Adrenal Insufficiency
Conditions
Keywords
hydrocortisone, Glucocorticoid-Induced Adrenal Insufficiency, methylprednisolone
Brief summary
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.
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.
Interventions
DRUGPatients 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).
DRUGPatients 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.
Sponsors
University Medical Centre Ljubljana
University of Ljubljana
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with recovery of the HPA axis. | 12 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Analysis: Superiority of Methylprednisolone | 12 months | 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. |
| Non-inferiority of Methylprednisolone at 24 Months | 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%). |
| 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 | Baseline, 3, 6, 12, 18, 24 months. | Morning serum cortisol levels (in nmol/L) measured to evaluate their predictive value for the short ACTH test outcome. |
| Predictive Value of Serum Dehydroepiandrosterone Sulfate (DHEA-S) | Baseline, 3 months, 6 months, 12 months, 18 months and 24 months | Morning serum DHEA-S levels measured to evaluate their predictive value for the short ACTH test outcome. |
| Predictive Value of Morning Salivary Cortisone | Baseline, 3 months, 6 months, 12 months, 18 months and 24 months | Cortisone levels in morning saliva evaluated as a potential non-invasive predictor for the short ACTH test outcome |
| Change from Baseline in Glycated Hemoglobin (HbA1c) | Baseline, 3, 6, 12, 18, 24 months | Long-term glycemic control assessed by measuring HbA1c levels, expressed as a percentage (%) |
| Change from Baseline in Fasting Glucose | Baseline, 3, 6, 12, 18 and 24 months | Plasma glucose concentrations are measured in mmol/L. |
| Change from Baseline in Lipid Profile | Baseline, 3 months, 6 months, 12 months, 18 months, 24 months | 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. |
| Change from Baseline in Body Fat Percentage and Visceral Fat Mass | Baseline, 12 months and 24 months | Body composition (total body fat percentage and visceral fat mass) measured using Dual-Energy X-ray Absorptiometry (DXA). |
| Change from Baseline in Bone Mineral Density (BMD) | baseline, 12 and 24 months | Bone mineral density measured using Dual-Energy X-ray Absorptiometry (DXA). |
| Change from Baseline in Quality of Life Assessed by the 36-Item Short Form Health Survey (SF-36) | Time Frame: Baseline, 6, 12, 24 months. | 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. |
| Change from Baseline in Treatment Satisfaction Assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM - 1.4) | 3, 12 and 24 months | 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. |
Countries
Slovenia
Contacts
CONTACTŽiva Dolenšek, MD
CONTACTTomaž Kocjan, MD PHD
Outcome results
None listed