Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) in Mild to Moderate Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease
Sponsor: Medical University of South Carolina

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Transcutaneous auricular Vagal Nerve Stimulation (taVNS) in mild to moderate Parkinson’s 
Disease 
NCT# 04157621 
Document Date 03/04/2021 
 
 
 

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PROTOCOL TITLE:  
 
Transcutaneous Auricular Vagal Nerve Stimulation (taVNS) in Mild to Moderate 
Parkinson’s Disease 
PRINCIPAL INVESTIGATOR: 
 
Vanessa Hinson, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 Transcutaneous Auricular Vagal Nerve Stimulation 
(taVNS) in Mild to Moderate Parkinson’s Disease 
 
 
 
Study Protocol 
 
 
  
 
 
 

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Summary 
_____________________________________________________________________ 
Existing treatment strategies for Parkinson's Disease (PD) are purely symptomatic and 
incompletely address symptoms, often with intolerable side effects. New strategies are vital to 
develop more effective treatments for PD. Recent pre-clinical studies conducted by our group 
indicate potential for symptomatic as well as disease modifying benefit of vagus nerve 
stimulation (VNS) in PD. Therefore, we propose an investigator initiated pilot study of the acute 
and subacute effects of transcutaneous auricular vagus nerve stimulation (taVNS) on motor 
function, cognition, and relevant biomarkers in mild to moderate PD patients.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CONTENTS 
1. Background and Significance 
 
2. Objectives 
 
3. Design 
Overview 
Schedule of activities 
Figure 1: Study flow 
 
4. Eligibility criteria 
 
5. Randomization and masking 
 
6. Treatment plan 
6.1. Treatment groups 
6.2. Treatment dosing   
6.3. Management and reporting adverse events 
 
7. Screening / Baseline Visit 
7.1. Overview 
7.2. Overview consent issues 
7.3. Review Medical History 
 
8. Stimulation visits 
 
9. Specimen Collection 
 
10. Follow up visit 
 
11. Outcome Assessments 
11.1. 
Primary outcome 
11.2. 
Secondary outcome 
11.3. 
Tertiary outcome 
 
12. Statistical Analysis 
12.1. 
Primary analysis    
12.2. 
Secondary analysis  
12.3. 
Power analysis 
 

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13. Data, safety, and quality assurance monitoring 
13.1. 
Data Safety Monitoring Board 
13.2. 
Quality assurance monitoring 
 
14. Protection of human subjects 
14.1. 
Human subjects 
14.2. 
IRB approval 
14.3. 
Recruitment and Consent procedures 
14.4. 
Potential risks and benefits 
14.5. 
Safety monitoring 
14.6. 
Confidentiality of patient data 
 
15. Literature cited 
 
 

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1. Background and Significance 
______________________________________________________________________  
VNS and PD: VNS is FDA approved for treatment-resistant epilepsy and depression.  The vagus 
nerve does not have direct connections to cortical regions but rather sends projections through 
brainstem nuclei, which then relay signals to upper cortical regions.  One of these brainstem 
nuclei used as a relay site is the locus coeruleus (LC), which contains noradrenergic (NA) 
neurons.1 VNS increases NA concentrations in the prefrontal cortex of rats, NA neuronal firing 
rate in LC,2 as well as brain derived neurotrophic factor (BDNF) expression in the cortex and 
hippocampus.3 The loss of LC-NA neurons is significant in PD4 and occurs earlier in the disease 
process than the loss of substantia nigra dopamine (SN-DA) neurons.5,6  Additionally, SN-DA 
neurons become more sensitive to various insults in the absence of NA nerve fibers.7,8  NA 
depletion itself has been implicated in a multitude of pathophysiologic mechanisms in PD, and 
includes gait dysfunction, dysautonomia, depression, apathy, inattention, and sleep disturbance.9 
Preliminary data from our neuroscience laboratory (PI-Boger) shows that stimulating the vagus 
nerve for two weeks improved motor function and resulted in neurorestorative effects on 
DAergic and NAergic systems, and reduced cellular expression of alpha-synuclein10 in DA/NA 
double-lesioned rats. In addition, VNS resulted in a significant increase in BDNF levels in the 
target regions of the DA and NA neurons. VNS has also been shown to produce an anti-
inflammatory effect by decreasing pro-inflammatory cytokines, increasing anti-inflammatory 
cytokines, and reducing gliosis in models of PD.10 These results provide pre-clinical evidence for 
VNS as a potential treatment strategy for PD patients; potentially addressing neuronal damage as 
well as motor and non-motor symptoms of the damaged noradrenergic and dopaminergic 
pathways.  
Transcutaneous auricular VNS (taVNS): Although cervical VNS is relatively safe, the risks 
involved in surgical implantation as well as its high cost (about $30-50k) make it less appealing 
and less available as a study modality. Recently, it has been shown that VNS can be administered 
non-invasively through stimulating the auricular branch of the vagus nerve located in the ear11-13 
with a transcutaneous electrical nerve stimulation (TENS) device. Our collaborators (Bashar et 
al.) in the MUSC Brain Stimulation Lab conducted initial safety and feasibility trials of 
transcutaneous auricular VNS (taVNS) in healthy adults. In these studies, there were no adverse 
effects of taVNS observed. Their work validates ideal parameters for delivering taVNS, 
suggesting that one-minute taVNS periods at 200% perceptual threshold delivered at 500μs 25Hz 
are safe and tolerable and produce regional brain changes consistent with activating the vagus 
nerve related brain regions involved in neuroplasticity.13 The same group developed and 
conducted a concurrent taVNS/fMRI trial and demonstrated that the neurobiological effect of 
taVNS mimics that of cervically implanted VNS and targets several cortical and subcortical 
vagus afferent pathway targets. It additionally suggested that taVNS for short time periods 
activates the vagus nerve (10-25Hz, average 1.8mA). No rapidly accelerated or sustained drops 

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in HR were seen during the one-minute taVNS stimulation periods. A follow-up study 
determined that the optimal parameter to modulate the parasympathetic response via taVNS was 
500μs pulse width, 10 & 25Hz for 60s duration.13 
The significance of this study lies in the novelty of stimulating the vagus nerve non-invasively, 
in order to increase LC-NA neuronal firing and BDNF, and to decrease neuroinflammation. 
Given the absence of side effects in our human pilot study, we are hopeful to explore a well 
tolerated treatment option with potential for neuroprotective as well as symptomatic benefits in 
PD. 
 
 
2. 
Objectives 
________________________________________________________________  
 
The primary objective of the study is to examine the effect of taVNS on motor symptoms in 
patients with mild to moderate motor symptoms of PD.  The study design is a single site, 
parallel, randomized, sham controlled, double blinded study, administering taVNS vs sham 
stimulation 5 days a week for 2 weeks to 35 study subjects. Additional outcomes will be effects 
on cognition, safety assessments, as well as stimulation effects on relevant biomarkers. 
Specific Aim 1: To examine in a 2-week, randomized, sham controlled, double blind trial the 
effect of taVNS on motor symptoms in patients with mild to moderate motor symptoms of PD.  
Hypothesis: taVNS will be superior to sham stimulation on its effects on the motor section of the 
Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS UPDRS; primary 
outcome measure). 
 
Specific Aim 2: To examine in a 2-week, randomized, sham controlled, double blind trial the 
effect of taVNS on cognitive symptoms in PD.  
Hypothesis: taVNS will be superior to sham stimulation on its effects on a composite score of 
the following cognitive assessment tools: DKEFS, Stroop, Digit symbol, Digit span forward and 
backwards, Fixation (control), Reflexive, and saccade inhibition tasks, CAARS, PROMIS 
(secondary outcome measure). 
 
Specific Aim 3: To assess safety and tolerability of taVNS in PD.  
Hypothesis: Treatment with taVNS will be as well tolerated as sham stimulation on the 
following parameters: acute monitoring of vital signs, MDS UPDRS motor evaluations and 
cognition testing to evaluate for worsening PD severity, adverse events or serious adverse events 
assessments, and the Columbia Suicide Severity Rating Scale (CSSRS). (tertiary outcome 
measure) 

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Specific Aim 4:(exploratory aim) To evaluate effects of taVNS versus sham stimulation on 
biomarkers relevant to VNS neurobiology.  
Hypothesis: taVNS and not sham stimulation will lead to a decrease in serum inflammatory 
biomarkers (TNF-alpha, and IL-6), increase in serum BDNF, and increase in resting pupil 
diameter. 
 
 
 
3. 
Design 
________________________________________________________________  
 
Overview:  
This pilot study of taVNS in PD intends to prove basic concepts of acute motor and cognition 
improvements with taVNS in PD patients. We will accomplish this by a two-week, single 
site, parallel, randomized, double blinded, sham-controlled pilot study of taVNS in 35 PD 
patients.  There will be 1 screening visit, 10 stimulation visits, and 1 follow up visit. 
At the screening visit (visit SC) we will obtain informed consent, review inclusion and 
exclusion criteria, medical history, demographics. We will obtain a baseline MoCA exam, 
based on proposed exclusionary criteria. For those enrolled, medications used in the 
treatment of PD will be held constant throughout the study. Baseline blood draw in the 
amount of 3 teaspoons (<15Ml) for biomarkers will be obtained by appropriately trained 
personnel.  Urine pregnancy test will be administered to women of childbearing potential.  
We will randomize the patient to sham (n=15) versus active taVNS stimulation (n=15), and 
obtain baseline cognition battery (in normal ON PD medication state) at this time. 
At visit 1, MDS UPDRS motor evaluation will be videotaped in the OFF PD medication state 
(defined as at least 12 hours without PD medication). Stimulation or sham will occur over 1 
hour as defined below, and then repeat MDS UPDRS motor evaluation will be videotaped. A 
blinded rater will later score the modified (minus rigidity) MDS UPDRS on all videos at 
completion of the study.  
Visits 2-4 are stimulation treatment visits in the ON med state with safety assessments, but no 
efficacy measures. 
Visit 5 (study mid point) includes OFF med motor evaluation pre/post stimulation as at visit 1, 
in addition to the stimulation session. 
Visit 6 is a taVNS treatment visits in the ON med state with additional behavioral saccade 
testing. 

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Visits 7-8 are stimulation treatment visits in the ON med state with safety assessments, but no 
efficacy measures. 
Visit 9 is an ON med stimulation visit, and includes repeat cognition battery following the 
stimulation session. 
Visit 10 (final day of stimulation) includes OFF med motor evaluation pre/post stimulation as 
at visit 1, in addition to the stimulation session. Repeat blood draw. 
Visit 11 (Safety follow up visit) six to fourteen days after visit 10, we will check for any adverse 
events that might have occurred since the last stimulation session. 
 
 

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SCHEDULE OF ACTIVITIES 
 
 
 
MDS-UPDRS- Movement Disorder Society- Unified Parkinson’s Disease Rating Scale (motor portion used) 
C-SSRS- Columbia-Suicide Severity Rating Scale  
taVNS- transauricular vagal nerve stimulation 
saccade- Fixation (control), Reflexive, and saccade inhibition tasks. This is INCLUDED in cognitive battery, 
but will be done as a stand-alone test on stim day 6 
Cognitive Battery- DKEFS, Stroop test, Digit-Symbol test, Digit Span, saccade,  
 
Patient reported measures- CAARS, PROMIS (fatigue, sleep related, Applied Cognitive Abilities) 
 
 
 
 
 
Screening 
Baseline 
 
 
Maintenance Phase 
Follow 
up 
 
Visit SC 
Week 0-2 
(-14d) 
Visit 1 
Stim 
day 1 
Visit 2-4 
Visit 5 
Visit 6 
Visit 7-8 
Visit 9 
Visit 10 
 
+6-14 
days 
Written Informed Consent 
x 
 
 
 
 
 
 
 
 
Eligibility Criteria 
x 
 
 
 
 
 
 
 
 
MoCA 
x 
 
 
 
 
 
 
 
 
Med/Neuro History 
x 
 
 
 
 
 
 
 
 
Physical Exam 
x 
 
 
 
 
 
 
 
x 
Blood Draw 
x 
 
 
 
 
 
 
 
 
Cognitive Battery 
x 
 
 
 
 
 
x 
 
 
C-SSRS 
x 
 
 
 
x 
 
x 
 
 
Pre-stim MDS UPDRS 
 
x 
 
x 
 
 
 
x 
 
stimulation thresholds 
 
x 
 
 
 
 
 
 
 
taVNS vs sham stimulation 
 
x 
x 
x 
x 
x 
x 
x 
 
pupillometry 
 
x 
 
 
 
 
 
 
 
saccade 
 
 
 
 
x 
 
 
 
 
Vital Signs 
 
x 
x 
x 
x 
x 
x 
x 
 
Post-stim MDS UPDRS 
 
x 
 
x 
 
 
 
x 
 
Monitoring AE 
 
x 
x 
x 
x 
x 
x 
x 
x 

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Figure 1:  Overview of Study Flow / Assessments 

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N=35 PD Patients with MoCA>24 
Randomization 
Screening/Initial Visit 
Blood draw, Cognitive Battery 
Sham stim 
taVNS 
Pre/post stim MDS 
 Pre/post stim MDS 
 Saccade 
 Placebo (sham) group 
(n=17) 
 Active taVNS group 
(n=18) 
Visit 1 
OFF  PD 
medication 
Visit 5  
OFF PD 
medication 
Visit 6 
ON  PD 
medication 
Visit SC 
ON  PD 
medication 
Visit 2-4 
ON  PD 
medication 
Visit 7-8 

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4. 
Eligibility Criteria  
________________________________________________________________  
 
Inclusion Criteria: 
Age: 40-82 y 
Idiopathic Parkinson’s Disease Diagnosis 
Disease Stage: Hoehn and Yahr stage 2-3  
Patient requires a minimum of 3 doses of levodopa daily 
Willingness to be videotaped 
 
Exclusion criteria:  
Dementia or MoCa <24 
PD psychosis 
Ear trauma 
Facial pain 
TBI or clinical history of stroke 
Metal implants above the shoulders 
History of myocardial infarction or arrhythmia, bradycardia 
Active respiratory disorder  
Alcohol or substance use disorders 
History of DBS or other brain surgery 
Epilepsy 
Pregnancy 
B-Blockers, dopamine blocking agent, antiarrhythmic medication, acetylcholine esterase 
inhibitor, midodrine, florinef, droxidopa, or anticholinergic drugs 
 
 
   
 
5. 
Randomization and masking 
________________________________________________________________  
 
Randomization of the 35 subjects will be designed to yield an expected assignment ratio 
of 1:1 for taVNS and sham stimulation. Treatment assignments will be masked to the patients 
and to all study personnel with exception of PI and others vital to providing the actual 
treatment. Patients will be masked to transcutaneous stimulation of the auricular branch of 
the vagus nerve at the tragus, versus sham stimulation.  Sham stimulation involves identical 
perceptual threshold finding and stimulation parameters as active stimulation, with the 
exception of stimulation target. Sham stimulation will be delivered to the left earlobe, a target 

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believed to have little to no vagal nerve innervation. A blinded MUSC Movement Disorder 
Neurologist will rate six videotaped MDS UPDRS examinations. Rater will be blinded to 
sham versus active stimulation, pre-stimulation versus post-stimulation state, and to the 
stimulation day of study. 
 
 
6. 
Treatment plan 
________________________________________________________________  
 
6.1  
Treatment groups 
Patients will be assigned to one of the following groups: 
 
- Active taVNS 
 
- Sham stimulation 
 
 
6.2  
Treatment dosing 
taVNS will be delivered to the left ear only in one configuration: active (tragus) using a 
Digitimer Type DS7AH (Digitimer Ltd, Hertfordshire, England) TENS unit cleared by the 
FDA for electrical nerve stimulation. A clip electrode will be used to stimulate at one of the 
two positions. 
Stimulation will be delivered at a constant current (200% perceptual threshold). 
Perceptual threshold is defined by the minimum amount of current perceived by the 
participant. This ranges between 0.5mA to 1.5mA depending on individual anatomical 
differences.  Each taVNS treatment visit will be identical: 1 hour of taVNS (duty cycle: 1min 
on, 30 sec off) 
 
6.3  
Management and reporting adverse events 
Management: All adverse events occurring after randomization and during the treatment 
period, regardless of adherence to study treatment, will be recorded at all visit contacts. 
Procedures will be promptly discontinued if the participant reports significant distress that 
does not improve with time or intractable side effect of taVNS. 
Importantly, all of these methods have been done before, and published by our and other 
groups in adults, and we believe these extra precautions will assure the safety and well-being 
of any participants enrolled. 
Patients and caregivers will be asked about visits to doctors, healthcare providers, and 
emergency departments for other than routine care. The Principal Investigator (PI) will be 
responsible for monitoring the safety of patients, as well as for appropriate medical care of 
patients during the study in connection with study procedures. 
Safety assessments will include physical exam, vital signs (heart rate primary measure, 
with additional blood pressure, respiratory rate and pulse oximetry monitoring), MDS 
UPDRS examinations and Cognitive examinations, Columbia- Suicide Severity Rating Scale 

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(C-SSRS), monitoring of adverse events, and monitoring and maintenance of concurrent 
medication records.  
 
 
Reporting:  
The supervising Institutional Review Board (IRB) will be notified of adverse events, 
risks, or unanticipated problems according to their reporting requirements. If any adverse 
events are noticed which are not described in the consent or are serious, we will inform the 
IRB before continuing with the next enrolled subject. Data collected regarding serious 
adverse events will include the treatment provided, outcome, and presumed relationship to 
study stimulation and will be updated as new information becomes available; a narrative 
description also will be provided.  
 
Data Safety Monitoring Board will be utilized. See full description below; An independent 
review committee charged to monitor the conduct of the protocol to ensure the safety of 
participants and the validity and integrity of the data.  
 
 
7. 
Screening and Baseline visit 
________________________________________________________________  
 
7.1  
Overview  
Obtain Informed Consent, as outlined below. Review inclusion and exclusion criteria, 
medical history, demographics. We will obtain a baseline MoCA exam, based on proposed 
exclusionary criteria. For those enrolled, medications used in the treatment of PD will be held 
constant throughout the study. Baseline blood draw for biomarkers will be obtained.  We will 
randomize the patient to sham (n=15) versus active taVNS stimulation (n=15), and obtain 
baseline cognition battery (in normal ON PD medication state) at this time.  Cognitive 
battery outlined below. 
 
7.2  
Overview of consent issues 
Informed consent will be obtained from the participant prior to the initiation of any study 
related procedures. Either the study coordinator or the physician investigator will obtain the 
consent. The informed consent session will be conducted and documented according to local 
IRB requirements, as outlined in consent procedure section below 
 
7.3  
Review Medical History 
The principal investigator or designated study physician must see the patient before 
randomization. The physician is responsible for fully assessing whether the patient has any of 
the conditions listed as contraindications, chiefly a history of myocardial infarction or 

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arrhythmia, bradycardia, epilepsy, metal implants above the shoulders, active respiratory 
disorder. The presence of any contraindicated condition or medication, which are itemized in 
the baseline eligibility, constitutes an exclusion criterion. 
 
8. 
Stimulation Visits 
________________________________________________________________  
 
At visit 1, MDS UPDRS motor evaluation will be videotaped in the OFF PD medication state 
(defined as at least 12 hours without PD medication).  
Stimulation dosing will be assessed as above. Then taVNS or sham stimulation will occur 
over 1 hour. Acute pupillometry testing will be done. Then repeat MDS UPDRS motor 
evaluation will be videotaped (assessment of acute taVNS effect). A blinded rater will later 
score the modified (minus rigidity) MDS UPDRS on all videos at completion of the study.  
Visits 2-4 are routine stimulation treatment visits in the ON med state with safety assessments, 
but no efficacy measures. 
Visit 5 (study mid point) includes OFF med motor evaluation pre/post stimulation as at visit 1, 
in addition to the stimulation session. (used as mid point motor evaluation). 
Visit 6 is a stimulation treatment visits in the ON med state with additional behavioral saccade 
testing. (used as mid point cognition marker free of practice effects, not administered at visit 
5, as visit 5 is an OFF med visit) 
Visits 7-8 are taVNS treatment visits in the ON med state with safety assessments, but no 
efficacy measures. 
Visit 9 is an ON med stimulation visit, and includes repeat cognition battery following the 
stimulation session. (The cognition battery is not administered at visit 10, as visit 10 is an 
OFF med day.) 
Visit 10 (final day of stimulation) includes OFF med motor evaluation pre/post stimulation as 
at visit 1, in addition to the stimulation session. Repeat blood draw. 
 
 
9. 
Specimen Collection 
________________________________________________________________  
 
Consented patient participants will be assigned a random *4-digit study ID number and 
blood serum samples will be drawn by appropriately trained staff.  There will be two blood 
draws per patient; one baseline and one at the conclusion of the study. Blood samples will be 
delivered to Dr. Boger’s lab as soon as possible, following all standard procedures for safe 
transportation and storage.  Dr. Boger’s personnel will be blinded to sample name, diagnosis, 
and all other personal identifiers.   

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A paper log containing names and corresponding study IDs will be kept in a locked room 
and locked filing cabinet in the Movement Disorder Program Suite. This room will not be 
accessed by patients, and is separate from the room where patient evaluations are performed.   
 
 
10. 
Follow up visit 
________________________________________________________________  
 
Visit 11 (Safety follow up visit) 6-14 days after visit 10, we will check for any adverse 
events that might have occurred since the last stimulation session, just as we have with every 
visit. 
 
 
 
11. 
Outcomes Assessments 
________________________________________________________________  
 
11.1   
Primary outcome:  Clinically meaningful treatment difference of the MDS - 
UPDRS motor section 
 
Videotaped, modified UPDRS evaluations have been established as a reliable research 
method with very high correlation to full UPDRS assessments.14 The UDPRS is modified 
due to the fact rigidity is not assessed by a rater watching a videotaped examination. 
The six motor examinations will be compared for both acute as well as cumulative effects 
of stimulation: 
 
1) 
Visit 1 pre-stimulation comparison to visit 1 post stimulation: acute effect 
2) 
Visit 5 pre-stimulation comparison to visit 5 post stimulation: acute effect 
3) 
Final Visit 10 pre-stimulation comparison to Visit 10 post stimulation: acute effect 
4) 
Visit 5 pre stimulation comparison to Visit 10 pre-stimulation: subacute effect 
5) 
Visit 1 pre-stimulation comparison to final Visit 10 pre-stimulation: subacute effect 
6) 
Visit 1 pre-stimulation comparison to final Visit 10 post-stimulation: subacute effect 
 
 
11.2   
Secondary outcomes: Cognition and Biomarkers 
 
To examine taVNS effect on cognition, a battery of behavioral and cognitive tasks 
relevant to PD will be assessed. We will utilize both objective and subjective measures. We 
will assess baseline, midpoint, and final cognitive function. 
 
 

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Cognitive battery: 
1) 
DKEFS (Delis-Kaplan Executive Function System) verbal fluency and switching: 
10 minutes 
2) 
Stroop written test: 4 minutes (including start up and instructions) 
3) 
Digit symbol computer based: 4 minutes (including start up and instructions) 
4) 
Digit span forward and backwards: 3 minutes  
5) 
Fixation (control), Reflexive, and saccade inhibition tasks: 5 minutes (including 
start up and instructions) 
 
Additional subjective patient reported measures: 
1) 
CAARS (Conners' Adult ADHD Rating Scales) (3 minutes) 
2) 
PROMIS Sleep-Related Impairment (1 minute), PROMIS Applied Cognitive 
Abilities (1 minute), PROMIS Fatigue (1 minute) 
 
To examine taVNS effect on serum markers associated with PD and neurobiology of 
VNS, measures of BDNF, TNF-alpha, and IL-6 will be obtained at baseline and after 
completion of final stimulation session. Laboratory samples will be assayed using ELISA.  
 
To examine whether taVNS leads to the predicted pupillary resting state dilation, Eye 
tracking with computerized software will be used. 
Pupillometry will involve a computer-based system in which an individual will receive 
stimulation while software records the movements and dilation of the pupil. The system used 
involves a setup in which infrared cameras are used to monitor the pupil in a luminance-
controlled room. Participants will look at a computer screen and be instructed to maintained 
gaze within a specific area of the screen. IR cameras will track and monitor pupil diameter 
during stimulation.   
 
11.3   
Tertiary outcome:   Safety and Tolerability 
Safety and tolerability will be monitored for mean change, at each visit, from baseline to 
follow up.    All stimulation visits include monitoring adverse events as well as vital signs. 3 
visits include C=SSRS admin, 2 visits include cognition battery, 2 visits include additional 
physician physical examination. The follow up visit will be one additional visit 6-14 
daysfollowing stimulation to specifically monitor for delayed adverse events, and will 
include a physical examination. Adverse events will be documented. 
 
 
 
 

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12. 
Statistical Analysis 
________________________________________________________________  
 
12.1   
Primary analysis:  MDS UPDRS 
A two-tailed independent samples t-test will be used to compare change in MDS UPDRS 
motor score (post-stimulation at final "on" visit" - baseline) in the treatment versus placebo 
group.  A priori alpha level=.05. Cohen’s d will be used to examine effect of stimulation on 
motor scores. 
 
12.2   
Secondary analysis:  Cognition and Serum markers    
Measures of central tendency and distribution characteristics will be examined for all 
measures.  Appropriate transformations and screening of outliers will be applied as indicated.   
Generalized eta-squared15 will be calculated from repeated measures ANOVAs to 
examine cognitive change between groups over the 2 time points. For each time point, a 
composite score for cognition will be estimated by the average of demographically-corrected 
raw scores. The subjective measures of cognitive functioning will be analyzed in a similar 
manner. Cohen’s d will be used to examine effect of stimulation on serum biomarkers. 
 
12.3   
Power Analysis 
This study has been designed to provide adequate power to address the primary 
hypothesis and corresponding analysis.  Significant placebo effects have been found in many 
clinical trials of pharmacologic interventions for motor symptoms in PD.  However, a recent 
meta-analysis found no significant placebo effect associated with sham rTMS on short or 
long-term changes in UPDRS in PD.16 Given that there are no prior studies from which to 
estimate treatment or placebo effects associated with taVNS in PD, we powered our study to 
detect a clinically meaningful change of -3.25 on the UPDRS,17 with treatment taVNS. 
assumed a small and statistically non-significant change of -1 on the UPDRS with sham 
taVNS, and a standard deviation (pooled) of 2.0.  At 80% power and alpha=.05, using a two-
tailed t-test for difference in means, the total sample size required is 26 (13 per group).  Prior 
studies in this clinic have found attrition to be about 10% for short-duration clinical trials.  
Accordingly, a sample of 35 participants will be enrolled. 
 
 

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13. 
Data, safety, and quality assurance monitoring 
________________________________________________________________  
 
13.1   
Data Safety Monitoring Board (DSMB) 
An independent review committee charged to monitor the conduct of the protocol to 
ensure the safety of participants and the validity and integrity of the data. The DSMB will 
include a movement disorder neurologist, an Epilepsy Neurologist with specialized 
knowledge of Vagal Nerve Stimulation use. 
Only the DSMB will review summary data that contains partially unblinded comparisons 
of AEs and outcomes. The actual study team members will be partially blinded to group 
assignment for portions of the study. The study reports for review by the DSMB will be 
prepared by the study coordinator. 
Meetings will be held every prior to commencing recruitment, mid enrollment and at the 
end of enrollment and data collection. The study reports for review by the DSMB will be 
prepared by the study coordinator. Each report provides cumulative summary statistics 
including: 1) the number of subjects in each phase of the protocol, and the number who have 
completed the protocol; 2) the amount of data lost (including subject withdrawal); 3) the 
presence of any AE, and 4) the presence of any new information, regarding the expected 
efficacy and safety of taVNS.  
From these data, the DSMB will make a determination of whether research progress is 
satisfactory, whether subjects' risk/benefit ratio has changed, and whether any changes need 
to be made to any protocol. The DSMB will consult with the database manager, for assurance 
that no breach of confidentiality has occurred and that quality control procedures are working 
well. The DSMB will write an annual letter stating that they have reviewed the data and 
approved the study to continue, that will be included in the annual IRB renewals of the 
protocol. 
 
13.2   
Quality assurance monitoring 
The best assurance device is quality-conscious personnel.  PI will meet regularly with the 
research staff, review data collected, and review consent documents for accuracy and 
completeness.  In addition, staff will be reminded of their responsibilities in adhering to high 
ethical standards, in protecting the privacy of trial participants and confidentiality of records, 
and in collecting accurate data. They will be reminded to make known to proper authorities 
any suspicious or wrongful actions in relation to the study. Each member of the research 
group will sign a statement indicating knowledge and understanding of the above and to 
disclose potential conflicts of interest. The next best set of assurances lies in the use of design 
strategies that protect the results from treatment-related biases. This includes random 
assignment of patients to active treatment or placebo, and masked data collection and 
outcome assessment. Assurances also depend on the documents, and procedures used for data 
collection and monitoring. 

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13.3 Safety Plan 
In the event that a participant discloses suicidal ideation or intent to harm him or herself 
during the formal interview (C-SSRS) or at any other time during the study visit, research 
staff will contact the PI as soon as possible.  The PI will further assess suicidality and 
develop an appropriate safety plan.  If at all possible, the study participant will not be left 
alone during this time; however, if it is necessary to leave the participant alone in order to 
contact the PI or enlist other resources, the time left alone will be minimized.  Although not 
anticipated, other situations requiring immediate response from a mandated reporter (i.e., 
intent to harm someone else, abuse or neglect of a child or dependent adult), will be handled 
similarly in accordance with applicable state and federal laws.  
 
 
14.     Protection of Human Subjects 
 
14.1   
Human subjects 
Participants will be men and women with idiopathic PD, with inclusion and exclusion 
criteria detailed above. There will be no restrictions to participation based on gender, race, or 
ethnicity. We expect to enroll participants that are representative of the ethnic and racial 
diversity of the geographic and patient populations of our institution (Medical University of 
South Carolina). 
 
14.2   
IRB approval 
Notice of IRB approval and the stamped consent form are required before any study 
activities may begin. The IRB will be informed promptly of any changes to the study 
protocol. The appropriate protocol amendment and changes will be submitted to the IRB in 
writing. Reporting of adverse events will be done according to MUSC IRB policy. A 
summary adverse event data (not by treatment assignment) will be submitted on an annual 
basis to the IRB. 
 
14.3   
Recruitment and Consent procedures 
Patients will be recruited from the Movements Disorders Program at MUSC, and local 
patient support groups. The MUSC Movement Disorders clinic neurologists are part of the 
PI’s group practice, but are not members of the study team (except for the sub-I). When a 
patient is seen in clinic, or contacts the site expressing interest, he/she will be informed of 
the nature of the study by their neurologist or the study coordinator.  If the patient chooses 
to learn more, there may be a short delay between discussing the nature of the study, and the 
coordinator contacting the patient for a screening visit. If the patient chooses to learn more, 
he/she will read the consent or have the consent read to him/her. Discussion(s) with 
prospective subjects will take place in private setting. The patient will then be given the 
opportunity to discuss the protocol and ask questions. The consent will be signed by the 

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participant at that time or they will agree to return for a research screening visit and sign the 
consent form at that time in the presence of the study coordinator. In addition to this 
recruitment effort, potential candidates will be contacted via telephone by the study 
coordinator after (or in advance of) their routine clinic visits if the patient's neurologist 
identifies that person as a potential participant. In this case, the neurologist will give the 
names of potential participants to the coordinator who will contact the patient, briefly 
explain the study, and assess the patient’s interest. If interested, the coordinator will ask the 
patient to come in for a screening visit at which time the consent form will be reviewed and 
signed. The signed consent form will be maintained in a specific study folder in a locked 
file cabinet. The participant will be given a copy of the signed consent. 
Those able to obtain consent include the Principal Investigator, Co-investigator(s), and 
site research coordinators. 
 
This study will not include patients with dementia. However, capacity to give consent 
will be carefully assessed in clinical interviews of patients by study staff experienced in 
clinical PD research. In the course of these interviews, study staff will assess the ability of 
patients to: 
• Comprehend the study and its consent form, by asking them to repeat the key elements 
of the research 
• Understand the study and its consent form, by answering questions about the key 
elements of the research 
• Appreciate the consequences of what will or could happen to them should they agree 
to participate 
• If in this process, a potential patient is found not capable of fully providing consent for 
participation, then this person will be excluded from study participation 
 
14.4 
Potential risks and benefits   
Potential Risks of taVNS 
taVNS is nothing more than transcutaneous electrical nerve stimulation (TENS) of the 
auricular branch of the vagus nerve that innervates the ear. Although this novel therapeutic 
modality is still in the development and optimization process, risks are a combination of 
those to be expected by both the peripheral TENS and implantable cervical VNS. 
TENS devices are FDA approved for pain relief and are available over the counter. The 
main risks associated with TENS are electrical hazards that may result in user discomfort or 
injury. The unit used in these studies (Digitimer DS7AH) is a 510(k) cleared electrical 
stimulator that meets the rigorous electrical standards of the FDA. Skin irritation, redness, or 
inflammation may occur under the stimulating electrodes if TENS current is delivered for a 
prolonged period of time.  
Implantable cervical VNS is FDA approved for the treatment of intractable epilepsy and 
treatment resistant depression. Cervical VNS has risks associated with the procedure of 

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implanting the nerve, and the surgery. None of those apply here. Cervical VNS does have 
some minimal risks that are due to the actual stimulation of the nerve within the neck such as 
skin irritation. taVNS also has associated risks that may arise from the direct brain effects 
stimulating the vagus nerve. These theoretical risks associated with neuromodulation of the 
parasympathetic nervous system would also be applicable in the administration of 
noninvasive taVNS. They are the following: reduction of heart rate, blood pressure, and 
vasovagal syncope. 
There have been dozens of studies in which taVNS has been used on humans, none of 
them reporting adverse events. A simple PubMed search for “transcutaneous vagus nerve 
stimulation” shows 24 peer-reviewed articles, 15 of which have been published within the 
past 3 years. See below table for 10 recent publications on PubMed involving taVNS on the 
auricular branch of the vagus in humans: 
 
Author, Year 
Aim (subject number) 
Side effects/Risks/AEs 
Aihua et al. 2014 
Epilepsy (n= 60) 
Dizziness, drowsiness 
Capone et al, 2014 
Cortical excitability 
(n=10) 
No modification of instantaneous HR, systolic 
BP, diastolic BP, and mean BP   
Kreuzer et al, 2014 
Tinnitus (n=50) 
Twitching and pressure at electrode site 
Rong et al, 2014 
Epilepsy (n=144) 
None reported 
Kraus et al, 2013 
taVNS/fMRI (n=16) 
A bright, prickling sensation, twinge or stabbing 
pain 
Rong et al, 2012 
Depression (n=120) 
None Reported – trial still under progress 
Kreuzer et al, 2012 
Safety Study (n=24) 
In those subjects with no known pre-existing 
cardiac pathology, preliminary data do not 
indicate arrhythmic effects of tVNS 
Busch et al, 2013 
Pain (n=48) 
No relevant alterations of cardiac or breathing 
activity or clinical relevant side effects were 
observed during t-VNS 
Stefan et al, 2012 
Epilepsy (n=10) 
Hoarseness, headache, or constipation 
Polak et al, 2009 
Far field potentials 
(n=20) 
Slight pain at electrode site 
 
An extremely through review of all taVNS literature has been performed and no harm or 
adverse events have been observed and any side effects were resolved by decreasing current 
intensity. There also is currently a commercial taVNS device available for purchase on the 
European market (Cerbomed - Nemos device; www.cerbomed.com) that is marketed as a 
take-home treatment for epilepsy.  
Not only does the current literature show a lack of harm done by taVNS, but implantable 
cervical VNS also has an incredible safety record. According to Cyberonics, the company 
that supplies the cervical VNS implantable devices, there has been over 100,000 implanted 
patients being monitored by over 3,000 providing physicians. Most side effects range from 

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alteration of voice, coughing, pharyngitis, hoarseness, headache, and nausea. Cardiac 
evaluations have been made on hundreds of VNS patients with no changes in cardiac 
function (Handforth et al, 1998; Sackeim et al, 2001; Morris and Mueller, 1999) with long-
term safety confirmed in recent large sample retrospective studies (Menascu et al, 2013; 
Ryvlin et al, 2014; Choi et al, 2013).  
Given the minimal risk both of these already FDA approved methods introduce, we 
suspect taVNS will be a very safe procedure. taVNS is not intended to be a therapy for 
currently existing conditions and all subjects will be healthy controls with no previous 
history of neurological disorders or trauma.  
Additionally, there has been study of acute taVNS in 50 PD subjects and 50 control 
subjects to assess peripheral structural integrity via short pulse stimulation sessions at 
relatively high amperage. Although not a specific outcome of study, there were no reported 
significant adverse events. However, an especially noteworthy outcome measured in this 
study was heart rate variability by several indices that did not differ significantly between the 
PD and control groups.18  
The blood draw may result in slight pain, bleeding, bruising, or infection. To decrease the 
likelihood of such complications, all blood draws will be performed by appropriately trained 
staff. To protect confidentiality, each subject will be identified with a unique numerical 
identifier, which will be used for all testing. The data will be kept in a locked file cabinet in a 
locked office when not being used.  
The Cognitive Assessments may cause fatigue or frustration.  Subjects will be free to stop 
a test at any time if they are frustrated, fatigued, embarrassed, or simply chose not to 
continue.  Questionnaires may contain questions that are sensitive in nature.  Subjects are 
able to refuse to answer a question that makes them feel uncomfortable.  If the subject has 
any concerns, they are urged to contact their doctor. 
Loss of confidentiality: There is a risk of a loss of confidentiality of personal information 
as a result of participation in this study. The information we collect will be maintained in a 
secure manner and access to this information will be limited to study team members only 
Participants will hold one dose of medication for the “off medication” condition with is a 
routine procedure for Parkinson’s studies.  Risks to the subjects during the “off medication” 
state include temporary increase in symptoms of slowness, stiffness, and tremors. 
 
Potential Benefits of taVNS:  
The severity of the participants PD symptoms might improve with study intervention. 
However, this is currently unknown and based on the study hypothesis only. The benefits to 
society of this study will include important new data on the treatment of PD. 
 
 
14.5 
Safety monitoring  

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Safety assessments will include physical exam, vital signs (heart rate primary measure, 
with additional blood pressure, respiratory rate and pulse oximetry monitoring), MDS 
UPDRS examinations and Cognitive examinations, Columbia- Suicide Severity Rating Scale 
(C-SSRS), monitoring of adverse events, and monitoring and maintenance of concurrent 
medication records. Prolonged stimulation or high amperage will not be used to minimize 
skin irritation. 
taVNS is easily discontinued if needed. Study personnel will have frequent contact with 
participants in person at study visits. 
 
14.6 
Confidentiality of patient data 
We will keep all patient and caregiver data in a secure locked office, in a locked cabinet 
and away from patient access areas. Names, addresses, and other such personal data will not 
be part of the REDcap database.  
Study data will be collected and managed in a REDCap database (Research Electronic 
Data Capture). The database will be managed by a data manager from the MUSC SCTR 
(SCTR= South Carolina Clinical and Translational Research Institute, that provides 
infrastructure for enhancing clinical research studies). The PI will perform error checking, 
and ensure that human subjects data is de-identified, that it meets all regulatory requirements, 
and that it is stored and backed-up in a secure fashion. REDCap is a secure, web application 
designed to support data capture for research studies, providing user-friendly web-based case 
report forms, real-time data entry validation, audit trails and a de-identified data export 
mechanism to common statistical packages.  The database is hosted at the MUSC Datacenter.  
The system is protected behind a login and Secure Sockets Layer encryption. 
Patient video will be collected within the secure “BOX” password protected network 
storage application that is MUSC IT security approved for patient PHI. There will be no end 
user device storage of PHI during collection or access. Single sign-in is required for access 
on any end user device. Folder access will be managed by the physician obtaining the video, 
the PI, and the blinded Movement Disorder Neurologist. Only after individual login will 
these key physicians be able to discover the study folder. Data collected from study 
evaluations and interviews will be identified only by study ID codes, which will be the 
patient ID and 4-letter code assigned at eligibility evaluation. 
Consented patient participants will be assigned a random *4-digit study ID number and 
blood serum samples will be drawn by appropriately trained staff.  There will be two blood 
draws per patient; one baseline and one at the conclusion of the study. Blood samples will be 
delivered to Dr. Boger’s lab as soon as possible, following all standard procedures for safe 
transportation and storage.  Dr. Boger’s personnel will be blinded to sample name, diagnosis, 
and all other personal identifiers.   
A paper log containing names and corresponding study IDs will be kept in a locked room 
and locked filing cabinet in the Movement Disorder Program Suite. This room will not be 
accessed by patients, and is separate from the room where patient evaluations are performed.   

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15.   Literature cited 
 
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