A Feasibility Study to Evaluate the Safety and Effect of the Optimization of Vagus Nerve Stimulation in Epileptic Patients to Induce Cardioprotection
Phase: NA
Conditions: Epilepsy, Sudden Cardiac Death
Sponsor: University of California, Los Angeles

A Feasibility Study to Evaluate the Safety and Effect of the Optimization of Vagus 
Nerve Stimulation in Epileptic Patients to Induce Cardioprotection 
 

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STUDY TITLE: A FEASIBILITY STUDY TO EVALUATE THE SAFETY AND EFFECT OF THE OPTIMIZATION OF
VAGUS NERVE STIMULATION IN EPILEPTIC PATIENTS TO INDUCE CARDIOPROTECTION 
PRINCIPLE INVESTIGATOR:  OLUJIMI AJIJOLA MD, PHD 
TABLE OF CONTENTS 
PAGE 
STUDY SUMMARY………………………………………………….. 2 
1. INTRODUCTION…………………………………………………. 3
A. BACKGROUND AND RATIONALE……………………. 3 
B. SUMMARY OF PRECLINICAL STUDIES……………….. 4 
C. OBJECTIVES………………………………………… 4 
2. STUDY DESIGN…………………………………………………. 4
3. SUBJECT SELECTION……………………………………………. 5
A. STUDY SITES………………………………………… 5 
B. RECRUITMENT………………………………………. 5 
C. ELIGIBILITY CRITERIA………………………………..5 
D. INCLUSION………………………………………….. 5 
E. EXCLUSION………………………………………….. 5 
4. STUDY METHODS……………………………………………….. 5
A. SCREENING AND ENROLLMENT ………………………5 
B. PATIENT SELECTION………………………………… 6 
C. PATIENT CONSENT…………………………………... 6 
5. STUDY PROCEDURES……………………………………………. 6
A. DATA COLLECTION…………………………………...6 
B. STUDY PROTOCOL……………………………… …..7 
C. STUDY DURATION……………………………………8 
6. STATISTICAL PLAN………………………………………………9
7. RISKS AND BENEFITS…………………………………………….9
A. RISKS………………………………………………... 9 
B. BENEFITS……………………………………………. 10 
8. ADVERSE EVENTS………………………………………………. 10
A. DEFINITION OF ADVERSE EVENTS…………………….10 
B. ADVERSE EVENT MONITORING……………………….10 
C. ADVERSE EVENTS…………………………………….10 
D. SERIOUS ADVERSE EVENTS………………………….. 11 
E. REPORTING ADVERSE EVENTS………………………..11 
9. DATA SAFETY MONITORING……………………………………. 11
10. DATA HANDLING………………………………………………...12
11. FINANCIAL CONSIDERATIONS…………………………………… 12
12. APPENDIX 1 ……………………………………………… ……..13
13. REFERENCES……………………………………………………. 14

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STUDY SUMMARY 
 
 
TITLE  
A Feasibility Study to Evaluate the Safety and Effect of the 
Optimization of Vagus Nerve Stimulation in Epileptic Patients to 
Induce Cardioprotection 
PRIMARY OBJECTIVES/AIMS 
The primary objective is to evaluate in epilepsy patients the effects of 
adjusting vagus nerve stimulation parameters to engage known 
cardioprotective aspects. 
SECONDARY OBJECTIVES 
The secondary objective is to quantify the effects of vagus stimulation 
on cardiac function by metrics of autonomic testing and a 
cardiopulmonary exercise testing. 
FDA APPROVED DEVICES 
LivaNova VNS Therapy (Vagus Nerve Stimulator (VNS) 
PROTOCOL NUMBER  
UCLA: IRB # 19-002279 
PRINCIPAL INVESTIGATOR 
Olujimi Ajijola, MD, PhD 
CO-INVESTIGATORS 
Kalyanam Shivkumar, MD PhD, Olujimi Ajijola, MD, PhD, Jason 
Bradfield, MD, Marmar Vaseghi, MD, PhD, Jeffrey L. Ardell, PhD, 
Ausaf A. Bari MA MD PhD FAANS 
 
STUDY SITE  
University of California Los Angeles (UCLA) 
FUNDING SOURCE (S) 
NIH-NCATS National Center For Advancing Translational Science 
NUMBER OF SUBJECTS 
12 
 

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1.  INTRODUCTION  
 
A. BACKGROUND AND RATIONALE 
The autonomic nervous system controls every aspect of cardiac function. This fine control is 
maintained by a concerted interplay of afferent impulses that reach the central nervous system (CNS) 
via multiple afferent pathways, and this information results in appropriate efferent sympathetic and 
parasympathetic responses. Thus, the nerves control cardiac excitation on a beat-by-beat basis. In the 
setting of myocardial injury, the autonomic nervous system plays an important role in the genesis and 
maintenance of ventricular tachyarrhythmias (VT). Sympathetic activation and parasympathetic 
dysfunction accompany cardiomyopathy and predispose to VT and ventricular fibrillation (VF). The 
neurohormonal response, although acutely beneficial, is chronically damaging. Blockade of the 
sympathetic nervous system has been the target of multiple successful therapeutic strategies, including 
beta-blockers and angiotensin converting enzyme inhibitors.  
 
Cardiovascular effects of vagus nerve stimulation (VNS) and delineation of optimal parameters 
VNS has shown mixed results in studies of heart failure patients likely due a variety of different 
stimulation parameters (frequency, pulse-widths, outputs) utilized, without clear human data on which 
parameters would provide optimal cardiac effect. In this study, a range of stimulation parameters will 
be evaluated in epilepsy patients with structurally normal hearts to delineate the “neural fulcrum” for 
cardiovascular effects. We will then utilize these “optimal” parameters to assess whether sympathetic 
responses to autonomic stressors are mitigated and exercise tolerance increased.  
 
Parasympathetic dysfunction accompanies cardiomyopathy and increases the risk of sudden cardiac 
death.  Indirect markers of parasympathetic dysfunction, such as decreased heart rate variability and 
abnormal baroreceptor reflex sensitivity (BRS), are associated with VT/VF in cardiomyopathy 
patients. Furthermore, in animals with myocardial infarction (MI), a higher parasympathetic tone 
portends a greater likelihood of survival in the setting of ischemia. The mechanism behind the 
cardiomyopathy-induced parasympathetic dysfunction is poorly understood, and could provide new 
targets for therapies.  VNS is an emerging technique that has the potential to impact cardiac function, 
the neural networks that control cardiac function and higher centers of the central nervous system.   
 
VNS for epilepsy 
 
30-35% of patients with epilepsy do not respond to medical treatment and benefit from surgical 
intervention.  Neurostimualtion is a less invasive alternative to resective surgery and one of the the few 
successful options for those for whom resection in not an option.  Vagus nerve stimulation (VNS) is 
the oldest neurostimulation technique, FDA approved to treat refractory generalzied and focal epilepsy 
with outcomes showing over 50% seizure reduction in 70% of patients.  
 
Epilepsy patients are at increased risk for sudden cardiac death. Mechanism behind this predisposition 
is poorly understood but parasympathetic dysfunction is heavily implicated. VNS protocols as 
currently set for seizure management are poorly optimized for cardioprotection, therefore this patient 
population presents a unique opportunity to assess VNS control of cardiac function, when VNS is 
appropriately titrated for cardiac and seizure benefit. 
 

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This proposed study leverages recent advances in VNS stimulation protocols that were developed 
primarily for treatment of heart failure.  From these studies we have defined what is referred to as the 
neural fulcrum hypothesis for VNS.  When VNS is delivered at the neural fulcrum, both ascending 
(afferent) and decending (parasympathetic efferent) nerves are functionally engaged such that 
homogeneous control is restored to cardiac reflex control.  This applies to both right and left cervical 
vagal stimulation.  VNS as current delivered for epilespy treatment is below that neural fulcrum point.  
This represents a missed opportunity to improve quality of life and patient outcomes. 
 
B. SUMMARY OF PRE-CLINICAL STUDIES 
The cardiac nervous system, composed of the intracardiac ganglia, intrathoracic extracardiac ganglia, 
spinal cord, brainstem, and higher centers, coordinates regional cardiac function on a beat-to-beat 
basis. Globally, the cardiac nervous system is optimized to handle physiological stressors (e.g. 
orthostatic changes). However, it has not evolved a mechanism to adequately deal with catastrophic 
events such as myocardial infarction or the central and peripheral consequences of epilepsy.   
 
Progression of cardiac disease reflects maladaptive interactions between the cardiac nervous system 
and the heart. Epilepsy patients are particularly susceptible to heart attacks with a survival rate ¼ of 
that of other populations (Stecker, Circ Arrhythm Electrophysiol, 6, 912-916, 2013). Our recent work 
has demonstrated that targeting select elements within this neural network can lead to efficacious 
results in select cardiac disease states, including atrial arrhythmias, myocardial infarction, and 
congestive heart failure. With appropriate neuromodulation therapy, myocytes are rendered stress 
resistance, autonomic responsiveness for control of the heart is preserved, and the potential for fatal 
arrhythmias is reduced (Hanna, Card Fail Rev 4, 92-98, 2018). Cervical VNS is at the forefront of such 
neuromodulation.   
 
C.   OBJECTIVES 
The primary objective is to evaluate in epilepsy patients the effects of adjusting vagus nerve 
stimulation parameters to engage known cardioprotective aspects. 
 
The secondary objective is to quantify the effects of vagus stimulation on cardiac function by metrics 
of autonomic testing and a cardiopulmonary exercise test (CPX). 
 
2.  STUDY DESIGN  
 
This is a single-center feasibility study. We plan to enroll 12 subjects (6 female, 6 male). Screening 
data will be reviewed to determine subject eligibility.  All subjects will undergo baseline autonomic 
testing and cardiopulmonary exercise testing.  Patients that agree to continue in the study will have  
VNS titration over a 2 - 4 week period to achieve the neural fulcrum for control of cardiac function 
(heart rate and heart rate variability index.  The neural fulcrum will be defined by less than 2% change 
(+/-) in heart rate, and a 5% shift (+/-) in variability in the SD1-SD2 (RR interval beat N=1 vs beat N). 
The Poincaré plot analysis is a geometrical and nonlinear method to assess the dynamics of HRV. It is 
a diagram in which each R-R interval is plotted as a function of the previous R-R interval where the 
values of each pair of successive R-R interval define a point in the plot.  SD refers to interval between 
beats. Once individual neural fulcrum is achieved, the patient will return after 4 weeks for the final 

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visit in which  autonomic testing and cardiopulmonary exercise testing will be repeated.  Subjects will 
be monitored for changes in seizure frequency or duration at each clinic visit as well as any adverse 
events during the study by having continuous 24 hours per day/7 days per week access to the study 
team with the neurologist on call.  
 
3.  SUBJECT SELECTION 
 
A. STUDY SITES 
The study will be performed at the University California Los Angeles (UCLA). 
 
B. RECRUITMENT 
Subjects with a diagnosis of epilepsy with scheduled or implanted VNS devices will be recruited. The 
investigators of this study will identify patients. Along with being told about the study, it will also be 
made clear to the subjects that they have the right to refuse to be in the study and that refusal will not 
affect their healthcare in anyway. 
 
C. ELIGIBILITY CRITERIA 
Eligible patients will be enrolled in the study by the principal investigator after meeting inclusion and 
exclusion criteria and informed consent is obtained.  
 
D. INCLUSION 
1. Clinical diagnosis of refractory epilepsy and implanted with a VNS device or are scheduled to 
be implanted with a VNS device. 
2. 18 years of age or older 
3. Subjects must demonstrate willingness and ability to comply with study requirements 
 
E. EXCLUSION 
1. Other implantable neuromodulatory device (e.g., brain stimulator) 
2. Treatment with cholinergic or anticholinergic medication in the past month  
3. Pre-existing cardiac arrhythmia or presence of cardiac pacemaker/defibrillator 
4. History of dysautonomias 
5. History of vasovagal syncope 
6. Progressive neurological diseases other than epilepsy 
7. Women that are pregnant 
8. Cognitive or psychiatric deficit that in the investigator's judgment would interfere with the 
subject's ability to accurately complete study assessments 
 
4.  STUDY METHODS 
 
A. SCREENING AND ENROLLMENT 
All patients who are being considered for enrollment into the clinical trial will be screened by the site 
investigator or a member of the designated study staff for study eligibility. Subjects who meet the 
inclusion criteria based on routine care and agree to participate in the study will be asked to sign a 
written informed consent that has been approved by the Institutional Review Board (IRB). No study 
related testing or procedures will take place until the informed consent is signed. The patient will be 

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assigned a study number after the consent is signed and the patient is enrolled. Study data will be 
stored using the study code.  
 
B. PATIENT SELECTION 
 
▪ Twelve (12) subjects with a clinical diagnosis of refractory epilepsy and implanted with a VNS 
device or are scheduled to be implanted with a VNS device will be enrolled. 
 
 
C. PATIENT CONSENT 
 
▪ Patient consent will be conducted in a private setting.  
 
▪ Member(s) of the study staff will meet with the prospective subjects/families to review the 
consent document(s) and/or provide an oral explanation of the study. Individuals will be given 
a chance to ask questions before making a considered decision about whether or not to 
participate in the study. 
 
▪ Prospective subjects/families will have the opportunity to review the consent form and/or take 
the consent form(s) home and to discuss the documents with others prior to deciding whether or 
not to participate in the study. 
 
▪ The consent form and other study documents will be available in the subjects’ primary 
language. Study staff or qualified translators will discuss the study in the subjects’ language. 
 
▪ Subjects will be given as much time as they need to consider enrollment. If they are not sure 
and believe they need more time they will not be enrolled. 
 
5.  STUDY PROCEDURES 
 
A. DATA COLLECTION 
The following data will be collected from the patient’s medical record. Study data will be stored using 
the patient’s study code. 
 
After written informed consent is obtained, the following screening procedures will be performed: 
▪ Demographics (date of birth, gender, race) 
▪ Medical History 
▪ Concomitant medication review 
▪ Assessment for presence of VNS or patient is scheduled to have a VNS implant 
▪ Seizure history over the last 3 months (semiology, frequency, duration of seizures). These 
parameters will be assessed at every study visit. 

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B. Study Protocol   
The study protocol involves changing the output current/frequency of the default device settings in a 
FDA approved device for VNS therapy systems manufactured by LivaNova. The LivaNova VNS 
Therapy Systems include the following models: Model 103, Model 105, Model 106, Model 1000, 
Model 302, Model 303, and Model 304. LivaNova’s Programming Wand Model 2000 version 1.1 will 
be used to change the device settings. The proposed frequency changes in this study are within the 
FDA approved output current/frequency levels. 
The VNS programmer device as used in current clinical practice comes with pre-set options, but no set 
standards exist given a physician freedom to decide how to change these parameters within the safety 
zone (duty cycle) as defined by the manufacturer.  Changing the parameters is done on a regular basis 
with hopes of improving seizure control.  However, there are times when parameter changes lead to 
worsening seizures; patients are routinely warned about this risk and are able to turn off the VNS 
themselves by a simple magnet (provided to them by the manufacturer or provider) 
The following are the available parameter ranges which could be modified during this study: 
Output current (miliamps, mA) - range:  0-3.5 [typical: 1-2] 
Signal frequency (Hz) – range: 1-30 [typical: 20-30] 
Pulse Width (microseconds) -  range: 130-1000 [typical: 250 or 500]  
Signal on-time (seconds) – range: 7-60 [typical: 30] 
Signal off-time (minutes) – range: 0.2-180 [typical: 5] 
 
Duty cycle is proportional to the time device is on 
 
 
Our objective for the parameter optimization is to define the neural fulcrum, i.e parameters which 
should be cardioprotective, for the individual patient based on the base frequency that have been 
titrated to (Ardell et al., 2017). Based on our prior experience with the ANTHEM studies, we 
anticipate that we will be able to define the neural fulcrum in 90% of patients. This protocol that has 
been validated in humans with quantitative beat-to-beat analysis (Libbus et al., 2016; Nearing et al., 
2016) and with efficacy for HFpEF (DiCarlo et al., 2018) and HFrEF (Premchand et al., 2016).  
 
Defining the neural fulcrum will be achieved in 1-5 sessions over a 2 – 4 week period. Each of the 
sessions may take up to one hour.    Autonomic studies and/or cardiopulmonary exercise stress tests are 
expected to take a maximum of 2 hours with the VNS turned off or on. The study neurologist will 
work with the patient to decide if they can do all of the testing or some of the testing. Our prior studies 
have indicated the VNS has a memory function for up to 30 min after termination of VNS.  We allow 
time between stresses to control for that memory function and for the hemodynamic status to return to 
baseline. Stimulation protocols as outlined above are within design for treatment of epilepsy and for 
cardiac disease – no IDE is required.  
 

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The following protocol will be used: 
Consent and Baseline Testing: Autonomic testing and/or cardiopulmonary exercise testing will be 
performed on all subjects. The study neurologist will work with the patient to decide if they can do all 
of the testing or some of the testing.  The VNS will be turned off or on during autonomic and 
cardiopulmonary exercise testing. The baseline visit will take up to 4 hours. Subjects that agree to 
baseline only will have completed the study.  
 
VNS Titration Visits: Subjects that agree to participate in titration visits will continue in the study. 
There will be up to 5 titration visits over 2 – 4 weeks.  The number of sessions will depend on how 
many parameters will need to be changed to achieve neural fulcrum and on the subject’s tolerability of 
change in parameters. Titration visits will take up to one hour. Subjects will be instructed to contact the 
study’s neurologist and/or study team with any issues in the interim. 
 
Final Visit:  Subjects that participated in titration visits will return to the clinic for the final visit 4 
weeks after the neural fulcrum was achieved. Autonomic testing and/or cardiopulmonary exercise 
testing will be performed. The study neurologist will work with the patient to decide if they can do all 
of the testing or some of the testing. The final visit will take up to 3 hours.  
 
Subjects will be monitored for changes in seizure frequency or duration at each clinic visit as well as 
any adverse events during the study by having continuous 24 hours per day/7 days per week access to 
the study team with the neurologist on call. 
 
C. STUDY DURATION 
Subjects will be in the study up to 9 weeks. All subjects will undergo baseline autonomic testing and/or 
cardiopulmonary exercise. Subjects that complete the baseline only testing will complete the study in 
one visit. Subjects that participate in titration visits will have VNS titration over a 2-4 week period. 
After titration is complete, the IPG’s will be programmed to the neural fulcrum stimulation protocol 
and left there for 4 weeks. Following the 4 week phase, the autonomic testing and/or cardiopulmonary 
exercise test will be repeated.   
D. Procedures to assess efficacy 
Autonomic Testing 
▪ Valsalva Maneuver: Improvements in late phase II and in phase IV of the Valsalva maneuver, 
and a normalized pressure recovery time (PRT) after up-titrated VNS. Poor adrenergic response 
is indexed by a prolonged PRT, absent or blunted phase IV or late phase II. A 10% 
improvement in these parameters in response to up-titrated VNS will be considered a 
significant clinical benefit. 
▪ Tilt Test: (orthostatic stress) A 10% decrease in tilt-induced hypotension or a 10% decrease in 
the heart rate response to a 70 degree heads up tilt after up-titration of VNS will be considered 
a significant clinical benefit. 
▪ Oximetry 
▪ Electrocardiogram: The ECG will be used to assess Tp-Te (a measure of repolarization 
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▪ Cold Pressor Test: A 10% reduction in evoked heart rate (HR) and blood pressure (BP) 
response to cold stimulus is considered a significant response of clinical benefit.  
Cardiopulmonary Testing 
This is a progressive dynamic exercise test. A 10% improvement in exercise duration and/or a 10% 
improvement heart rate recovery after exercise will be considered a significant clinical benefit.  Heart 
rate and blood pressure will also be plotted against time. At 85% of the maximum exercise achieved 
before up-titration of VNS a 5% decrease in heart rate at the same intensity point will be considered a 
significant clinical benefit with VNS. 
 
E. Procedures to assess safety 
 
▪ Incidence of adverse events 
 
F. Schedule of study visits 
 
▪ Please see Schedule of Events in Appendix 1 
 
 
6.  STATISTICAL PLAN  
 
This is primarily an exploratory study. Descriptive statistics will be used including paired Student’s T 
test to detect difference in cardiac physiology parameters at baseline vs. during stimulation, for the 
sample size of n=12. The sample size ‘n’ will consist of 6 females and 6 males. Each subject will be 
their own control. 
 
7.  RISKS AND BENEFITS 
 
Risks associated with stimulation are addressed in the standard consent form and are considered 
acceptable in the opinion of the investigator.  
 
A.  RISKS 
 
▪ The subject can experience coughing and hoarseness during VNS changes. If this occurs the 
parameters will be immediately reversed to previously tolerated parameters. 
▪ A risk to VNS changes is a change in seizure frequency. The subject will be asked his/her 
seizure history at each visit and have access to the neurologist. The study neurologist will 
adjust the VNS parameters per routine seizure management guidelines..  
 
▪ Additional risk of VNS modulation can include a decrease in heart rate and blood pressure. 
The parameters can be adjusted or set back to those before the study initiation and if deemed 
necessary, the subject will exit the study.  

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▪ Risks related to monitor pads and electrodes: Some people can have minor skin irritation or an 
allergic reaction from the sticky patches that are placed on the chest and limbs. The irritation 
should go away once the patches are removed.  
▪ Risks related to tilt table test, valsalva maneuver or deep breathing: Some people may report 
feeling dizzy or lightheaded from these tests. The technician can stop the test at any time if this 
is reported. 
▪ Risk related to cold pressor test: Some people may be uncomfortable with having their arm 
cooled for 15 minutes.  The technician can adjust the temperature or stop the test if this is 
reported. 
▪ Risks related to Cardiopulmonary Exercise Test (CPX): Some people may report feeling short 
of breath, fatigue, dizzy, or have an arrhythmia. The technician can stop the test at any time if 
this is reported. 
▪ As with any use of electronic means to store data, there is a risk of breach of data security. A 
special code (number combination) and the patient initials will be used to identify personal 
health information. No personal health information about the patient, their illness, or their 
treatment will be made public. 
 
B. BENEFITS 
 
This study is not being done to immediately improve the patient’s condition or health. It is aimed at 
acquiring scientific information regarding the heart’s electrical behavior. Information obtained in this 
study does not have any immediate application for planning treatments for any heart condition. 
Patients have the right to refuse to participate in this study. There will be no personal benefit for 
participating in this study. However, information gained from this study helps us better understand the 
mechanisms of sudden cardiac death, which effects >400,000 people each year in the U.S. 
 
8.  ADVERSE EVENTS 
 
A. DEFINITION OF ADVERSE EVENT 
 
An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical treatment or procedure 
regardless of whether it is considered related to the medical treatment or procedure (attribution of 
unrelated, unlikely, possible, probable, or definite). 
 
All Adverse Events (AE) will have the following assessed by the study team, as defined below: 
 
▪ Diagnosis 
▪ Event description 
▪ Dates of onset and resolution 
▪ Causality: assessment of relatedness to procedure  
▪ Severity 
▪ Outcome 
 
 

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B. ADVERSE EVENTS MONITORING 
The patient’s status will be closely monitored by the study team to assess adverse events. The study 
team that includes neurosurgery, neurology, and electrophysiology, will be conducting the study 
protocol and are the primary care team for the patient.  
 
C. ADVERSE EVENTS 
All reported AEs will be monitored by the study team until they are adequately resolved or explained.   
 
Potential Adverse Events  
Most common adverse events seen in long-term treatment with VNS (12mo and 5yrs) as reported in 
the literature. These symptoms were rated as mild-moderate and did not require adjustment of 
parameters: 
• 
Voice alternation 55/18.7% 
• 
Headache 16% 
• 
Cough 15/1.5% 
• 
Pain 15/4.7% 
• 
Paresthesia (abnormal skin sensation) 15/1.5% 
• 
Dyspnea 13/12.3% 
• 
Pharyngitis 10% 
• 
Depression 5% 
• 
Infection 6% 
 
Increase in seizure frequency is also a potential adverse event and will be discussed with patients 
during screening. 
 
D. SERIOUS ADVERSE EVENTS 
 
▪ An event that is fatal, resulting in death 
▪ An event that is life threatening. In the opinion of the study center physician, the patient was at 
immediate risk of death due to the event as it occurred; 
▪ An event that results in persistent or significant disability/incapacity; 
▪ An event that requires inpatient hospitalization or prolongs hospitalization; 
▪ An important medical event that, based upon appropriate medical judgment, may jeopardize the 
patient and may require medical or surgical intervention to prevent one of the outcomes listed 
above. 
 
NOTE: Prolonged hospitalizations for a pre-existing condition is not considered a serious adverse 
event. 
 
E. REPORTING SERIOUS ADVERSE EVENTS 
The site investigator is responsible for ensuring that all SAEs are fully recorded and reported to the IRB 
per IRB reporting requirements. 
 
 
 

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9. DATA SAFETY MONITORING PLAN (DSMP) 
 
The Principal Investigator and co-investigators will be the primary data safety monitors for this clinical 
trial.  They will provide “real time” adverse event review and actively monitor the trial for adverse event 
reporting, regulatory and protocol compliance, and data accuracy. A physician group that is separate 
from the study will also provide Data Safety Monitoring. The group will review the protocol, study data, 
and safety information, such as any adverse events, twice per year. This group will include a cardiologist, 
a neurologist that specializes in autonomics and epilepsy, and a statistician.  
 
The following may be reviewed: 
 
▪ Annual accrual numbers and study drop-out rates.   A description of any problems with 
recruitment or enrollment, study enrollment, and a determination as to whether the current 
accrual rate is sufficient to meet the intended accrual goal. 
 
▪ A summary of any problems with study implementation. 
 
▪ A list of all adverse events and each one’s frequency from the study population.  
 
They may determine at any time, that the study should be modified or terminated due to patient harm 
and/or futility considerations.  
 
10. DATA HANDLING 
 
The patient will be assigned a study number after the consent is signed and the patient is enrolled. 
Study data will be collected and stored using the study code. Personally, identifiable data will not be 
collected, transmitted, or stored via the internet.  A secure network server will be used to store data. A 
study code will link the data to the study subject. A key to the code exists. Only the study team 
members listed in the IRB will have access to the code.  
 
This is a safety and feasibility study, therefore the data will be maintained for future research in the 
case that:  
 
▪ The study team wants to use the data set to investigate any additional research questions. 
▪ The study team uses the data set as part of a larger study in the future. 
 
11. FINANCIAL CONSIDERATIONS 
 
▪ Subjects will be not billed for any research procedures.  
▪ Subjects will be provided a parking voucher for each research visit.  
▪ Patients will receive a gift card for each visit completed, up to $200 for the entire study:  
o Screening and Baseline: $100 
o VNS Titration Visits (up to 5 visits): $50 
o Final Visit: $50 
 

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APPENDIX 1.  SCHEDULE OF STUDY VISITS 
 
Screening 
and Baseline 
Visita 
VNS Titration 
Visits (up to 5 
visits at UCLA) 
Final Visit 
Early Study 
Withdraw Visit 
Informed Consent 
X 
 
 
 
Medical History 
X 
 
 
 
Seizure History 
X 
X 
X 
X 
 
 
 
 
 
VNS Titration  
 
X 
 
 
Autonomics Test:  
Tilt Table Test 
Deep Breathing 
Valsalva Maneuver 
Cold Pressor Test 
X 
 
X 
 
Cardiopulmonary 
Exercise Test 
X 
 
X 
 
Medication Review 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
 
 
a  ±2 days 
 
 

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References 
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Shivkumar K (2017). Sympathetic modulation of electrical activatino in normal and infarcted 
myocardium: implications for arrhythmogenesis. Am J Heart Circ Phys 312: H608-21. 
2. Ardell JL, Andresen MC, Armour JA, Billman GE, Chen PS, Foreman RD, Herring N, O'Leary 
DS, Sabbah HN, Schultz HD, Sunagawa K & Zucker IH. (2016). Translational 
neurocardiology: preclinical models and cardioneural integrative aspects. J Physiol 594, 3877-
3909. 
3. Ardell JL, Nier H, Hammer M, Southerland EM, Ardell CL, Beaumont E, KenKnight BH & 
Armour JA. (2017). Defining the neural fulcrum for chronic vagus nerve stimulation: 
implications for integrated cardiac control. J Physiol 595, 6887-6903. 
4. Ardell JL, Rajendran PS, Nier HA, KenKnight BH & Armour JA. (2015). Central-peripheral 
neural network interactions evoked by vagus nerve stimulation: functional consequences on 
control of cardiac function. Am J Physiol Heart Circ Physiol 309, H1740-1752. 
5. DiCarlo LA, Libbus I, Kumar HU, Mittal S, Premchand RK, Amurthur B, KenKnight BH, 
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