Using Electrical Nerve Stimulation to Control Atrial Fibrillation
Phase: NA
Conditions: Atrial Fibrillation
Sponsor: Cedars-Sinai Medical Center

 
 
 
 
Using Electrical Nerve Stimulation to Control 
Atrial Fibrillation 
   
National Clinical Trial (NCT) Identified Number:  NCT04529941 
Principal Investigator: Peng-Sheng Chen, MD 
IDE #G190241, Sponsor: Peng-Sheng Chen, MD 
Funded by: NIH Award #1OT2OD028190 – 01 
Version Number:  Revision 12 
19 April 2023 
 
 
Summary of Changes from Previous Version: 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
5.2 
• 
We are removing history of latex 
allergy as an exclusion criteria for 
our study. “People with a history of 
allergy to ECG electrodes, adhesive 
tape, or nylon” 
 
Due to improved technology, 
the medical devices used in 
the present study no longer 
contain natural rubber latex. 
This was confirmed by 
Preventice, who provide our 
MCT monitors and patches, 
as well as with the 
neurosurgeons who perform 
the implant procedure. 
Therefore, it is not a valid 
exclusion criteria.  

  
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 3 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 7 
2 
INTRODUCTION ............................................................................................................................................ 8 
2.1 
Study Rationale .................................................................................................................................... 8 
2.2 
Background........................................................................................................................................... 8 
2.3 
Risk/Benefit Assessment .................................................................................................................... 9 
2.3.1 
Known Potential Risks ..................................................................................................... 9 
2.3.2 
Known Potential Benefits .............................................................................................. 10 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 10 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 11 
4 
STUDY DESIGN ........................................................................................................................................... 12 
4.1 
Overall Design .................................................................................................................................... 12 
4.2 
Scientific Rationale for Study Design.............................................................................................. 13 
4.3 
Justification for Device setting ......................................................................................................... 13 
4.4 
End of Study Definition ..................................................................................................................... 13 
5 
STUDY POPULATION ................................................................................................................................ 13 
5.1 
Inclusion Criteria ................................................................................................................................ 13 
5.2 
Exclusion Criteria ............................................................................................................................... 14 
5.3 
Lifestyle Considerations .................................................................................................................... 14 
5.4 
Screen Failures .................................................................................................................................. 15 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 15 
6 
STUDY INTERVENTION ............................................................................................................................ 16 
6.1 
Study Intervention(s) Administration ............................................................................................... 16 
6.1.1 
Study Intervention Description ..................................................................................... 16 
6.1.2 
Device Energy and Administration .............................................................................. 17 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 17 
6.2.1 
Acquisition and accountability ...................................................................................... 17 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 17 
6.2.3 
Product Storage and Stability ....................................................................................... 17 
6.2.4 
Preparation ...................................................................................................................... 18 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 18 
6.4 
Study Intervention Compliance ........................................................................................................ 18 
6.5 
Concomitant Therapy ........................................................................................................................ 19 
6.5.1 
Rescue Medicine ............................................................................................................ 19 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 19 
7.1 
Discontinuation of Study Intervention ............................................................................................. 19 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 20 
7.3 
Lost to Follow-Up ............................................................................................................................... 20 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 21 
8.1 
Efficacy Assessments ....................................................................................................................... 21 
8.2 
Safety and Other Assessments ....................................................................................................... 26 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 27 

  
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 27 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 27 
8.3.3 
Classification of an Adverse Event .............................................................................. 27 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 28 
8.3.5 
Adverse Event Reporting .............................................................................................. 28 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 29 
8.3.7 
Reporting Events to Participants ................................................................................. 29 
8.3.8 
Events of Special Interest ............................................................................................. 29 
8.3.9 
Reporting of Pregnancy ................................................................................................ 29 
8.4 
Unanticipated Problems .................................................................................................................... 29 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 29 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 30 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 30 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 31 
9.1 
Statistical Hypotheses ....................................................................................................................... 31 
9.2 
Sample Size Determination .............................................................................................................. 31 
9.3 
Populations for Analyses .................................................................................................................. 32 
9.4 
Statistical Analyses............................................................................................................................ 32 
9.4.1 
General Approach .......................................................................................................... 32 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 32 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 33 
9.4.4 
Safety Analyses .............................................................................................................. 35 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 36 
9.4.6 
Planned Interim Analyses ............................................................................................. 36 
9.4.7 
Sub-Group Analyses ..................................................................................................... 36 
9.4.8 
Tabulation of Individual participant Data .................................................................... 36 
9.4.9 
Exploratory Analyses ..................................................................................................... 36 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 36 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 36 
10.1.1 
Informed Consent Process ........................................................................................... 36 
10.1.2 
Study Discontinuation and Closure ............................................................................. 37 
10.1.3 
Confidentiality and Privacy ........................................................................................... 38 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 39 
10.1.5 
Key Roles and Study Governance .............................................................................. 39 
10.1.6 
Safety Oversight ............................................................................................................. 39 
10.1.7 
Clinical Monitoring .......................................................................................................... 40 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 40 
10.1.9 
Data Handling and Record Keeping ............................................................................ 40 
10.1.10 
Protocol Deviations ........................................................................................................ 42 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 42 
10.1.12 
Conflict of Interest Policy .............................................................................................. 42 
10.2 
Additional Considerations ................................................................................................................. 43 
10.3 
Abbreviations ...................................................................................................................................... 44 
10.4 
Protocol Amendment History ........................................................................................................... 46 
11 
REFERENCES ............................................................................................................................................. 49 
 

Using Electrical Nerve Stimulation to Control Atrial Fibrillation 
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STATEMENT OF COMPLIANCE 
 
  
The trial will be carried out in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.] 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
 
Title: 
 
Using Electrical Nerve Stimulation to Control Atrial Fibrillation 
 
Study Description: 
 
Patients will have a 1:1 randomization to receive subcutaneous electrical 
nerve stimulation (ScNS) to observe if the stimulation can reduce atrial 
fibrillation burden in patients with symptomatic atrial fibrillation (AF). All 
subjects will undergo the implant of a neurostimulator lead. The 
experimental group will receive stimulation and the control group will not 
receive stimulation.  All subjects will complete the same follow up visits to 
compare the 2 groups. The control group will have an option to cross over 
to the experimental group 3 weeks post-randomization to receive the 
stimulation. They will repeat the baseline visit, procedure visit and all 
follow-up visits post-procedure.  
 
 
Objectives: 
 
 
 
 
 
 
 
Primary Objective:  To test the hypothesis that chronic subcutaneous 
nerve stimulation can reduce AF burden in patients with severe 
symptomatic AF unresponsive to conventional therapies 
 
The secondary objective:   
To test the hypotheses that the effect of ScNS on the following endpoints 
is different between the two randomization groups: 
1) Time-dependent reduction of AF burden  

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Endpoints: 
 
2) Effects of ScNS on ventricular rate control during AF  
3) Reduction of SKNA 
4) Improvement of quality of life 
5) Reduction of AF burden after cross over from control to experimental 
group 
 
• 
The primary Efficacy Endpoint: 
 
               The average AF burden. 
 
•            The secondary Efficacy Endpoint(s): 
 
               1) Time-dependent reduction of AF burden 
               2) Ventricular rate during AF 
               3) average SKNA 
               4) Quality of life 
 
Study Population: 
The study will enroll patients with symptomatic atrial fibrillation 
unresponsive to conventional therapy defined by not responding to at 
least 1 antiarrhythmic drug.   The study will enroll 30 patients, including 15 
men and 15 women between the 18 and 75 years old. There will be no 
sex/gender/racial/ethnic based exclusion. Patients will be enrolled from 
the Cedars Sinai Medical Center. 
Phase: 
Not applicable 
 
Description of 
Sites/Facilities Enrolling  
Participants: 
 
The study will enroll patients treated at the Cedars-Sinai Medical Center. 
This is a single site study. 
 
 
Description of Study 
Intervention: 
 
The patients will undergo surgical implantation of an externalized lead 
under the skin on the chest wall. The wire is then connected to a 
neurostimulator. The experimental group (Group A) will receive ScNS (3.5 
mA) for two weeks. The sham group (Group B) will receive sham (0 mA) 
stimulation for two weeks. The AF burden will be assessed by a 7-day 
mobile cardiac telemetry device provided by Preventice. An additional 
mobile cardiac telemetry device, Bittium Faros, will also be worn at similar 
time points to monitor skin sympathetic nerve activity. An Apple watch will 
be used to collect additional information on the frequencies of AF 
between the Baseline Visit until the 3 Month Visit 7 Day Mobile Cardiac 
Telemetry is complete. After completion of the week 3 visit,, the sham 
group (Group B) will be able to receive ScNS (3.5 mA) for two weeks. The 
AF burden will be assessed post-procedure by mobile cardiac telemetry by 
Preventice and Bittium Faros.  
 
Study Duration: 
36 months 
 
Participant Duration: 
Up to 5 months. 
 
 

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1.2 
SCHEMA 
 
Eligibility visit 
 
 
 
 
Baseline visit 
Within 1 Mo  
Before 
procedure 
 
 
 
Procedure Day 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
1 week visit 
 
 
 
 
2-week visit 
 
 
3-week visit 
 
 
Screening and eligibility, obtain informed consent, Echocardiogram, subject stipend and 
parking pass, assess for serious adverse events and adverse events, 7-day mobile cardiac 
telemetry* 
Medical history/demographics, height, weight, BMI, 12 lead EKG, INR(subjects taking 
Coumadin), pre-op instructions, SKNA recording at rest and 6 minute walk or mental math 
test, AFEQT-AF QOL, EQ-5D-5L QOL, Labs (CBC, BMP, BNP, Catecholamine levels), parking 
pass, assess for serious adverse events and adverse events, Echocardiogram, Apple Watch 
Monitoring 
Hospital Admission, 12 Lead EKG, INR (in subjects taking Coumadin), Pregnancy test-
Blood or urine for females with child bearing potential, Pre procedure antibiotic, Surgical 
Implantation 
12 Lead EKG, SKNA recording at rest and 6-minute walk or mental math test, Mobile 
Cardiac   Telemetry for 7 days, Apple Watch Monitoring, subject stipend and parking pass, 
assess for serious adverse events and adverse events 
Post Randomization 
  Telemetry, Neuro-Stimulator programming, SKNA recording at rest, Discharge/patient 
teaching, Mobile Cardiac Telemetry for 7 days, Apple Watch Monitoring, Subject Stipend 
and parking pass, assess for serious adverse events and adverse events 
Control Group 
(Sham), N=15 
Experimental 
Group (ScNS), 
N=15 
Randomize 
12 Lead EKG, SKNA recording at rest and 6-minute walk or mental math test, Apple Watch 
Monitoring, AFEQT-AF QOL questionnaire, EQ-5D-5L QOL questionnaire, subject stipend 
and parking pass, assess for serious adverse events and adverse events, INR(subjects 
taking Coumadin)**, pre-op instructions**, Labs (CBC, BMP)** 
12 Lead EKG, SKNA recording at rest and 6-minute walk or mental math test, removal of 
lead, 7-day mobile cardiac telemetry, Apple Watch Monitoring, parking pass, assess for 
serious adverse events and adverse events 

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3-month visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
1 week visit 
 
 
 
 
2-week visit 
 
 
3-week visit 
 
3-month visit 
 
 
 
 
 
 
 
 
 
* Eligibility monitoring with mobile cardiac telemetry provided by Preventice will only serve as an option for potential patients that do not have 
any clinical ePatch monitoring completed in the past 6 months. Potential patients that have ePatch monitoring results with no change in 
medication since then, do not have to undergo mobile cardiac telemetry during Eligibility visit. ** Activities are to be repeated for control 
subjects only who choose to crossover to experimental group prior the second procedure. ***Second procedure is to be done within two 
weeks of the Week 3 Visit for crossover patients, if not, patient must complete another pre-op visit two weeks before the procedure. Pre-op 
visit will entail Labs (CBC, BMP), INR if patient is taking Coumadin, 12 Lead EKG and pre-op instructions.  
 
 
All patients will have baseline cardiac rhythm monitoring using standard ECG patch electrodes. Cardiac 
rhythm monitoring will be done with clinically available 7-day non-invasive Mobile Cardiac Telemetry. 
12 Lead EKG, SKNA recording 
at rest and 6-minute walk or 
mental math test, 7-day mobile 
cardiac telemetry, Apple Watch 
Monitoring, Labs (CBC, BMP, 
BNP, Catecholamine levels), 
subject stipend and parking 
pass, assess for serious 
adverse events and adverse 
events 
Experimental 
Group (ScNS), 
N<=15 
12 Lead EKG, SKNA recording at rest and 6-minute walk or mental math test, Mobile 
Cardiac   Telemetry for 7 days, Apple Watch Monitoring, subject stipend and parking pass, 
assess for serious adverse events and adverse events 
Second Procedure***  
  Telemetry, Neuro-Stimulator programming, SKNA recording at rest, Discharge/patient 
teaching, Mobile Cardiac Telemetry for 7 days, Apple Watch Monitoring, Subject Stipend 
and parking pass, assess for serious adverse events and adverse events 
12 Lead EKG, SKNA recording at rest and 6-minute walk or mental math test, Apple Watch 
Monitoring, AFEQT-AF QOL questionnaire, EQ-5D-5L QOL questionnaire, subject stipend 
and parking pass, assess for serious adverse events and adverse events 
12 Lead EKG, SKNA recording at rest and 6-minute walk or mental math test, removal of 
lead, 7-day mobile cardiac telemetry, Apple Watch Monitoring, parking pass, assess for 
serious adverse events and adverse events 
12 Lead EKG, SKNA recording at rest and 6-minute walk or mental math test, 7-day mobile 
cardiac telemetry, Apple Watch Monitoring, Labs (CBC, BMP, BNP, Catecholamine levels), 
subject stipend and parking pass, assess for serious adverse events and adverse events 
Cross over 
(optional)  
No 
yes 

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Among them, the 7-day non-invasive Mobile Cardiac Telemetry provided by Preventice will be 
performed during the two weeks of ScNS to ensure patient safety. The Bittium Faros monitor, a non-
invasive patch electrode, will be applied at similar time points as Preventice Mobile Cardiac Telemetry 
device to monitor skin sympathetic nerve activity. Mobile cardiac telemetry will also be performed for a 
week after the end of stimulation and for a week at 3 months after surgery. An Apple watch will be used 
to detect AF episodes1, if any, until the completion of the 3 Month Visit 7-day Mobile Cardiac Telemetry.  
The patients will be admitted to the hospital and undergo surgical procedure for implantation of 
externalized subcutaneous neurostimulation lead for ScNS. The patients will be monitored while the 
stimulation protocol is started. The stimulation in the experimental group will continue for two weeks 
while all the patients are continuously monitored by the Mobile Cardiac Telemetry system. The lead will 
be removed at the 2 weeks visit. 7-day mobile cardiac telemetry will be performed at the 2 week and 3-
month visits.  The study ends after the final week of outpatient cardiac monitoring is performed. The 
control group will have an option to cross over to the experimental group 3 weeks post-procedure. They 
will undergo a second procedure and receive stimulation for two weeks. The lead will be removed after 
stimulation is complete. 7-day mobile cardiac telemetry will be performed for three weeks and at the post 
3-month visit.  
Surgical procedure:  
• 
Preoperative 
o The patient will complete a standard hibiclens wash the night before the procedure and 
the morning of the procedure.  
o The patient will be NPO after midnight 
o Instructed to have a driver the day of the procedure 
 
• 
Procedure Day 
o Antibiotics orders will be written for the procedure based on the patient’s known drug 
allergies 
o Standard institutional procedural consent will be obtained by the investigator 
performing the procedure. All risks will be explained to the patient.  
o 12 lead EKG performed 
o INR if patient is taking Warfarin (Coumadin) 
o Pregnancy test on females with child bearing potential 
o Mild sedation for the procedure may be used, such as versed or a drug chosen by the 
investigator performing the procedure 
 
• 
Implantation  
The patients will be placed in a supine position. The left subclavian area is prepped and 
draped in the usual sterile manner as in pacemaker surgeries. The skin is anesthetized 
with lidocaine or a combination of lidocaine and bupivacaine hydrochloride. A 
Medtronic 977D260 trial screening lead kit is opened and the content placed on the 
sterile field. A Tuohy needle from that kit will be inserted into the subcutaneous space 
approximately 3 cm below the clavicle. The stylet inside the needle is removed and the 
spinal cord trial screening lead is inserted via the lumen of the Tuohy needle. The 

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externalized portion of the wire is sutured to the skin using a silk suture. The wire is 
then connected to a Medtronic 97725 neurostimulator, which has an adhesive tape for 
fixation to the skin. The operating field and the externalized hardware are then covered 
with sterile dressing. Lead impedance will be checked at this time because swelling or 
hematoma could increase the impedance. 
For the optional second procedure offered to the control group, the implantation 
protocol will remain the same, however, the Tuohy needle from that kit will be inserted 
into the subcutaneous space at least 1 cm below or above from the initial implantation 
site. Lead impedance will be checked after the procedure because swelling or 
hematoma could possibly increase impedance.  
• 
Post-Operative 
o Programming of the device is completed  
o Discharge patient teaching 
o Apply Mobile Cardiac Monitoring system 
o Patients continue wearing Apple watch for secondary monitoring system  
 
• 
Removal 
o  The patient is placed in a supine position. The sterile dressing is removed. The silk 
suture is cut and removed. The stimulating lead is then pulled out of skin. The skin is 
cleaned with alcohol. The puncture site is left open to air. 
 
• 
Risks of the procedure 
o Pain at the time of insertion: This will be minimized by local anesthesia. 
o Swelling and/or mild hematoma  
Note: The surgical procedure will remain the same for both first and second procedure. However, the 
second procedure will be done 1cm below or above the initial implantation site on the left chest area. 
 
 
 
 
 
 
 
 
 
 
 
 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
  
Eligibility visit 
Baseline 
Procedure Day 
(lead implant) and 
post-operative 
observation**** 
1-week 
visit**** 
2-week 
visit**** 
3-week 
visit**** 
3-month 
visit***** 
Screening and eligibility 
x 
  
  
  
  
  
  
Obtain Informed consent 
x 
  
  
  
  
  
  
Medical history/demographics 
  
x 
  
  
  
  
  
Height/Wt/BMI 
  
x 
  
  
  
  
  
Hospital Admission 
  
  
x 
  
  
  
  
12 Lead EKG 
  
x 
x 
x 
x 
x 
x 
INR (in subjects taking 
Coumadin) 
  
x 
x 
  
  
  
  
Pre-op instructions 
  
x 
  
  
  
 Xb 
  
Pregnancy test-Blood or urine 
for females with childbearing 
potential 
  
  
x 
  
  
  
  
Pre procedure antibiotic 
  
  
x 
  
  
  
  
Surgical Implantation 
  
  
x 
  
  
  
  
Randomization (after surgery) 
  
  
x 
  
  
  
  
Apple Watch Monitoring 
 
x 
x 
x 
x 
x 
x 
Telemetry 
  
  
x 
  
  
  
  
NeuroStimulator programming 
  
  
x 
  
  
  
  
SKNA recording at rest 
  
x 
 x 
x  
x  
x  
x  
SKNA recording during 6-min 
walk* 
  
x 
  
x 
x 
x 
x 
Mental Math Test ** 
  
x 
 
 x 
 x 
 x  
x  
Discharge/patient teaching*** 
  
  
x 
  
  
  
  
Removal of Lead  
  
  
  
  
x 
  
  

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Echocardiogram 
x 
  
  
  
  
x 
x 
Mobile Cardiac Telemetry 
Xa 
  
x 
x 
 x 
  
 x 
AFEQT-AF QOL questionnaire 
  
x 
  
  
  
x 
x 
EQ-5D-5L QOL questionnaire 
  
x 
  
  
  
x 
x 
CBC 
  
x 
  
  
  
 Xb 
x 
BMP 
  
x 
  
  
  
 Xb 
x 
BNP 
  
x 
  
  
  
  
x 
Catecholamine levels 
  
x 
  
  
  
  
x 
Subject Stipend 
x 
 x 
x 
x 
x  
x 
x 
Subject Parking fee 
x 
x 
x 
x 
x  
x 
x 
Assess for Serious Adverse 
events and Adverse Events 
x 
x 
x 
x 
x 
x 
x 
The materials and the times of collection for Aim 1A. Labs=laboratory tests; CBC=complete blood count; BMP=basic metabolic panel; BNP=B type 
natriuretic protein; INR=international normalized ratio. *if subject is able to complete, **will complete only if unable to complete 6 min walk, ***discharge 
day is based on PI decision. **** will only be repeated for control subjects that crossover to experimental group *****will only be done on experimental 
group and control subjects that do not cross over a. Eligibility 7-Day Mobile Cardiac Telemetry is available for potential subjects who may not have had 
an ePatch monitor completed b. will only be repeated by the crossover group before second procedure  
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
 
Atrial fibrillation (AF) is the most common arrhythmia in the United States, affecting 
approximately 2.7-6.1 million adults that results in $26 billion in healthcare costs.  AF prevalence is 
expected to double over the next 25 years, further contributing to an already high economic burden.  AF 
is associated with significant morbidity and mortality, including a four to five-fold increase in stroke risk, 
a doubling of dementia risk, a tripling of heart failure risk, and a 40-90% increase in risk for overall 
mortality.  The significant impact that AF has upon healthcare costs, morbidity and health quality has 
spurred numerous investigations to develop more effective treatments.  Despite the aggressive 
management of hypertension, heart failure and other risk factors for AF, numerous patients in the 
United States are suffering from this arrhythmia.  Current drug treatment and catheter ablation 
techniques are effective, but a significant number of patients continue to suffer from this arrhythmia in 
spite of the recent advancements in therapies. In addition, both drug treatment and catheter ablation 
may be associated with significant complications. There is room for improvement in managing patients 
with AF. 
 
2.2 
BACKGROUND  
The autonomic nervous system plays an important role in the initiation and maintenance of AF.2, 
3  Neuromodulation procedures include cryoablation of the stellate ganglion that suppress AF and 
ablation of ganglionated plexi that modulate extrinsic cardiac autonomic inputs.4 These findings support 
the importance of the autonomic nervous system in the etiology of AF, but it is not clear how this 
system can be leveraged utilizing less invasive and resource intensive methods for assessment and 
treatment of AF.  In ambulatory dogs, sympathetic nerve activation as measured by the stellate ganglion 
nerve activity (SGNA) is a trigger of paroxysmal AF. SGNA can also accelerate the atrioventricular (AV) 
node conduction, resulting in increased ventricular rate response to AF. Because it is difficult to record 
nerve activities from humans, we devoted significant amount of time to develop such method. First, we5 

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discovered that subcutaneous nerve activity (ScNA) and superficial skin sympathetic nerve activity 
(SKNA) correlate positively with SGNA. Further, ScNA is more accurate in estimating cardiac sympathetic 
tone in ambulatory dogs with myocardial infarction than the heart rate variability parameters.6  We7 
next discovered that it is possible to record skin sympathetic nerve activity (SKNA) using conventional 
ECG patch electrodes. We call this method the “neuECG” because we can use different filter settings on 
the same signal to display both ECG and SKNA. Using this new method, we8 showed a positive 
correlation between SKNA and intrinsic cardiac nerve activity recorded from fat pads of humans in the 
postoperative period.  Subsequent studies show that SKNA precedes both onset and termination of 
paroxysmal atrial tachycardia and paroxysmal AF episodes.2, 3 These data suggest that sympathetic nerve 
activity is a major trigger of paroxysmal cardiac arrhythmias, including AF. A second implication is that 
the nerves in the thoracic skin connects directly to the stellate ganglion. If there is a connection between 
these two nerve structures, then stimulating the skin sympathetic nerve may rapidly active the stellate 
ganglion to cause excessive calcium accumulation and stellate ganglion remodeling.  
We9-12 tested the latter hypothesis in canine models and discovered that subcutaneous nerve 
stimulation (ScNS) can remodel the stellate ganglion and control AF. Because ScNS involves stimulating 
the skin without directly accessing the internal organs, it may be more clinically feasible than many 
other neuromodulation methods. The purpose of the present study is to translate these findings to 
humans. We will implant externalized electrodes under the skin on the chest wall to perform ScNS in 
patients with symptomatic paroxysmal AF. The results will be used to test the hypothesis that ScNS can 
be used to reduce the AF burden in patients with paroxysmal AF. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
The Immediate risks include the risks associated with surgery such as pain, allergic reaction to the drugs 
used during surgery, bleeding and death. The possibility of a second surgery increases the previous risks. 
 
The long-range risks include the following:  
Because ScNS remodels the stellate ganglion and reduces sympathetic outflow, it is possible to slow 
down the sinus rate or atrioventricular (AV) conduction. If the following serious side effects are 
observed, the ScNS will be terminated: 
• 
Third-degree AV block at any anatomic level associated with any one of the following conditions: 
o Bradycardia with symptoms presumed to be due to AV block.  
o Arrhythmias and other medical conditions that require drugs that result in symptomatic 
bradycardia. 
o Documented periods of asystole ≥3.0 seconds or any escape rate <40 beats per minute 
(bpm) in awake, symptom-free patients. 
 
• 
Second-degree AV block regardless of type or site of block, with associated symptomatic 
bradycardia 

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• 
Infection of the implanted devices 
• 
Persistent pain at the lead site not responsive to drug therapy. 
• 
Allergic response to the implanted lead or materials used 
• 
Lead, extension or migration that results in loss of ability to perform ScNS 
The following adverse events will be managed medically 
• 
Skin irritation related to prolonged placement of 7-day Mobile Cardiac Telemetry patch. 
• 
Pain, goosebumps, hot flashes, and other uncomfortable feelings related to electrical 
stimulation of the subcutaneous nerves. 
. 
 
Alternative methods of treating drug resistant symptomatic AF include catheter ablation procedures and 
open-heart surgery, both carry significant risks of morbidity and mortality. 
 
 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
• 
Immediate potential benefits. Based on the results of canine experiments, ScNS immediately 
reduces the sympathetic outflow from the stellate ganglion. This could be confirmed both by the 
direct measurements of nerve activity and by measuring plasma norepinephrine levels.9 The 
reduced sympathetic outflow may then lead to reduced AF burden (primary outcome). The 
benefit may be time-dependent, i.e., the AF is better controlled in the second week of ScNS than 
in the first week of ScNS. In addition, the reduced sympathetic outflow may also reduce the 
ventricular rate, leading to better rate control if AF occurs. The improve rhythm and rate control 
of AF may lead to better quality of life (secondary outcomes). 
 
• 
Long-range potential benefits. The stellate ganglion remodeling may persist after the 
stimulation, resulting in persistent reduction of sympathetic outflow and AF control. We will 
reassess the AF burden 3 months after the ScNS to test that hypothesis. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Potential benefits 
Drug resistant paroxysmal AF is a common and serious clinical condition that happens to a small subset 
of patients with AF. The risk and benefit of the current management option versus the experimental 
procedure are as follows: 
 
• 
Continue the current treatment. The risk is the continued suffering from the symptoms and side 
effects of drug-resistant paroxysmal AF. 
 
• 
Catheter ablation of AF,14 which is a standard treatment for symptomatic AF. Multiple non-
randomized and randomized controlled trials have shown that radiofrequency catheter ablation 
of AF is associated with a > 50% success rate at one year. Roughly 27% of patients have to 
undergo a second ablation. Even then, the success is not assured. A third or fourth ablation 
procedures are sometimes performed in the same patient.  In addition to the risk of AF 

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recurrences, the patients may also suffer from complications related to the ablation procedures. 
A worldwide survey showed that the rate of major complications were 4.5%- 6%, including a 
procedural death rate of 0.05%-0.15%.15, 16  
 
• 
Surgical ablation of AF.14 Stand-alone AF surgery should be considered for symptomatic AF 
patients who prefer a surgical approach, have failed one or more attempts at catheter ablation, 
or are not candidates for catheter ablation. The success rate for single procedure (without re-
intervention) was 49%.14 The referral of patients for surgery with symptomatic, medically 
refractory AF in lieu of catheter ablation remains controversial.  
 
Comparing with the catheter or surgical ablation of AF, the proposed experimental procedure (ScNS) 
requires only the insertion of an electrode under the skin. The electrode and neurostimulator are FDA-
approved for spinal cord stimulation. Compared with the risk of catheter or surgical ablation of AF, the 
proposed procedure is much less invasive and may be associated with lower complication rate. If ScNS 
can achieve AF control, then the patients do not need to undergo catheter or surgical AF ablation. That 
is the potential benefit of participating in the study. Because the risk is low and the potential benefit is 
high, we propose that the benefit to risk ratio of participating in the study is favorable. 
Potential risks 
o Redness/Infection: The overall infection rate is expected to be 1.2%. All infection will be 
promptly treated with antibiotics and assess if lead removal is necessary.  It is expected 
to the patient will experience skin irritation/edema 3-7 days post procedure. If an 
infection is mild can be treated with an oral antibiotic and watched closely.   
o Lead extension or migration: This will be managed by repositioning or removing the 
lead. The lead cannot be advanced.  
o Persistent pain at the lead site not relieved with OTC medication: Persistent pain or 
discomfort will result in lead removal.  
o Allergic reaction: The patients may be allergic to the local anesthetic agent, the dressing 
material or the device itself. These allergic reactions will be treated medically and by the 
device removal. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Primary Objective: The primary 
objective is to test the hypothesis 
that ScNS may significantly reduce 
the AF burden in patients with 
symptomatic paroxysmal AF. 
 
 
Total AF burden (the % of time in AF). 
 
AF burden is an 
objective measure of 
the severity of AF. It is 
commonly used in 
clinical trials. The FDA 
suggested that we use 
AF burden as the end 
point for this IDE study. 
Secondary 
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
To test the hypotheses that the 
following findings are statistically 
significant: 
1) Time-dependent reduction of AF 
burden  
2) Effects of ScNS on ventricular 
rate control during AF  
3) Reduction of SKNA 
4) Improvement of quality of life 
5) Reduction of AF burden after 
cross over from control to 
experimental group 
 
1) Time-dependent reduction of AF 
burden 
2) Ventricular rate during AF 
3) average SKNA 
4) Quality of life 
 
We hypothesize that 
ScNS causes stellate 
ganglion remodeling, 
leading to time-
dependent changes of 
AF burden the 
ventricular rate. We 
also hypothesize the 
ScNS will reduce aSKNA 
and improve quality of 
life. 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
• 
A statement of the hypothesis.  
o To test the hypothesis that ScNS can be used to reduce the AF burden in patients with 
paroxysmal AF 
 
• 
Phase of the trial.  
o Not applicable. 
 
• 
A description of the type/design of trial to be conducted (e.g., randomized, placebo-controlled, 
double-blinded, parallel design, open-label, dose escalation, dose-ranging, adaptive, cluster 
randomized, group sequential, multi-regional, superiority or non-inferiority design).  
o This is a prospective randomized IDE study. The patients are randomized into 
Experimental and Control groups. There is an option for the Control group to crossover 
into the Experimental group after completion of obtaining the primary endpoint.  
 
• 
A description of methods to be used to minimize bias.  
o The investigators are responsible for programming the device and cannot be blinded to 
the study. However, we will not tell the patients whether they are randomized into the 
experimental or the control group until the primary endpoint is complete. Technicians 
and physicians responsible for echocardiogram and ECG monitoring will be blinded. 
 
• 
The number of study groups/arms and study intervention duration.  
o We will randomize the patients into: 
 
Group A: Experimental group will undergo 3.5 mA ScNA for two weeks.  
 
Group B: Sham control group will receive 0 mA stimulation for two weeks. 

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• 
Indicate if single site or multi-site.  
o This is a single site study. 
 
• 
Name of study intervention(s).  
o Subcutaneous nerve stimulation (ScNS). 
 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Medical device is known to have strong placebo effects.17 Therefore, we chose to perform a prospective 
randomized study with a sham control group. The only difference between experimental and sham 
control groups is the strength of neurostimulator output (3.5 mA versus 0 mA).  
 
 
 
4.3 
JUSTIFICATION FOR DEVICE SETTING 
 
Our recent studies in canine models showed that ScNS may be either proarrhythmic or antiarrhythmic 
depending on the stimulus strength.9 Very low strength (0.5 mA) ScNS causes nerve sprouting and 
increases plasma norepinephrine concentration, leading to increased cardiac arrhythmia in ambulatory 
dogs. On the other hand, high output (3.5 mA) ScNS is antiarrhythmic. Because of these findings, we will 
only use 3.5 mA output in the Experimental group. No patients will receive low output stimulation. 
 
4.4 
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 shown in the Schedule of Activities (SoA), Section 1.3. 
 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
• 
18 to 75 years of age  
• 
Symptomatic paroxysmal AF unresponsive to conventional therapy.  
o 
Symptomatic paroxysmal AF is defined by paroxysmal AF with patient-reported 
perception of one or more of the following symptoms: palpitations, 
dizziness/presyncope, syncope, dyspnea, chest pain, malaise, and fatigue and activity 
intolerance.  
o 
There is at least one ECG-documented AF episode.  
o Unresponsive to conventional therapy is defined by not responding to at least 1 
antiarrhythmic drug (class I, class III, or atrioventricular nodal blocker).  

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• 
The left atrial size <50 mm by transthoracic echocardiography documented by eligibility visit 
• 
Documented atrial fibrillation as defined as atrial fibrillation >30 seconds in duration with an 
atrial fibrillation burden determined by a minimum of 7 days of continuous ePatch monitoring 
within 6 months before surgery. 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
• 
Patients without AF episodes during monitoring period will be excluded from the study and 
count as screen failure 
• 
Left ventricular ejection fraction <40% 
• 
Heart failure with functional classes III or IV 
• 
Recurrent vasovagal syncope 
• 
Valvular AF (severe mitral regurgitation, mitral stenosis) 
• 
Congenital heart diseases  
• 
Wolff Parkinson-White Syndrome 
• 
Stroke within the past 6 months  
• 
Any history of myocardial infarction 
• 
Malignancies with a life expectancy of < 1 year 
• 
A history of ablation procedures to treat left atrial tachyarrhythmias or other serious 
comorbidity 
• 
Any history of sustained ventricular tachycardia (VT) defined by (1) > 30 s in duration or (2) < 30 
s in duration, but is associated with hemodynamic consequences such as hypotension and 
syncope. 
• 
Patients with a vagal nerve stimulator 
• 
Active thyrotoxicosis 
• 
Sick sinus syndrome with symptomatic bradycardia  
• 
Heart rate < 50 beats per minute in sinus rhythm on 12-lead ECG 
• 
Systolic blood pressure < 90 mm Hg  
• 
Any experimental medication concomitantly or within 4 weeks of participation in the study 
• 
Subjects with cardiac implantable electronic device (CIED) such as pacemakers and implantable 
cardioverter-defibrillators (ICDs) 
• 
Pre-existing neuromodulation devices, such as vagal nerve stimulators, spinal cord stimulators 
and sacral nerve stimulators 
• 
People with a history of allergy to ECG electrodes, adhesive tape, or nylon  
• 
Pregnant women 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
During this study, participants are asked to: 
 
• 
Day before the implant: 
o Plan to use the wash 2 times.  Once the night before procedure, and again the 
morning of your procedure.   
o Use about 2 oz. or ¼ cup with each wash 

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o Take a complete bath or shower with regular soap.  Then get a clean wash cloth. 
o Do not use Hibiclens soap on your face, ears, or hair 
o Use Hibiclens soap on the neck, chest, as far as they can reach over the shoulder 
and down to the waist, your arms down to the elbows and under the arms 
o A gentle wash is good, rubbing and scrubbing is not necessary. Leave on the skin 
for 1 minute, then rinse off 
o Use clean fresh towels and washcloths each time 
o The night before the procedure, dress in fresh clean pajamas and sleep on fresh 
clean sheets 
o Dress in fresh, clean clothes after the morning bath/shower to come to the 
hospital 
o Please do not put on lotion, cream, powder, or deodorant after the bath or 
shower 
o Nothing to eat or drink starting at midnight the night before surgery 
o Required driver for all patients the day of surgery 
 
 
• 
After implant: 
o Sponge bath only until the device is removed 
o Do not get the dressing wet.  Remember electricity and water do not mix 
o No ointments, powders, lotions, creams, or antibiotic medications on the 
implant site 
o Abstain from driving during the time the lead is implanted 
o No bending, lifting, or twisting 
o No elbows above your ears, and no reaching up, over, across, or down 
o Your lifting limit is 5 lbs, which is approximately a half gallon of milk 
o No strenuous activities like yard work, vacuuming, lifting laundry baskets or 
grocery sacks 
o If you smoke, stop. Smoking is not health and can make pain worse, and 
prolongs healing time 
o No driving or operating machinery, making legal decisions, work, or drinking 
alcohol until the study is completed 
o May use ice packs on the implant site dressing, but no heat.  Heat will affect the 
way the stimulator works 
  
5.4 
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. Patients without AF 
episodes during monitoring period and have an ejection fraction (EF) less than 40% will be excluded 
from the study and count as screen failure. 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). 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 

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• 
Sample size: Total of 30 subjects-15 males and 15 females between 18 and 75 years old.  
• 
Anticipated accrual rate: 30 subjects over 36 months 
• 
All subjects will be enrolled at one US site 
• 
Vulnerable subjects will not be recruited 
• 
All sex, racial and ethnic group members will be recruited to participate in the study 
 
Investigators and co-investigators will approach eligible subjects about the study in person at clinical 
visits. The patients will be consented by investigator or one of the co-investigators utilizing the informed 
consent form as a guide. After the questions about the research have been answered the patient will be 
asked to sign the form. We plan to distribute the study brochure to physicians’ offices to help patient 
recruitment. We will include the study information in the Smidt Heart Institute Current Research 
website. We do not plan to use any other advertising material.  
Subjects will receive payment in the form of a reloadable card for study visits completed. They will not 
receive more than $600.00 total or $900.00 total for study participation depending if they are 
randomized in the experimental group or control group, respectively. In addition to stipend, the patient 
will also receive parking passes.  
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Device Information: 
 
• 
Medtronic spinal cord stimulation 60-cm trial Lead, model No. 977D260. 
• 
Medtronic wireless external neurostimulator (WENS, model 97725).  
• 
Medtronic Neuromodulation Clinician Programmer (App A710) 
o Description of each component 
 
Medtronic spinal cord 60 cm trial lead and wireless external neurostimulator are 
designed to deliver electrical stimulation for the subcutaneous nerve 
stimulation (ScNS) 
 
Medtronic Neuromodulation Clinician programmer will allow the programming 
of the lead to be set at 3.5mA to deliver the protocol required electrical 
stimulation 
o Device settings and programming- The programming of the lead will set at 3.5mA in the 
experimental group 
o Duration of implant Subjects will have the Medtronic neurostimulator lead implanted 
subcutaneously for 2 weeks 
o Device has not been approved or cleared for the indications the protocol is designed to 
investigate. Investigator has obtained an IDE for this protocol. See FDA IDE approval 
letter 
The following device will be donated by Medtronic Inc. for implantation: Medtronic spinal cord 
stimulation 60-cm trial Lead, model No. 977D260 and Medtronic wireless external neurostimulator 

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(WENS, model 97725). These devices are currently FDA approved for pain control through spinal cord 
stimulation. 
 This IDE study is funded by NIH. Medtronic Inc. will donate the device.  The final labeling of the device 
may change according to the results of the study. 
6.1.2 DEVICE ENERGY AND ADMINISTRATION 
The experimental group will receive stimulation ScNS at 3.5mA output, while the control group will 
receive no stimulation for 2 weeks.  
The control group will have an option to crossover to the experimental group after three weeks from the 
first procedure and receive stimulation ScNS at 3.5 mA output.  
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
Medtronic Inc will donate the following devices for this trial: 
Medtronic spinal cord stimulation 60-cm trial Lead, model No. 977D260. 
Medtronic wireless external neurostimulator (WENS, model 97725).  
 
These devices are approved by FDA for human use, but an investigator-initiated IDE will be required.  
This allows the trial to be conducted using the devices for symptomatic atrial fibrillation unresponsive to 
conventional therapies.  
 
Indications for Use: Symptomatic atrial fibrillation unresponsive to conventional drug therapies.  
 
The unused devices will be returned to Medtronic, Inc.  
 
Accountability of the device will be tracked by the study team using a device accountability log.  The log 
will track the inventory of the device including device type, serial number, and expiration date.  All 
devices used on subjects will be also tracked in Red Cap.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Medtronic Inc has committed to donate FDA approved neurostimulator units and nerve stimulation lead 
for the study. These devices are designed to deliver electrical stimulation of internal organs such as 
spinal cord and bladder. All devices are FDA approved for human implantation with specific clinical 
indications. However, because ScNS is not an approved indication, we have obtained Investigator-
initiated IDE approval. All devices will be recorded in the redcap database. After the study, the unused 
devices will be returned to the manufacturer. 
 
 
6.2.3 PRODUCT STORAGE AND STABILITY 

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Devices will be sent to CSMC – Smidt Heart Institute and received by clinical research coordinator. These 
will be stored on a safety cabinet located at the Cath lab after accountability log completed.   
 
 
6.2.4 PREPARATION 
 
The device comes in a sterile package. It is opened in a sterile manner at the time of procedure.  The 
Medtronic 60cm lead is connected to the Medtronic wireless external neurostimulator (WENS, model 
97725).  The device is programmed by using the Medtronic Neuromodulation Clinician programmer App 
A710.   
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
The patient will be consented to undergo surgery. After the device implantation, the patients will be 
randomized to experimental and control groups using Redcap. We will attempt to blind the patients, 
although the tingling or pain associated with the stimulation may make blinding difficult. All data 
analyses performed by the co-investigatorsand the rhythm analyses performed by the Mobile Cardiac 
Telemetry system technicians will be blinded. The experimental group will receive stimulation at 3.5 mA 
output, while the control group will receive no stimulation. Data will be obtained during this time to 
determine atrial arrhythmia frequencies in both groups. The device will then be removed at the end of 
the second week. After the third week, we will give the option to the control group to crossover to the 
experimental group. This group of patients will undergo a second procedure to receive stimulation at 3.5 
mA and we will follow up for another 3 weeks and 3 months post second procedure.  
 
We will tell the patients that they will be randomized into experimental group or control group during 
surgery. We will attempt to blind the patients, although the tingling or pain associated with the 
stimulation may make blinding difficult. We will explain to all patients they may or may not feel tingling 
and/or pain during the 2-week stimulation time but will not tell them which group they are assigned to.  
All data analyses performed by the co-investigators and the rhythm analyses performed by the 7-day 
non-invasive monitoring system technicians will be blinded. After 3 weeks post-procedure, we will 
unblind the control group to give them the option of crossing over to the experimental group to receive 
the treatment. If they agree, these group of patients will forego the 3-month follow-up visit and will 
proceed with a second procedure along with follow up visits post-second procedure. Data will be 
obtained during this time to determine AF burden in all groups. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
The study team will assess compliance with the study intervention by: 
• 
Maintaining accurate study records and documentation of all required visit tests and procedures 
• 
All research staff will be trained in all study activities 
• 
All research staff will be trained in using the HIPAA compliant Redcap electronic data capture 
system 
• 
Continuous inpatient telemetry. The patient will be continuously monitored in the hospital  
based on the Principal Investigator’s discretion. Additional ECG electrodes will be used for 
telemetry recordings. The ECG signals will be transmitted to the heart station staffed by 
experienced technicians for heart rhythm monitoring.  

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• 
Outpatient rhythm monitoring. The patient will undergo continuous outpatient near real time 
telemetry using a Mobile Cardiac Telemetry system.  Significant arrhythmia episodes will be 
reported to the PI or one of the co-investigators for management. 
• 
An Apple watch will be used to monitor AF between Baseline visit and at the end of the study. 
• 
All tests, labs and procedures will be reviewed by a designated research team member 
o Any abnormal result will be reported to the PI immediately 
 
6.5 
CONCOMITANT THERAPY 
 
• 
Current medications will be recorded at the baseline visit 
• 
Documentation that patient has been treated with at least 1 antiarrhythmic drug (class I, class 
III, or atrioventricular nodal blocker) 
• 
In patients treated with warfarin, the investigators will review the data to determine if the INR 
was > 2.0 for at least a month prior to procedure. In addition, the surgery will not be performed 
if the INR is > 3.0. For patients on DOAC, we will interview the patient to ensure compliance. 
We plan to perform the implant procedures with uninterrupted anticoagulation to reduce the 
possibility of stroke. We estimate that the small bleeding risk does not justify interruption of 
anticoagulation in most patients. 
 
6.5.1 RESCUE MEDICINE 
   
Not applicable.  
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
The study intervention is the subcutaneous nerve stimulation with an externalized neurostimulation 
lead. The electrical stimulation may be terminated when there are serious adverse events or when 
patient declines to continue with the stimulation. Discontinuation from electrical stimulation does not 
mean discontinuation from the study, and remaining study procedures should be completed as 
indicated by the study protocol.  If a clinically significant finding is identified (including, but not limited 
to changes from baseline) after enrollment, the investigator or qualified designee will determine if any 
change in participant management is needed. Any new clinically relevant finding will be reported as an 
adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
The reasons for discontinuing the subcutaneous nerve stimulation 
• 
The removal of the subcutaneous electrodes 
• 
Any adverse events 
 
 

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7.2 
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 study intervention non-compliance  
• 
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 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive subcutaneous nerve stimulation after the electrode is implanted 
for any reason. 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF) using the Redcap database. Subjects who sign the informed consent form and are 
randomized but do not receive the study intervention may be replaced.  Subjects who sign the informed 
consent form, and are randomized and receive the study intervention, and subsequently withdraw, or 
are withdrawn or discontinued from the study, will not be replaced.  
Based on the results of the canine study, reduced sympathetic nerve discharges may be associated with 
reduced heart rate. Therefore, we will terminate the study if the patients are found to have the 
following symptoms/signs which require cardiac pacemaker implantation according to the current 
ACC/AHA guidelines: 
    1. Third-degree AV block at any anatomic level associated with any one of the following conditions: 
     
a. Bradycardia with symptoms presumed to be due to AV block.  
     
b. Arrhythmias and other medical conditions that require drugs that result in symptomatic 
bradycardia. 
    
c. Documented periods of asystole ≥3.0 seconds or any escape rate <40 beats per minute (bpm) 
in awake, symptom-free patients. 
 
    2. Second-degree AV block regardless of type or site of block, with associated symptomatic 
bradycardia. 
 
7.3 
LOST TO FOLLOW-UP 
  
A participant will be considered lost to follow-up if he or she fails to return for any scheduled visits and 
is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 

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• 
The site will attempt to contact the participant and reschedule the missed visit as soon as 
possible 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. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
Procedures/tests/evaluations 
 
• 
Medical history/demographics will be performed by the investigator 
• 
Height, weight, BMI will be collected by the research team 
• 
12 lead EKG will be collected to assess rhythm and intervals-will be read by a core lab following 
a standardized interpretation form 
• 
In patients treated with warfarin, the investigators will review the data to determine if the INR 
was > 2.0 for at least a month prior to procedure. In addition, the surgery will not be performed 
if the INR is > 3.0.  The study subjects may be anticoagulated for stroke prevention. We will 
manage the peri-operative anticoagulation according to the standard protocol18 to minimize 
bleeding and the risk of stroke. 
• 
Pre-op instructions-all patients will be required to complete a standard hibiclens wash the night 
before the procedure and the morning of the procedure 
• 
Pregnancy test will be performed on females with child-bearing potential 

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• 
Surgical implantation-  The study design is inspired by spinal cord stimulation, which is a 
procedure used for pain control.19, 20 It is standard for spinal cord stimulation to include a trial 
period that last 4-29 days during which the 
patient carries an externalized lead 
connected to a neuromodulator.20 All 
devices are removed at the completion of 
the trial period.19, 20 The overall infection 
rate of the trial period was 1.2% (one out 
of 84 patients).20 The low infection rate 
was attributed to strict asepsis, double 
layer hydrocolloid dressing during the 
trial, prophylactic antibiotics, operator 
experience, and patient education. With 
these techniques, two-stage procedures 
with extended trials do not seem to 
increase the incidence of infections for 
spinal cord stimulation.20 The PI and 
several co-investigators are cardiac 
electrophysiologists with experience in 
pacemaker/ICD implantations. Dr. Tiffany 
Perry or Dr Alexander Tuchman, 
experienced neurosurgeons who are 
familiar with spinal cord stimulator 
implantations, will serve as a co-
investigator. They will train the PI and 
other co-investigators in performing the 
procedure using externalized lead. Both of them have agreed to perform the implant 
procedures.  The implantation procedures will be performed in full aseptic conditions. 
Antibiotics will be administered at the beginning of the procedure. Because this is a 
subcutaneous implantation, no fluoroscopy is needed. In our initial canine studies, we used 
Cyberonics wrap VNS electrodes to wrap around a small subcutaneous nerve and delivered 
electrical current only to that nerve.10 While effective, that approach requires a large incision to 
identify the subcutaneous nerves. A large incision is highly undesirable and may increase the 
complications. Therefore, in most recent NIH-funded canine studies, we have inserted 
subcutaneous electrodes without specifically identifying subcutaneous nerves. Because the skin 
is extremely well innervated, we posit that a blindly inserted lead will come in contact of 
subcutaneous nerves. The results showed that within a week of the stimulation, the average 
ventricular rate of persistent AF had dropped significantly. Therefore, we will insert electrode 
lead in the subcutaneous tissues blindly through a Tuohy needle. Figure 1 shows the site of 
insertion is in the left upper thorax, which is convenient to the patient.  In canine studies, 
multiple other stimulation sites in the thorax had the same antiarrhythmic effects.10, 12 The exact 
site of insertion will be determined by patient and/or operator preference. The leads will be 
secured to the skin by a skin suture similar to that is done with spinal cord stimulation. The 
remaining lead is externalized and connected to a neurostimulator. Double layer hydrocolloid 
dressing will be used to cover the externalized lead and the neurostimulator.  Lead impedance 
will be checked at this time because swelling or hematoma could increase the impedance. This 
surgical procedure will be repeated for the control group crossing over to the experimental 
group. The second procedure will take place no more than 2 weeks from the Week 3 Visit. If the 
 
Figure 1. Site for lead insertion. We will insert the lead in 
the upper thorax 3 cm beneath the clavicle where the 
skin is innervated by nerves from the stellate ganglion. 

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second procedure has to take place more than two weeks, the subject will have to undergo a 
separate pre-op visit which will include a 12-lead EKG, Labs (CBC,  BMP), INR if the patient is 
taking coumadin and pre-op instructions. The procedure will be exactly the same but for the 
second time, the implant site will be 1-2 cm above or below the original implant site and the 
stimulation will be turned on. Lead impedance will be checked again once the lead is placed into 
the chest.  
• 
Randomization-will occur after the implant of the first lead implantation. Randomization will 
be done electronically within Red Cap. 
• 
Telemetry- The patient will be continuously monitored in the hospital per PI’s discretion.. 
Additional ECG electrodes will be used for telemetry recordings. The ECG signals will be 
transmitted to the heart station staffed by experienced technicians for heart rhythm 
monitoring.  
• 
NeuroStimulator programming-program the output to 3.5mA  
• 
SKNA Recording-Skin Nerve Activity recording will be done to compare interactions. The 
methods of recording are summarized in Figure 2 below. 
 
 
• 
A 6-min walk will be conducted to estimate the functional status at baseline (prior to 
implantation) and during follow up visits (Figure 2). The test will be performed according to 
the protocol used by Bittner et al.21 Briefly, we will measure a 30-meter (roughly 100 ft) 
course in the clinical and recovery area. The patients will be instructed to walk from end to 
end at their own pace while attempting to cover as much ground as possible in the allotted 
period of 6 minutes. A research coordinator will time the walk test, called out the time every 
2 minutes, and encourage the patient every 30 seconds in a standardized fashion (while 
facing the patient and using one of the two phrases "You're doing well" or " Keep up the 
good work"). Patients will be allowed to stop and rest during the test, but are instructed to 
resume walking as soon as they felt they are able to do so.  
o After 6 minutes had elapsed, patients will be instructed to stop walking and the 
total distance walked will be measured to the nearest meter. Symptoms 
experienced by patients during the walk (angina, dyspnea, fatigue, dizziness, and 
syncope) will be recorded. The primary purpose of the 6-min walk is not to measure 
its distance and predict the prognosis through the measurement of heart rate 
changes, as it is known that the heart rate alone does not predict the prognosis in 
 
Figure 2. SKNA recording during 6-min walk. The colored dots show electrode location. A shows the ME6000 
device. B shows the location of ECG patch electrodes (red buttons) and reference electrode (black button). C shows 
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patients in the rate-control arm of the AFFIRM trials. Furthermore, 6-min walk is not 
effective in measuring the functional status of the healthy volunteers. However, 
with this standard exercise protocol, we expect to increase both the average SKNA 
(aSKNA) and the heart rate in these patients. The correlation between aSKNA and 
heart rate will be calculated and compared with the total AF burden documented by 
the event monitor. The results will be used to test the hypothesis that the r values 
between aSKNA and ventricular rate is predicative of the AF burden.2 Furthermore, 
the 6-min walk will give us the ability to compare the aSKNA before and after 
stimulation under conditions of sympathetic activation. 
• 
Mental Math test-In patients who cannot complete 6-min walk, they will be asked to do 
mental math which will provoke sympathetic nerve activities. The test will have the patient 
start counting at 100 and subtract by 3 for two minutes.  
• 
Apple Watch Monitoring – An Apple Watch Series 7 and Apple iPhone 6s or later model will 
be given to the patient during Baseline visit and serve as a secondary monitoring system 
from Baseline to the completion of the 3 month visit 7-day Mobile Cardiac Telemetry. AF 
monitoring via Apple iPhone and Apple Watch will not be for safety monitoring. Previous 
studies have shown that the Apple Watch is able to detect episodes of Atrial Fibrillation in 
patients with high AF burden.1 The patients will wear the watch starting Baseline visit and 
will continue to wear it until the completion of the 3 Month Visit 7-day Mobile Cardiac 
Telemetry. The patient is to wear the watch as much as possible throughout the day and 
night. We will encourage subjects to use the Apple Watch’s ECG App to record ECGs when 
the subject suspects they are in Atrial Fibrillation or receive a notification generated by the 
Apple Watch that a Low Heart Rate, High Heart Rate, or Irregular Rhythm was detected. This 
is a single-lead ECG that is able to provide information about heart rate, heart rhythm, and 
has ability to classify Atrial Fibrillation. ECG tracings can also be determined as inconclusive, 
meaning that the recording cannot be classified.  iPhone 6s and later models are the only 
Apple devices that have the WatchApp, which is required for any data collected on the 
Watch to be transmitted to the HealthApp on the iPhone. 
• 
 If the patient has their own personal Apple Watch Series 7 and Apple iPhone 6s or later 
model and would like to use their device for secondary monitoring during the Apple Watch 
Monitoring periods, we will ask patients to share their Heart Rhythm Data from their Apple 
devices with the Principal Investigator or study-dedicated iPhone from Baseline to the end 
of the 3 Month Follow up procedures. They are to disclose their subject identifying 
information including their cellular number and Apple ID in order to share their Apple health 
app data with the Principal Investigator and research staff. The subject identifiable 
information disclosed to the research team will remain confidential from any other parties 
beside the Principal Investigator and research coordinators. Any Apple Health data received 
from the patient will be de-identified prior to data entry and storage. The study settings for 
the Apple devices described below will remain the same including abnormal arrythmia 
notifications and timeline of sharing data with the Principal Investigator or study-dedicated 
iPhone until the 3 Month Follow Up procedures are complete. After the sharing of health 
data is complete, we will remove all study data off of the Principal Investigator and/or 
study-dedicated iPhone. We will set up the research Apple Watch and Apple iPhone on site. 

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To access the HealthApp, our research team will work with Cedars-Sinai IT Support (EIS). 
Cedars-Sinai EIS will create an Apple ID that will be assigned to the subject’s iPhone and 
Apple Watch. This Apple ID will not be associated with the subject’s identifiable information 
such as name or email address. EIS and our research team will input the EIS-created Apple 
ID into the subject’s Apple Watch and iPhone and connect the Watch to the iPhone’s 
HealthApp. The HealthApp of the subject(s) will then be shared to a study-dedicated iPhone 
utilized only by the research team. This study-dedicated iPhone will be associated with an 
Apple ID created by Cedars-Sinai’s IT Support (EIS). Since our team is using an Apple ID 
created by Cedars-Sinai IT Support (EIS), no subject identifiable information will be stored on 
the subject’s Apple Watch, subject’s iPhone, or study-dedicated iPhone.If the patient 
decides to use their personal Apple devices, the data on the subject’s personal Apple 
devices will not be removed. The patients will provide subject identifiable information in 
order to share their Health App data that will only be accessible to the Principal Investigator 
and research staff.Our study team will configure the research and/or personal Apple 
Watches to enable notifications to appear on the subject’s Watch and the on-site iPhones. 
We will set the Low Heart Rate parameter to 40 beats per minute. We will allow the 
Principal Investigator to set the High Heart Rate parameter at their discretion for each 
subject. We will also turn on the Irregular Rhythm parameter. Our study team will 
encourage subjects to use the Apple Watch’s ECG App when they suspect they are in Atrial 
Fibrillation or receive notifications of Low Heart Rate, High Heart Rate, and Irregular 
Rhythm, however, this is optional and will not be mandatory for the subjects. ECG results 
include Normal Sinus Rhythm, Atrial Fibrillation or Inconclusive. ECG tracings determined as 
Inconclusive will be given to our study investigators, who will provide their interpretations 
of the tracings. If their interpretations include any tracings that indicate Atrial Fibrillation, 
we will incorporate this data into our Atrial Fibrillation logs to determine AF occurrences.  
• 
To share the subject’s HealthApp with our study-dedicated or PI’s iPhone, our study team 
will press “Share with someone” on the subject’s HealthApp. The HealthApp vitals will be 
shared with the research team including: Cardio fitness, Electrocardiogram (ECG), Heart 
Rate, Heart Rate Variability, Resting Heart Rate, and Walking Heart Rate Average. By 
enabling these features, our study team will be able to monitor our subject’s Apple Watch 
recordings via our study-dedicated iPhone or Principal Investigator’s phone. The subject’s 
iPhone and Apple Watch will be shared with an onsite iPhone Baseline visit until the 
completion of the 3 Month Visit 7-day Mobile Cardiac Telemetry. Once the 3 Month Visit 7-
day Mobile Cardiac Telemetry is complete, our study team will contact the subject and 
direct the subject to turn off the sharing feature by pressing “Stop Sharing Health Data” with 
the research staff.On our on-site iPhone we will select “Stop sharing health data” and “Stop 
receiving health data”. We will reach out to the patient to confirm they are no longer able to 
send health data. We will instruct Cedars-Sinai IT Support (EIS) to remove the Apple ID that 
is associated with both the subject’s iPhone and Apple Watch and carry out any procedure 
that will wipe data pertaining to the research study from the subject’s research iPhone and 
Watch. Once Cedars-Sinai IT Support (EIS) confirms the subject’s devices are removed from 
Cedars-Sinai control, the subject can enter their own personal Apple ID for their own 

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personal use of the devices. At this point, the subject is permitted to keep the research 
iPhone and Watch. If the Apple Watch and/or the Apple iPhone are lost, damaged and/or 
stolen, the subjects will not be financially responsible, and the site may provide  
replacements. This will only cover the Apple devices that are provided to patients for the 
study excluding personal Apple devices. If a subject withdraws or discontinues with the 
study after Randomization, they will be able to keep the research Apple Watch and Apple 
iPhone.  
• 
Mobile Cardiac Telemetry – The patient will be continuously monitored during the following 
time points: Eligibility (optional), Procedure, Week 1, Week 2 and the 3 Month Visit.  
o Preventice – The BodyGuardian Mini Plus monitors are a non-invasive, light weight, 
waterproof and highly portable device. This monitor is connected to an electrode 
patch that may be worn up to 7 days or 21 days. The BodyGuardian Mini Plus 
monitor will monitor hearth rhythm and are used for safety monitoring. The ECG 
signals will be transmitted to Preventice staffed by experienced technicians for 
heart rhythm monitoring. If the subject developed serious heart rhythm disorder, 
Preventice technicians will notify the Principal Investigator at the time of the event. 
The Principal Investigator will then make a clinical judgement based on the status of 
the patient.  
o Bittium Faros—The Bittium Faros monitors are a non-invasive, light weight, 
waterproof, and highly portable device. The Bittium Faros monitor is connected to 
an electrode patch that may be worn for up to 7 days. We will use the Bittium Faros 
monitor to monitor skin sympathetic nerve activity at the specified time points.  This 
device will not be used for safety monitoring.  
• 
Discharge/patient teaching-subject teaching for restrictions and dressing care 
• 
Removal of lead- The patient is placed in a supine position. The sterile dressing is removed. 
The silk suture is cut and removed. The stimulating lead is then pulled out of skin. The skin is 
cleaned with alcohol. The puncture site is left open to air 
• 
Echocardiogram-We will obtain an echocardiogram for research purpose at baseline, after 
the device removal and again during the 3-month follow up visit. The data will be analyzed 
by Dr. Robert Siegel to determine if ScNS changes the ventricular function 
• 
AFEQT-AF QOL-the symptoms of AF will be assessed by standard questionnaires 
• 
EQ-5D-5L QOL—the symptoms of AF will be assessed by standard questionnaires 
• 
Labs-CBC, BMP, BNP, Catecholamine levels- Blood will be submitted at baseline and again at 
final follow up visit for laboratory tests that include CBC, metabolic panel, BNP, and serum 
catecholamine concentration. The BNP will be used as a measure of heart failure, which may 
improve after better rhythm or rate control. Catecholamine concentration will used to 
estimate the sympathetic tone.   
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Each patient will receive mobile telemetry monitoring during the subcutaneous nerve stimulation (2 
weeks). Their heart rhythm is recorded and transmitted to the central monitoring station of the patch 
manufacturer. The technician will inform the PI or one of the co-investigators for any significant 

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arrhythmic events. The PI or co-investigator will review the tracings, make the diagnosis and take steps 
to ensure patient safety.  
 
After surgery, the patients will be examined at one week, two-weeks, three-weeks and three-month 
time points. The wound will be examined for signs of infection. If the patient had any symptoms related 
to the experimental procedure, he/she can report the symptoms to the investigators. Additional clinical 
visits may be arranged to manage those symptoms. 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic reactions to the 
drug or devices, symptomatic bradycardia, dizziness, syncope and death. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
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”. 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention 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 suspect.  

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• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
  
 
8.3.3.3 EXPECTEDNESS  
 
Principal 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 study intervention.  
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
  
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF) in Redcap. Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship to study product (assessed only by those 
with the training and authority to make a diagnosis), and time of resolution/stabilization of the event. 
All AEs occurring while on study must be documented appropriately regardless of relationship. All AEs 
will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Principal investigator will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit.  Events will be followed for outcome information until resolution or stabilization.  
 
 
8.3.5 ADVERSE EVENT REPORTING  
 

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Adverse events (AEs) and, Serious adverse events (SAEs) will be reported to IRB following its guidelines. 
Adverse events will be reported to the DSMB.  The PI will follow the DSMB charter guidelines.  The sign 
off on the adverse event will be done following the DSMB charter and IRB guidelines.   
 
8.3.6 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) as soon as possible, but no later 
than 10 working days after the investigator first learns of the effect.  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 within 10 working days after the sponsor first receives notice of the effect. Thereafter, the 
sponsor shall submit such additional reports concerning the effect as FDA requests. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
The patients are continuously monitored by a mobile cardiac telemetry system. The insertion site will be 
examined to determine if there are signs of infection or electrode migration. The PI will inform the 
patients of the AEs and SAES when they occur and again during the routinely scheduled follow up. The PI 
will coordinate with the patient’s physician in managing these AEs and SAEs to ensure patient safety.  
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
We do not expect to observe events of special interest in this study. 
 
8.3.9 REPORTING OF PREGNANCY  
Not applicable. 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 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 of 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. 
 

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This definition could include an unanticipated adverse device effect, any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects (21 CFR 812.3(s)). 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). 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 to the IRB and to the DCC/study 
sponsor within 24 hours of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor as soon as possible, but 
no later than 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) as soon as possible, but no later than 10 business days of 
the IRB’s receipt of the report of the problem from the investigator. 
 
An investigator shall submit to the sponsor and to the reviewing Institutional Review Board (IRB) a 
report of any unanticipated adverse device effect occurring during an investigation as soon as possible, 
but in no event later than 10 working days after the investigator first learns of the effect (21 CFR 
812.150(a)(1)), A sponsor who conducts an evaluation of an unanticipated adverse device effect under 
812.46(b) shall report the results of such evaluation to the Food and Drug Administration (FDA) and to 
all reviewing IRB's and participating investigators within 10 working days after the sponsor first receives 
notice of the effect. Thereafter the sponsor shall submit such additional reports concerning the effect as 
FDA requests (21 CFR 812.150(b)(1)).    
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
The PI will inform the patients of unanticipated problems when they occur and again during the 
routinely scheduled follow up. The PI will coordinate with the patient’s physician in managing these 
unanticipated problems to ensure patient safety. 
 

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9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
State the formal and testable null and alternative hypotheses for primary and key secondary endpoints, 
specifying the type of comparison (e.g., superiority, equivalence or non-inferiority, dose response) and 
time period for which each endpoint will be analyzed. 
 
• 
Primary Efficacy Endpoint(s):  
The average AF burden.  
• 
Secondary Efficacy Endpoint(s): 
1) Time-dependent reduction of AF burden 
2) Ventricular rate during AF 
3) Average SKNA 
4) Quality of life 
5) Reduction of AF burden after cross over from control to experimental group 
 
Our primary research hypothesis is that chronic subcutaneous nerve stimulation can control AF in 
patients with severe symptomatic AF unresponsive to conventional therapies. 
 
The primary endpoint is the average of AF burden at the end of the first week. Patients who do not 
experience AF during the first week will have a value of 0 as AF burden. The average of AF burden at the 
end of the first week will be calculated per patient as the proportion of time spent in AF during the first 
week divided by the number of days a patient is under observation during the first week.   
 
We will test the null hypothesis of no difference in the average AF burden between the treatment 
groups versus the alternative hypothesis that the average AF burden is lower in the intervention group 
than the sham group.  
 
The following pairs of secondary null and alternative hypotheses will be tested:   
1) that the trajectories of reduction of AF burden by time between treatment and control groups are the 
same versus that the trajectories are different;   
2) that reduction of AF burden in treatment group does not depend on time versus that the reduction of 
AF burden is dependent on time; 
3) that effects of ScNS and sham stimulations on ventricular rate control during AF are the same for the 
treatment and the control groups versus that the effects are different between the two groups; 
4) that reduction of SKNA is the same between the treatment and the control groups versus that the 
reduction of SKNA is different between the two groups; 
5) that improvement of quality of life is the same between the treatment and the control groups versus 
that the improvements of QoL is different between the two groups. 
6) There is a reduction of AF burden after crossing over from control to experimental group 
 
9.2 
SAMPLE SIZE DETERMINATION 

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The AF burden is determined by the amount of time spent in AF detected by Mobile Cardiac Telemetry 
patch.  A recent study22 analyzed the results of ambulatory single-lead ECG patch sensor monitoring for 
11.4 days on average in 7934 men and 5359 women with paroxysmal AF. During the monitoring period, 
there were a total of 1,041,504 paroxysmal AF episodes. The median daily rate of paroxysmal AF was 
1.21 episodes per day (interquartile range [IQR] 0.31-4.99), and the median maximum duration per 
individual was 7.5 hours (IQR 2.4-18.6 hours). The median burden of AF (% of time in AF relative to 
entire period of monitoring) was 8.9% (IQR 3.4%–25.2%). Assuming that we implant the lead and 
randomize patients into experimental group (stimulation) and control group (no-stimulation), we expect 
to see the same average AF burden among our patients. In our previous study in canine models,9 
subcutaneous nerve stimulation reduced atrial arrhythmia burden per 48 hours from 211.0 ± 204.8 s to 
134.8 ± 165.2 s (delta=-76.3 ± 44.8 s) versus a reduction of -5 ± 9.5 seconds in the sham group. Assuming 
the same standard deviation of the change of AF burden from baseline in the two randomized groups as 
44.8 and accounting for the patient retention rate of 70%, we need 15 per arm (total 30 patients) for 
80% power at 2-sided alpha 0.025 to detect an effect size of 1.59at the end of one week between Group 
A (experimental) and Group B (control) using the Wilcoxon rank sum test. If the treatment suppresses 
AF by 75% while the sham does not suppress AF at the end of one week, we have 86% power to detect 
this difference at 2-sided alpha 0.025 using Fisher’s exact test.  We have budgeted for 32 patients to 
ensure that we have sufficient funds to complete the study. 
 
9.3 
POPULATIONS FOR ANALYSES 
1. Safety set: the set of patients who have undergone surgery to insert the subcutaneous lead  
2. modified intention-to-treat set: the set of patients who have either the subcutaneous nerve 
stimulation or the sham stimulation performed AND have baseline average AF burden AND at least the 
first week’s post-stimulation average AF burden.  
Our sensitivity analysis on the modified intention-to-treat set will be using the safety set: we will assume 
0 reduction in AF burden for patients missing either the baseline or the first week post-baseline AF 
burden.   
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Patient characteristics will be summarized per randomized group using percentages if categorical, or 
means with standard deviations if continuous.  These characteristics will be compared using the 
Wilcoxon rank sum test if continuous, or Fisher’s exact test if categorical.  Nominal two-tailed p values 
will be reported. Repeated measures will be analyzed either by linear mixed effects models or by GEE. 
Standard model diagnostics will be performed. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
The primary endpoint is the average of AF burden at the end of the first week. 

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We will use Mobile Cardiac Telemetry to determine AF burden before surgery (eligibility visit), for two 
weeks during ScNS, 3 weeks following surgery and 3 months following surgery.  
The average of AF burden at the end of the first week will be calculated per patient as the time spent in 
AF during the first week divided by the total time a patient is under observation during the first week.  
Change of the average AF burden from the baseline will be computed for each patient.  The change in 
the average AF burden will be compared between group A (experimental) and group B (control) using 
the Wilcoxon rank sum test at a two-sided significance level of 0.025.  
The following secondary analyses of the primary endpoint will be performed:  
1) We will compare the baseline AF burden and the baseline number of Apple watch-detected AF 
episodes between groups.  The number of Apple watch-detected AF will be standardized by the number 
of days that a subject is under observation in the respective time period.  Further we will compare 
reduction in AF burden from baseline at weeks 1, 2, 3 and 12 in both Group A and Group B to test the 
null hypothesis that there is no reduction of AF burden in the two groups and between the two groups. 
We will also compare the reduction in the number of Apple watch-detected AF episodes from the 
baseline in the period between week-3 and the end of study in both Group A and Group B to test the 
null hypothesis that there is no difference in detected AF episodes in the two groups and between the 
two groups.  Linear mixed effect models will be used for the comparisons, with Group, Week and Group 
by Week interaction as fixed effects, and a random intercept per subject.  Week will be coded first as a 
categorical variable, and appropriate contrasts will be set up for the temporal comparisons.  If outcome 
variables appear to be linear in time, we may model Week as a continuous fixed effect.  
2) We may also compute the difference-in-difference statistics for the treatment for the 4 time intervals 
of the treatment, baseline and t weeks 1, 2, 3 and 12.  
We may also use generalized estimating equations (GEE) instead of linear mixed effect models if the 
validity of the latter is suspect.  If there is differential drop-out between the randomized groups, we will 
adjust the group-comparisons using baseline covariates, such as age, sex and heart failure status. 
Standard approaches for both model checking and selection based QIC will be applied.23 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The analyses of the secondary endpoints will be performed on the modified ITT data set. Unless 
otherwise stated, two-tailed nominal p values will be reported.  
Analysis of mean VR at the end of week 1  
In dogs, ScNS reduces ventricular rate during AF. The mean VR was 149±36 bpm after the induction of 
AF. The VR significantly decreased to 84±16 bpm (p=0.011) at the final week of ScNS.11  The same device 
that produces AF burden will also generate VR.    First, we will summarize the proportion of patients 
who are AF-free at the end of week 1. Fisher’s exact test will be performed to test if the proportions of 
AF-free patients are the same between the two treatment arms at a two-sided significance level of 

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0.025. Second, we will summarize the mean VRs using mean and standard deviation by time and by 
randomization group among the patients who experience AF.  
We will classify patients into 3 groups based on the week 1 average VR: patients who do not experience 
AF as category 1, patients who experience AF with VR <= 110 bpm as category 2,24 and patients who 
experience AF with VR > 110 bpm as category 3.  Fisher’s exact test will be performed to test if the 
distribution of the three categories are the same between the two treatment arms and the nominal p-
value will be reported.  
We will categorize average VR at other time points into three groups as described above, and analyze 
repeated average VR using ordinal repeated measure analysis with patient as the blocking variable, 
week and group as well as their interaction as independent variables. Proportional odds assumption will 
be checked.   
Analysis of SKNA and QOL 
Subcutaneous nerve stimulation achieves its effects through neuromodulation, resulting in reduced 
sympathetic nerve activity. A non-invasive method to measure sympathetic nerve activity is through the 
skin sympathetic nerve activity (SKNA) recording. We will record SKNA using two different equipment. 
The first is ME6000 which makes high fidelity SKNA recordings with 10,000 Hz sampling rate. However, 
ME6000 is not sufficiently portable for ambulatory recordings. Therefore, we added Bittium Faros 
recorder for ambulatory recording at 1,000 Hz sampling rate. 
The quality of life (QOL) is measured using the standard questionnaire to assess the overall effects of 
treatment on the study subjects.     
SKNA recorded with ME6000 at rest and during 6-minute walk will be summarized at each time point  
using mean and standard deviation.  
SKNA recorded with Bittium Faros when patients were ambulatory will be summarized at each time 
point using mean and standard deviation. 
Quality of life (AFEQT-AF, EQ-5Q-5L) will be summarized by item and by overall score at the following 
time points, baseline, 3 week and 3-month visits using mean and standard deviation. 
Change in the average values of SKNA (aSKNA) recording at rest on the procedure day from the baseline 
will be compared between the randomization groups using the Wilcoxon Rank Sum test. Values of 
aSKNA recording in ambulatory subjects and during 6-minute walk at baseline, 1 week, 2-week, 3 week 
and 3-month visits will be compared between randomization groups using linear mixed models, with 
Group, Week and Group-Week interaction as fixed effects, and a random intercept per subject. Week 
will be coded first as a categorical variable. If aSKNA appear to be linear in time, we may model Week as 
a continuous fixed effect.  Missing at random will be assumed in the above stated linear mixed models.  
Additionally, the strategy of last-value-carried-forward (LVCF) will be employed to fill in missing data 
values as an alternative to the missing-at-random assumption and the linear mixed models will be re-

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run. The LVCF analysis serves as a sensitivity analysis.  Similar analyses will be performed for SKNA 
during 6-minute walk. 
We will compare the number of Apple watch-detected AF episodes between week-3 and the end of 
study between Group A and Group B to test the null hypothesis that there are no differences in detected 
AF episodes between the two groups.  For each patient, we will record the number of days that the 
patient is under observation, and the number of days that AF episodes are detected.  Assuming that 
each patient’s data follows a binomial distribution and the probability of AF daily detection is the same 
within group.  Since patients’ data are independent from each other and the sum of independent 
binomials are still a binomial, we can compare the two groups as two binomials with potentially 
different rates of AF detections.  Fisher’s exact test will be performed for this comparison at a two-sided 
significance level of 0.05.   
The overall scores of Quality of life (AFEQT-AF, EQ-5Q-5L) questionnaires will be compared at the 
following time points, baseline, 3 week and 3 month visits by the same linear mixed effect models as 
described for aSKNA.  The same missing data treatment as stated above will be employed in the linear 
mixed model analyses of these two outcomes.  Item and total scores may be transformed if deemed 
necessary to fulfil model assumptions. 
Analysis of AF burden in patients crossed over from sham control to experimental group 
At the end of week three, patients in the sham control group will be given the option to receive the 
active treatment and treated the same way as patients on the treatment arm for weeks 1-3. Patient 
characteristics will be summarized for the subset of patients who accept this option to cross over to 
active treatment. The averages and SDs of AF burden will be computed for each week from baseline to 
week 6 for this group, and displayed graphically.   Linear mixed models may be employed to explore the 
temporal changes in this subset of patients.   
 
 
9.4.4 SAFETY ANALYSES 
 
• 
Safety Endpoints 
o Safety shall be evaluated throughout participation in the study: 
o Freedom of major implant adverse events related to the procedure   
o Infection 
o Lead, extension or migration 
o Persistent pain at the lead site 
o Freedom of Third Degree AV Block at any anatomic level associated with any one of the 
following conditions 
o Bradycardia with symptoms presumed to be due to AV Block 
o Arrhythmias and other medical conditions that require drugs that result in symptomatic 
bradycardia 
o Documented periods of asystole > 3.0 seconds or any escape rate <40 beats per minute 
in awake, symptom-free patients 

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o Freedom of Second-degree AV block regardless of type or site of block, with associated 
symptomatic bradycardia 
o Freedom of skin irritation related to the ECG patches, Mobile Cardiac Telemetry patch 
o Freedom of allergic response to the implanted lead or materials used 
 
The number as well as percent of patients experiencing a safety outcome listed above will be 
summarized overall and by randomized group in the safety set. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Patient characteristics will be summarized per randomized group using percentages if categorical, or 
means with standard deviations if continuous.  These characteristics will be compared using the 
Wilcoxon rank sum test if continuous, or Fisher’s exact test if categorical.  Nominal p values will be 
reported. 
 
9.4.6 PLANNED INTERIM ANALYSES  
 
No interim analysis is planned.   
 
9.4.7 SUB-GROUP ANALYSES 
 
We will not perform subgroup analyses based on age, sex, race/ethnicity or other demographic 
characteristics because: 
 
1) there is no biological basis for those factors to affect the primary outcome, 
2) the sample size is small that we will not consider those subgroup analyses. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Not applicable.  
 
9.4.9 EXPLORATORY ANALYSES 
 
Not applicable. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
In obtaining and documenting informed consent, the investigator must comply with applicable 
regulatory requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and should adhere to ICH 
GCP. Prior to the beginning of the trial, the investigator should have the IRB’s written approval for the 

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protocol and the written informed consent form(s) and any other written information to be provided to 
the participants.  
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting study 
intervention. The following consent materials are submitted with this protocol; Informed consent and 
HIPAA form. Additional information will be given to the patient at baseline visit; pre-operative 
instructions and after the implant; post-procedures instructions and a study Participant ID card.  
 
10.1.1.2 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. A 
copy of the signed informed consent will be uploaded on patient medical record. 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. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated 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 study participants, investigator, funding agency, 
Investigational Device Exemption (IDE) sponsor and 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    

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• 
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). 
 
10.1.3 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. 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  device 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) 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 at the Indiana CTSI in Indianapolis, IN. The identifiable information is 
included in the database but will be made visible only with specific authorization from the PI. Each 
participant and their research data will be identified by a unique study identification number. This de-
identified information will be provided to investigators for analyses.  
The study data entry and study management systems used by clinical sites and by Indiana CTSI in 
Indianapolis, IN research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the Indiana CTSI in Indianapolis, IN.  
 
 
Certificate of Confidentiality  
 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure. It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 
or other proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 

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Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy to participants.] 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed by Xiaochun Li, PhD and stored in the Redcap database at 
the Indiana CTSI in Indianapolis, IN. After the study is completed, the de-identified, archived data will be 
transmitted to and stored at the Data and Resource Center (DRC) of NIH Stimulating Peripheral Activity 
to Relieve Conditions (SPARC) program, for use by other researchers including those outside of the 
study. Permission to transmit data to the NIH SPARC DRC will be included in the informed consent.  
 
When the study is completed, access to study data will be provided through the Data and Resource 
Center (DRC) of NIH Stimulating Peripheral Activity to Relieve Conditions (SPARC) program. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Peng-Sheng Chen, MD 
Cedars Sinai Medical Center  
127 South San Vicente Blvd. 
A3100 
Los Angeles, CA 90048 
310-423-3300 
ChenP3@cshs.org 
 
The study is funded by NIH SPARC program.  The PI and the co-investigators will form a steering 
committee to manage the trial. There is a regularly scheduled monthly teleconference for the steering 
committee to report the progress to NIH, with the participation of Medtronic Inc. 
 
10.1.6 SAFETY OVERSIGHT 
 
A Data Safety Monitoring Board [DSMB] will provide ongoing independent review of the data, further 
ensuring the continued safety of subjects, as well as the validity and scientific merit of the trials.  The 
DSMB consists of at least three voting members and one non-voting member that is a biostatistician, 
with relevant expertise. 
 
The DSMB members include an experienced clinical trialist (chair), a clinical cardiac electrophysiologist, a 
clinical cardiologist and a biostatistician. None of the DSMB voting members are not related to the study 
or employed by the Cedars-Sinai Medical Center. The DSMB together with the PI will be charged with 
determining if the study should be stopped based on interim data reports that they will receive from the 
data coordinating center.  IU will evaluate safety information that is reported in the time frame specified 
in the protocol.  It is the responsibility of the PI to oversee the safety of the study.  All SAEs will be 
processed for review to the DSMB within 7- 10 days of receipt.  

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10.1.7 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 Harmonization Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
Monitoring for this study will be performed by Cedars Sinai Medical Center IRB: 
• 
The Clinical Research Monitor will work with the Site PI and Site Contact(s) to schedule 
monitoring visits. The monitor will contact the study team at least 30 days prior to the visit to 
schedule a designated date/time to review subject charts and regulatory data. 
• 
Prior to the visit, the PI and other pertinent site personnel will receive a monitoring visit 
confirmation letter and a list of subjects to be monitored. The monitor will ensure that this 
information is communicated to the site personnel at least 14 days prior to the mutually agreed 
upon visit date to allow sufficient time for record acquisition and preparation. 
• 
Monitoring visit findings, resulting action items and suggestions for quality improvement will be 
documented in the Monitoring Visit Follow-Up Report. The Clinical Research Monitor will send a 
completed report to the study team within 30 days of the last day of the monitoring visit.   
• 
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The CMP 
describes in detail who will conduct the monitoring, at what frequency monitoring will be done, 
at what level of detail monitoring will be performed, and the distribution of monitoring reports. 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
There is only one site for recruitment. The investigators 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 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 biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonization Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements  and 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. 
 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  

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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 Redcap database, a 21 CFR Part 11-compliant data 
capture system provided by the Indiana CTSI. 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. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
All records produced or collected in connection with the research project, including primary (e.g., 
laboratory, medical, interview), financial, statistical, supporting, administrative, and regulatory 
documentation, shall be retained for a minimum of three (3) years from the date of submission of the 
final expenditure report to the funding agency or the date of study closure with the IRB, whichever is 
longer. 
 
Records may need to be retained beyond this date, specifically: 
• 
For studies subject to HIPAA, signed HIPAA authorization forms must be retained for a minimum 
of six (6) years from the date it was obtained. 
 
 
• 
For studies conducted under an IDE or HDE, records must be retained during the investigation 
and for a period of two (2) years after the latest of either: the date on which the investigation is 
terminated or completed, or the date that the records are no longer required for purposes of supporting 
a premarket approval application, a notice of completion of a product development protocol, a 
humanitarian device exemption application, a premarket notification submission, or a request for De 
Novo classification. 
• 
If the research involves intellectual property, data must be kept for as long as may be necessary 
to protect any intellectual property claims resulting from the work. 
• 
If any charges regarding the research arise, such as allegations of misconduct in research or 
financial conflict of interest, data must be retained until such charges are fully resolved. 
• 
If the research is conducted pursuant to a contract or agreement, data must be retained in 
accordance with the contract or agreement. 
 
After the specified period of time has elapsed, research personnel may dispose of the documentation 
relating to a research study in an appropriate manner, including encrypting, shredding, incinerating, 

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mutilating, erasing, and otherwise rendering the information illegible or unusable. Source 
documentation must be retained in its original form until this time. 
 
10.1.10 
PROTOCOL DEVIATIONS  
  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonization Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations as soon as possible but not later than 10 working days of identification of the protocol 
deviation, or within 10 working days of the scheduled protocol-required activity.  All deviations must be 
addressed in study source documents, uploaded to the Redcap database at Indiana University and 
reported to NIH SPARC program staff.  Protocol deviations must be sent to the reviewing Institutional 
Review Board (IRB) per their policies. The site investigator is responsible for knowing and adhering to 
the reviewing IRB requirements. Further details about the handling of protocol deviations will be 
included in the MOP.  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
The PI and co-investigators will generate manuscripts for publication and will present the data in 
national scientific meetings. All data will be shared with SPARC investigators and public according to the 
SPARC program rules. In addition, this study will be conducted in accordance with the following 
publication and data sharing policies and regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers one year after the 
completion of the primary endpoint by contacting NIH SPARC program. 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 

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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.  The study 
leadership in conjunction with the NIH SPARC program has established policies and procedures for all 
study group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
 

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10.3 ABBREVIATIONS 
 
ACC/AHA 
American College of Cardiology/American Heart Association 
AE 
Adverse Event 
AF 
Atrial fibrillation 
AV 
Atrioventricular  
AFEQT-AF-QOL 
Atrial Fibrillation Effect on Quality of Life 
aSKNA 
Average skin sympathetic nerve activity 
BMI 
Body Mass Index 
BMP 
Basic Metabolic Panel 
BNP 
B-type natriuretic peptide 
bpm 
Beats per minute 
CBC 
Complete blood count 
CIED 
Cardiac implantable electronic device 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CRF 
Case Report Form 
CSMC 
Cedars Sinai Medical Center 
CTSI 
Clinical and Translational Sciences Institute 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DOAC 
Direct oral anticoagulants  
DSMB 
Data Safety Monitoring Board 
DRC 
Data and Resource Center 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
ECG or EKG 
Electrocardiogram 
EF 
Ejection fraction 
EQ-5D-5L QOL 
5-level EQ-5D version (EQ-5D-5L) quality of life 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GEE  
Generalized estimating equations 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICDs 
Implantable cardioverter-defibrillators 
ICH 
International Conference on Harmonization  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 

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ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LVCF 
Last Value Carried Forward 
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 
NPO 
Nothing through the mouth 
OHRP 
Office for Human Research Protections 
OTC 
Over the counter 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
QIC 
Quasilikelihood under the Independence model Criterion 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
ScNS 
Subcutaneous nerve activity 
SKNA 
Skin sympathetic nerve activity 
SMC 
Safety Monitoring Committee 
SPARC 
Stimulant Peripheral Activity to Relieve Conditions 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
VNS  
Vagal nerve stimulation 
VR 
Ventricular rate 
VT 
Ventricular tachycardia 
WENS 
Wireless external neurostimulator  
Wt 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
7 
1-25-2022 
1. Specification of Mobile 
Cardiac Telemetry devices 
2. Apple Watch Monitoring 
The Bittium Faros was 
approved as a device by the IRB 
on 3/10/21 (MOD00003064). 
This monitors the change in skin 
sympathetic nerve activity 
throughout the study at the 
desired time points, however, 
this specific device is not used 
for safety monitoring. 
 
The Preventice mobile cardiac 
telemetry device was added to 
the IRB study application 
approved by the IRB on 
3/29/2021 (MOD00003361). 
This mobile cardiac telemetry 
device will be used for safety 
monitoring. 
 
Indication that the Apple Watch 
will act as secondary monitoring 
system to the Mobile Cardiac 
Telemetry devices. There are 
recent studies that provide 
significant evidence that Apple 
watches can accurately detect 
Atrial Fibrillation episodes. 
However, AF monitoring via 
Apple Watch will not be used 
for safety monitoring.  
 
In October 2021, Apple 
obtained FDA regulatory 
clearance for a new ImF 
Photoplethysmograph analysis 
that assists with irregular heart 
rhythm detection on Apple 
Watches. Since then, there is 
greatly increased interest in 
using Apple watch to detect 
atrial fibrillation. We wish to 
incorporate this new technology 
into our study. This new method 
is highly portable, accurate and 

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non-invasive. It will help us 
bridge the gap between 3-wk 
and 3-month visits to determine 
the frequencies of AF in study 
participants.   
8 
6-22-2022 
1. Addition of Adverse Events  
2. Addressing Inconclusive 
ECGs from Apple Watch  
3. Apple Watch Monitoring and 
Timeline  
Based on patient reported 
adverse events and past 
literature, goosebumps and hot 
flashes are known to have 
association with spinal cord 
stimulation. We are adding them 
as potential adverse events. 
 
In the event that the subject 
does not want to wear the 
research Apple devices for 
Apple Watch Monitoring, we 
want to provide an option of 
allowing them to continue the 
monitoring between Week 3 and 
Month 3 procedures. Apple 
Watch Monitoring will allow 
the Principal Investigator and 
research staff to know when the 
patient is having AF determined 
by the Apple Watch detection.  
 
To account for Apple watch 
ECG readings that result as 
Inconclusive.   
 
We found that Apple Watch is 
effective in detecting AF after 
randomization. However, 
because we do not have data 
before randomization, there are 
no baseline AF data to compare 
with. Therefore, we request the 
permission to give the patient an 
Apple Watch and iPhone during 
baseline visit. The patient will 
wear the watch before 
randomization to collect 
baseline information. We also 
revised the statistical analysis. 
These changes do not affect the 
primary outcomes of the study. 
9 
9-28-2022 
1. Inclusion criteria – expand to 
use of clinical ePatch 
recordings for AF burden  
Most of the patients with atrial 
fibrillation (AF) had AF burden 
determined clinically by ePatch 
recordings. If the ePatch 

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2. Optional Crossover study 
after Week 3  
3. Addition of Secondary 
Endpoint regarding the 
optional crossover study  
recordings were done within 6 
months prior to enrollment and 
there are no changes in 
antiarrhythmic medications after 
the recording, then the AF 
burden recorded by the ePatch 
will be used as baseline AF 
burden. This change will 
eliminate the need of repeating 
the ePatch recording for 
eligibility determination and 
thus improve recruitment. 
 
Based on our DSMB 
recommendations from 9/22/22, 
we are doing a crossover after 
week 3 to improve recruitment 
because all participants are 
guaranteed an opportunity to 
receive subcutaneous 
stimulation. In our original 
protocol, after the first 3 weeks, 
additional data collection will 
be performed with Apple Watch 
and with a final one-week 
ePatch monitoring. However, 
since the latter data are used for 
secondary exploratory analysis 
only, we do not need those data 
to determine the primary 
endpoint of the study. 
10 
12-30-2022 
1. Removed Catecholamines 
and BNP for Week 3 Visit. 
The labs required for a 
second procedure are only to 
ensure that the subject is 
ready for surgery. 
Per PI, we do not need 
catecholamines nor BNP to 
undergo the second surgery. 
11 
01-18-2023 
1. We are removing the 
verbiage that states 
postdocs will be blinded 
during SKNA data 
analysis. 
In the first 4 patients who 
underwent stimulation, large 
stimulation artifacts were 
noted in the recording. 
Therefore, the postdoc can 
immediately recognize who’s 
been stimulated and who’s 
not just by looking at the 
data. It is not possible to 
blind the postdoc during data 
analyses 
 
 
 
 

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