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

INTRODUCTION: Glucocorticoid therapy is prescribed for a variety of inflammatory conditions and is associated with severe adverse effects. A glucocorticoid withdrawal syndrome (GWS) may occur after prolonged glucocorticoid treatment-with or without biochemical glucocorticoid-induced adrenal insufficiency (GIAI). Previously, GWS was not considered an entity, probably due to the overlap between symptoms of GWS and GIAI. The Addison's disease-specific quality of life questionnaire (AddiQoL-30) is a validated tool for quantifying symptoms of adrenal insufficiency resembling GWS. In the present study, we test the hypothesis that patients with a low AddiQoL-30 score and/or low cortisol response to a short Synacthen test (SST), after cessation of prednisolone treatment, may benefit from low-dose hydrocortisone therapy without increasing the risk of metabolic and cardiovascular disease during prolonged cortisol exposure.

METHODS AND ANALYSIS: REPLACE is a multi-centre, double-blinded, placebo-controlled randomised controlled trial in patients with polymyalgia rheumatica or giant cell arteritis after cessation of prednisolone treatment. Criteria for randomisation are an AddiQoL-30 score ≤85 and/or plasma cortisol response to SST, 30-min p-cortisol >100 and <420 nmol/L. Patients will be randomised to oral hydrocortisone (10 mg two times a day) or placebo for 16 weeks. Baseline and follow-up examinations comprise AddiQoL-30 questionnaire, SST, blood samples, standardised blood pressure, physical function tests and assessment of bone quality and body composition. At baseline, two comparator groups include: (1) patients with a SST-stimulated cortisol ≥420 nmol/L and AddiQoL-30 score >85; and (2) patients with a SST-stimulated cortisol ≤100 nmol/L.

ETHICS AND DISSEMINATION: The study is conducted in accordance with the Declaration of Helsinki, registered at the Clinical Trials Information System (CTIS: 2024-513822-53-00) and Clinicaltrials.gov (NCT05193396), and publications will be in accordance with the recommendations of the International Committee of Medical Journal Editors. The trial is monitored by local independent Good Clinical Practice units and overseen by the Danish Data Protection Agency (journal no. 21/27119), the Regional Committees on Health Research Ethics for Southern Denmark (project ID: S-20210076), the Danish Patient Safety Authority and the Danish Medicines Agency.

TRIAL REGISTRATION NUMBER: NCT05193396.