Vagal Nerve Stimulation for Gastroparesis

Study Overview
=================
Brief Summary
-----------------
This study is investigating a new form of treatment for a digestive disorder called gastroparesis. Gastroparesis is thought to be caused by a mix of inflammation and neural dysfunction. The vagal nerve is a large nerve originating from the brain that regulates digestive function. Patients with gastroparesis have what is a called a low vagal tone which results in gastrointestinal motility problems and inflammation; therefore, investigators hypothesize that increasing vagal tone through a hand-held vagal nerve simulator will reduce inflammation and gastrointestinal motility problems in gastroparesis patients. Investigators will evaluate this hypothesis through the use of upper endoscopy testing, breath testing, and blood, stool, urine, heart rate variability, and saliva testing before and after 4 weeks of vagal nerve stimulation (VNS) treatment. There are 6 research visits Visit 1 and visit 2 may take up to 8 weeks (screening/baseline) Visit 3 and visit 4 will take 4 weeks (VNS treatment) visit 5 and 6 will take approximately 4 weeks (VNS followup/washout) Consequently, it is possible that if a patient were to be at the farthest ends of visit windows, they could potentially be in the study for approx 16 weeks. Visit 1 and 2 may be less than 8 weeks which would shorten the patient's overall involvement in the study. The treatment phase of the study will always be 4 weeks with an additional 4 week washout phase. Use of the VNS device takes 4 weeks. Endoscopy and blood work are taken before and after the treatment period.

Official Title
-----------------
Therapeutic Potential and Neuroimmune Mechanisms of Vagal Nerve Stimulation on Gastrointestinal Motility and Inflammation

Conditions
-----------------
Gastroparesis

Intervention / Treatment
-----------------
* Device: Vagal Nerve Stimulation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female. Age 21-65 years old. Established diagnosis of functional dyspepsia, idiopathic or diabetic gastroparesis as per AGA (American Gastroenterology Association) guidelines. Patient is capable of giving informed consent and undergo upper endoscopy. Patient is on stable doses of other medications for gastroparesis for preceding 4 weeks prior to enrollment (baseline measures). Exclusion Criteria Surgical-related gastroparesis Extrinsic myopathy or neuropathy causing gastroparesis. Use of narcotic pain medications in the preceding 2 weeks of study enrollment. Patients with enteric feeding tubes or requiring parenteral nutrition (Patients with g-tubes who are stable for 3 months and not using the g-tube for venting may be eligible. patient with J-tubes are not eligible. Patients with severe flare requiring hospitalization. Untreated significant depression or suicidal thoughts. Pregnant or breast-feeding women. History of gastric pacemaker implantation. Patients with prior gastric surgery, including fundoplication, partial/total gastrectomy, or gastric bypass. Patients with malabsorption of enteric, pancreatic, or hepatibiliary etiology. Patients with primary pulmonary disorders that affect the spirulina breath test. Patients with implantable electronic devices. Patients with carotid artery atherosclerosis.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 15 participants planned enrollment in each arm: Diabetic Gastroparesis Functional Dyspepsia Idiopathic Gastoparesis
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Idiopathic Gastroparesis<br>Patients with idiopathic gastroparesis and delayed gastric emptying. All patients in trial will be giving themselves vagal nerve stimulation for two minutes on each side twice a day in the morning and the night for four weeks starting at visit 3 and ending at visit 5. | Device: Vagal Nerve Stimulation<br>* Patients will be giving themselves vagal nerve stimulation for four weeks at interval of two times a day for two minutes on each side for four weeks. The impact of the intervention on gastroparesis symptoms will be measured by upper endoscopy biopsies, blood work, autonomic function tests, survey data, stool samples, urine sample, and saliva samples before after after the four weeks of stimulation treatment.<br>|
| Experimental: Diabetic Gastroparesis<br>Patients with diabetic gastroparesis and delayed gastric emptying. All patients in trial will be giving themselves vagal nerve stimulation for two minutes on each side twice a day in the morning and the night for four weeks starting at visit 3 and ending at visit 5. | Device: Vagal Nerve Stimulation<br>* Patients will be giving themselves vagal nerve stimulation for four weeks at interval of two times a day for two minutes on each side for four weeks. The impact of the intervention on gastroparesis symptoms will be measured by upper endoscopy biopsies, blood work, autonomic function tests, survey data, stool samples, urine sample, and saliva samples before after after the four weeks of stimulation treatment.<br>|
| Experimental: Functional Dyspepsia<br>Patients with functional dyspepsia and normal gastric emptying. All patients in trial will be giving themselves vagal nerve stimulation for two minutes on each side twice a day in the morning and the night for four weeks starting at visit 3 and ending at visit 5. | Device: Vagal Nerve Stimulation<br>* Patients will be giving themselves vagal nerve stimulation for four weeks at interval of two times a day for two minutes on each side for four weeks. The impact of the intervention on gastroparesis symptoms will be measured by upper endoscopy biopsies, blood work, autonomic function tests, survey data, stool samples, urine sample, and saliva samples before after after the four weeks of stimulation treatment.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Vagal Nerve Stimulation on Gastroparesis Symptoms as Measures by the Gastroparesis Cardinal Symptom Index Daily Diary (GCSI-DD) Questionnaire. | Investigators will send daily GCSI-DD to patients for 8 weeks. This 10 item questionnaire measures the severity of gastroparesis symptoms on a scale 0-5. 0=none, 1=very mild, 2=mild, 3=moderate, 4=severe, 5=very severe. Investigators hypothesize a change of more than 0.75 points. Scored were recorded daily at each time point and scores then averaged to produce an overall score (range: 0 to 5, higher scores correspond to worse symptoms). | Baseline (2 weeks prior to initiation), week 4 (7 days), week 8 (7 days) | 
| Effect of Vagal Nerve Stimulation on the Gastric Emptying Spirulina Breath Test Emptying Time | Investigators will measure a change in gastric emptying time before and after vagal nerve stimulation as measured in minutes. Higher number (longer times) indicate more severe gastroparesis. | Baseline and week 4 (3 hours to assess at each time point) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PROMIS Pain Interference Questionnaire Score as a Measure of the Effect of VNS Therapy on Overall Pain | The effect of VNS therapy on overall pain interference as assessed by the PROMIS (Patient Reported Outcomes Measurement Information System) pain interference questionnaire which is a 6 item questionnaire on a 5 point scale to assess the impact of pain on daily life. Scores are summed and converted to percentiles normalized for the population (normalized T-score). 50 indicates the population mean with a standard deviation of 10. The higher the T-score, the more severe the symptoms. | Baseline, week 4, week 8 | 
| Short Form 12 (SF-12) Score the Effect of VNS Therapy on Overall Wellbeing and Health | The effect of VNS therapy on overall wellbeing and health as assessed by the SF-12. Score range: 0-100, higher scores correspond to better quality of life. | Baseline, week 4, week 8 | 
| Number of Participants With Any Serious or Treatment-emergent Adverse Event (AE) as a Measure of the Safety and Tolerability of VNS in Patients With Gastroparesis | The safety and tolerability of VNS in patients with gastroparesis assessed by recording any side effects or adverse events. Number of patients reporting serious or treatment related adverse events are reported | 8 weeks | 
| Heart Rate Variability (HRV) as a Measure of the Effect of VNS Therapy on Vagal Tone | The effect of VNS therapy on vagal tone as measured bv HRV (accounting for respiratory rate variability) using electrocardiogram (ASNAR) device. HRV is measured as an RFa value, a measure of the high-frequency heart rate (bpm^2 per hertz). Normal RFa is 0.5 to 8.0. | Baseline, week 4, week 8 | 
| Effect of VNS on Mucosal Inflammation | Median fluorescence intensity (MFI) data were preprocessed for each cytokine through a sequence of averaging over duplicate wells, natural-logarithm transformation to reduce variance heterogeneity, and isolation and removal of plate effects. The effects of VNS therapy on gastric and small intestine inflammation was measured as average fold change across all tissue cytokines from endoscopic mucosal biopsies before and after VNS, using cytokine multiplex assays, which report relative levels of various cytokines as adjusted mean fluorescence intensity (MFI). | Baseline (pre-VNS) and 4 weeks (post-VNS) | 
| The Effect of VNS Therapy on Gastric and Small Intestine Leukocyte Infiltration. | The effects of VNS therapy on gastric and small intestine leukocyte infiltration was measured as relative abundance (normalized ratio) of immune cells (identified via CD45 marker) to total live cells across tissue leukocytes from endoscopic mucosal biopsies before and after VNS, using flow cytometry. | Baseline (pre-VNS) and 4 weeks (post-VNS) |