Therapeutic Potential and Neuroimmune Mechanisms of Vagal Nerve Stimulation on Gastrointestinal Motility and Inflammation
Phase: NA
Conditions: Gastroparesis
Sponsor: Stanford University

June 14, 2017 
 
NCT03120325 
Vagal Nerve Stimulation Protocol 
 
Therapeutic potential and neuroimmune mechanisms of vagal nerve stimulation 
on gastrointestinal motility and inflammation 
Stanford IRB Protocol 
 
Andres C Gottfried Blackmore, MD PhD; Hong Namkoong, PhD; Aida Habtezion, MD; 
and Linda Nguyen, MD. 
 
Stanford University School of Medicine 
 
1 
Introduction 
This document is a protocol for a human research study. This study is to be 
conducted according to US and international standards of Good Clinical Practice 
(International Conference on Harmonization ICHE6), the Code of Federal Regulations 
Title 21 parts 803 and 812, and other applicable government regulations and 
Institutional research policies and procedures. 
 
1.1 
Background/Significance 
The vagus nerve (VN) provides a bidirectional link between the brain and the 
gastrointestinal tract, and as such, is involved in maintaining the homeostasis of gut 
functions such as sensitivity, motility, and immunity both through its sensing and 
modulatory roles (Matteoli & Boeckxstaens 2013). The VN classically innervates the 
digestive tract from the esophagus to the splenic flexure, however for some anatomists, 
the VN innervates all the digestive tract in human.  Dysfunction of the vagal tone has 
been observed in functional and inflammatory digestive disorders (Bonaz et al 2016 
Rev). Being a major component in the control of upper gastrointestinal motility, low 
vagal tone has been associated with gastrointestinal motility disturbances (Bonaz et al 
2016 Rev).  
Gastroparesis is a disorder associated with delayed gastric emptying in the 
absence of mechanical obstruction. Patients with gastroparesis are often malnourished 
and experience a range of symptoms from nausea, vomiting, postprandial fullness, early 
satiety, and abdominal pain leading to significantly compromised quality of life and 
economic burden (Wang et al 2008; Talley et al 2001). Implicated etiologic factors 
include diabetes mellitus, although a third of the cases are idiopathic. Physiological 
vagal input to cholinergic enteric neurons is necessary to maintain a basal gastric tone 
and is important for gastric accommodation in humans (Lunding et al 2008; Azpiroz & 
Malagelada 1987). Antral dysmotility is a consistent finding in diabetics with delayed 
gastric emptying and impaired gastric autonomic innervation probably contributes to this 
dysmotility. An additional layer of complexity is provided by the fact that the digestive 
tract is exposed to a variety of luminal signals derived from the microbiota (Guarino et al 
2016). Beyond the well-documented effects on gut immune responses, recent data 
suggest that dysbiosis of gut microbiota can affect gastrointestinal motility (Guarino et al 
2016), although this has not been studied in gastroparesis.   
Inflammation is increasingly recognized as playing an important role in 
gastrointestinal motility disorders such as gastroparesis (Spiller & Major 2016). Immune 

cells such as macrophages and mast cells are found in close proximity to neurons 
within the enteric nervous system (Gabanyi et al 2015). Alterations in inflammatory 
mediators such as cytokines and number of leukocytes are found in gastroparesis and 
other gastrointestinal motility disturbances (Spiller & Major 2016). Moreover, leukocytes 
release mediators (e.g. cytokines, neurotransmitters) that alter neuronal activity and 
have been termed “neuroimmune synapse” leading to pro- and anti-inflammatory neural 
reflexes (Franco et al 2007). In addition, immune cells express receptors for 
neurotransmitters, including dopamine, acetylcholine, and norepinephrine, which can 
regulate leukocyte activity and differentiation. Thus neuroimmune interaction is a 
bidirectional process important in health and disease, particularly if inflammation is 
implicated (Franco et al 2007).  
The VN is a major constituent of a neural reflex mechanism—the inflammatory 
reflex—that controls innate immune responses and inflammation during pathogen 
invasion and tissue injury. VN anti-inflammatory properties are mediated through the 
activation of the hypothalamic–pituitary–adrenal axis (HPA) by its afferents and by 
activating the cholinergic anti-inflammatory pathway locally through its efferents (rev by 
Tracy 2016). VN stimulation (VNS) has potent anti-inflammatory effects (Zhao et al 
2012; Cialotto et al 2014) and can improve colitis in rats (Meregnani et al 2011; Ji et al 
2014). In a small study with healthy volunteers, it was demonstrated that 
transcutaneous VNS enhances gastric motility and reduces somatic pain sensitivity 
(Frøkjaer et al 2016). VNS has further been shown to induce a clinical, biological, and 
endoscopic remission at 6 months in small cohorts of patients with active Crohn’s 
disease (Bonaz et al 2016, Haens et a. 2016). However, VNS mechanisms of anti-
inflammatory responses in the gut have not been established, nor described in detail. 
Further investigations are needed to explore the intestinal component of digestive tract 
inflammation and motility under the modulation of vagal tone reinforcement.  
Given that autonomic dysfunction has been frequently reported in patients with 
gastrointestinal motility disorders and inflammatory bowel disease, the central 
hypothesis of our project is that improving vagal tone can have pro-kinetic and anti-
inflammatory effects of clinical relevance.We further hypothesize that gastroparesis is 
associated with improper immune interactions and microbial dysbiosis leading to 
disruption of neuronal function. In addition to supportive measures (e.g. dietary 
changes, glycemic control) and symptomatic control (e.g. anti-emetics), active treatment 
with pharmacologic agents and vagal/electrical stimulators has led to variable efficacy. 
Detailed molecular and neuroimmune studies are likely to identify patient heterogeneity 
and those that are likely to benefit from specific therapies – “precision medicine”. Thus 
with these in mind we propose the following specific aims (see below).   
 
1.2  
Specific Study Aims 
 
Study Aim 1: Investigate molecular and neuroimmune signaling pathways in 
gastroparesis patients prior to treatment as compared to non-gastroparesis 
controls.  
 
Study Aim 2: Investigate molecular and neuroimmune signaling pathways in 
gastroparesis patients post-treatment with VNS, and compared to pre-treatment.  

 
 
Study Aim 3: Define microbial features and investigate microbial dysbiosis 
associated with gastroparesis.  
 
2 
Innovation 
 
The etiology and pathophysiology of gastroparesis remains enigmatic despite 
evidence of underlying inflammation and dysautonomia. Additionally, therapies for 
delayed gastric emptying and its associated symptoms are limited. Given its extensive 
innervation of the stomach and its predominant role in parasympathetic regulation of 
inflammation and motility, the VN may be utilized as a powerful therapeutic target. As 
such, we are proposing to use VNS to induce pro-kinetic and anti-inflammatory changes 
of clinical relevance. Although gastric pacemakers are available as therapy for 
medically-refractory gastroparesis, these devices require surgery and have not 
demonstrated significant pro-kinetic effects (Ross et al, 2014; Yin et al 2012). VNS 
appears to be safe, well tolerated, and effective in the treatment of other inflammatory 
disorders with associated dysautonomia, such as rheumatoid arthritis (Koopman et al 
2016) and Crohns disease (Bonaz et al 2016, Haens et a. 2016). The therapeutic effect 
of VNS in these disorders is based on stimulation of the cholinergic anti-inflammatory 
pathway (Tracy 2009; Howland 2014), which specifically targets pro-inflammatory 
macrophages in the myenteric plexus (Matteoli et al 2013), which have been implicated 
in the pathogenesis of gastroparesis.  As such, VNS could potentially act as a disease 
modifier in gastroparesis. There are no therapies to date that have the potential to 
reverse underlying pathologic abnormalities in gastroparesis. VNS, through its anti-
inflammatory and pro-kinetic effects, may offer a safe and well tolerated therapy for 
treatment of  gastroparesis. In this study we propose establishing proof of concept for a 
novel therapy for gastroparesis. Additionally, we will attempt to fill the large gaps in 
pathophysiology of this disease by a detailed study of the neuro-immune interactions in 
patients with gastroparesis. 
 
3 
Study Design  
 
3.1 
General Design 
 
This is a prospective interventional pilot study assessing the safety and 
tolerability, as well as efficacy of the use of VNS in patients with idiopathic and 
functional gastroparesis. We will also include patients with functional dyspepsia, which 
have almost identical clinical symptomatology and are believed to share similar 
underlying inflammation and dysautonomia. We plan to recruit a total of 45 patients, 15 
patients of each subgroup, for 4 weeks of therapy with VNS. Patients will undergo 
baseline measures of symptoms, gastric emptying testing, vagal tone, and 
inflammation. After enrollment, patients will undergo two upper endoscopies (pre and 
post therapy). Pt will be seen in clinic for recruitment, day 0, for follow-up at 4 weeks, 
and again at 8 weeks, for a total of six visits including their appointed endoscopy days.  
 
3.2 
Study Objectives 

1. Establish the effect of VNS on gastric emptying time and on cardinal 
symptoms of gastroparesis (nausea, vomiting, bloating, abdominal pain, and 
early satiety). 
2. Assess the effects of VNS on various measures of quality of life, including global 
health and overall pain interference. 
3. Investigate molecular and neuroimmune signaling pathways in different 
gastroparesis patients. 
4. Determine the effects of VNS on measurable serum inflammatory markers and 
cytokines.  
5. Determine the effects of VNS on measurable cytokines, nerve growth factors, 
and neurotransmitters in the gastric and duodenal submucosa. 
6. To characterize the submucosal enteric nervous system in gastroparesis 
subtypes and identify novel neuro-immune interactions. 
5. Determine if gastric emptying and symptom response to VNS is associated 
with changes in inflammatory markers and neuro-immune signaling. 
6. Determine if there is a difference in response to VNS in patients with idiopathic 
vs. diabetic gastroparesis. 
7. Evaluate the safety and tolerability of VNS therapy in patients with 
gastroparesis and functional dyspepsia. 
 
 
 
3.3 
Study Endpoints 
I. Primary Study Endpoints 
1.1 The primary outcome measure will be the effect of VNS on 
gastroparesis cardinal symptoms as measured by the gastroparesis 
cardinal symptom index (GCSI) questionnaire. 
1.2 The second primary outcome measure will be the effect of VNS on 
gastric emptying time as measured by the gastric emptying spirulina 
breath test.  
 
 
II. Secondary Study Endpoints 
2.1 The effect of VNS therapy on overall pain interference as assessed by 
the PROMIS pain interference questionnaire 
2.2 The effect of VNS therapy on overall wellbeing and health as 
assessed by the short form 12 (SF-12).  
2.3. The safety and tolerability of VNS in patients with gastroparesis will 
be assessed by recording any side effects or adverse events. 
2.4 The effect of VNS therapy on vagal tone as assessed bv heart rate 
variability (HRV) and respiratory variability using electrocardiogram 
(ASNAR) device and an HRV App called Heart Rate Variability Camera.  
2.5 The effect of VNS therapy on systemic inflammation as measured by 
serum inflammatory markers and cytokines (as assessed by the Human 
63-plex assay), as well as by activation markers in circulating leukocytes 
by flow cytometry.  

2.6 The effect of VNS therapy on gastric and small intestine inflammation 
as measured by endoscopy biopsy tissue expression of inflammatory 
mediators (cytokines, chemokines, etc), and tissue infiltration of immune 
cells by flow cytometry and immunohistochemistry.  
 
III. Exploratory Study Endpoints 
3.1 Enteric neuro-immune interactions in distinct types of gastroparesis as 
measured by analyses of the submucosal plexus and infiltrating immune 
cells from endoscopy tissue biopsies via immunofluorescence, gene 
expression assays, and expression of neurotransmitters, nerve growth 
factors, cytokine receptors, and trafficking receptors. 
3.2 Dysbiosis and bile acid metabolism in distinct types of gastroparesis 
as measured by stool sample 16S rRNA microbiome sequencing and 
metabolomics. 
3.3 Assess the effect of VNS on neuro-immune interactions and dysbiosis 
in gastroparesis patients as measured in 3.1 and 3.2.  
 
3.4 
Study Duration 
 
1. Up to 8 weeks for screening period and baseline measures 
2. Four weeks of active VNS therapy  
 
3. Four weeks follow up period following discontinuation of therapy 
 
 
4 
Subject Selection and Withdrawal 
 
4.1 
Study Population 
Adult patients, age 21 to 65 years old, with diagnosed functional dyspepsia, 
diabetic or idiopathic gastroparesis. 
 
4.2.  Sample size justification 
• 
Total of 45 patients; 15 with functional dyspepsia, 15 with diabetic 
gastroparesis, and 15 with idiopathic gastroparesis. 
• 
Primary comparison: Gastric emptying half time score and GCSI, pre and 
post VNS 
• 
Error protection:  Type I = 0.05 two-sided and Type II = 0.10 (80% power). 
To detect a clinically significant change of >30% in gastric emptying time, 
and a reduction in >1 GCSI aggregate.   
 
 
 
4.3 
Inclusion Criteria 
1. Male or female. 
2. Age 21-65 years old. 
3. Established diagnosis of functional dyspepsia, idiopathic or diabetic 
gastroparesis as per AGA (American Gastroenterology Association) guidelines. 
4. Patient is capable of giving informed consent and undergo upper endoscopy. 
5. Patient is on stable doses of other medications for gastroparesis for preceding 4 
weeks prior to enrollment (baseline measures).  

 
4.4 
Exclusion Criteria 
1. Surgical-related gastroparesis 
2. Extrinsic myopathy or neuropathy causing gastroparesis. 
3. Use of narcotic pain medications in the preceding 2 weeks of study enrollment.  
4. Patients with enteric feeding tubes or requiring parenteral nutrition.  
5. Patients with severe flare requiring hospitalization. 
6. Untreated significant depression or suicidal thoughts.  
7. Pregnant or breast-feeding women.  
8. History of gastric pacemaker implantation. 
9. Patients with prior gastric surgery, including fundoplication, partial/total 
gastrectomy, or gastric bypass. 
10. Patients with malabsorption of enteric, pancreatic, or hepatibiliary etiology. 
11. Patients with primary pulmonary disorders that affect the spirulina breath test. 
12. Patients with implantable electronic devices. 
13. Patients with carotid artery atherosclerosis. 
14. Patient with HX of embolic stroke or TIA, arterial vascular disease, active 
unexplained neurologic symptoms, or men 65 above who smoke tobacco. 
15. Any patient who has had a botox injection in their abdominal region within the past 6 
months prior to enrollment. 
 
4.5 
Subject Recruitment and Screening 
Patients seen at the Stanford University Digestive Health Clinic in the Principal 
Investigator’s clinical practice will be screened for appropriateness in the study and 
recruited. Those meeting eligibility criteria will be recruited. Informed consent will be 
obtained and the patients will be scheduled for first upper endoscopy and instructed on 
the use of the GCSI questionnaire and other surveys. After baseline endoscopy is 
completed, patients will return to clinic for blood sample collection, including complete 
blood count, comprehensive metabolic panel, serum or urine β-HCG (women of 
reproductive age only), ESR, CRP, serum cytokines (Human 63-plex Luminex assay 
custom-built by eBioscience), and two additional blood vials for flow cytometry and in-
vitro re-stimulation assays, and a third vial for blood banking. Banked blood in the 
Habtezion lab will be used for subsequent studies of exploratory markers of 
inflammation, immunity, metabolism, and neurotransmission. No genetic testing will be 
done with fresh or banked patient samples. Stool collection and saliva collection will 
also occur. At this same visit, patients will undergo HRV testing and gastric emptying 
testing, which are non-invasive and office-based tests. Patients will then be given the 
gammaCore vagal nerve stimulator and be instructed on its use with a first time 
stimulation in the office and a repeat blood collection 90-120 minutes later. Patients will 
then self-administer daily VNS twice a day for total of 4 weeks’ duration.  
 
4.6 
Early Withdrawal of Subjects 
1. Patients may withdraw from the trial at any time.  
2. Patients must be withdrawn from the trial for any of the following:  
• The patient withdraws consent. 

• The patient develops serious adverse effect (none anticipated) during the 
study period. 
 
5 
Study Device 
 
5.1 
Description 
 
GammaCore is a hand held device used for transcutaneous vagal nerve 
stimulation. The manufacturer, electroCore, has regulatory approval for the use of 
gammaCore therapy in the acute and/or prophylactic treatment of cluster headache, 
migraine and medication overuse headache throughout the European Union, South 
Africa, India, New Zealand, Australia, Colombia, Brazil and Malaysia. In Canada the 
therapy is indicated for the acute and/or prophylactic treatment of cluster headache and 
for the treatment of migraine. It is not FDA-approved in the USA, but is registered as an 
investigational new device in various clinical trials. GammaCore is CE marked and 
indicated for the acute and/or prophylactic treatment of Migraine, Cluster, Hemicrania 
Continua and Medication Overuse Headache in adults. Thus, the purpose of this 
protocol is to provide VNS to patients with gastroparesis and functional dyspepsia. 
Our IDE number is: 
. Our NCT number is: NCT03120325 
 
5.2 
Treatment Regimen 
1. Patients seen at Stanford University Digestive Health Center who meet study 
inclusion criteria will be screened for enrollment. Those patients with diagnosed 
functional dyspepsia, idiopathic or diabetic gastroparesis will be considered 
eligible. Those who do not meet any exclusionary criteria will then be actively 
enrolled in the study. Study subjects who sign informed consent to participate in 
the study will have a baseline history and physical exam, and baseline laboratory 
tests to be completed after baseline endoscopy and at the time of first (pre-
treatment) gastric emptying testing.  
2. Patients will complete the following forms at the time of study enrollment: 
• GCSI-DD (Gastroparesis Cardinal Symptom Index Daily Diary) 
• GI PROMIS belly pain questionnaire.  
• PROMIS Global Health Short Form questionnaire.  
PROMIS Pain Interference Short Form 8a questionnaire.  
• Short Form SF-12 questionnaire. 
• Compass 31 Survey  
3. After successful baseline upper endoscopy and subsequent gastric emptying 
testing with associated baseline HRV, blood, urine, saliva, and stool tests, 
patients will start active VNS treatment. The first gammaCore device therapy will 
be done in the office to ensure proper use, tolerability, and address any 
questions or concerns patients may bring up. The dosing of therapy will be 
personalized for each patient at this first session (by asking subject to increase 
dose until they experience a tug on the ipsilateral side of their mouth). This dose 
will then be maintained for the duration of the study. Posteriorly, 90-120 minutes 
after the first stimulation, a repeat blood collection will take place (two vials for 
Human 63-plex Luminex assay and banking) to assess the acute effect of the 
VNS treatment on inflammatory markers.  

4. Total treatment duration will be 4 weeks. GammaCore administration will occur 
twice daily, in the morning and evening. Each treatment will entail a 2-minute 
application to the R and L cervical vagus nerve, each side separated by 3-5 
minutes, for a total of 4 applications daily (total of 8 minutes).  
5. Patients will receive weekly calls to assess compliance, tolerability, and 
reminders for their symptoms questionnaires.  
6. Patients will present to endoscopy for their post-treatment upper endoscopy 4 
weeks after initiation of therapy. No later than 3 days after endoscopy, patients 
will present to clinic at which time post-treatment gastric emptying testing, HRV 
testing, and laboratory tests (blood and stool) will be obtained, and the 
aforementioned forms will again be completed.  
7. Patients will be seen in clinic again at 4 weeks after discontinuation of therapy, 
and undergo a repeat medical history and physical exam. At this time gastric 
emptying testing, HRV testing, and laboratory tests (blood and stool) will again 
be obtained; and the aforementioned forms will again be completed to assess 
whether any change in symptoms and disease severity has occurred off therapy. 
 
 
Study Assessment and Monitoring 
 
1. Spirulina Gastric Emptying Breath Test (Viramontes et al 2001): Gastric 
emptying times will be measured at baseline and after 4-week therapy. As part of 
standard of care procedures, diabetic patients will have their blood sugar 
measured prior to this test. They will need to have a blood sugar level of less 
than 275 mg/dl, as this high level will results in artificially delayed emptying. 
Patients will be asked to reschedule if this is the case.  
2. GCSI-DD[3]: Gastroparesis-specific symptom severity scale. Obtained at 
baseline (1 week prior to randomization) and daily throughout the duration of the 
study. 
3. GI PROMIS[2]: publically available patient related outcome (PRO) measure that 
covers 8 symptom domains (Abdominal pain, Gas/Bloating, Diarrhea, 
Constipation, Bowel Incontinence, Reflux, Nausea and Vomiting, Disruptive 
Swallowing) that can be used together or individually to assess GI symptoms in 
clinical practice and research. Symptoms are assessed via 7-day recall. The 
questionnaire will be filled out one week prior to starting therapy and at each 
follow up visit.  
4. PROMIS Global Health 
5. PROMIS Pain Interference 
6. Compass 31 Survey  
7. Human 63-plex Luminex assay: The Human Immune Monitoring Center 
(HIMC) at the Stanford Institute for Immunity, Transplantation and Infection has a 
standardized immunoassay for the detection of 63 human serum cytokines and 
chemokines using a Luminex assay. 
8. Flow Cytometry: additional blood samples will be processed for storage, or for 
same-day in vitro re-stimulation assays in Dr Aida Habtezion research Laboratory 
at Stanford SOM.  

9. Dysbiosis: stool samples will be frozen for storage until all subjects are enrolled. 
Subsequent metabolomics and 16S rRNA sequencing experiments will be done 
with collaborators of Dr Habtezion’s Laboratory at Stanford SOM.  
10. Upper GI Endoscopy: All patients will receive standard of care and standard 
precautions for GI endoscopy as per Stanford Outpatient Endoscopy guidelines. 
Patients will undergo a baseline endoscopy, and again after VNS treatment to 
assess the impact of therapy on the target organ, i.e. the stomach. During the 
procedure, detailed endoscopic assessment of the mucosa will take place, 
including tissue biopsies that will be collected and processed in Dr Habtezion’s 
Laboratory at Stanford SOM.  
 
 
 
 
(baseline) 
Visit 1 
Enrollment 
< 8 wk prior 
(baseline) 
Visit 2 
Endoscopy 
Day 0 
(start VNS) 
Visit 3 
Clinic  
Day 28  
() 
Visit 4 
Endoscopy 
VNS 4 
Weeks  
Day 31 
End 
VNS) 
Visit 5 
Clinic  
Day 51  
(Washout) 
Visit 6 
Clinic 
Inclusion criteria 
met, no 
exclusion criteria 
met 
X 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
Medical History 
X 
 
X 
 
X 
X 
Physical Exam 
X 
 
X 
 
X 
X 
Medication Rev 
X 
 
X 
 
X 
X 
Blood collection: 
CBC, BMP, LFT, 
A1C, β-HCG, 
ESR, CRP,  
63-plex  
Luminex ,and 
Heparin vials for 
FACS analysis 
 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
Forms 
GI PROMIS pain 
PROMIS Health 
PROMIS Pain  
SF_12_Health  
COMPASS 31  
 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
GCSI-DD 
HRV-app  
 
 
8 weeks. (2 weeks before VNS, 4 weeks of VNS, 2 weeks after VNS) 
EGD 
 
X 
 
X 
 
 
HRV / EKG 
 
 
X 
 
X 
X 
Gastric 
Emptying 
 
 
X 
 
X 
X 
Stool collection 
 
 
X 
 
X 
X 
Saliva collection 
 
 
X 
 
X 
 

Adverse 
reactions 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.3 
Implementation of Study Device 

 
Patients will be instructed in the application of the gammaCore device in clinic, and 
will receive printed materials to guide them in the proper use and implementation of the 
device.  
 
5.4 
Subject Compliance Monitoring 
 
Compliance will be assessed by weekly phone communications, during clinic visits 
at 4 weeks after initiation of therapy, and at study completion (8 weeks), by VNS device 
dosimeter reading.  
 
5.5 
Prior and Concomitant Therapy 
 
Participants will be allowed to continue steady doses of medications they are on 
for gastroparesis for 4 weeks prior to study enrollment. No new scheduled medications 
for gastroparesis can be initiated during the study period and they must remain on stable 
doses of any pre-existing medications being used for gastroparesis. The following as-
needed rescue medications for symptom control will be allowed for use on a PRN basis 
during the study: ondansetron, promethazine, diphenhydramine, and Tylenol, toradol. 
Patients on daily use of narcotic pain medications within the preceding 4 weeks of 
screening will be excluded from the study and patients will be prohibited from taking opioid 
medications during the study period.  
 
6 
Safety and Adverse Events 
 
6.1 
Risks 
 
There is a low reported incidence of adverse side effects with the use of 
transdermal VNS using gammaCore. There have been no reported incidences of cardiac 
arrest, respiratory depression, or other serious adverse events. In an IDE, prospective, 
multi-centered pilot study, no adverse events were reported during or after stimulation. 
There were no significant changes in electrocardiogram, heart rate or systolic or diastolic 
blood pressure (Engel et al Poster). Reported side effects are mild and include 
hoarseness, shortness of breath, change in voice, & skin irritation.  
 
6.2 
Recording of Adverse Events 
 
The principal investigator (PI) is responsible for monitoring the conduct of the study 
and the safety of the study subjects. The participants will be closely monitored by the PI 
for the development of any adverse events. If adverse events occur (whether expected 
or unexpected), the PI will evaluate the severity of the adverse event and will initiate 
immediate corrective measures. The PI will determine if any adverse event is attributed 
to the research study. All serious and/or unexpected adverse events will be reported to 
the IRB and appropriate federal agencies in a timely fashion. In particular, the investigator 
of an IDE such as this must notify in a written IDE safety report of any adverse experience 
associated with the use of the device that is both serious and unexpected. This notification 
must be made as soon as possible and no later than 15 calendar days after initial receipt 
of the information.   
The PI will submit a yearly written progress report to the IRB for review.  This report 
will also be sent to the FDA for review (see data collection section). This report will 
delineate the number of subjects entered into the study (in the past year and total), any 

adverse events that have occurred in the past year, and the reason for any subject 
dropout/withdrawal from the study. 
 
6.3 
Reporting of Adverse Events 
 
Within 60 days of the anniversary date that the IDE goes into effect (an IDE goes 
into effect 30 days after FDA receives it), a brief report of the progress of the investigation 
must be submitted to the FDA.  This must include: 1) a brief summary of the status of 
each patient enrolled in the protocol; 2) the total number of subjects you plan to treat 
under the protocol; the number entered into treatment to date, and the number who 
dropped out of the study for any reason; 3) a description of the general investigational 
plan for the coming year. 
 
7. Statistical Analysis Plan 
The mean baseline GCSI aggregate score will be compared with the mean 
aggregate score at the end of each treatment week, and in the 4 subsequent weeks 
after therapy discontinuation. Paired Student T-tests will be done comparing baseline 
with all other subsequent time points. Gastric emptying times will be plotted before 
treatment, at the end of treatment, and four weeks after end of treatment and compared 
by ANOVA. Similarly, differences among the three subgroups of patients will be 
determined at baseline and after treatment. 
 
Appendix 
I. Layman’s Narrative of Project: 
Gastroparesis is thought to be caused by a mix of inflammation and neural dysfunction. 
The vagus nerve is a large nerve originating from the brain, which innervates the 
stomach and intestine, and plays a key role in maintaining normal gastrointestinal 
function. Research shows that a high vagal tone makes your body better at regulating 
blood glucose levels, reducing the likelihood of diabetes, stroke and cardiovascular 
disease. Low vagal tone, however, has been associated with chronic inflammation. 
Research also shows that patients with gastrointestinal motility problems, such as 
gastroparesis, have a low vagal tone. Further, in animal models, stimulation of the 
vagus nerve can have an anti-inflammatory effect in the the bowels, and improve 
gastrointestinal motility. Stimulation of the vagus nerve is an FDA-approved therapy for 
seizures and depression, but it has not been studied carefully in patients with 
gastroparesis. In this study, our aim will be to improve gastric motility and measures of 
inflammation by vagal nerve stimulation. We will stimulate the vagus nerve using a 
hand-held device which every study subject will be trained to use in their home. 
Stimulations will last only a few minutes and will be conducted twice a day for total 
duration of 4-8 weeks. To evaluate the potential benefits of vagal nerve stimulation, we 
will assess gastric emptying and inflammation by routine, standard of care tests such as 
upper endoscopy, breath testing, and sampling of blood, stool, urine, and saliva. We will 
also measure autonomic dysfunction via the Ansar autonomic functioning machine and 
the Heart Rate Variability Camera App. A recent autonomic evaluation of gastroparesis 
patients undergoing neurostimulation suggests that heart rate variability and systematic 
autonomic testing are both reliable methods of measuring autonomic changes before 
and after neurostimulation (Stocker et al, 2016).  Utilizing mobile apps to measure heart 

rate variability has been reliably tested (Scully et al 2012), and preliminary results from 
our studies specific mobile app suggests that the specific technology of 
photoplethysymography has provided accurate and non-invasive cardiac measures that 
can be integrated into research settings. ( Altini et al, 2017; Plews et al 2017)  
 
II. Gastric Emptying Breath Test (GEBT) is a non-radioactive, non-invasive, orally 
administered test for measurement of the rate of solid phase gastric emptying in adults. 
The GEBT has been validated against the reference method of gastric scintigraphy.   
 
III. gammaCore VNS device: 
 
 
 
IV. Vagal Anti-Inflammatory Reflex: 
 

 
 
 
 
 
 
 
 
 
 
 
References 
 
Poster Ref: P1.292: Emily Rubenstein Engel, Justyna Blake, and Eric Liebler. Non-
invasive Vagus Nerve Stimulator (gammaCore®) Was Not Associated With 
Meaningful Cardiovascular Adverse Effects.  Presented at the 67th American 
Academy of Neurology Annual Meeting • Washington, DC • April 18-25, 2015  
 
Poster Ref: PI20: Geert D’Haens, Zeljko Cabrijan, Michael Eberhardson, Silvio Danese, 
Yaakov Levine, Ralph Zitnik. A Clinical Trial of the Effects of Vagus Nerve Stimulation in 
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