Hydrocortisone replacement therapy in patients with glucocorticoid withdrawal syndrome after cessation of glucocorticoid treatment: REPLACE, a multicentre, randomised, double-blinded, placebo-controlled, 16-week study protocol.
REPLACE is a multicentre, randomised, double-blinded, placebo-controlled trial testing whether low-dose hydrocortisone therapy benefits patients with glucocorticoid withdrawal syndrome after cessation of prednisolone treatment, without increasing metabolic and cardiovascular risk.
Key Findings
Background
Glucocorticoid withdrawal syndrome (GWS) may occur after prolonged glucocorticoid treatment with or without biochemical glucocorticoid-induced adrenal insufficiency (GIAI).
GWS was previously not considered a distinct entity, 'probably due to the overlap between symptoms of GWS and GIAI'.
The study distinguishes between GWS and biochemical GIAI as potentially separate or co-occurring conditions.
The AddiQoL-30 questionnaire is identified as a validated tool for quantifying symptoms of adrenal insufficiency resembling GWS.
Methods
The REPLACE trial uses specific criteria for randomisation based on AddiQoL-30 scores and cortisol response to short Synacthen test (SST).
Randomisation criteria include an AddiQoL-30 score ≤85 and/or plasma cortisol response to SST with 30-min p-cortisol >100 and <420 nmol/L.
Patients are randomised to oral hydrocortisone (10 mg two times a day) or placebo for 16 weeks.
The trial targets patients with polymyalgia rheumatica or giant cell arteritis after cessation of prednisolone treatment.
Methods
The trial includes two non-randomised comparator groups defined by SST cortisol thresholds and AddiQoL-30 scores at baseline.
Comparator group 1 consists of patients with SST-stimulated cortisol ≥420 nmol/L and AddiQoL-30 score >85, representing those without adrenal insufficiency or significant symptom burden.
Comparator group 2 consists of patients with SST-stimulated cortisol ≤100 nmol/L, representing those with severe adrenal insufficiency.
These comparator groups are assessed at baseline alongside the randomised intervention groups.
Methods
The study protocol includes comprehensive baseline and follow-up assessments covering symptom burden, endocrine function, metabolic parameters, physical function, bone quality, and body composition.
Assessments include the AddiQoL-30 questionnaire, SST, blood samples, standardised blood pressure, and physical function tests.
Bone quality and body composition are also measured at baseline and follow-up.
The trial is designed to assess whether hydrocortisone treatment increases risk of metabolic and cardiovascular disease during prolonged cortisol exposure.
Methods
The REPLACE trial is a multicentre, 16-week, double-blinded, placebo-controlled randomised controlled trial registered in both the EU Clinical Trials Information System and ClinicalTrials.gov.
The trial is registered at CTIS (2024-513822-53-00) and ClinicalTrials.gov (NCT05193396).
The study is conducted in accordance with the Declaration of Helsinki.
The trial is monitored by local independent Good Clinical Practice units and overseen by the Danish Data Protection Agency, Regional Committees on Health Research Ethics for Southern Denmark, the Danish Patient Safety Authority, and the Danish Medicines Agency.