Bioequivalence Study of Prednisolone and Dexamethasone (CORE)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Prednisolone; Drug: Dexamethasone

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 Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Suzanne P. Stam, MD; Phone Number: 0031503617293; Email: s.p.stam@umcg.nl

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Recruiting
    • University Medical Center Groningen
    • Contact: Suzanne P. Stam, MD; Phone Number: 0031503617293; Email: s.p.stam@umcg.nl
    • Contact: Annet Vulto, MD; Phone Number: 0031503617293; Email: a.vulto@umcg.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Prednisolone-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).	Drug: Prednisolone; 7,5 mg prednisolone (low dose) 30 mg prednisolone (high dose); Drug: Dexamethasone; 1,125 mg dexamethasone 4,5 mg dexamethasone
ACTIVE_COMPARATOR: Dexamethasone-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).	Drug: Prednisolone; 7,5 mg prednisolone (low dose) 30 mg prednisolone (high dose); Drug: Dexamethasone; 1,125 mg dexamethasone 4,5 mg dexamethasone

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Investigators: Principal Investigator: André P. van Beek, MD,PhD, University Medical Center Groningen; Principal Investigator: Stephan J.L. Bakker, MD,PhD, University Medical Center Groningen

Publications and helpful links

General Publications

• Stam SP, Vulto A, Vos MJ, Kerstens MN, Rutgers A, Kema I, Touw DJ, Bakker SJ, van Beek AP. Rationale and design of the CORE (COrticosteroids REvised) study: protocol. BMJ Open. 2022 Apr 26;12(4):e061678. doi: 10.1136/bmjopen-2022-061678.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 4, 2021
• Primary Completion (ANTICIPATED): May 31, 2022
• Study Completion (ANTICIPATED): May 31, 2022

Study Registration Dates

• First Submitted: January 15, 2021
• First Submitted That Met QC Criteria: January 29, 2021
• First Posted (ACTUAL): February 1, 2021

Study Record Updates

• Last Update Posted (ACTUAL): April 12, 2022
• Last Update Submitted That Met QC Criteria: April 4, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Prednisolone
• Other Study ID Numbers: 201900874; 2019-004983-23 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After deidentification, individual data that are the foundation of the results reported in future manuscripts can be made available (text, tables, figures, and appendices).
• IPD Sharing Time Frame: Beginning 6 months and ending 10 years following article publication
• IPD Sharing Access Criteria: Researchers should provide a methodologically sound proposal to a.p.van.beek@umcg.nl
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No