Effect of supplemental hydrocortisone during stress in prednisolone-induced adrenal insufficiency: a study protocol for a multicentre, randomised, double-blinded, placebo-controlled clinical trial on health-related quality of life in patients with polymyalgia rheumatica/giant cell arteritis on low-dose prednisolone treatment (the RESCUE study).

Abstract

Patients on low-dose prednisolone may develop adrenal insufficiency causing reduced health-related quality of life (HRQoL) and increased risk of adrenal crisis. This study examines whether supplemental hydrocortisone during mild to moderate stress improves HRQoL in patients with polymyalgia rheumatica/giant cell arteritis (PMR/GCA) with adrenal insufficiency on low-dose prednisolone. A multicentre, randomised, double-blinded, placebo-controlled, clinical trial including patients with PMR/GCA receiving ongoing prednisolone ≤5 mg/day. Eligible patients undergo an adrenocorticotropic hormone (ACTH) test, and 250 patients with a stimulated cortisol<420 nmol/L (biochemical adrenal insufficiency) are randomised 1:1 to supplemental hydrocortisone or placebo during mild to moderate stress ('sick-days') for 6 months or until daily prednisolone is stopped. The goal is 200 patients completing ≥3 months intervention period. Patients continue prednisolone tapering according to PMR/GCA guidelines. In the event of severe stress (risk of adrenal crisis), patients receive open-label hydrocortisone treatment. 95 patients with stimulated cortisol ≥420 nmol/L serve as control group. The primary outcome is HRQoL measured as fatigue using ecological momentary assessments (EMA) of the General Fatigue scale from the Multidimensional Fatigue Inventory-20, five times daily in situations of stress ('sick-days'). EMA will be administered via a smartphone application 'EMA live'. Differences in mean fatigue scores during sick-days between hydrocortisone and placebo will be analysed using mixed models for repeated measures. Secondary outcomes include daily smartphone-based symptom reporting, additional HRQoL questionnaires, adrenal crises, adverse effects from glucocorticoid excess, serial ACTH tests and biomarkers of adrenal insufficiency. The study is approved by the Ethics Committee of the Capital Region of Denmark and the Danish Medicines Agency. Recruitment began June 2022. The last patient's last visit is expected in 2026. Results will be disseminated via peer-reviewed publication and conference presentations. EudraCT:2021-002528-18, CTIS:2024-518272-30-00, NCT05435781.