Effect of CRH on Duodenal Markers and Gastric Sensorimotor Function

Study Overview
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Brief Summary
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In the present study, during Part 1, after a baseline gastroduodenoscopy, the investigators will perform a gastroduodenoscopy twice, to take duodenal biopsies before and 2 hours after administration of CRH/placebo. The investigators will measure mucosal integrity and markers of immune activation as outlined in Parts A and B, and will use transmission electron microscopy to evaluate mast cell and eosinophil degranulation. After an interval period of at least 1 week, CRH or placebo will be administrated again in a crossover fashion. As a complementary study, the investigators will also test the effect of ex vivo mast cell blockade by lodoxamide to evaluate whether mast cells are involved in the hypothesized effect of CRH on duodenal permeability. In a second part of this study, Part 2, the investigators will perform a gastric barostat, to measure the gastric accommodation and sensitivity to distension, and a carbon-13-octanoic acid breath test to measure the gastric emptying time after administration of CRH/placebo. Healthy volunteers will have the option to choose to which part of the study (part 1 or 2) they wish to participate. They can also choose to cooperate to both study parts if preferred.

Official Title
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The Effect of Corticotropin Release Hormone on Duodenal Markers and Gastric Sensorimotor Function in Healthy Volunteers

Conditions
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GI Motility Disorder

Intervention / Treatment
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* Drug: Corticotropin-release hormone
* Drug: Corticotropin-release hormone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary written informed consent of the participant has been obtained prior to any screening procedures Women of child-bearing potential agree to apply a highly effective methods of birth control; defined as those that, alone or in combination, result in low failure rate (i.e., less than 1% per year) when used consistently and correctly; such as implants, injectables, combined oral contraceptives, some IUDs, true sexual abstinence (i.e. refraining from heterosexual intercourse during the entire period of risk associated with the Trial treatment(s)) or commitment to a vasectomised partner. Women of non-childbearing potential may be included if surgically sterile (tubal ligation or hysterectomy) or postmenopausal with at least 2 year without spontaneous menses. Healthy volunteers Subjects aged 18-55 years old (55y included). Male or female subjects. Subjects who are capable to understand the study and the questionnaires, and to comply with the study requirements. Exclusion Criteria: Any disorder, which in the Investigator's opinion might jeopardise the participant's safety or compliance with the protocol Any prior or concomitant treatment(s) that might jeopardise the participant's safety or that would compromise the integrity of the Trial Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate, highly effective contraceptive Presence of a history of gastrointestinal surgery other than appendectomy Presence of organic or functional gastrointestinal disease Presence of gastro-intestinal symptoms Major psychiatric disorder such as major depression Presence of any disease affecting the gastrointestinal tract or hepatobiliary system. History of allergic reaction to CRH BMI equal to 30 mg/kg² or higher. Use of drugs included in this list: Opioids (unless short intake for acute pain and > 1month ago) Amitriptyline or mirtazapine; other antidepressants are allowed if the HV is on a stable dose and the drug is not combined with other antidepressants. Corticosteroids Antihistaminic drugs (last 2 weeks) Proton pump inhibitors (last 2 weeks) Disodiumchromoglycate or other mast cell stabilizers (last 2 weeks) Leukotriene receptor antagonists (last 2 weeks) NSAIDs (last 2 weeks) Antibiotics (last 2 months) Probiotics (last 2 weeks) Other medication: to be discussed with physician

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: To assess the effect of the CRH on on duodenal mast cell count, eosinophil count, immune activation and mucosal permeability, gastric accommodation, gastric sensitivity to distension and gastric emptying time, an interventional study will be conducted in 20 healthy subjects. The study is designed as a double-blind randomized crossover study with at least 7 days between the different study days.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cortisol releasing hormone group<br>HVs will start with CRH infusion. | Drug: Corticotropin-release hormone<br>* intravenous CRH (100 µg)<br>Drug: Corticotropin-release hormone<br>* a bolus dose (CRH 100 µg or placebo) will be administered, followed by a continuous infusion (CRH 1 µg/kg/h or placebo)<br>|
| Placebo Comparator: Placebo (sodium choride) group<br>HVs will start with NaCl 0.9% (placebo) infusion | Drug: Corticotropin-release hormone<br>* intravenous CRH (100 µg)<br>Drug: Corticotropin-release hormone<br>* a bolus dose (CRH 100 µg or placebo) will be administered, followed by a continuous infusion (CRH 1 µg/kg/h or placebo)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of corticotrophin release hormone (CRH) on duodenal mast cell count | Duodenal mast cells (c-kit) will be counted per mm2 via stained duodenal biopsy sections. | 2 hours after CRH/placebo | 
| The effect of CRH on sensitivity to gastric distention (part 2) | Visceral sensitivity will be measured by barostat. Discomfort threshold will be defined as the first level of pressure and the corresponding volume that provokes discomfort. Pressure thresholds will be expressed both as pressures relative to minimal distending pressure and as absolute pressures. | 30 minutes after CRH/placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of CRH on duodenal eosinophilia | Duodenal eosinophils (H&E) will be counted per mm2 via stained duodenal biopsy sections. | 2 hours after CRH/placebo | 
| The effect of CRH on duodenal mucosal permeability | Duodenal mucosa permeability on duodenal biopsies using adapted mini-Ussing chambers | 2 hours after CRH/placebo | 
| The effect of CRH on gastric emptying time | Gastric emptying time in minutes t (1/2) will be measured by 13C-octanoic acid breath test. | 30 minutes after CRH/placebo | 
| The effect of CRH on gastric accommodation | Gastric accommodation will be measured by barostat. Accommodation to a meal will be expressed as the average increase in intragastric volume during the first 4 postprandial hours. | 30 minutes after CRH/placebo | 
| The effect of CRH on gastroduodenal symptoms. | Assessments using Visual Analog Score for GI symptoms which including pain, nausea, bloating, vomiting. | Every 15 minutes during CRH/placebo infusion for 4 hours | 
| The effect of CRH on salivary cortisol level | Salivary cortisol level in nmol/L during placebo or CRH infusion | Right before CRH/placebo injection, 15, 30, 60, 120 minutes after injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cortisol releasing hormone, 3.1 Functional dyspepsia