Pilot Study of Aprepitant Effect on Aldosterone Secretion in Diabetic Patient (Diabetes Mellitus) With Hypertension Associated With Low Renin (APHOS-02)

Aldosterone regulation is mediated by hormonal control, and nervous control. Autonomic nervous system action could be mediated by neuropeptides in the adrenal gland. Therefore, in pathological conditions and especially in diabetes, low-renin hypertension with normal or high plasma aldosterone could be caused by sympathetic nervous system hypertonia.

Data from the literature and previous in vitro research conducted in the investigators' laboratory (INSERM U982, 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. A previous clinical trial conducted at the University Hospital of Rouen, APHOS (NCT00977223) studied the effects of a NK1 receptor antagonist, aprepitant, on adrenocortical secretions in healthy volunteers.

The aim of the present study is to investigate the effects of a NK1 receptor antagonist, aprepitant, on adrenocortical secretions in volunteers with diabetes associated with low-renin hypertension. Aprepitant is a drug already available for the treatment of nausea induced by chemotherapy.

In the present phase II 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 upright posture. All volunteers will be given the two substances (aprepitant and placebo) in a random order during two 14 day-periods separated by a 21 day-wash-out.

This study should allow to determine the role of substance P in the control of corticosteroid production in human with diabetes, associated with a low-renin hypertension.

Study Overview

• Status: Unknown
• Conditions: Hypertension; Type 2 Diabetes
• Intervention / Treatment: Biological: Blood sampling; Procedure: Blood Pressure Measurement; Device: electrocardiogram; Procedure: orthostatic test; Drug: Administration of Aprepitant; Drug: Administration of placebo

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Julien WILS, Pharm; Phone Number: 8265 +3323288; Email: julien.wils@chu-rouen.fr

Study Locations

• France
  • Rouen, France
    • Recruiting
    • ROUEN university hospital
    • Principal Investigator: Gaétan PREVOST, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or menopausal female 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 ago before inclusion,
• Subscription to national social security,
• Signed informed consent.

Exclusion Criteria:

• Female subject potentially pregnant,
• Subject younger than 18 year-old and older than 70 year-old,
• Subject without diabetes condition or with diabetes but normal blood pressure (below 130/80 mmHg),
• Subject with glycated hemoglobin HbA1c < 6.5% or >11%,
• Subject with leuconeutropenia (neutrophils below 1700/mm3),
• Subject with severe medical or surgical history,
• Patients treated with drugs metabolized by CYP3A4 and CYP2C9: corticosteroids, vitamin K , hormonal contraceptives, tolbutamide, benzodiazepines, derived from ergot, antiepileptics, hypericum, macrolides, azole antifungals.
• Patients treated with drugs interfering with the renin-angiotensin- aldosterone system : beta-blockers, diuretics , anti -aldosterone drugs , direct renin inhibitors , insulin,
• type 2 diabetes patients with a vegetative autonomic neuropathy,
• Patients with adrenal mass was diagnosed at imaging,
• hepatic or renal impairment (defined respectively by secondary clinical and biological manifestations altered hepatocyte functions or estimated glomerular filtration rate less than 60 mL / min / 1.73 m2);nephrotic syndrome (defined by hypoalbuminemia less than 30 g / L associated with proteinuria at 3 grams / 24 hours);edematous syndrome (defined by the presence of edema of the lower limbs),
• Orthostatic hypotension (defined by a decrease in systolic blood pressure of 20 mmHg and at least the diastolic blood pressure of 10 mmHg or more),
• arrhythmias or cardiac conduction,
• heart failure (NYHA class II minimum),
• epilepsy,
• serious psychiatric condition,
• Severe allergic history, hypersensitivity to aprepitant,
• People with hereditary problems of fructose intolerance, glucose malabsorption, galactose, or sucrase-isomaltase,
• People with lactose intolerance,
• subject unwilling or cannot be followed regularly. Persons deprived of their liberty by a judicial or administrative decision, those hospitalized without consent and those admitted to a health or social establishment for purposes other than research, the adults subject to a measure of legal protection or unable to consent may not be included.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Administration of Aprepitant; Administration of Aprepitant 80 mg once per day during 14 days; Blood sampling, electrocardiogram, orthostatic test and Blood Pressure Measurement are done after 14 days	Biological: Blood sampling; Blood sampling for Plasma aldosterone, Plasma cortisol, plasma renin, plasma electrolytes after before and after administration of Aprepitant 80 mg once per day during 14 days or Administration of placebo once per day during 14 days; Procedure: Blood Pressure Measurement; Blood Pressure Measurement before and after Administration of Aprepitant 80 mg once per day during 14 days or administration of placebo once per day during 14 days; Device: electrocardiogram; Electrocardiogram before and after Administration of Aprepitant 80 mg once per day during 14 days or administration of placebo once per day during 14 days; Procedure: orthostatic test; Orthostatic test after Administration of Aprepitant 80 mg once per day during 14 days or administration of placebo once per day during 14 days; Drug: Administration of Aprepitant; Administration of Aprepitant 80 mg once per day during 14 days
Placebo Comparator: Administration of placebo; Administration of Placebo once per day during 14 days; Blood sampling, electrocardiogram, orthostatic test and Blood Pressure Measurement are done after 14 days	Biological: Blood sampling; Blood sampling for Plasma aldosterone, Plasma cortisol, plasma renin, plasma electrolytes after before and after administration of Aprepitant 80 mg once per day during 14 days or Administration of placebo once per day during 14 days; Procedure: Blood Pressure Measurement; Blood Pressure Measurement before and after Administration of Aprepitant 80 mg once per day during 14 days or administration of placebo once per day during 14 days; Device: electrocardiogram; Electrocardiogram before and after Administration of Aprepitant 80 mg once per day during 14 days or administration of placebo once per day during 14 days; Procedure: orthostatic test; Orthostatic test after Administration of Aprepitant 80 mg once per day during 14 days or administration of placebo once per day during 14 days; Drug: Administration of placebo; Administration of placebo once per day during 14 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference from baseline in Plasma aldosterone concentration	Plasma aldosterone concentration is analyzed	Baseline and Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference from baseline in Plasma cortisol	Plasma cortisol concentration is analyzed	Baseline and Day 14
Difference from baseline in plasma renin	plasma renin concentration is analyzed	Baseline and Day 14
Difference from baseline in blood electrolytes measurement	blood electrolytes concentration is analyzed	Baseline and Day 14
Difference from baseline in HOMA index		Baseline and Day 14

Collaborators and Investigators

• Sponsor: University Hospital, Rouen
• Investigators: Principal Investigator: Gaétan PREVOST, MD, ROUEN university hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2017
• Primary Completion (Anticipated): July 1, 2019
• Study Completion (Anticipated): July 1, 2019

Study Registration Dates

• First Submitted: May 25, 2016
• First Submitted That Met QC Criteria: June 20, 2016
• First Posted (Estimate): June 23, 2016

Study Record Updates

• Last Update Posted (Actual): August 22, 2017
• Last Update Submitted That Met QC Criteria: August 21, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hypertension; Diabetes Mellitus; 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
• Other Study ID Numbers: 2013/142/HP

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No