Effect of Secretin in Functional Dyspepsia and Healthy Subjects

Study Overview
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Brief Summary
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Insights into the pathophysiology of functional dyspepsia, with recent demonstration of inflammation with eosinophilia and mastocytosis in the duodenum (3, 6, 7), providing a possible lead toward reduced secretion of a potential mediator of post-prandial gastric accommodation, the gastrointestinal peptide hormone secretin. The dominant site of synthesis and secretion of this hormone are enteroendocrine S cells in the duodenum. Inflammation-induced damage to these cells could produce a deficiency. Since intraluminal acid is a prominent stimulant of S cell secretion, the attempts to treat functional dyspepsia with anti-secretory medications could actually exacerbate a secretin deficiency syndrome. This raises the possibility of the therapeutic use of a secretin agonist or a positive allosteric modulator of the secretin receptor for patients with functional dyspepsia.

Detailed Description
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The investigators will utilize single photon emission computed tomography (SPECT) methodology and gamma scintigraphy present in the GI laboratory of the outpatient Clinical Research Unit to study fasting gastric volumes and postprandial gastric accommodation responses and gastric emptying rates of a standardized meal in patients with functional dyspepsia and healthy subjects. Both groups will be studied twice, using crossover design, once with administration of secretin and once with placebo.

Official Title
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Effect of Secretin on Gastric Accommodation, Emptying and Post-nutrient Challenge Symptoms in Functional Dyspepsia and Healthy Subjects

Conditions
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Dyspepsia, Healthy

Intervention / Treatment
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* Drug: Human Secretin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Patients with FD and prior documentation of normal or accelerated gastric emptying and/or reduced gastric accommodation. Inclusion criteria: Able to provide written informed consent prior to any study procedures and be willing and able to comply with study procedures No medical problems or chronic diseases, other than functional dyspepsia, for that group Body mass index of 18-35 kg/m2 Female subjects must have negative urine pregnancy tests and must not be lactating prior to receiving study medication and radiation exposure. For females able to bear children, a hormonal (i.e., oral, implantable, or injectable) and single-barrier method, or a double-barrier method of birth control must be used throughout the study. Female subjects unable to bear children must have this documented in the medical record [i.e., tubal ligation, hysterectomy, or post-menopausal (defined as a minimum of one year since the last menstrual period)]. Exclusion criteria: Unable or unwilling to provide informed consent or to comply with study procedures Diagnosis of other gastrointestinal diseases besides functional dyspepsia Structural or metabolic diseases that affect the GI system Unable to avoid the following over-the-counter medications 48 hours prior to the baseline period and throughout the study: Medications that alter GI transit or motor function including laxatives, magnesium and aluminum containing antacids, prokinetics, erythromycin, buspirone, clonidine, tricyclic antidepressants, and secretin-norepinephrine reuptake inhibitors Analgesic drugs including NSAIDs and COX-2 inhibitors NOTE: Stable doses of thyroid replacement, estrogen replacement, low-dose aspirin for cardio-protection, low stable dose antidepressants of the SSRI class, and birth control (but with adequate backup contraception, as drug interactions with birth control have not been conducted) are permissible. History of recent surgery (within 60 days of screening) Acute or chronic illness or history of illness which in the opinion of the investigator could pose a threat or harm to the subject or obscure interpretation of laboratory test results or interpretation of study data, such as frequent angina, Class III or IV congestive heart failure, moderate impairment of renal or hepatic function, poorly controlled diabetes, etc. Any clinically significant abnormalities on physical examination or laboratory abnormalities identified in the medical record, as determined by the investigator Acute GI illness within 48 hours of initiation of the baseline period Females who are pregnant or breastfeeding History of excessive alcohol use or substance abuse Participation in an investigational study within the 30 days prior to dosing in the present study Any other reason, which in the opinion of the investigator, would confound proper interpretation of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy Controls: Secretin Then Placebo<br>Healthy subjects first receive human Secretin 0.2 mcg/kg via IV over 1 min on Visit Day 1. After a 1 to 4 week washout period, they received the placebo treatment (normal saline, matching Secretin dose) via IV over 1 min on Visit Day 2. | Drug: Human Secretin<br>* Injected once over one minute<br>* Other names: ChiRhoStim;Drug: Placebo<br>* Injected once over one minute<br>* Other names: Normal Saline;|
| Experimental: Healthy Controls: Placebo Then Secretin<br>Healthy subjects first receive placebo treatment (normal saline, matching Secretin dose) via IV over 1 min on Visit Day 1. After a 1 to 4 week washout period, they received the human Secretin 0.2 mcg/kg via IV over 1 min on Visit Day 2. | Drug: Human Secretin<br>* Injected once over one minute<br>* Other names: ChiRhoStim;Drug: Placebo<br>* Injected once over one minute<br>* Other names: Normal Saline;|
| Experimental: Functional Dyspepsia: Secretin Then Placebo<br>Functional Dyspepsia subjects first receive human Secretin 0.2 mcg/kg via IV over 1 min on Visit Day 1. After a 1 to 4 week washout period, they received the placebo treatment (normal saline, matching Secretin dose) via IV over 1 min on Visit Day 2. | Drug: Human Secretin<br>* Injected once over one minute<br>* Other names: ChiRhoStim;Drug: Placebo<br>* Injected once over one minute<br>* Other names: Normal Saline;|
| Experimental: Functional Dyspepsia: Placebo Then Secretin<br>Functional Dyspepsia subjects first receive placebo treatment (normal saline, matching Secretin dose) via IV over 1 min on Visit Day 1. After a 1 to 4 week washout period, they received the human Secretin 0.2 mcg/kg via IV over 1 min on Visit Day 2. | Drug: Human Secretin<br>* Injected once over one minute<br>* Other names: ChiRhoStim;Drug: Placebo<br>* Injected once over one minute<br>* Other names: Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Satiation | Thirty (30) minutes after ingesting the meal of 300 mL radio-labeled Ensure drink, an additional Ensure drink was ingested at a constant rate of 30 mL/min until maximum tolerated volume was reached. | 60 minutes | 
| Fasting Gastric Volume | Gastric fasting volume was measured prior to a meal of 300 mL standardized radio-labeled Ensure drink using an intravenous injection of Technetium Tc-99m pertechnetate and noninvasive single photon emission-computed tomography (SPECT). | Baseline | 
| Postprandial Volume | Postprandial volume was measured 15 minutes after ingestion of 300 mL standardized radio-labeled Ensure drink using an intravenous injection of Technetium Tc-99m pertechnetate and noninvasive single photon emission-computed tomography (SPECT). | 15 minutes | 
| Change in Gastric Accommodation | The change in gastric accommodation was measured in mL using the difference between the fasting gastric volume and the postprandial volume. | Baseline, 30 minutes | 
| Gastric Emptying | Gastric emptying was measured via scintigraphy 30 minutes after ingestion of 300 mL of radio-labeled Ensure drink and was reported as the percentage of the radio-labeled liquid meal emptied from the stomach. | 30 minutes | 
| Change in Postprandial Symptoms | 30 minutes after ingesting a meal of 300 mL of Ensure drink postprandial symptoms of fullness, nausea, bloating and pain were measured using a horizontal visual analog scales from 0 to 100, where 0 was 'none' and 100 was 'worst ever'. | Baseline, 30 minutes |