Bioequivalence Study of Prednisolone and Dexamethasone

Study Overview
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Brief Summary
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The purpose of this study is to compare two different glucocorticoids, prednisolone and dexamethasone at two different doses for their organ specific effects, utilizing modern day standards.

Detailed Description
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Study design: A randomised, double blind, cross-over clinical trial. Study population: healthy human adult volunteers including 12 males and 12 females aged 18-75 years old. Intervention: In random order, subjects will receive 7,5 mg prednisolone for one week, directly followed by 30 mg of prednisolone for one week. After a washout period of 4 weeks (or by exception 8 weeks), subjects will receive 1,125 mg dexamethasone for one week, directly followed by 4,5 mg dexamethasone for one week. Main study parameters/endpoints: The main study endpoint is the difference in total urinary cortisol excretion as measured in 24h-urine between the lower doses of prednisolone and dexamethasone as well as between the higher doses of prednisolone and dexamethasone.

Official Title
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An Bioequivalence Study of Prednisolone and Dexamethasone; Corticosteroids Revised - The CORE Study

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Prednisolone
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be healthy with no relevant medical history and no use of medication. Female participants aged <50 years must be using oral contraceptives and female participants age ≥50 years must be in the postmenopausal state Command of the Dutch language Providing written IC BMI between 18.5 and 30 kg/m2 Participants must be between 18 and 75 years of age Exclusion Criteria: Potential participants who are unlikely to adhere to the study protocol (for instance subjects which have a history of substance abuse or non-compliance) Potential participants with a medical history of: Diseases affecting the HPA-axis: e.g. primary and secondary adrenal insufficiency, pituitary tumors, and nightshift workers Diseases affecting the HPG-axis: e.g. Cushing disease. Chronic inflammatory diseases: e.g. rheumatoid arthritis, polymyalgia rheumatic, and asthma Psychiatric diseases Diabetes Shift workers Potential participants with a kidney function <60 ml/min/1.73m2, abnormalities in liver enzymes, and/or abnormalities in thyroid function Potential participants who are dependent on corticosteroids, e.g. asthmatic patients, and transplant recipients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prednisolone-Dexamethasone<br>Participants will receive 1 week of low dose (7,5 mg) prednisolone directly followed by 1 week of high dose prednisolone (30 mg). After a wash-out period, participants in this arm will receive 1 week of low dose dexamethasone (1,125 mg) directly followed by 1 week of high dose dexamethasone (4,5 mg). | Drug: Prednisolone<br>* 7,5 mg prednisolone (low dose) 30 mg prednisolone (high dose)<br>Drug: Dexamethasone<br>* 1,125 mg dexamethasone 4,5 mg dexamethasone<br>|
| Active Comparator: Dexamethasone-Prednisolone<br>Participants will receive 1 week of low dose (1,125 mg) dexamethasone directly followed by 1 week of high dose dexamethasone (30 mg). After a wash-out period, participants in this arm will receive 1 week of low dose prednisolone (7,5 mg) directly followed by 1 week of high dose prednisolone (30 mg). | Drug: Prednisolone<br>* 7,5 mg prednisolone (low dose) 30 mg prednisolone (high dose)<br>Drug: Dexamethasone<br>* 1,125 mg dexamethasone 4,5 mg dexamethasone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Suppression of the hypothalamic-pituitary-adrenal axis - low dose | Difference in HPA-axis suppression as measured by the difference of total urinary cortisol excretion in 24h-urine between 7,5 mg prednisolone and 1,125 mg dexamethasone | 1 week per treatment | 
| Suppression of the hypothalamic-pituitary-adrenal axis - high dose | Difference of total urinary cortisol excretion in 24h-urine between 30 mg prednisolone (preceded by 7,5 mg prednisolone for one week) and 4,5 mg dexamethasone (preceded by 1,125 mg dexamethasone for one week) | 1 week per treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in hypothalamic-pituitary-adrenal axis suppression - 1 | Effect of a dosage increase from low dose to high dose prednisolone on total urinary cortisol excretion in 24h-urine | 1 week per treatment | 
| Changes in hypothalamic-pituitary-adrenal axis suppression - 2 | Effect of a dosage increase from low dose to high dose dexamethasone on total urinary cortisol excretion in 24h-urine | 1 week per treatment | 
| Suppression of the hypothalamic-pituitary-adrenal axis - plasma cortisol | The between-group difference in plasma cortisol levels | 1 week per treatment | 
| Suppression of the hypothalamic-pituitary-adrenal axis - ACTH | The between-group difference in adrenocorticotropic hormone levels | 1 week per treatment | 
| Suppression of the hypothalamic-pituitary-adrenal axis - metabolites of the 24h-urine steroid profile | The between-group difference in metabolites of the 24h-urine steroid profile | 1 week per treatment | 
| Suppression of the hypothalamic-pituitary-gonadal axis - androgen profile | The between-group difference in androgen profiles | 1 week per treatment | 
| Suppression of the hypothalamic-pituitary-gonadal axis - gonadotropins | The between-group difference in luteinizing hormone and follicle stimulating hormone | 1 week per treatment | 
| Suppression of the hypothalamic-pituitary-gonadal axis - metabolites of the 24h-urine steroid profile | The between-group difference in metabolites of the 24h-urine steroid profile | 1 week per treatment | 
| Pharmacokinetics | Area under the curve | 1 week per treatment | 
| Suppression of the immune system - granulocyte count | The between-group difference in granulocyte count | 1 week per treatment | 
| Suppression of the immune system - PBMCs | The between-group difference in peripheral blood mononuclear cell count | 1 week per treatment | 
| Effect on blood pressure | The between-group difference in systolic and diastolic blood pressure | 1 week per treatment | 
| Effect on the Renin-angiotensin-aldosterone system - plasma renin | The between-group difference in plasma renin | 1 week per treatment | 
| Effect on the Renin-angiotensin-aldosterone system - aldosterone | The between-group difference in aldosterone | 1 week per treatment | 
| Effect on the Renin-angiotensin-aldosterone system - plasma potassium | The between-group difference in plasma potassium | 1 week per treatment | 
| Effect on the Renin-angiotensin-aldosterone system - 24h-urine potassium | The between-group difference in 24h-urine potassium | 1 week per treatment | 
| Effect on the Renin-angiotensin-aldosterone system - trans-tubular potassium gradient | The between-group difference in trans-tubular potassium gradient | 1 week per treatment | 
| Metabolic parameters - OGTT | The between-group difference in oral glucose tolerence tests | 1 week per treatment | 
| Metabolic parameters - lipid profile | The between-group difference in lipid profile | 1 week per treatment | 
| Metabolic parameters - NEFAs | The between-group difference in non-esterified fatty acids | 1 week per treatment | 
| Muscle mass | The between-group difference in 24h urinary creatinine excretion rate | 1 week per treatment | 
| Muscle strength | The between-group difference in handgrip strength | 1 week per treatment | 
| Clinical parameters - Weight | The between-group difference in weight in kg | 1 week per treatment | 
| Clinical parameters - Body Mass Index (BMI) | The between-group difference in BMI in kg/m2 | 1 week per treatment | 
| Clinical parameters - Waist circumference | The between-group difference in waist circumference in cm | 1 week per treatment | 
| Clinical parameters - Hip circumference | The between-group difference in hip circumference in cm | 1 week per treatment | 
| Questionnaires - Quality of life | The between-group difference in quality of life, measured using the 36-Item Short Form Health Survey (SF-36). The score ranges from 0-100, with lower scores indicating a worse health status. | 1 week per treatment | 
| (Serious) Adverse Events | The between-group difference in (serious) adverce events | 1 week per treatment |