Hydrocortisone Versus Methylprednisolone for the Treatment of Glucocorticoid-Induced Adrenal Insufficiency

This study aims to compare the use of methylprednisolone and hydrocortisone as replacement therapies in patients with glucocorticoid-induced adrenal insufficiency.

The primary goal is to evaluate and compare the recovery of the hypothalamic-pituitary-adrenal (HPA) axis.

Study Overview

• Status: Not yet recruiting
• Conditions: Adrenal Insufficiency
• Intervention / Treatment: Drug: Patients will receive 15 mg of hydrocortisone daily. The dose is split into 10 mg in the morning after breakfast and 5 mg after 6-7 hours.; Drug: Patients will receive 3 mg of methylprednisolone once daily. The dose is administered in the morning (1 ½ tablets of 2 mg Medrol after breakfast).

Detailed Description

Glucocorticoids in supraphysiological doses are the most frequent cause of adrenal insufficiency due to the suppression of the hypothalamic-pituitary-adrenal (HPA) axis.

In cases of confirmed adrenal insufficiency, current guidelines recommend replacement therapy with physiological doses of short- and intermediate-acting glucocorticoids to prevent adrenal crises without inhibiting HPA axis recovery.

While hydrocortisone is the most commonly used short-acting glucocorticoid, methylprednisolone is widely prescribed in Slovenia.

Because methylprednisolone lacks mineralocorticoid effects, it appears to be a particularly suitable choice for patients with glucocorticoid-induced adrenal insufficiency, where mineralocorticoid secretion is not impaired.

This randomized, prospective, open-label interventional study will primarily evaluate non-inferiority regarding HPA axis recovery after 12 months, with a long-term assessment at 24 months.

Patients will undergo testing at baseline, 3, 6,12, 18, 24 months (or until HPA axis recovery), including laboratory tests, short ACTH tests, body composition measurements, and quality of life questionnaires.

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Živa Dolenšek, MD; Phone Number: +38615223114; Email: ziva.dolensek@kclj.si
• Study Contact Backup: Name: Tomaž Kocjan, MD PHD; Phone Number: 0038615223114; Email: tomaz.kocjan@kclj.si

Study Locations

• Slovenia
  • Ljubljana, Slovenia, 1000
    • UMC Ljubljana
    • Contact: Tomaž Kocjan, MD PHD; Phone Number: 0038615223114; Email: tomaz.kocjan@kclj.si
    • Contact: živa dolenšek, MD; Phone Number: 003865223114; Email: ziva.dolensek@kclj.si

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age over 18 years.
• Suspected adrenal insufficiency due to receiving supraphysiological doses of methylprednisolone for more than 4 weeks.
• Receiving methylprednisolone 4 mg for at least the last 4 weeks.
• Morning cortisol lower than 300 nmol/L.
• Inadequate result of a short ACTH test performed on a physiological dose of methylprednisolone (cortisol rise after 30 min under 470 nmol/L AND after 60 min under 500 nmol/L).
• No further indication for treating the underlying disease, and retreatment with glucocorticoids is not expected in the next 2 years.
• Consent to participate in the research.

Exclusion Criteria:

• Known organic disease of the pituitary-adrenal axis.
• Body mass over 130 kg.
• Advanced comorbidities.
• Advanced heart failure (NYHA IV).
• Chronic kidney disease IV, eGFR under 30 ml/min.
• Liver cirrhosis.
• Active malignant disease.
• Immune deficiencies.
• Planned major surgery during the study duration.
• Receiving drugs affecting cortisol metabolism or interfering with cortisol measurements (e.g., systemic estrogens, strong inducers or inhibitors of CYP3A4).
• Conditions affecting cortisol metabolism (pregnancy, liver disease, nephrotic syndrome).
• Alcohol dependence syndrome (consuming more than 21 units of alcohol per week).
• Shift (night) work.
• Presence of comorbidities with an expected life expectancy of less than 3 years.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: patients with hydrocortisone; Patients will receive 15 mg of hydrocortisone daily. The dose is split into 10 mg in the morning after breakfast and 5 mg after 6-7 hours.	Drug: Patients will receive 15 mg of hydrocortisone daily. The dose is split into 10 mg in the morning after breakfast and 5 mg after 6-7 hours.; Patients will receive 15 mg of hydrocortisone daily. The dose is split into 10 mg in the morning after breakfast and 5 mg after 6-7 hours.
Experimental: patients with metylprednisolone; Patients will receive 3 mg of methylprednisolone once daily. The dose is administered in the morning (1 ½ tablets of 2 mg methylprednisolone after breakfast).	Drug: Patients will receive 3 mg of methylprednisolone once daily. The dose is administered in the morning (1 ½ tablets of 2 mg Medrol after breakfast).; Patients will receive 3 mg of methylprednisolone once daily. The dose is administered in the morning (1 ½ tablets of 2 mg methylprednisolone after breakfast).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with recovery of the HPA axis.	Replacement therapy for glucocorticoid-induced adrenal insufficiency with methylprednisolone in a physiologically equivalent morning dose is being evaluated for non-inferiority compared to hydrocortisone. Methylprednisolone is considered not inferior regarding the proportion of patients with HPA axis recovery after 12 months, provided the difference between the groups does not exceed the pre-specified non-inferiority margin of 10%. Recovery of the HPA axis is assessed via a short ACTH test, defined as a cortisol rise to at least 470 nmol/L after 30 minutes or at least 500 nmol/L after 60 minutes.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary Analysis: Superiority of Methylprednisolone	If the non-inferiority of methylprednisolone is confirmed, we will also evaluate the superiority of methylprednisolone as part of the secondary analyses: The proportion of patients with recovery of the HPA axis will be higher after 12 months in the group receiving methylprednisolone.	12 months
Non-inferiority of Methylprednisolone at 24 Months	Methylprednisolone is not inferior to hydrocortisone in the treatment of glucocorticoid-induced adrenal insufficiency after 24 months. The difference in the proportion of patients with HPA axis recovery between the groups does not exceed the pre-specified non-inferiority margin (15%).	24 months
Number of adrenal crises.		24 months
Time required for HPA axis recovery based on the duration of previous glucocorticoid treatment.		up to 24 months
Predictive Value of Morning Serum Cortisol Concentration	Morning serum cortisol levels (in nmol/L) measured to evaluate their predictive value for the short ACTH test outcome.	Baseline, 3, 6, 12, 18, 24 months.
Predictive Value of Serum Dehydroepiandrosterone Sulfate (DHEA-S)	Morning serum DHEA-S levels measured to evaluate their predictive value for the short ACTH test outcome.	Baseline, 3 months, 6 months, 12 months, 18 months and 24 months
Predictive Value of Morning Salivary Cortisone	Cortisone levels in morning saliva evaluated as a potential non-invasive predictor for the short ACTH test outcome	Baseline, 3 months, 6 months, 12 months, 18 months and 24 months
Change from Baseline in Glycated Hemoglobin (HbA1c)	Long-term glycemic control assessed by measuring HbA1c levels, expressed as a percentage (%)	Baseline, 3, 6, 12, 18, 24 months
Change from Baseline in Fasting Glucose	Plasma glucose concentrations are measured in mmol/L.	Baseline, 3, 6, 12, 18 and 24 months
Change from Baseline in Lipid Profile	Metabolic assessment including total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides, measured in mmol/L via a standard fasting blood test.	Baseline, 3 months, 6 months, 12 months, 18 months, 24 months
Change from Baseline in Body Fat Percentage and Visceral Fat Mass	Body composition (total body fat percentage and visceral fat mass) measured using Dual-Energy X-ray Absorptiometry (DXA).	Baseline, 12 months and 24 months
Change from Baseline in Bone Mineral Density (BMD)	Bone mineral density measured using Dual-Energy X-ray Absorptiometry (DXA).	baseline, 12 and 24 months
Change from Baseline in Quality of Life Assessed by the 36-Item Short Form Health Survey (SF-36)	the SF-36 is a self-administered questionnaire measuring health-related quality of life across eight domains. Scores range from 0 to 100, where higher scores indicate a better health state and lower disability.	Time Frame: Baseline, 6, 12, 24 months.
Change from Baseline in Treatment Satisfaction Assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM - 1.4)	The TSQM is a validated questionnaire assessing patient satisfaction with medication across domains such as effectiveness, side effects, and convenience. Scores for each domain range from 0 to 100, where higher scores indicate greater satisfaction with the treatment.	3, 12 and 24 months

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana
• Collaborators: University of Ljubljana

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2029
• Study Completion (Estimated): September 1, 2030

Study Registration Dates

• First Submitted: July 2, 2026
• First Submitted That Met QC Criteria: July 8, 2026
• First Posted (Actual): July 14, 2026

Study Record Updates

• Last Update Posted (Actual): July 14, 2026
• Last Update Submitted That Met QC Criteria: July 8, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: methylprednisolone; hydrocortisone; Glucocorticoid-Induced Adrenal Insufficiency
• Additional Relevant MeSH Terms: Endocrine System Diseases; Adrenal Gland Diseases; Adrenal Insufficiency
• Other Study ID Numbers: 0120-87/2026-2711-4

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No