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).
This paper describes a protocol for a multicentre, randomised, double-blinded, placebo-controlled clinical trial examining whether supplemental hydrocortisone during mild to moderate stress improves health-related quality of life in patients with polymyalgia rheumatica/giant cell arteritis with adrenal insufficiency on low-dose prednisolone.
Key Findings
Background
Patients on low-dose prednisolone may develop adrenal insufficiency, causing reduced health-related quality of life and increased risk of adrenal crisis.
The study targets patients with polymyalgia rheumatica/giant cell arteritis (PMR/GCA) receiving ongoing prednisolone ≤5 mg/day.
Adrenal insufficiency in this context is defined biochemically as a stimulated cortisol <420 nmol/L on an ACTH test.
The rationale for the trial is that current management of this patient group during stress situations ('sick-days') is uncertain.
Methods
The trial uses a multicentre, randomised, double-blinded, placebo-controlled design with 250 patients with biochemical adrenal insufficiency randomised 1:1 to supplemental hydrocortisone or placebo.
Eligible patients undergo an ACTH test, and those with stimulated cortisol <420 nmol/L are randomised.
The intervention is 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 at least 3 months of the intervention period.
An additional 95 patients with stimulated cortisol ≥420 nmol/L serve as a non-randomised control group.
In the event of severe stress (risk of adrenal crisis), patients receive open-label hydrocortisone treatment.
Methods
The primary outcome is health-related quality of life measured as fatigue using ecological momentary assessments (EMA) of the General Fatigue scale from the Multidimensional Fatigue Inventory-20, administered five times daily during sick-days.
EMA is administered via a smartphone application called 'EMA live'.
Differences in mean fatigue scores during sick-days between the hydrocortisone and placebo groups will be analysed using mixed models for repeated measures.
The use of EMA allows real-time symptom capture in ecologically valid stress situations rather than retrospective recall.
Methods
Secondary outcomes include daily smartphone-based symptom reporting, additional health-related quality of life questionnaires, adrenal crises, adverse effects from glucocorticoid excess, serial ACTH tests, and biomarkers of adrenal insufficiency.
Patients continue prednisolone tapering according to PMR/GCA guidelines throughout the trial.
Serial ACTH tests are included to monitor changes in adrenal function over the intervention period.
Adverse effects from glucocorticoid excess are monitored as a safety outcome given that participants are already on prednisolone.
Methods
The trial received ethics approval and regulatory authorisation, with recruitment beginning in June 2022 and the last patient's last visit expected in 2026.
The study is approved by the Ethics Committee of the Capital Region of Denmark and the Danish Medicines Agency.
Trial registrations: EudraCT 2021-002528-18, CTIS 2024-518272-30-00, and NCT05435781.
Results will be disseminated via peer-reviewed publication and conference presentations.
What This Means
This paper describes the design and protocol for a clinical trial called the RESCUE study. The study is investigating a common but underrecognised problem: people taking low-dose steroid tablets (prednisolone) for inflammatory conditions like polymyalgia rheumatica or giant cell arteritis can develop a condition called adrenal insufficiency, where their body's own steroid-producing system becomes suppressed. When these patients get sick or experience physical stress, their bodies may not be able to produce enough cortisol to cope, which can cause fatigue, poor wellbeing, and in serious cases, a potentially life-threatening 'adrenal crisis.' The trial tests whether giving these patients extra hydrocortisone (a stress-dose steroid) during mild to moderate illness days improves how they feel.
The trial is randomised and placebo-controlled, meaning participants are assigned by chance to receive either real hydrocortisone or a dummy treatment, and neither patients nor researchers know which they are receiving. Around 250 patients with confirmed adrenal insufficiency (identified by a hormone stimulation test) are being enrolled across multiple centres. A notable feature of the study is its use of ecological momentary assessment — patients report their fatigue and symptoms up to five times a day via a smartphone app during sick-days, capturing real-time experiences rather than relying on memory.
This research suggests that if supplemental hydrocortisone is shown to reduce fatigue and improve quality of life during illness in this patient group, it could change clinical practice for the many people worldwide who take long-term low-dose steroids for rheumatic diseases. Currently, there is limited evidence to guide doctors on how to manage these patients during stressful situations, and this trial aims to fill that gap. The results are expected to be published after the trial completes in 2026.
Borresen S, Hansen S, Al-Jorani H, Tei R, Dreyer A, Boesen V, et al.. (2026). 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).. BMJ open. https://doi.org/10.1136/bmjopen-2025-113110