Clinical trial NCT02140918: Fludrocortisone in Healthy Volunteers (AFLUCO4)
Official title: Hemodynamic and Biological Effects of 3 Increasing Doses of Fludrocortisone in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Healthy Volunteers
Keywords: Fludrocortisone
Mineralocorticoids
Hemodynamics
Pharmacokinetics
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
First posted: 2014-05-16
Enrollment: 16
Sex: MALE
Minimum age (years): 20
Maximum age (years): 25
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Phenylephrine mean blood pressor dose-response relationship.
timeFrame: 1.5 hour after fludrocortisone administration
Secondary outcomes:
measure: Cardiac systolic and diastolic function assessed par transthoracic echocardiography during phenylephrine administration
timeFrame: between 1.5 and 2.5 hours after fludrocortisone administration
measure: Systemic hemodynamic parameters
timeFrame: 30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
measure: Arterial stiffness : carotid-femoral pulse wave velocity
timeFrame: 30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
measure: Central aortic hemodynamic parameters
timeFrame: 30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
measure: Plasma parameters
timeFrame: 30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
measure: Urinary parameters
timeFrame: 30min before and 2h, 4h, 6h after fludrocortisone administration
measure: Area under the plasma concentration versus time curve (AUC)
timeFrame: Just before and 5min, 10min, 20min, 30min, 1h, 1h30, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
measure: Plasma half-life of fludrocortisone
timeFrame: Just before and 5min, 10min, 20min, 30min, 1h, 1h30, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
measure: Total Body Clearance
timeFrame: Just before and 5min, 10min, 20min, 30min, 1h, 1h30, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
measure: Apparent volume of distribution
timeFrame: Just before and 5min, 10min, 20min, 30min, 1h, 1h30, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration
Other outcomes:
Locations:
city: Rennes
country: France
facility: Rennes University Hospital
Study officials:
affiliation: Centre d'Investigation Clinique Inserm 1414, Service de Pharmacologie Clinique, Hôpital de Pontchaillou
name: Bruno Laviolle, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre d'Investigation Clinique Inserm 1414, Service de Pharmacologie Clinique, Hôpital de Pontchaillou
name: Eric Bellissant, MD, PHD
role: STUDY_CHAIR
References: