Fludrocortisone in Healthy Volunteers (AFLUCO4)

Sponsor

Rennes University Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT02140918

Collaborator

(none)

Enrollment

Location

Arms

21.7

Actual Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Fludrocortisone 100 μg Drug: Fludrocortisone 200 μg Drug: Fludrocortisone 400 μg Drug: Placebo	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

16 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Basic Science

Official Title:

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

Actual Study Start Date :

Jul 1, 2014

Actual Primary Completion Date :

Apr 20, 2016

Actual Study Completion Date :

Apr 20, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Phenylephrine mean blood pressor dose-response relationship. [1.5 hour after fludrocortisone administration]

Secondary Outcome Measures

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 [30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration]
Systolic, diastolic and mean arterial pressures, heart rate, peripheral pulse pressure, cardiac output, stroke volume, systemic vascular resistances
Arterial stiffness : carotid-femoral pulse wave velocity [30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration]
Central aortic hemodynamic parameters [30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration]
Aortic systolic, diastolic and mean arterial pressures, central pulse pressure, central pressure augmentation index (AIx)
Plasma parameters [30min before and 1h, 2h, 3h, 4h, 5h, 6h after fludrocortisone administration]
Blood electrolytes, urea, creatinine, glucose, renin, aldosterone
Urinary parameters [30min before and 2h, 4h, 6h after fludrocortisone administration]
Diuresis, urinary electrolytes, urea, creatinine, glucose
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 25 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rennes University Hospital	Rennes		France	35033

Sponsors and Collaborators

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