Healthy Volunteers
Conditions
Keywords
Fludrocortisone, Mineralocorticoids, Hemodynamics, Pharmacokinetics
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.
Interventions
DRUGFludrocortisone 100 μg
Fludrocortisone 100 μg/day
DRUGFludrocortisone 200 μg
Fludrocortisone 200 μg/day
DRUGFludrocortisone 400 μg
Fludrocortisone 400 μg/day
DRUGPlacebo
Sponsors
Rennes University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
20 Years to 25 Years
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phenylephrine mean blood pressor dose-response relationship. | 1.5 hour after fludrocortisone administration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Cardiac systolic and diastolic function assessed par transthoracic echocardiography during phenylephrine administration | between 1.5 and 2.5 hours 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 | — |
| Urinary parameters | 30min before and 2h, 4h, 6h after fludrocortisone administration | Diuresis, urinary electrolytes, urea, creatinine, glucose |
Countries
France
Outcome results
None listed