Effects of Ondansetron on Gastrointestinal Sensorimotor Dysfunctions in Diabetes Mellitus and Dyspepsia

Study Overview
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Brief Summary
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Researchers are trying to understand why people with indigestion and diabetes mellitus have gastrointestinal symptoms and in particular to understand whether symptoms are related to increased sensitivity to nutrients in the small intestine. As part of this investigation, a medication called ondansetron will also be studied to determine its effects on gastrointestinal function and associated symptoms.

Detailed Description
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The primary objectives of this study are to evaluate the effects of ondansetron, on symptoms (i) during a gastric emptying study, (ii) during enteral lipid infusion and (iii) in daily life.

Official Title
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Effects of Ondansetron on Gastrointestinal Sensorimotor Dysfunctions in Diabetes Mellitus and Dyspepsia

Conditions
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Indigestion, Diabetes Mellitus

Intervention / Treatment
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* Drug: Ondansetron 8mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or non-pregnant, non-breastfeeding female volunteers; 18-75 years old; Able to provide written informed consent before participating in the study Able to communicate adequately with the investigator and to comply with the requirements for the entire study; including the willingness and ability to consume the components of the test meals Symptoms of dyspepsia (i.e., early satiety, postprandial discomfort, nausea, vomiting, regurgitation) Patients in the DM group will also require Type 1 or 2 DM of ≥ 3 years duration; in patients with type 2 DM, the dyspepsia symptoms should have begun or worsened after DM was diagnosed Exclusion Criteria: Major abdominal surgery (i.e., appendectomy, cholecystectomy, tubal ligation, hysterectomy, herniorrhaphy, and limited colonic resection are permissible) Clinical evidence (including physical exam and EKG) of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric or other disease that may interfere with the objectives of the study and/or pose safety concerns Current use of opiates, alpha adrenergic agonists, metoclopramide, monoamine oxidase inhibitors, more than one serotonergic medication, and high doses of anticholinergic agents (eg, amitriptyline greater than 50 mg daily). If medically safe, these drugs may be discontinued for four half lives prior to study assessments. Treatment with GLP-1 agonists and amlyin which cause vagal blockade and may affect central processing of pain Bleeding or clotting disorders or medications that increase risk of bleeding from mucosal biopsies Positive tissue transglutaminase antibodies (TTG), Pregnant or breast-feeding females Known intolerance or allergy to eggs Poor peripheral venous access, if central venous access is not available Any other condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study History of Long QT Syndrome or prolonged QT interval (i.e., corrected QT interval > 480 ms) Current symptoms of a functional gastrointestinal disorder assessed by questionnaire Severe vomiting that would preclude tube placement or participation in the study Structural cause for symptoms by endoscopy within the past 12 months Patients with gastric pacemakers

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Control Ondansetron 8 mg<br>Oral Ondansetron 8 mg administered in a single does dose during gastric emptying and duodenal infusion. | Drug: Ondansetron 8mg<br>* Oral Ondansetron 8 mg<br>* Other names: Zofran;|
| Experimental: Diabetic (DM) gastroenteropathy Ondansetron 8 mg<br>Oral Ondansetron 8 mg administered in a single does dose during gastric emptying and duodenal infusion. Oral Ondansetron 8 mg administered three times a day for weeks 3-6 | Drug: Ondansetron 8mg<br>* Oral Ondansetron 8 mg<br>* Other names: Zofran;|
| Experimental: Non-ulcer dyspepsia (NUD) Ondansetron 8 mg<br>Oral Ondansetron 8 mg administered in a single does dose during gastric emptying and duodenal infusion. Oral Ondansetron 8 mg administered three times a day for weeks 3-6 | Drug: Ondansetron 8mg<br>* Oral Ondansetron 8 mg<br>* Other names: Zofran;|
| Placebo Comparator: Healthy Control Placebo<br>Oral matched placebo administered in a single does dose during gastric emptying and duodenal infusion. | Drug: Placebo<br>* Oral matched placebo<br>|
| Placebo Comparator: Diabetic (DM) gastroenteropathy Placebo<br>Oral matched placebo administered in a single does dose during gastric emptying and duodenal infusion. Oral matched placebo administered three times a day for weeks 3-6 | Drug: Placebo<br>* Oral matched placebo<br>|
| Placebo Comparator: Non-ulcer dyspepsia (NUD) Placebo<br>Oral matched placebo administered in a single does dose during gastric emptying and duodenal infusion. Oral matched placebo administered three times a day for weeks 3-6 | Drug: Placebo<br>* Oral matched placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in severity of symptoms during enteral infusion | Visual analog scale (VAS) used to measure the change in symptom severity with a scale of 0=absent, 1=light, 2=moderate, 3=severe, 4=intolerable | baseline, every 15 minutes up to 8 hours | 
| Change in severity of symptoms during gastric emptying study | Visual analog scale (VAS) used to measure the change in symptom severity with a scale of 0=absent, 1=light, 2=moderate, 3=severe, 4=intolerable | baseline, every 15 minutes up to 2 hours | 
| Change in severity of daily symptoms | Gastroparesis Cardinal Symptom Index - Daily Diary (GCSI-DD) used to measure the change in symptoms severity with a scale of 0=none, 1= very mild, 2=mild,3=moderate, 4=severe, 5= very severe | Baseline, daily for six weeks | 
| Change in severity of gastrointestinal symptoms | Gastrointestinal Disorders - Symptom Severity Index (PAGI-SYM) used to measure the change in symptoms severity with a scale of 0=none, 1= very mild, 2=mild,3=moderate, 4=severe, 5= very severe | Baseline, 2 weeks, 6 weeks | 
| Change in severity of gastrointestinal symptoms effect on Quality of Life | Gastrointestinal Disorders - Quality of Life and Well-Being (PAGI-QOL) used to measure the change in symptoms severity with a scale of 0=none, 1= very mild, 2=mild,3=moderate, 4=severe, 5= very severe | Baseline, 2 weeks, 6 weeks | 
| Change in effect of Gastrointestinal symptoms on Quality of Life | Nepean Dyspepsia Index used to measure symptoms severity with a scale of 0=none, 1= very mild, 2=mild,3=moderate, 4=severe, 5= very severe | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose level | Compare the changes in glucose level during a lipid infusion | baseline, approximately 60-120 minutes | 
| Insulin level | Compare the changes in insulin level during a lipid infusion | baseline, approximately 60-120 minutes | 
| C-peptide level | Compare the changes in C-peptide level during a lipid infusion | baseline, approximately 60-120 minutes | 
| Glucagon-like Peptide 1 (GLP-1) | Compare the changes in Glucagon-like Peptide 1 (GLP-1) level during a lipid infusion | baseline, approximately 60-120 minutes | 
| Cholecystokinin (CCK) | Compare the changes in Cholecystokinin (CCK) level during a lipid infusion | baseline, approximately 60-120 minutes | 
| Ghrelin | Compare the changes in Ghrelin level during a lipid infusion | baseline, approximately 60-120 minutes | 
| Peptide YY (PYY) | Compare the change in Peptide YY (PYY) level during a lipid infusion | baseline, approximately 60-120 minutes | 
| Plasma | Compare the change in plasma level during a lipid infusion | baseline, approximately 60-120 minutes | 
| Effect of gastrointestinal symptoms on Quality of Life - Nepean Dyspepsia index | Score is derived from 25 items pertaining to QOL | Baseline | 
| Severity of gastrointestinal symptoms - Nepean Dyspepsia index | Nepean Dyspepsia Index is used to measure symptom severity with a scale of 0=none, 1= very mild, 2=mild,3=moderate, 4=severe, 5= very severe | Baseline |