................. 34 
8.3 
Protocol Amendment History ............................................................................ 34 
9 
References ................................................................................................................. 35 
Pachon JC et al. Cardioneuroablation: Catheter Vagal Denervation as a New 
Therapy for Cardioinhibitory Syncope. J Cardiac Arrhythmia. 
2019:32(3)182-196 ............................................................................................... 35 
10 APPENDIX ............................................................................................................... 36 
 
 
 

 
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Abbreviations 
 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CT 
Computed Tomography 
MP 
Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GP 
Ganglionated Plexus 
GWAS 
Genome-Wide Association Studies 
HFS 
High Frequency Stimulation 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 

 
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IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-Squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
DSMC 
Data Safety Monitoring Committee 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UADE 
Unanticipated Adverse Device Effect 
UP 
Unanticipated Problem 
US 
United States 
 
 
 
 

 
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1 STUDY SUMMARY 
1.1 
Synopsis 
Title:  
PROSPECTIVE EVALUATION OF COMPUTED TOMOGRAPHY 
GUIDED MAPPING AND ABLATION OF CARDIAC 
GANGLIONATED PLEXI IN PATIENTS WITH ATRIAL 
FIBRILLATION 
Short Title: 
CT Guided Ablation of Ganglionated Plexi  
Study 
Description:  
Single-arm prospective study to evaluate the role of high frequency 
stimulation (HFS) and computed tomography (CT) guided mapping and 
ablation of ganglionated plexi (GP) in patients with atrial fibrillation. 
 
 
Objectives:  
Primary: 
  
 
Secondary: 
To assess the effects of GP ablation on local HFS response and global 
vagal stimulation in order to characterize the neural pathways connecting 
GPs 
Primary 
Endpoint:  
The primary outcome of interest will be the successful identification of 
GP signals by high frequency stimulation and anatomic correlation 
between these points and CT identified epicardial adipose tissue within 3 
pixels (0.625x3=1.875mm). 
Secondary 
Endpoints: 
 
• Elimination of local of HFS response following GP ablation 
• Elimination of global vagal response to non-invasive ear stimulation  
• Characterization of amplitude, duration, and fractionation of signals at 
sites with HFS responses and successful HFS elimination 
Study 
Population: 
19 patients with atrial fibrillation undergoing catheter ablation of atrial 
fibrillation 
Description of 
Sites/Facilities  
All ablation procedures will be performed at the Hospital of the 
University of Pennsylvania. 
 
 

 
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1.3 Schema 
 
Prior to  
Enrollment 
 
Visit 1 
Time Point  
 
Visit 2 
Time Point  
 
 
 
 
 
 
 
 
 
 
 
Total N=19:  Obtain informed consent. Screen potential participants by 
inclusion and exclusion criteria; obtain history, document. 
Perform CT scan 
Catheter ablation for Atrial Fibrillation with Pulmonary Vein Isolation and 
mapping/ablation of ganglionated plexi  
 
Routine clinical follow-up 

 
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2 INTRODUCTION AND RATIONALE 
The heart has a complex network of autonomic innervation with the majority of input occurring at a series of ganglionated plexi. These 
ganglionated plexi are found in the epicardial adipose tissue around the base of the heart and interruption of these regions, most 
commonly through endocardial ablation, has been a potential treatment for multiple cardiac arrhythmias. This approach has become an 
accepted strategy for treating atrial fibrillation but may also be of value for vasovagal syncope, sinus node dysfunction, and heart block. 
Identification of the ganglionated plexi is challenging and multiple techniques have been utilized. We anticipate that using standard 
cardiac computed tomography (CT) to identify epicardial adipose tissue can provide a safe, non-invasive option to locate these regions 
and guide appropriate intervention. We also anticipate that a consistent network of innervation between the GPs will be identifiable with 
distinct innervation of the sinus and AV nodes. 
2.1 
Study Rationale 
Despite progress made in treating atrial fibrillation with catheter ablation, outcomes remain suboptimal with pulmonary vein isolation 
alone. Ablation of ganglionated plexi has been shown to be beneficial in patients with atrial fibrillation although optimal strategies of 
localization of these regions have yet to be determined. We aim to develop a novel strategy of CT guided ganglionated plexi 
localization to guide ablation in patients with atrial fibrillation.  We also aim to clarify the network of innervation between GP to 
clarify the optimal ablation strategy. 
2.2 
Background 
Autonomic cardiac innervation arises from the brainstem and travels to the heart via the cervical and thoracic stellate ganglion 
(sympathetic system) and the vagus nerve (parasympathetic system). The two systems combine to innervate the heart in a dense network 
of post-ganglionic axons called the ganglionated plexi (Hou Y, et al). These ganglionated plexi are located at the base of the heart in the 
epicardial adipose tissue (Goudis CA, et al; Armour JA, et al).  
 
With direct visualization of the epicardial adipose tissue at the time of cardiac surgery, autonomic modulation with injection of botulinum 
toxin has been shown to reduce short and long term burden of atrial fibrillation (Romanov A et al; Waldron et al).  Several techniques 
have been proposed to identify the ganglionated plexi at the time of endocardial procedures. Anatomic approaches have been utilized 
targeting classical regions of autonomic innervation, although this procedure has several limitations including individual anatomic 

 
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Atrial Fibrillation 
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variation.  In addition, high frequency stimulation mapping to identify local vagal responses has been used (Kim MY, et al; Hu F, et al). 
This technique is limited by the need for general anesthesia and the duration of time required to map the entire atrium, which is especially 
relevant for non-atrial fibrillation ablation procedures where such mapping would not otherwise be required. More recently, techniques 
to evaluate local electrograms have been developed based on the principle that fractionated electrical activity may be noted in the 
endocardium beneath ganglionated plexi due to the inter-myocardial nerve fibers that interrupt normal myocardial-to-myocardial 
conduction (Pachon M JC, et al; Lellouche N, et al). 
 
We have recently shown that there is an association between left atrial epicardial adipose tissue identified by CT imaging and 
electrogram fractionation (Zghaib T, et al). This association is consistent with other descriptions of local electrograms at the site of 
successful ablation of ganglionated plexi.  Given the routine nature of pre-procedure imaging, which is frequently performed prior to 
atrial fibrillation ablation to clarify relevant anatomy, and the ability to identify this epicardial adipose tissue, we anticipate CT can 
provide a safe, non-invasive option to locate these regions and guide appropriate intervention.  Ablation targeting ganglionated plexi 
have been used to treat atrial fibrillation as well as vasovagal syncope, sinus node dysfunction, and heart block. A simple and reliable 
method of identifying ablation target could improve the safety and efficacy of these procedures.  
 
Update to 1/23/24 version: Although tragus stimulation has been frequently utilized, there is evidence to suggest more robust vagus 
nerve innervation in the region of the cymba concha (Frangos et al 2015; Rong et al 2012; Courties et al 2022).  For this reason, electrodes 
positioned in this area may have more consistent physiologic effects related to vagus nerve stimulation. 
2.2.1 
Clinical Adverse Event Profile 
Potential complications of catheter ablation of atrial fibrillation include bleeding, vascular injury, cardiac perforation, atrioesophageal 
fistula formation, phrenic nerve injury, bradycardia, arrhythmia induction, myocardial infarction, and stroke. These complications are 
related to the insertion of catheters from the femoral veins into the heart and across the intra-atrial septum to the left atrium as well as 
the delivery of radiofrequency energy in the left atrium.  We do not anticipate the mapping portion of the procedure, which will be 
performed with a standard ablation catheter, to confer significant additional risk. The most likely increased risk from high frequency 
stimulation is the induction of atrial fibrillation, which is common as part of routine ablation procedures and does not pose significant 
risk. We do not anticipate these risks to be significant modified by the additional ablation targeting ganglionated plexi, which are 
located in regions frequently targeted in ablation of atrial fibrillation and atypical atrial flutters.  

 
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2.3 
Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
As discussed above, potential risks of ablation of ganglionated plexi include the risk factors associated with catheter ablation for atrial 
fibrillation as discussed above. An additional theoretical risk includes increased sinus rates following vagal denervation, which has 
been described as transient in the literature and not seen in our own experience. Potential risks of ear stimulation include local 
discomfort or skin irritation/burns. Potential risks of high frequency stimulation include pain, which will not be perceived given the 
use of general anesthesia, and the induction of atrial fibrillation, which routinely occurs during atrial fibrillation ablations. 
2.3.2 
Known Potential Benefits 
Potential benefits include the reduction in burden of atrial fibrillation by eliminating vagal triggers for atrial fibrillation.  In addition, 
societal benefits include the development of procedural techniques that may improve treatment of atrial fibrillation, vasovagal 
syncope, and other conditions. 
2.3.3 
Assessment of Potential Risks and Benefits 
The risks of participating in the study are not significant beyond the risks associated with routine clinical care (including pre-
procedural CT imaging, atrial mapping and ablation). Therefore, the potential benefits to the individual subject and to society 
outweigh the risks of participating in the study.  

 
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3 STUDY OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
 
• 
Successful identification of GP signals by high 
frequency stimulation and anatomic correlation 
between these points and CT identified epicardial 
adipose 
tissue 
within 
3 
pixels 
(0.625x3=1.875mm). 
This correlation with allow us to 
determine the ability of pre-
procedural CT imaging to predict 
GP location. 
Secondary 
 
 
To assess the effects of GP ablation on local HFS 
response and global vagal stimulation in order to 
characterize the neural pathways connecting GPs 
• 
Elimination of local of HFS response following 
GP ablation 
• 
Elimination of global vagal response to non-
invasive ear stimulation 
 
 
• 
Amplitude, duration, and fractionation of signals 
at sites with HFS responses and successful HFS 
elimination  
 

 
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4 STUDY PLAN 
4.1 
Study Design 
This is an observational, single-center study evaluating feasibility and efficacy of CT and high frequency stimulation guided GP 
mapping and ablation in patients with AF undergoing catheter ablation with pulmonary vein isolation.  
4.2 
Scientific Rationale for Study Design 
This study is designed to characterize the association between CT identified epicardial adipose tissue and HFS mapping identified GP 
sites in the right and left atrium. Given the evidence that GP ablation can be beneficial for patients undergoing catheter ablation for 
atrial fibrillation, all patients will undergo GP ablation following mapping in addition to standard pulmonary vein isolation. The 
hierarchical relationship within the network of cardiac GPs is unknown as is the optimal order of GP ablation. Given equipoise in the 
order of GP ablation, we will equally allocate the site of initial ablation between the 8 major GP ablation locations.  
4.3 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all phases of the study including the last visit. 

 
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STUDY POPULATION 
4.4 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the study 
3. Male or female, aged >18 years 
4. History of AF with plan to undergo catheter ablation  
4.5 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Contraindication or unwillingness to undergo CT imaging or catheter ablation. 
2. Pregnancy or lactation 
4.6 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are not subsequently randomly assigned to 
the study intervention or entered in the study. A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any serious adverse event (SAE). 
4.7 
Strategies for Recruitment and Retention 
Participants will be recruited from the investigator’s clinical practice. We anticipate an accrual rate of approximately 4 subjects per 
month. Long term follow-up for the study will include the standard of care monitoring of patients following catheter ablation. 

 
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STUDY INTERVENTION 
4.8 
Study Intervention(s) Administration 
4.8.1 
Study Intervention Description 
All patients will have GP mapping performed using the Nicolet (Natus) Cortical Stimulator (see attached) with 12V output at 20Hz 
frequency with 10ms pulse duration with at least 3grams of contact force. Stimulation will be provided for up to 10 seconds or until 
vagal response is noted (>2s ventricular asystole, AV block, or R-R interval increase by at least 50%). Natus stimulator had FDA 
clearance (K072964) for cortical stimulation. Prior to ablation, baseline ear vagus nerve stimulation will be performed via stimulation 
of bilateral cymba concha to document response using Parasym tragal stimulator (IDE information attached). Ablation of mapped GPs 
will be performed using standard ablation catheter with routine approaches to ablation energy delivery and monitoring (see below 
flowchart). Following ablation of each GP, local HFS will be repeated in all GP regions and ear vagus nerve stimulation will be 
repeated via bilateral cymba concha. After all GP are ablated, all patients be given IV atropine (0.04mg/kg max: 4mg) to assess global 
vagal tone. Following this, patients will undergo pulmonary vein isolation using standard equipment and techniques.   
Devices will be obtained from the manufacturer (Natus and Parasym respectively) and will be stored in a secured laboratory space. No 
particular temperature or climate requirements are present for either device.  All devices will be labeled according to the manufacturer 
guidance and will be returned to the manufacturer in the event of any device failure.  Devices will be stored and managed in 
compliance with OCR guidelines. 

 
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4.9 
Study Intervention Compliance 
Following the ablation procedure, compliance will only be necessary for follow-up visits, which will be performed per clinical routine. 

 
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5 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
5.1 
Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• Pregnancy 
• Significant non-compliance with follow-up visits 
• If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation occurs such that continued 
participation in the study would not be in the best interest of the participant 
• If the participant meets an exclusion criterion (either newly developed or not previously recognized) that precludes further 
study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case Report Form (CRF). Subjects 
who sign the informed consent form and are randomized but do not undergo ablation may be replaced. Subjects who sign the informed 
consent form and are randomized and undergo ablation, and subsequently withdraw, or are withdrawn or discontinued from the study, 
will not be replaced.] 
5.2 
Lost To Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for two scheduled visits and is unable to be contacted by 
the study site staff. 

 
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The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• The site will attempt to contact the participant and reschedule the missed visit within 3 months and counsel the participant on 
the importance of maintaining the assigned visit schedule and ascertain if the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to regain contact with the 
participant (where possible, 3 telephone calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the participant’s medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have withdrawn from the study with a 
primary reason of lost to follow-up. 

 
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6 STUDY ASSESSMENT AND PROCEDURES 
6.1 
Efficacy Assessments 
• Elimination of local HFS response and ear vagus nerve stimulation will determine acute procedural efficacy 
• Loop recorder or ambulatory monitors interrogations to evaluate presence and burden of atrial fibrillation 
• History to identify symptomatic atrial fibrillation and to identify episodes of AF that may have been vagally mediated 
6.2 
Safety and Other Assessments 
• Physical examination will be performed following the ablation procedure to identify any procedural complications including 
vascular or neurological injury. 
• Repeat examination and history will be performed at follow-up visit to identify any potential procedural complications. 
6.3 
Adverse Events and Serious Adverse Events 
6.3.1 
Definition of Adverse Events (AE) 
An adverse event (AE) is any untoward medical occurrence associated with the use of an intervention in humans, whether or not 
considered intervention related. Intercurrent illnesses or injuries should be regarded as adverse events. 
A pre-existing condition should be recorded as an adverse event if the frequency, intensity or the character of the condition changes. 
6.3.2 
Definition of Serious Adverse Events (SAE)  
Serious Adverse Events (SAE) 

 
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Adverse events are classified as serious or non-serious. A serious adverse event is any AE that, in the view of either the investigator or 
the sponsor, is: 
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event when the event does not fit the other outcomes, but the event may jeopardize the patient and may 
require medical or surgical intervention (treatment) to prevent one of the other outcomes. 
• required intervention to prevent permanent impairment or damage (for devices only) 
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. For example, drug 
overdose or abuse, a seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency 
department would typically be considered serious. 
6.3.3 
Classification of an Adverse Event 
6.3.3.1 
Severity of Event 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will be used to describe 
severity. 

 
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• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities.  
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. Moderate events may 
cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or other treatment. Severe 
events are usually potentially life-threatening or incapacitating. Of note, the term “severe” does not necessarily equate to 
“serious”. 
6.3.3.2 
Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to procedure assessed by the clinician who examines and evaluates the 
participant based on temporal relationship and his/her clinical judgment. The degree of certainty about causality will be graded using 
the categories below. In a clinical trial, the study product must always be considered. 
• Related – The AE is known to occur with the GP mapping or ablation, there is a reasonable possibility that the procedure 
caused the AE, or there is a temporal relationship between the procedure and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the procedure and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the procedure caused the event, there is no 
temporal relationship between the procedure and event onset, or an alternate etiology has been established. 
6.3.3.3 
Expectedness  
The primary investigator will be responsible for determining whether an adverse event (AE) is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously described 
for the procedure. 
 

 
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6.3.4 
Time Period and Frequency for Event Assessment and Follow-Up 
Safety will be assessed by monitoring and recording potential adverse effects using the CTCAE grading system at each study visit. 
Participants will be monitored by medical histories, physical examinations, and loop recorder interrogations. If CTCAE grading does 
not exist for an adverse event, the severity of mild, moderate, severe, life-threatening, and death, corresponding to Grades 1-5, will be 
used whenever possible. 
At each contact with the subject, the investigator will seek information on adverse events by non-directive questioning and, as 
appropriate, by examination. Adverse events may also be detected when they are volunteered by the subject during the screening 
process or between visits, or through physical examination, laboratory test, or other assessments. Information on all adverse events 
will be recorded in the source documentation. To the extent possible, adverse events will be recorded as a diagnosis and symptoms 
used to make the diagnosis recorded within the diagnosis event. 
As much as possible, each adverse event or follow-up information will be evaluated to determine: 
1. Severity grade (CTCAE Grade 1-5) 
2. Duration (start and end dates) 
3. Relationship to the study treatment or process – [Reasonable possibility that AE is related: No (unrelated/ not suspected) or 
Yes (a suspected adverse reaction)]. If yes (suspected) - is the event possibly, probably or definitely related to the 
investigational treatment? 
4. Expectedness to study treatment or process – [Unexpected – if the event severity and/or frequency is not described in the 
investigator brochure (if applicable) or protocol]. 
5. Action taken with respect to study or investigational treatment or process (none, dose adjusted, temporarily interrupted, 
permanently discontinued, unknown, not applicable) 

 
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6. Whether medication or therapy taken (no concomitant medication/non-drug therapy, concomitant medication/non-drug 
therapy) 
7. Whether the event is serious 
Once an adverse event is detected, it should be followed until its resolution or until it is judged to be permanent, and assessment 
should be made at each visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to the study 
treatment, the interventions required to treat it, and the outcome. 
 
 
6.3.5 
Adverse Event Reporting 
Reporting Period 
Adverse events will be reported from the time of informed consent until study completion. 
Investigator Reporting: Notifying the Study Sponsor 
Every SAE, regardless of suspected causality (e.g., relationship to study product(s) or study procedure(s) or disease progression) must 
be reported to the sponsor within 24 hours of learning of its occurrence. 
Recurrent episodes, complications, or progression of the initial SAE must be reported to the Sponsor as a follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. A SAE considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
New information regarding the SAE will be reported as it becomes available and in the same manner that the initial SAE (i.e. SAE 
form). The investigator must follow the event to resolution or until the event is deemed and documented irreversible, whichever is 
longer. 

 
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Investigator Reporting: Local Reporting Requirements 
The investigator will report AEs and SAEs to the IRB/EC of record and other local regulatory groups per the local requirements. 
6.3.6 
Serious Adverse Event Reporting  
The study investigator shall complete an Unanticipated Adverse Device Effect Form and submit to the study sponsor and to the 
reviewing Institutional Review Board (IRB) . The study sponsor is responsible for conducting an evaluation of an unanticipated 
adverse device effect and shall report the results of such evaluation to the Food and Drug Administration (FDA) and to all reviewing 
IRBs and participating investigators per the applicable regulation. 
6.4 
Unanticipated Problems 
6.4.1 
Definition of Unanticipated Problems (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to participants or others to 
include, in general, any incident, experience, or outcome that meets all the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in the protocol-
related documents, such as the Institutional Review Board (IRB)-approved research protocol and informed consent document; 
and (b) the characteristics of the participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm (including physical, psychological, economic, 
or social harm) than was previously known or recognized. 
6.4.2 
Unanticipated Problem Reporting 
Unanticipated problems (UPs) such as: 

 
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• 
Post-marketing withdrawal of a drug, device, or biologic used in a research protocol due to safety concerns. 
• 
FDA ban of a drug, device, or biologic used in a research protocol due to safety concerns. 
• 
Complaint of a participant when the complaint indicates unexpected risks, or the complaint cannot be resolved by the research 
team 
• 
Breach of confidentiality 
• 
Incarceration of a participant when the research was not previously approved under Subpart C and the investigator believes it 
is in the best interest of the subject to remain on the study 
• 
Premature closure of a study (e.g., due safety, lack of efficacy, feasibility, financial reasons, etc.) 
should be reported by the investigator to the Institutional Review Board (IRB). The UP report will include the following information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or outcome represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been taken or are proposed in response to the 
UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
• UPs that are serious adverse events (SAEs) will be reported as any other SAE. 
• Any other UP will be reported to the IRB 10 business days of the investigator becoming aware of the problem. 
• All UPs should be reported to appropriate institutional officials (as required by an institution’s written reporting procedures), 
the supporting agency head (or designee), and the Office for Human Research Protections (OHRP) within 10 business days of 
the IRB’s receipt of the report of the problem from the investigator. 

 
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7 STATISTICAL CONSIDERATIONS 
7.1 
Statistical Hypotheses 
• Primary Efficacy Endpoint(s): We anticipate anatomic correlation between CT identified epicardial adipose tissue within 3 
pixels (0.625x3=1.875mm) of an endocardial mapping point where HFS confirmed a vagal response consistent with ganglionated 
plexus innervation.  
• Secondary Efficacy Endpoint(s): Acute procedural success defined by elimination of ear vagus nerve stimulation response will 
be achievable in all patients. 
 
7.2 
Statistical Analyses 
7.2.1 
General Approach 
• For descriptive statistics, categorical data will be presented as percentages and continuous data will be presented as medians 
with intraquartile ranges.  
• All statistical tests will be 2-sided, with p<0.05 indicating statistical significance. 
7.2.2 
Analysis of the Primary Efficacy Endpoint(s) 
• Anatomic correlation between CT and GP mapping will be defined based on review of electroanatomic maps from the ablation 
procedure merged with segmented pre-procedural CT images. 
7.2.3 
Analysis of the Secondary Endpoint(s) 
• AF burden will be defined based on loop recorder interrogation and patient history of requiring cardioversion 

 
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7.2.4 
Safety Analyses 
A summary statistic for all adverse events will be reported. All adverse events will be presented based on severity, frequency, and 
relationship to study intervention.  Adverse events leading to premature discontinuation from the study intervention and serious 
treatment-emergent AEs will be separately listed.  
7.2.5 
Baseline Descriptive Statistics 
Patients will be compared based on baseline characteristics, including demographics and laboratory measurements, using descriptive 
statistics including Chi-squared tests for categorical variables, and analysis of variance for continuous variables. All statistical tests 
will be 2-sided, with p<0.5 indicating statistical significance.  
7.2.6 
Sub-Group Analyses 
Primary and secondary endpoints will be analyzed based on age, sex, race/ethnicity or other demographic characteristic(s). 
7.2.7 
Tabulation of Individual Participant Data 
Individual participant data will not be listed by measure and time point. 

 
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8 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
8.1 
Regulatory, Ethical, and Study Oversight Considerations 
8.1.1 
Informed Consent Process 
8.1.1.1 
Consent/Assent and Other Informational Documents Provided To Participants 
Consent forms describing in detail the GP mapping and ablation study procedures, and risks are given to the participant and written 
documentation of informed consent is required prior to enrollment. The following consent materials are submitted with this protocol: 
Consent and HIPAA authorization form.  
8.1.1.2 
Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and continues throughout the 
individual’s study participation. Consent forms will be Institutional Review Board (IRB)-approved and the participant will be asked to 
read and review the document. The investigator will explain the research study to the participant and answer any questions that may 
arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of the purposes, procedures, and 
potential risks of the study and of their rights as research participants. Participants will have the opportunity to carefully review the 
written consent form and ask questions prior to signing. The participants should have the opportunity to discuss the study with their 
family or surrogates or think about it prior to agreeing to participate. The participant will sign the informed consent document prior to 
any procedures being done specifically for the study. Participants must be informed that participation is voluntary and that they may 
withdraw from the study at any time, without prejudice. A copy of the informed consent document will be given to the participants for 
their records. The informed consent process will be conducted and documented in the source document (including the date), and the 
form signed, before the participant undergoes any study-specific procedures. The rights and welfare of the participants will be 
protected by emphasizing to them that the quality of their medical care will not be adversely affected if they decline to participate in 
this study. 
 

 
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8.1.2 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated by the Sponsor or the PI at any site if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to regulatory authorities. If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will provide the 
reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the sponsor, IRB 
and/or Food and Drug Administration (FDA). 
In terminating the study, the Sponsor and the Principal Investigator will assure that adequate consideration is given to the protection of 
the subjects’ interests. 

 
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8.1.3 
Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the sponsor(s) and their 
interventions. This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical 
information relating to participants. Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional Review Board (IRB), regulatory 
agencies or pharmaceutical company supplying study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal use during the study. At the end of 
the study, all records will continue to be kept in a secure location for as long a period as dictated by the reviewing IRB, Institutional 
policies, or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be transmitted to and stored in 
our Data Coordinating Center. This will not include the participant’s contact or identifying information. Rather, individual participants 
and their research data will be identified by a unique study identification number. The study data entry and study management systems 
used by clinical sites research staff will be secured and password protected. At the end of the study, all study databases will be de-
identified and archived. 
8.1.4 
Future Use of Stored Specimens and Data  
Data collected for this study will be analyzed and stored in an encrypted, password protected file After the study is completed, the de-
identified, archived data will be transmitted to and stored in an encrypted, password protected file for use by other researchers 
including those outside of the study.  

 
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8.1.5 
Safety Oversight 
Safety oversight will be under the direction of a primary investigator and co-investigators, who will review safety data for each patient 
following enrollment and randomization. 
8.1.6 
Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are protected, that the reported trial 
data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable 
regulatory requirement(s). The primary investigator and co-investigator will be responsible for clinical site monitoring. 
8.1.7 
Quality Assurance and Quality Control 
All monitoring and audits are to be performed according to ICH GCP E6(R2). 
Each clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation 
and completion. An individualized quality management plan will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be run on the 
database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are 
generated, and specimens are collected, documented (recorded), and reported in compliance with the protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of 
monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 

 
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8.1.8 
Data Handling and Record Keeping  
8.1.8.1 
Data Collection and Management Responsibilities  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site investigator. The investigator is 
responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data. 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for recording data for each 
participant enrolled in the study. Data recorded in the electronic case report form (eCRF) derived from source documents should be 
consistent with the data recorded on the source documents. 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions data) and clinical laboratory 
data will be entered into our data collection system. The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from 
the source documents. 
8.1.8.2 
Study Records Retention  
Study documents should be retained for a minimum of 2 years after the last approval of a marketing application in an International 
Conference on Harmonization (ICH) region and until there are no pending or contemplated marketing applications in an ICH region or 
until at least 2 years have elapsed since the formal discontinuation of clinical development of the trial. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed without the written consent of the 
sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when these documents no longer need to be 
retained. 
8.1.9 
Protocol Deviations 
The PI and the study team should document all scenarios where the protocol is not followed and provide, in particular: 

 
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• Who deviated from the protocol 
• What was the deviation 
• When did the deviation occur 
• How did the deviation happen 
• What is the impact of the deviation 
• A root cause analysis of why the deviation occurred 
If the assessment results in a determination that any of the following are potentially affected, the deviation would be considered of 
significant impact: 
• having the potential to adversely affect subject safety; OR 
• increases risks to participants; OR 
• adversely affects the integrity of the data; OR 
• violates the rights and welfare of participants, OR 
• affects the subject’s willingness to participate in research.  
• there is a potential for an overall impact on the research that should be shared with the IRB for consideration and development 
of next best steps to address it 
8.1.10 
Publication and Data Sharing Policy 
This study will comply with the data sharing agreement. 
 

 
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8.1.11 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, 
any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts 
managed in a way that is appropriate to their participation in the design and conduct of this trial. 
8.2 
Additional Considerations 
Not-applicable.  
8.3 
Protocol Amendment History 
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
9 REFERENCES 
Pachon JC et al. Cardioneuroablation: Catheter Vagal Denervation as a New Therapy for Cardioinhibitory Syncope. J Cardiac 
Arrhythmia. 2019:32(3)182-196 
Armour JA et al. Gross and Microscopic Anatomy of the Human Intrinsic Cardiac Nervous System. The Anatomical Record 
1997;247:289-298 
Nakagawa H, Scherlag BJ, Patterson E, Ikeda A, Lockwood D, Jackman WM. Pathophysiologic basis of autonomic 
ganglionated plexus ablation in patients with atrial fibrillation. Heart Rhythm. 2009:6(12):S26-34. 
Drissen AHG, Berger WR, Krul SPJ, et al. Ganglionated plexus ablation in advanced atrial fibrillation: The AFACT Stidy. J 
Am Coll Cardiol. 2016;68(11):1155-1165 
Brignole M, Deharo JC, Menozzi C, Moya A, Sutton R, Tomaino M, Ungar A. The benefit of pacemaker therapy in patients 
with neurally mediated syncope and documented asystole: a meta-analysis of implantable loop recorder studies. Europace. 
2018;20(8):1362.   
Romanov A, Pokushalov E, et al. Long-term supression of atrial fibrillation by botulinum toxin injection into epicardial fat 
pads in patients undergoing cariac surgery: three year follow up of a randomized study, Heart Rhythm 2019;16(2):172-177 
Herring N, Kalla M, Paterson DJ. The Autonomic nervous system and cardiac arrhythmias: current concepts and emerging 
therapies. Nature Reviews Cardiology. 2019(16):707-726 

 
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Zghaib T, et al. Association of left atrial epicardial adipose tissue with electrogram bipolar voltage and fractionation: 
Electrophysiologic substrates for atrial fibrillation. Heart Rhythm. 2016 (8) 232-239 
Frangos, Et, Ellrich, J, et al. Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the 
External Ear. Brain Stimul. 2015 (8)3:624-36 
Rong P, Fang JL, et al. Transcutaneous vagus nerve stimulation for the treatment of depression: a study protocol for a double 
blinded randomized clinical trial. BMC Complement Altern Med. 2012 (12)255 
Courties A; Deprouw C, et al. Effects of Transcutanous Vagaus Nerve Stimulation in Erosive Hand Osteoarthritis. J Clin Med. 
2022(11)4 
 
10 APPENDIX  
 
 
 
 
 
END OF DOCUMENT

 
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