Fludrocortisone in Healthy Volunteers (AFLUCO4) (AFLUCO4)

Hemodynamic and Biological Effects of 3 Increasing Doses of Fludrocortisone in Healthy Volunteers

Fludrocortisone, in association with hydrocortisone, has demonstrated an improvement in survival in septic shock patients with relative adrenal insufficiency. However, the utility of low doses of steroids and in particular of mineralocorticoids in septic shock is still discussed.

The purpose of the investigators study is to investigate the effects of 3 increasing doses of fludrocortisone (100 μg, 200 μg, 400 μg) in order to determine which dose allows the best pressor response to phenylephrine in healthy volunteers, and simultaneously assess their respective hemodynamic and biological effects.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Placebo; Drug: Fludrocortisone 100 μg; Drug: Fludrocortisone 200 μg; Drug: Fludrocortisone 400 μg

Detailed Description

In a previous study (AFLUCO2) in healthy volunteers with saline-induced hypoaldosteronism, the investigators found that single doses of both hydrocortisone and fludrocortisone induced a significant decrease in the pressor response to phenylephrine, probably due to a rapid non-genomic vasodilatory mechanism, and that these effects were additive.

The investigators also showed that, at the doses used in septic shock, hydrocortisone induced more pronounced mineralocorticoid effects than fludrocortisone and also induced systemic hemodynamic effects whereas fludrocortisone did not.

The investigators now want to perform a dose-response study under normal conditions (ie without saline-induced hypoaldosteronism) and after repeated administrations, to determine the optimal dose of fludrocortisone that allows an increase in the pressor response to phenylephrine and to characterize its concomitant hemodynamic and biological effects.

This placebo-controlled, randomized, double-blind, cross-over, 4-periods (fludrocortisone 100 μg/day, 200 μg/day, 400 μg/day, or placebo) study aims to investigate hemodynamic and biological effects of fludrocortisone administered orally during 5 days, in healthy volunteers.

Each period will be separated from the next one by a washout interval of at least 14 days.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Rennes, France, 35033
    • Rennes University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 25 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Men aged 20 to 25 years
• Body Mass Index between 20 kg/m² and 25 kg/m²
• Nonsmoker since at least 6 months
• Normal clinical examination, electrocardiogram and transthoracic echocardiography
• Normal routine biological parameters
• Written informed consent

Exclusion Criteria:

• History of significant allergy
• Resting heart rate < 50 bpm
• Subjects with abnormal hepatic or renal function, or cardiovascular, pulmonary, endocrine or psychiatric disease
• Ongoing medication during the study
• Alcohol consumption more than 30g/day or drug addiction
• Exclusion period mentioned on the national registry for clinical trials volunteers.
• Subject under legal protection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fludrocortisone 100 μg; 100 μg/day (25 µg four times daily) of fludrocortisone during 5 days; Investigations the sixth day	Drug: Fludrocortisone 100 μg; Fludrocortisone 100 μg/day
Experimental: Fludrocortisone 200 μg; 200 μg/day (50 µg four times daily) of fludrocortisone during 5 days; Investigations the sixth day	Drug: Fludrocortisone 200 μg; Fludrocortisone 200 μg/day
Experimental: Fludrocortisone 400 μg; 400 μg/day (100 µg four times daily) of fludrocortisone during 5 days; Investigations the sixth day	Drug: Fludrocortisone 400 μg; Fludrocortisone 400 μg/day
Placebo Comparator: Placebo; Placebo (four times daily) during 5 days; Investigations the sixth day	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Phenylephrine mean blood pressor dose-response relationship.	1.5 hour after fludrocortisone administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac systolic and diastolic function assessed par transthoracic echocardiography during phenylephrine administration		between 1.5 and 2.5 hours after fludrocortisone administration
Systemic hemodynamic parameters	Systolic, diastolic and mean arterial pressures, heart rate, peripheral pulse pressure, cardiac output, stroke volume, systemic vascular resistances	30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
Arterial stiffness : carotid-femoral pulse wave velocity		30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
Central aortic hemodynamic parameters	Aortic systolic, diastolic and mean arterial pressures, central pulse pressure, central pressure augmentation index (AIx)	30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
Plasma parameters	Blood electrolytes, urea, creatinine, glucose, renin, aldosterone	30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
Urinary parameters	Diuresis, urinary electrolytes, urea, creatinine, glucose	30min before and 2h, 4h, 6h after fludrocortisone administration
Area under the plasma concentration versus time curve (AUC)		Just before and 5min, 10min, 20min, 30min, 1h, 1h30, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
Plasma half-life of fludrocortisone		Just before and 5min, 10min, 20min, 30min, 1h, 1h30, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
Total Body Clearance		Just before and 5min, 10min, 20min, 30min, 1h, 1h30, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
Apparent volume of distribution		Just before and 5min, 10min, 20min, 30min, 1h, 1h30, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Investigators: Principal Investigator: Bruno Laviolle, MD, Centre d'Investigation Clinique Inserm 1414, Service de Pharmacologie Clinique, Hôpital de Pontchaillou; Study Chair: Eric Bellissant, MD, PHD, Centre d'Investigation Clinique Inserm 1414, Service de Pharmacologie Clinique, Hôpital de Pontchaillou

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2014
• Primary Completion (Actual): April 20, 2016
• Study Completion (Actual): April 20, 2016

Study Registration Dates

• First Submitted: May 12, 2014
• First Submitted That Met QC Criteria: May 14, 2014
• First Posted (Estimate): May 16, 2014

Study Record Updates

• Last Update Posted (Actual): August 29, 2018
• Last Update Submitted That Met QC Criteria: August 28, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Hemodynamics; Fludrocortisone; Mineralocorticoids
• Additional Relevant MeSH Terms: Anti-Inflammatory Agents; Fludrocortisone
• Other Study ID Numbers: 2013-004794-27