Effects of Substance P Antagonists on Adrenal Secretion (APHOS)

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: aprepitant/placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Haute Normandie
    • Rouen, Haute Normandie, France, 76031
      • Rouen Clinical research Centre (CIC 0204)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 30 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University Hospital, Rouen
• Investigators: Principal Investigator: Hervé Lefebvre, PHD, Rouen university hospital

Publications and helpful links

General Publications

• Wils J, Duparc C, Cailleux AF, Lopez AG, Guiheneuf C, Boutelet I, Boyer HG, Dubessy C, Cherifi S, Cauliez B, Gobet F, Defortescu G, Menard JF, Louiset E, Lefebvre H. The neuropeptide substance P regulates aldosterone secretion in human adrenals. Nat Commun. 2020 May 29;11(1):2673. doi: 10.1038/s41467-020-16470-8.

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: September 14, 2009
• First Submitted That Met QC Criteria: September 14, 2009
• First Posted (Estimate): September 15, 2009

Study Record Updates

• Last Update Posted (Estimate): February 16, 2012
• Last Update Submitted That Met QC Criteria: February 14, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: Cortisol; Substance P; Aldosterone; Aprepitant; Adrenal glands
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Neurokinin-1 Receptor Antagonists; Aprepitant; Fosaprepitant
• Other Study ID Numbers: 2007/049/HP; 2008-003367-40 (EudraCT Number)