Effects of Substance P Antagonists on Adrenal Secretion

Study Overview
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Brief Summary
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Data from the literature and previous in vitro research conducted in the investigators' laboratory (INSERM U413/EA4310, University of Rouen) suggest that adrenal corticosteroid secretion might be controlled by sympathetic nervous system. This neurocrine regulation of corticosteroid secretion involves locally released neuropeptides. Among them, substance P is able to stimulate aldosterone and cortisol production via NK1 receptors. The aim of the present study is to investigate the effects of a NK1 receptor antagonist, aprepitant, on adrenocortical secretions in healthy volunteers. Aprepitant is a drug already available for the treatment of nausea induced by chemotherapy. In the present phase IV trial, plasma aldosterone and cortisol levels will be measured under treatment with aprepitant versus placebo, in both basal conditions and after activation of the adrenocortical function by various stimuli, including upright posture, metoclopramide, and insulin-induced hypoglycaemia. All healthy volunteers will be given the two substances (aprepitant and placebo) in a random order during two one-week periods separated by a 14 day-wash-out. This study should allow to determine the role of substance P in the control of corticosteroid production in normal man.

Detailed Description
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STUDY DESIGN Phase IV, proof of concept, interventional, monocentric, randomised, double blind, cross-over study: The effects of a substance P antagonist (Emend) on corticosteroid secretion will be compared to those of a placebo. STUDY OBJECTIVES Main objective: to verify that adrenal corticosteroid secretion is actually controlled by substance P. Secondary objective: to determine the physiological conditions that involve the control of adrenocortical function by tachykinins. NUMBER OF SUBJECTS 20 healthy volunteers ELIGIBILITY CRITERIA (see below) DURATION OF STUDY Overall duration: 13 months Inclusion period: 12 months Follow up period (for 1 subject): 5 weeks Exclusion period: 1 month ENDPOINTS PRIMARY ENDPOINT: blood aldosterone variation during orthostatic test SECONDARY ENDPOINTS Basal aldosterone alteration Aldosterone variation during metoclopramide & hypoglycaemia tests Basal and stimulated (3 different tests) alterations of renin, cortisol & ACTH REGULATORY AUTHORIZATIONS Ethics committee authorization: dec 18th, 2008 Regulatory authorization: march 3rd, 2009

Official Title
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Pilot Study of the Action of the Substance P Antagonist Aprepitant on Aldosterone and Cortisol Secretion in Healthy Volunteers.

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: aprepitant/placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male subjects; Age ranging 18 - 30 years old; Submitted to a social security regimen; Agreeing to the study & Informed consent form signed; Body mass index ([weight (kg)/height (m)]²) < 27; No treatment received 6 weeks before inclusion; No anomaly after: complete clinical examination, pulse and blood pressure measurement, ECG; No biological abnormality after the following biological testing: Hematology: white & red blood cells & platelets count, haemoglobin, hematocrit Blood biochemistry: sodium, potassium, chloride, bicarbonate, creatinine, urea Urinary biochemistry (24 h collection): cortisol, aldosterone Serologies: HIV, HBV, HCV No participation in a clinical trial 3 months before inclusion. Exclusion Criteria: Subject not agreeing to the study or impossible to follow-up; Known history of significant medical or surgical pathology, notably endocrine; Renal or hepatic insufficiency; Nephrotic syndrome; Edematous syndrome; Hypertension or postural hypotension; Cardiac rhythm or conduction pathologies; Cardiac insufficiency; Epilepsy; Significant psychiatric disorder; Known history of severe allergy, hypersensitivity to aprepitant ant/or metoclopramide; Hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficit; Impaired lactose tolerance.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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Male

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

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aprepitant<br>7 days treatment with study drug, order of periods (active treatment or placebo) being sorted out. | Drug: aprepitant/placebo<br>* Aprepitant, 125 MG at day 1 then 80 MG day 2-7, once a day, per os, at 8 AM during breakfast<br>* Other names: Brand name : Emend;|
| Placebo Comparator: placebo<br>7 days treatment with study drug, order of periods (active treatment or placebo) being sorted out. | Drug: aprepitant/placebo<br>* Aprepitant, 125 MG at day 1 then 80 MG day 2-7, once a day, per os, at 8 AM during breakfast<br>* Other names: Brand name : Emend;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma aldosterone variation during orthostatic test |  | Day 5 of treatment, at each period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Basal aldosterone alteration; Aldosterone variation during metoclopramide & hypoglycaemia tests; Basal and stimulated (3 different tests) alterations of renin, cortisol & ACTH |  | Day 4, 5 and 7 of treatment, at each period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aldosterone, Substance P, Cortisol, Aprepitant, Adrenal glands