Bioequivalence Study of Prednisolone and Dexamethasone

Phase 1

• Conditions: Healthy Volunteers
• Interventions: Drug: Prednisolone; Drug: Dexamethasone

• Registration Number: NCT04733144
• Lead Sponsor: University Medical Center Groningen

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2021-01-15
• Study First Submitted QC: 2021-01-29
• Study First Posted: 2021-02-01
• Study Start: 2021-03-04
• Status Verified: 2022-04
• Last Update Submitted: 2022-04-04
• Last Update Posted: 2022-04-12
• Primary Completion: 2022-05-31
• Study Completion: 2022-05-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 24

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:

  1. Diseases affecting the HPA-axis: e.g. primary and secondary adrenal insufficiency, pituitary tumors, and nightshift workers
  2. Diseases affecting the HPG-axis: e.g. Cushing disease.
  3. Chronic inflammatory diseases: e.g. rheumatoid arthritis, polymyalgia rheumatic, and asthma
  4. Psychiatric diseases
  5. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Prednisolone-Dexamethasone	Prednisolone	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).
Prednisolone-Dexamethasone	Dexamethasone	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).
Dexamethasone-Prednisolone	Prednisolone	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).
Dexamethasone-Prednisolone	Dexamethasone	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).

Primary Outcome Measures

Name	Time	Method
Suppression of the hypothalamic-pituitary-adrenal axis - low dose	1 week per treatment	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
Suppression of the hypothalamic-pituitary-adrenal axis - high dose	1 week per treatment	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)

Secondary Outcome Measures

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

Trial Locations

Locations (1)

University Medical Center Groningen; 🇳🇱 Groningen, Netherlands