Fludrocortisone in Healthy Volunteers (AFLUCO4)

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Fludrocortisone 100 μg
* Drug: Fludrocortisone 200 μg
* Drug: Fludrocortisone 400 μg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fludrocortisone, Mineralocorticoids, Hemodynamics, Pharmacokinetics