Non-invasive Vagal Nerve Stimulation (nVNS) for Symptomatic Exacerbation of Nausea in Patients With Gastroparesis and Related Disorders
Phase: NA
Conditions: Chronic Unexplained Nausea and Vomiting, Gastroparesis
Sponsor: Johns Hopkins University

NCT04857281 
Non-invasive Vagal Nerve Stimulation (nVNS) for Symptomatic Exacerbation of Nausea 
in Patients With Gastroparesis and Related Disorders 
Date: 11/14/2022 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
Revision 4 (11/14/2022)            Proprietary confidential information           Treisman, G. MD    
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
l 
 
Principal Investigator 
Glenn Treisman, MD 
Johns Hopkins University 
School of Medicine 
Non-invasive vagal nerve stimulation (nVNS) for 
symptomatic exacerbation of nausea in patients with 
gastroparesis and related disorders 
CONFIDENTIAL 
 
 
 
Version: November 2022 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
Revision 4 (11/14/2022)            Proprietary confidential information           Treisman, G. MD    
1 
 
 
1. Study Rationale  
 
Chronic nausea and vomiting disorders have been referred to by many names in the literature, 
including chronic unexplained nausea and vomiting (CUNV), gastroparesis-like syndrome (GLS), 
functional vomiting, and vomiting of unexplained etiology (VUE). Chronic nausea and vomiting 
disorders are also included in the classification of functional gastrointestinal disorders (FGIDs). 1 
 
Gastroparesis is a digestive disorder in which the motility of the stomach is either abnormal or 
absent. 2 The symptoms of gastroparesis can range from mild to severe, requiring prolonged 
hospitalizations and interventions. Patients may present with predominant nausea, vomiting, 
bloating and early fullness while eating meals, heartburn, and epigastric pain. The symptoms can 
cause life-threatening complications can significantly affect the quality of life in affected individuals 
such as weight loss, dehydration, hypoglycemia, malnutrition, bacterial overgrowth from the 
fermentation of food and benzoars that may cause and obstruction in the stomach.3-5 
 
The causes of gastroparesis are extensive and varied. One of the most common causes of 
gastroparesis is diabetes probably due to damage to nerves that supply the stomach. Some 
people with idiopathic gastroparesis report symptoms following a virus infection and sometimes 
the cause are unknown (idiopathic). 6-8  
 
Other possible causes include endocrine disorders like hypothyroidism, connective tissue 
disorders such as scleroderma, autoimmune conditions (systemic lupus erythematosus), some 
nervous system link disorders such as Parkinson’s disease or migraines, neuromuscular 
diseases, eating disorders, 9-11 certain cancer radiation treatment applied over the chest or 
abdomen, 12 some chemotherapy agents. Less frequently, gastroparesis is seen to occur after 
certain medications such as opioids,13 some antidepressants, and high blood pressure.8,14 
 
Any surgery on the esophagus, stomach or duodenum may result in injury to the vagus nerve that 
is responsible for many sensory and motor (muscle) responses of the intestine.15 In health, the 
vagus nerve sends neurotransmitter impulses to the smooth muscle of the stomach that result in 
contraction and forward propulsion of gastric contents. If the vagus nerve is injured by trauma or 
during surgery, gastric emptying may be reduced. Symptoms of postoperative gastroparesis may 
develop immediately, or months to years, after a surgery is performed. The vagus nerve helps 
manage the complex processes in the digestive tract, including signaling the muscles in the 
stomach to contract and push food into the small intestine. A damaged vagus nerve cannot send 
signals normally to the stomach muscles. This may cause food to remain in the stomach longer, 
rather than move normally into the small intestine to be digested. 16   
 
Several medications are used to treat gastroparesis and CUNV to control the symptoms specially 
nausea and vomiting such as the 5-HT3 antagonist (e.g. ondansetron) or D2 receptor antagonist 
(e.g. Promethazine). 17 Other medications stimulate the stomach muscles and help with digestion 
with prokinetics. These include metoclopramide, erythromycin and domperidone. 1,18 However, 
the drugs can cause side effects. 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
Revision 4 (11/14/2022)            Proprietary confidential information           Treisman, G. MD    
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When gastroparesis does not respond to standard medical management, including drugs and 
dietary changes, the condition is said to refractory. Gastric Electrical Stimulation (GES) uses a 
device, surgically implanted in the abdomen, to deliver mild electrical pulses to the nerves and 
smooth muscle of the lower part of the stomach. This procedure reduces the nausea and vomiting 
and may be considered for compassionate treatment in patients with refractory symptoms, 
particularly in patients with persisting symptoms and GES.19 
 
The vagus nerve plays a key role in regulation of nausea and vomiting, and there is evidence of 
vagus afferent effects on nociception, which suggests that electrical stimulation modulates 
nauseas and vomiting. The current proof of concept study explores the possibility that non-
invasive vagus nerve stimulation (nVNS) could have clinical effects similar those of an implanted 
gastric electrical stimulation device in patients with symptoms of gastroparesis. GES report some 
complications, the main one being the infections of subcutaneous pocket, inflammation over 
implant site, device migration/erosion, lead penetration, extra-abdominal pain, seroma and 
hematoma. Less common complications include erosions of the abdominal wall by the device, 
penetration of the leads through the gastric wall, or tangling of wires in the generator pocket and 
formation of adhesions. GES is relatively expensive treatment with the high cost of the device and 
for the surgical procedure. 20-22 
 
gammaCore (nVNS) is the first non-invasive, handheld medical device23 applied on the side of 
the neck and sends gentle, patented mild electrical stimulation through the skin to activate the 
vagus nerve. nVNS offers a potential alternative to GES that could eliminate significant risks of 
injury or illness or identify likely responders to implantable neurostimulator including implanted 
VNS (iVNS). nVNS could provide a more effective and safer alternative to the use of traditional 
rescue medications.  
 
nVNS primarily stimulates myelinated sensory afferent vagus nerve fibers as they ascend through 
the neck in the carotid sheath. nVNS has been cleared for the acute and preventive treatment of 
migraine and the acute and preventive treatment of cluster headache by the Food and Drug 
Administration (FDA) and is also CE marked and used in several all forms of primary headache. 
24, 25 
 
The hypothesis of the pilot study is that nVNS will result in relief of nausea by modulation of vagal 
nerve activity.  
 
2. 
Objectives (include all primary and secondary objectives) 
 
• 
The principal objective of this open label pilot study is to evaluate whether acute treatment 
of nausea exacerbations with nVNS will be effective in reducing the use of rescue 
medications.  
 
• 
Secondary objectives of this study include:  
o Determine the nature and incidence of adverse effects.  

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
Revision 4 (11/14/2022)            Proprietary confidential information           Treisman, G. MD    
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• 
Exploratory objectives 
o Determination of the effects of nVNS (or correlation with response) use on: 
 
Patient Assessment of Upper Gastrointestinal Symptom Severity Index 
(PAGI-SYM) and the Gastrointestinal Symptom Rating Scale (GSRS). 
 
Depression and anxiety using the Beck Depression Inventory and State-Trait 
Anxiety Scores. 
 
Frequency of migraines and headaches (since many patients with 
gastroparesis have concomitant migraine) defined as, ‘migraine day’= a 
migraine headache occurring in a 24-hour period, and a ‘headache day’= any 
headache occurring in a single calendar day. 
 
Autonomic symptoms as determined by the COMPASS-31 score. 
 
3. 
Background (briefly describe pre-clinical and clinical data, current experience with 
procedures, drug or device, and any other relevant information to justify the research) 
 
Chronic nausea and vomiting are the clinical hallmarks of gastroparesis and Chronic Unexplained 
Nausea and Vomiting or CUNV (very similar to Functional Dyspepsia of the postprandial subtype, 
FD-PPS, by Rome criteria) or related disorders and in most cases, are constant and daily 
symptoms. However, in addition, the majority of these patients also experience periodic 
exacerbations of these symptoms either on a daily basis or several times in a week. These 
exacerbations require them to use “rescue” medications such as 5-HT3 antagonists (e.g. 
ondansetron) or D2 receptor antagonists (e.g. Promethazine). These are only partially effective 
at best and often associated with adverse effects. Our hypothesis is that nVNS may provide a 
more effective and safer alternative to the use of traditional rescue medications. We therefore 
believe that while nVNS may not necessarily be a stand-alone treatment for gastroparesis, it has 
the potential for meeting a large unmet “niche” need in this condition. 
 
4. 
Study Procedures 
 
Patients who appear to be eligible after chart review and completion of standard of care tests and 
procedures for gastroparesis, CUNV or related disorders will be invited to undergo screening for 
study. Patients considered by the clinical center investigator as likely to be eligible for participation 
in the trial may be consented, registered and screened at a visit that is part of the ongoing clinical 
care of the patient. 
 
After informed consent is obtained, patients will fill out a validated symptom-based questionnaires 
and assessment daily.  
 
Visit schedule  
• 
At least 2 weeks of pre-treatment observation (screening). 
• 
8 weeks of treatment  
• 
2 weeks of post-treatment observation.  
• 
Length of recruitment: 9 months 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
Revision 4 (11/14/2022)            Proprietary confidential information           Treisman, G. MD    
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1. Screening visit and baseline data collection 
 
Study participants will come from the patient rosters of study physicians. Patients who appear to 
be eligible after chart review and completion of standard of care test and procedures will be invited 
to undergo screening for the trial. Patients considered by the clinical center investigator as likely 
to be eligible for participation in the trial may be consented, registered and screened at a visit that 
is a part of the ongoing clinical care of the patient.  
 
An open label pilot study to be conducted at Johns Hopkins Bayview Medical Center over 9 
months to evaluate with nVNS for the symptomatic exacerbations of nauseas in patients with 
gastroparesis or CUNV. Approximately 30 patients will be enrolled in the study. Inclusion criteria 
will include patients 18 years or older with symptomatic nausea, vomiting and other symptoms 
suggestive of chronic nausea and vomiting of presumed gastric origin (Gastroparesis or CUNV). 
All the participants will come from the patient roster of the study physicians from the Division of 
Gastroenterology, Department of medicine: Dr. Glenn Treisman (Principal Investigator), and Dr. 
Robert Bulat.  
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be 
substituted for in person clinical trial visits or portions of clinical trial visits where determined to be 
appropriate and where determined by the investigator not to increase the participants risks. Prior 
to initiating telemedicine for study visits the study team will explain to the participant, what a 
telemedicine visit entails and confirm that the study participant is in agreement and able to 
proceed with this method. Telemedicine acknowledgement will be obtained in accordance with 
the Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed 
feasible, the study visit will proceed as an in-person visit. Telemedicine visits will be conducted 
using HIPAA compliant method approved by the Health System and within licensing restrictions 
 
Revisions to the informed consent process are being permanently adopted for this research. 
Teleconsent will be used as opposed to in person consenting where possible to reduce 
unnecessary in person encounters specifically for a consent procedure. In the event teleconsent 
is utilized, participants will be provided with a copy of the Informed Consent prior to the 
teleconsent meeting either via email, fax, mail or previously provided during an in person visit. 
 
Participants will be given adequate time to consider the research study and ask questions prior 
to signing the consent form. The consent designee must verify the participant physically signed 
the consent document by either viewing via video conference, obtaining a photo of the signed 
consent document; or obtaining verbal confirmation from the participant that he/she signed the 
consent form or agreed to participate electronically. The participant will sign and date/time the 
informed consent document. The document is then mailed, emailed or faxed to the consent 
designee. The participant will be asked to return the original signed document on their first in 
person visit. If the Informed Consent form is mailed to the consent designee by the participant the 
study coordinator will sign the copy, which they possess after the participant has acknowledged 
signature on their copy. Once the original is received by the consent designee the copies will be 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
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attached to make a single document. In all other instances, once received, the research 
coordinator signs, dates/times the informed consent document. 
 
At the time of the first clinical encounter post teleconsent, research coordinator will review any 
additional study participant questions and discuss the risks, benefits and alternatives of the study 
in full detail, completing the physician/mid-level component of the consent process. After the 
Informed Consent process is completed, a study team member will file the consent document in 
EPIC. The entire consent document is also then filed in the research record. 
 
Only patients who are sufficiently proficient in English will be recruited for this study. All potential 
study candidates will be able to obtain a consent form in advance and review it at their own time, 
as needed. All contact information for the lead study coordinator and the study PI will be given to 
the potential candidate when they are given a copy of the consent form. 
 
As part of the screening process for the trial, the patient must have a diagnosis of gastroparesis 
or CUNV  with delayed gastric emptying documented by gastric emptying scintigraphy (4-hour 
emptying after a low-fat meal with any combination of 2- and 4-hour retention of >60% and 10% 
respectively) and ongoing symptoms such as: nausea, vomiting, abdominal pain, etc. for at least 
3 months without any other obvious cause. Patients must also have a normal upper endoscopy 
or standard radiography, to rule out other potential causes of symptoms such as mechanical 
obstruction, inflammatory or other structural lesions of the GI tract or non-gastrointestinal causes.  
 
Recording of screening data on trial forms may not start until the patient has signed the informed 
consent form (ICF). Screening and baseline data collection procedures will include 
questionnaires, urine pregnancy test, 12 lead EKG, and review of the patient’s medical chart.  
 
All participants who sign the ICF will be registered in the trial database. Each participant who 
starts screening will be accounted for at the end of the screening, as either success or a screening 
failure. Screening failure is defined as a participant who signed the consent form and was 
registered in the trial data system, but is found to be ineligible prior to start of treatment. Screening 
failures include patients who meet medical eligibility criteria but change their mind and do not 
consent to participate in the trial. The reason for screening failure will be recorded and keyed into 
the database.  
 
Screening visit: 
 
The patient will undergo a medical history to identify other illness and contraindications for 
participations such as use of narcotics for more than 3 days per week, previous surgery of the 
upper gastrointestinal tract, history of prolonged QT interval or clinical significant arrhythmia, etc.  
 
In addition, the patient will be provided with the questionnaires and will be administered on a daily 
basis for up two weeks before treatment with following questionnaires (delivered electronically): 
 
- Gastroparesis Cardinal Symptom Index Daily Diary (GCSI-DD)  

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
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- Rescue medication uses daily diary- number of pills and type. Rescue medications that will 
be allowed for this trial are ondansetron, promethazine and prochlorperazine. 
- Migraine and headache daily diary 
- Gastrointestinal Symptom Rating Scale (GSRS) 
- Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) 
- Beck Depression Inventory (BDI-II) 
- State- Trait Anxiety Inventory (STAI) 
- Average weekly frequency of migraine headaches for the last 4 week period 
- COMPASS-31 score.  
 
 
Anthropomorphic assessments (body weight, body height, body mass index [BMI]. Pregnancy 
test results that need to be recorded from chart review or obtained as part of the screening and 
EKG to rule out any abnormal baseline electrocardiogram such as second and third degree heart 
block, atrial fibrillation, atrial flutter, recent history of ventricular tachycardia or ventricular 
fibrillation, or clinically significant premature ventricular contraction, history of prolonged QT 
interval or a history of clinically significant arrhythmia. 
 
Data will be captured on REDCAP and stored on the secure Hopkins server for this purpose. 
 
2. Treatment Start Visit 
 
At this visit, the patient will receive the gammaCore (nVNS) device and a video instruction will 
be use to explain how to properly handle the device. Treatment can only start after eligibility has 
been fully checked and all data collected at screening have been keyed into the trial database. 
Women of childbearing potential must have a negative urine pregnancy test.  
 
After eligibility is confirmed with the clinical center staff the treatment can begin. The date of 
starting treatment is the start (ZERO) time for the timing of follow-up visits. 
 
Frequency and duration of nVNS treatment.  
The treatment will be self-administered using nVNS and will be applied for 8 weeks; 4 weeks will 
be used on one side of the neck and other 4 weeks in the contralateral side. A member of the 
study will provide the proper training on the correct use of nVNS. The patient will be instructed to 
use the nVNS in place of the rescue medications. When the nauseas gets bad enough that they 
feel to use a rescue medication they will first use the device on one side of the neck for two  2-
minute stimulations and wait fifteen minutes to check if the stimulation works. If this does not help 
either, they will stimulate with an additional 2 stimulations and wait for another fifteen minutes. If 
there is no improvement rescue medication will be used. nVNS can be used up to, but no more 
than, 8 times a day. 
 
3. Follow-up Visits 
 
Patients will return for follow-up visits at 4 and 10 weeks after treatment initiation. The specific 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
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procedures to be completed at each of the follow-up visits are: 
 
• 
Week 4 visit: The following questionnaires should be completed and collected: 
- Gastroparesis Cardinal Symptom Index Daily Diary (GCSI-DD)  
- Rescue medication uses daily diary- number of pills and type 
- Migraine and headache daily diary 
- Gastrointestinal Symptom Rating Scale (GSRS) 
- Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) 
- Beck Depression Inventory (BDI-II) 
- State- Trait Anxiety Inventory (STAI) 
- Average weekly frequency of migraine for the last 4 week period 
- COMPASS-31 score. 
- Global patient impression (GCPI) questionnaire.   
 
Laboratory test results that need to be collected are EKG and urine pregnancy test. 
Review study of adverse events will be addressed.  
 
• 
Week 8 visit: This will be the end of study visit. A medical history, including side effect or 
symptom profile will be collected. The following questionnaires should be completed and 
collected: 
 
- Gastroparesis Cardinal Symptom Index Daily Diary (GCSI-DD)  
- Rescue medication uses daily diary- number of pills and type 
- Migraine and headache daily diary 
- Gastrointestinal Symptom Rating Scale (GSRS) 
- Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) 
- Beck Depression Inventory (BDI-II) 
- State- Trait Anxiety Inventory (STAI) 
- COMPASS-31 score.  
- Global patient impression (GCPI) questionnaire. 
 
• 
Week 10 visit: This will be the end of study visit. A medical history, including side effect or 
symptom profile will be collected. The following questionnaires should be completed and 
collected: 
 
- Gastroparesis Cardinal Symptom Index Daily Diary (GCSI-DD)  
- Rescue medication uses daily diary- number of pills and type 
- Migraine and headache daily diary 
- Gastrointestinal Symptom Rating Scale (GSRS) 
- Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM) 
- Beck Depression Inventory (BDI-II) 
- State- Trait Anxiety Inventory (STAI) 
- COMPASS-31 score.  
- Global patient impression (GCPI) questionnaire. 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
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noninvasive Vagal Nerve Stimulation (nVNS) device Study Data Collection Schedule 
 
Screening & 
GammaCore treatment 
Visits 
(Weeks) 
Follow-up Visits: Weeks from start of 
treatment 
 
Screening 
(0) 
Treatment 
initiation  
(2) 
 
4 
 
8 
 
10 
Consent 
X 
 
 
 
 
Baseline medical 
history 
X 
 
 
 
 
GCSI-DD 
X 
 
X 
X 
X 
Rescue Medication 
Daily Diary 
X 
 
X 
X 
X 
Migraine and 
Headache Daily Diary 
X 
 
X 
X 
X 
Collection of GCSI-
DD 
 
X 
X 
X 
X 
Collection of Rescue 
Medication Daily 
Diary 
 
X 
X 
X 
X 
Collection of Migraine 
and Headache Daily 
Diary 
 
X 
X 
X 
X 
PAGI-SYM 
questionnaire 
X 
 
X 
X 
X 
GSRS questionnaire 
X 
 
X 
X 
X 
Beck Depression 
Inventory-II 
X 
 
X 
X 
X 
State Trait Anxiety 
Inventory 
X 
 
X 
X 
X 
COMPASS 31-score 
 
 
X 
X 
X 
Noninvasive Vagal 
Neural Stimulation 
(VNS) device 
dispensed 
 
X 
 
 
 
Follow-up medical 
history, including 
review of adverse 
events 
 
 
X 
 
X 
 
 
 
 
 
 
12-lead EKG 
X 
 
X 
 
 
Urine pregnancy test 
X 
 
X 
 
 
 
 
 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
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Specific Tests and Questionnaires 
 
 
• 
Pregnancy test: Women of childbearing potential must have a negative urine pregnancy 
test. 
 
• 
12-lead EKG: To rule out any abnormal baseline electrocardiogram such as second and 
third degree heart block, atrial fibrillation, atrial flutter, recent history of ventricular 
tachycardia or ventricular fibrillation, or clinically significant premature ventricular 
contraction, history of prolonged QT interval or a history of clinically significant arrhythmia. 
 
• 
Gastroparesis Cardinal Symptom Index (GCSI) Daily Diary:26 Consists of five core 
symptoms (nausea, vomiting, early satiety, postprandial fullness, upper abdominal pain). 
Each night, participants grade the severity of symptoms over the prior 24 hours. The GCSI-
DD core symptom composite score (an average of the five core symptoms) is designed to 
detect clinical improvement in symptoms of gastroparesis and to be used as a PRO 
outcome for clinical trials.  
 
• 
Rescue medication daily diary: Must contain the name of the antiemetic medications, 
dosage, frequency and number of pills during the day.  
 
• 
Gastrointestinal Symptom Rating Scale (GSRS): 27 The GSRS is a disease-specific 
instrument of 15 items combined into five symptom clusters depicting Reflux, Abdominal 
pain, Indigestion, Diarrhea, and Constipation. The GSRS has a seven-point graded Likert-
type scale where 1 represents the absence of troublesome symptoms and 7 represents 
very troublesome symptoms. The reliability and validity of the GSRS are well-documented 
and normative values for a general population are available. 
 
• 
Patient Assessment of Upper Gastrointestinal Disorders-Symptoms (PAGI-SYM): 28 The 
self-reported questionnaire is composed of 20 items and 6 subscales. The severity of each 
symptom item over a 2-week recall period is scored from 0 (none or absent) to 5 (very 
severe). The GCSI, a 9-symptom survey relevant to gastroparesis stratified in 3 subscales 
– nausea/vomiting, fullness/early satiety, and bloating, is contained in the PAGI-SYM. The 
GCSI correlates with patient severity ratings and is responsive to changes in overall 
symptoms. Two additional items for constipation and diarrhea also will be recorded and 
scored and their main symptom will be determined. 
 
• 
Beck Depression Inventory, Second Edition (BDI-II): 29 The BDI-II is a commonly used, 
reliable 21-item self-report measure designated to assess for depression. 
 
• 
State Trait Anxiety Inventory:30 The STAI is a 40-item self-report measure designed to 
assess both situational and characterological anxiety. This measure provides two 
subscale scores (State and Trait) and has been shown to exhibit good reliability and 
internal consistency. 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
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• 
Migraine and headache daily diary: is going to record various aspects of headache or 
migraine attacks, monitor the frequency, type, duration, severity, symptoms,  possible 
triggers and track medication use.  
 
• 
Migraine Frequency:  This will be obtained from the Migraine and headache daily diary. 
 
• 
COMPASS-31:31 Is a self-report measure for assessing symptoms of dysautonomia. Scale 
contains 31 questions in six domains, yielding an overall autonomic symptom score from 
0 to 100. The domains are orthostatic intolerance (4 questions), vasomotor (3 questions), 
secretomotor (4 questions), pupillomotor (5 questions), bladder (3 questions), and 
gastrointestinal (including diarrhea, constipation, and gastroparesis, 12 questions). For 
each question there is a numeric rating based on factors such as site, consistency, 
severity, frequency, or trends. 
 
Recruitments Procedures: 
 
Individuals Responsible for Approaching Participants: 
Prospective participants will be approached by their own physicians who are study team members 
Recruitment will take place while the potential participants are present for clinic appointments. 
Potential participants will be informed that participation is voluntary and that their care at Johns 
Hopkins will not be affected if they considered not participating it this study. 
 
How Privacy Issues will be addressed: 
The study team member will approach the participants when they are alone in the exam rooms to 
ensure privacy so that others cannot hear the conversation between the participant and study 
team members. After ensuring that sufficient privacy is achieved and that the potential subjects 
are at ease and comfortable with their surroundings, the consent designee will obtain informed 
consent to enter the study and explain the study procedures verbally and encourage the potential 
subjects to ask questions. 
 
The questionnaires will also be filled out during the treatment and during the 2 weeks after nVNS 
treatment has been completed. All questionnaires are short and easy to fill out with multiple-
choice type responses. Adverse events (AEs) will also diarized. 
 
All participants who sign the ICF will be registered in the trial database. Each participant who 
starts screening must be accounted for at the end of the screening, as either a screening success 
or a screening failure. A screening failure is defined and a participant who signed the consent 
form and was registered in the nVNS trial data system, but is found to be ineligible prior to start 
of treatment; screening failures include patients who meet medical eligibility criteria but change 
their mind and do not consent to participate in the trial. The reason for screening failure will be 
recorded and keyed into the trial database. 
 
5. 
Inclusion/Exclusion Criteria 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
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Inclusion criteria 
• 
Age 15 years or older at registration.  
• 
Diagnosis of gastroparesis as documented by gastric emptying scintigraphy (4-hour 
emptying after a low-fat meal with any combination of 2- and 4-hour retention of >60% and 
10%, respectively), or Chronic Unexplained Nausea and Vomiting (CUNV). 
• 
Ongoing symptoms (i.e. Nausea and vomiting, bloating, and abdominal pain) with a 
nausea score of 3 or more on the PAGI-SYM scale at baseline (moderate to severe 
nausea). 
• 
Exclusion of other causes of symptoms such as mechanical gastrointestinal obstruction, 
uncontrolled esophagitis, peptic ulcer disease, etc. By standard radiographic or 
endoscopic tests. 
• 
Use of the following medications on an as-needed basis: ondansetron, promethazine or 
prochlorperazine but no more than four times a day. 
 
Exclusion criteria 
• 
Another active disorder, which could explain symptoms in the opinion of the investigator. 
• 
Age < than 15 years. 
• 
Pregnancy or nursing. 
• 
A previous surgery of the upper gastrointestinal tract, including vagotomy. 
• 
Use of narcotics more than 3 days per week. 
• 
History of prolonged QT interval or a history of clinically significant arrhythmia. 
• 
Abnormal baseline ECG (e.g. Second- and third-degree heart block, atrial fibrillation, atrial 
flutter, recent history of ventricular tachycardia or ventricular fibrillation, or clinically 
significant premature ventricular contraction). 
• 
Previous bilateral or right cervical vagotomy. 
• 
Uncontrolled high blood pressure. 
• 
Currently implanted with an electrical and/or neurostimulator device, including but not 
limited to cardiac pacemaker or defibrillator, vagal neurostimulator, deep brain stimulator, 
spinal stimulator, bone growth stimulator, or cochlear implant. 
• 
History of carotid endarterectomy or vascular neck surgery on the right side. 
• 
Implanted with metal cervical spine hardware or has a metallic implant near the 
gammaCore stimulation site. 
• 
Any other condition, which in the opinion of the investigator would impede compliance or 
hinder the completion of the study. 
• 
Failure to give informed consent. 
 
6. 
Drugs/ Substances/ Devices 
 
gammaCore Sapphire (nVNS) 23-25 
 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
Revision 4 (11/14/2022)            Proprietary confidential information           Treisman, G. MD    
12 
 
Description: 
  
nVNS is a multi-use, hand-held, rechargeable, portable device consisting of a rechargeable 
battery, signal-generating and -amplifying electronics, and a control button for the patient to 
control the signal amplitude. The device provides visible (display) and audible (beep) feedback 
on the device and stimulation status. A pair of stainless steel surfaces, which are the skin contact 
surfaces (“stimulation surfaces”), allow the delivery of a proprietary electrical signal. The patient 
applies electroCore-approved gel to the stimulation surfaces to maintain an uninterrupted 
conductive path from the stimulation surfaces to the skin on the neck. Tubes of electroCore-
approved gel are provided with each unit and refill kit for this purpose. The stimulation surfaces 
are capped when not in use. 
 
7. 
Study Statistics 
 
Data analysis will be performed at Mayo Clinic Scottsdale, Arizona by Dr. Jay Pasricha,  
(Pasricha.Jay@mayo.edu). This site will no recruit participants.   
Johns Hopkins will serve as coordinating center, responsible for overall data management, 
monitoring and communication among both sites, and general oversight of the conduct of this 
protocol.  
  
Outcome measures 
 
Primary:   The primary outcome measure is the average daily use of rescue medications for 
exacerbation of nausea/vomiting. 
 
Sample size justification 
• 
Primary endpoint: Improvement in nausea control, as defined by a 50% reduction n the 
number of weekly doses of rescue medications, compared with baseline.  
• 
Total of 45 patients. This is a pilot study to assess the strength of the signal 
(improvement) with peripheral VNS for nausea. Since there is evidence that the left and 
right vagus may have different pathways within the CNS, with the left side being 
dominant in innervation of center involved in food aversion and nausea (Cell 175, 665–
678, 2018), we are proposing to study three groups as follows 
Group 1; Start with left sided stimulation - 15 patients 
Group 2. Start with right sided stimulation - 15 patients 
Group 3. Both sided stimulation - 15 patients 
• 
Our assumptions are as follows, in terms of the number of patients improving in each 
group 
Group 1: 4/15 
Group 2: 11/15 
Group 3: 7/15 
If these assumptions are true, the type I error will be < 0.05 
 
8. 
Risks32-34 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
Revision 4 (11/14/2022)            Proprietary confidential information           Treisman, G. MD    
13 
 
The adverse reactions observed in nVNS studies include: 
i. 
Shortness of breath (dyspnea), hoarseness, or change in voice during treatment. 
ii. 
Muscle twitching, discomfort, or pain during stimulation. 
iii. 
Change in taste (dysgeusia). 
These first three reactions resolved after treatment was completed. 
iv. 
Local skin irritation/inflammation. 
v. 
Any progression of headache symptoms. 
 
Adverse reactions not seen in the studies, but associated with implanted vagal nerve stimulation 
devices include: 
vi. 
Tingling, pricking, or a feeling of “pins and needles” on the skin where the device is applied 
(paresthesia or dysaesthesia) lasting beyond the treatment period. 
vii. 
Fainting (syncope), light-headedness, and/or dizziness. 
viii. 
Sweating. 
ix. 
Fatigue, depressed mood. 
x. 
Tinnitus. 
xi. 
Diarrhea. 
xii. 
Abnormal heart rhythm. 
 
Adverse events will be evaluated in every follow-up visit. A form of Adverse Event will be 
completed if the candidate complains of any symptoms, sign, abnormal assessment or any 
combination of these. An adverse event can be expected side effect that is of a serious nature, 
or an unexpected side effect/event regardless of severity.  
 
This study will monitor and report adverse events to ensure patient safety to IRB and FDA. Signs 
and symptoms associated with the adverse event will be graded as to severity by the clinical site 
staff as mild, moderate, or sever using Version 5.0 of the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (CTCAE). 
 
9. 
Benefits 
 
Description of the probable benefits for the participant and for society. 
 
The benefit to the participant includes the opportunity to have their rare, debilitating disease 
studied and better identified through specific diagnostic testing. 
 
Benefit/Risk Conclusion 
 
nVNS has been cleared as a low-risk Class II treatment. This indicated that the likely benefit 
outweighs the risks across the cleared indications. 
 
 
10. 
Payment and Remuneration 
 

Non-invasive vagal nerve stimulation (nVNS) for symptomatic exacerbations of nausea in patients with 
gastroparesis and related disorders (IRB00265410) 
 
Revision 4 (11/14/2022)            Proprietary confidential information           Treisman, G. MD    
14 
 
Participation in the study will be voluntary and there will be no additional compensation. There 
will be no penalties for not completing the protocol. 
 
11. 
Costs 
 
The study team will cover all the procedures, material and logistics. Electrocore will supply the 
Sapphire devices at no cost to the Investigator. 
 
12. 
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