Effect of Supplemental Hydrocortisone During Stress in Prednisolone-induced Adrenal Insufficiency (RESCUE)

RESCUE - Effect of Supplemental Hydrocortisone During Stress in Prednisolone-induced Adrenal Insufficiency; A Multicentre, Randomised, Double Blinded, Placebo-controlled Clinical Trial on Health-related Quality of Life in Patients With Polymyalgia Rheumatica/Giant Cell Arteritis Receiving Ongoing Low-dose Prednisolone Treatment.

In this double-blinded randomised placebo-controlled clinical trial, the aim is to determine the effect of supplemental hydrocortisone compared with placebo during mild to moderate physical or mental stress on health related quality of life in patients with polymyalgia rheumatica (PMR)/giant cell arteritis (GCA) on ongoing low-dose prednisolone diagnosed with glucocorticoid-induced adrenal insufficiency. The main emphasis is on fatigue (primary outcome) and daily variation hereof during periods of stress.

Study Overview

• Status: Recruiting
• Conditions: Giant Cell Arteritis; Polymyalgia Rheumatica; Adrenal Insufficiency
• Intervention / Treatment: Drug: Hydrocortisone; Drug: Placebo for hydrocortisone

Detailed Description

The study will include patients with PMR/GCA on ongoing prednisolone treatment in a low dose of > 0 mg/day and ≤5mg/day. Eligible patients will undergo a Synacthen® test and 250 patients with a stimulated cortisol level <420 nmol/l (biochemical adrenal insufficiency) will be randomised to either placebo or hydrocortisone supplemental doses during stress. Patients will continue prednisolone treatment and tapering hereof according to current clinical guidelines for PMR/GCA and add supplemental hydrocortisone/placebo in situations of stress according to study protocol. In situations of severe stress (potential adrenal crisis) patients will receive open label hydrocortisone treatment according to routine clinical care. The duration of RESCUE is 6 months but stops earlier if the patient stops prednisolone treatment earlier. In case of a flare of PMR/GCA during the study where prednisolone is increased to >5mg/day for e.g. 5 weeks the study is prolonged accordingly 5 weeks.

Ninety-five patients with stimulated cortisol ≥420 nmol/l (normal adrenal function) will be used as a reference group. The participants will undergo screening and baseline examinations, 3 month's reporting of HRQoL, and with patient consent follow-up through medical records on prednisolone treatment characteristics, and number of hospitalisations.

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Stina W. Borresen, MD, PhD; Phone Number: +4525347551; Email: stina.borresen@regionh.dk
• Study Contact Backup: Name: Marianne Klose, MD, PhD; Phone Number: +4530237532; Email: marianne.christina.klose.01@regionh.dk

Study Locations

• Denmark
  • Aarhus, Denmark
    • Recruiting
    • Department of Endocrinology, Aarhus University Hospital
    • Contact: Jens Otto L. Jørgensen, Professor
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet
    • Principal Investigator: Ulla Feldt-Rasmussen, Professor
    • Contact: Ulla Feldt-Rasmussen, Professor; Email: ufeldt@rh.dk
    • Contact: Stina W. Borresen, MD, PhD
  • Odense, Denmark
    • Recruiting
    • Department of Endocrinology, Odense University Hospital
    • Contact: Marianne S. Andersen, professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 50 years
• Women must be postmenopausal (FSH is measured at the screening visit)
• A diagnosis of PMR/GCA, or both conditions combined.
• Treatment with prednisolone ≥12 weeks
• Ongoing prednisolone treatment, with current daily prednisolone dose > 0 mg and ≤5 mg. The dose must have been ≤5 mg for minimum 2 weeks at the time of the screening visit.

Exclusion Criteria:

• Known primary or secondary adrenal insufficiency
• Known Cushing's Syndrome
• Known allergy towards study medication ingredients
• Severe comorbidity: Heart failure (New York Heart Association class IV); Kidney failure with an estimated glomerular filtration rate <30 mL/min (Chronic kidney disease stage 4-5); Liver disease in the form of cirrhosis; Active cancer; Known severe immune deficiency; A history of psychiatric disease requiring treatment by a psychiatric department (for affective disorders only if within the last year before study entry)
• Alcohol consumption >21 units per week
• Planned major surgery during the study period at study entry.
• Use of drugs that interfere with cortisol metabolism/measurements: Systemic oestrogen treatment (discontinued < 1 month before inclusion), Treatment with strong CYP3A4 inhibitors or inducers, Use of other glucocorticoid formulations (Inhaled corticosteroids, intraarticular or intramuscular injections, steroid creams European steroid group IV-V used in the genital area. Note: Permitted glucocorticoid formulations: Eye-drops, nasal spray, glucocorticoid creams European steroid group I-III, and European steroid group IV-V used in the non-genital area only.)
• Inability to provide written informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: RCT group - hydrocortisone; Patients with polymyalgia rheumatica/giant cell arteritis with glucocorticoid-induced adrenal insufficiency (Synacthen test response <420 nmol/l) that are randomised to receive hydrocortisone	Drug: Hydrocortisone; Patients are randomised to either placebo or hydrocortisone supplemental doses in situations of stress. Patients will continue prednisolone treatment and tapering hereof according to current clinical guidelines for PMR/GCA , prednisolone is not part of the intervention.
Placebo Comparator: RCT group - placebo; Patients with polymyalgia rheumatica/giant cell arteritis with glucocorticoid-induced adrenal insufficiency (Synacthen test response <420 nmol/l) that are randomised to receive placebo	Drug: Placebo for hydrocortisone; Patients are randomised to either placebo or hydrocortisone supplemental doses in situations of stress. Patients will continue prednisolone treatment and tapering hereof according to current clinical guidelines for PMR/GCA , prednisolone is not part of the intervention.
No Intervention: Control group; Patients with polymyalgia rheumatica/giant cell arteritis with normal adrenal function (Synacthen test response ≥420 nmol/l)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ecological momentary assessments (EMA) of the Multidimensional Fatigue Inventory (MFI-20) General Fatigue scale, adjusted for EMA	EMA in situations of stress. EMA reporting will be conducted electronically on a smartphone.	In situations of stress, participants are asked to answer the EMA items 5 times daily at semi-randomised time points, for 3 days. Diurnal profiles are generated and one diurnal profile summarizes responses during the day across all 'sick-days'.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily 'end-of-day' app-facilitated patient reported outcome (PRO) assessments	Key secondary outcome - obtain information about intercurrent illness, injury, or stress, and symptoms of fatigue, nausea, and general malaise. The questions about symptoms originate from the Danish version of the PRO-CTCAE.	Patients are asked daily throughout the study period as 'end-of-day' assessments.
SF-36	Key secondary outcome	At baseline, 3 months and 6 months
AddiQol-30	Key secondary outcome	At baseline, 3 months and 6 months
PMR/GCA treatment characteristics -accumulated glucocorticoid dose	Key secondary outcome. accumulated glucocorticoid dose	Information from 6 months before baseline to end-of study
PMR/GCA treatment characteristics -prednisolone treatment duration	Key secondary outcome. Duration of prednisolone treatment, duration of prednisolone tapering (5 mg - 0 mg)	Information from 6 months before baseline to end-of study
Number of 'sick days'	Key secondary outcome	Throughout study period (6 months)
Incidens of adrenal crises and hospitalisations	Incidence rate of adrenal crises and hospitalisations	Throughout study period (6 months)
Adrenal crises grading	Grade of adrenal crises.	Throughout study period (6 months)
Body composition and muscle strength - DXA scan	Safety outcome for exogenous Cushing's Syndrome (Dual-energy X-ray absorptiometry (DXA) scan: fat percentage, body composition	Baseline and 6 months
Body composition and muscle strength - Waist, hip, height	Safety outcome for exogenous Cushing's Syndrome (Waist, hip, height)	Baseline and 6 months
Body composition and muscle strength -weight	Safety outcome for exogenous Cushing's Syndrome (weight)	Baseline and 6 months
Body composition and muscle strength - body mass index (BMI)	Safety outcome for exogenous Cushing's Syndrome (BMI)	Baseline and 6 months
Body composition and muscle strength - Timed up and go	Safety outcome for exogenous Cushing's Syndrome (Timed up and go)	Baseline and 6 months
Body composition and muscle strength - Handgrip strength	Safety outcome for exogenous Cushing's Syndrome (Handgrip strength)	Baseline and 6 months
Body composition and muscle strength - Short Physical Performance Battery	Safety outcome for exogenous Cushing's Syndrome (Short Physical Performance Battery)	Baseline and 6 months
Body composition and muscle strength - Chair rising test	Safety outcome for exogenous Cushing's Syndrome (Chair rising test)	Baseline and 6 months
Bone quality - Dual-energy X-ray absorptiometry (DXA) scan	Safety outcome for exogenous Cushing's Syndrome (DXA scan, vertebral and hip)	Baseline and 6 months
Bone quality - bone markers in blood and urine	Safety outcome for exogenous Cushing's Syndrome (bone markers in blood and urine)	Baseline and 6 months
Metabolic and cardiovascular risk - Automated office blood pressure	Safety outcome for exogenous Cushing's Syndrome (Automated office blood pressure)	Baseline and 6 months
Metabolic and cardiovascular risk (Coagulation and Inflammation markers in blood)	Safety outcome for exogenous Cushing's Syndrome (Coagulation and Inflammation markers in blood)	Baseline and 6 months
Metabolic and cardiovascular risk - Metabolic and cardiovascular markers in blood and urine	Safety outcome for exogenous Cushing's Syndrome (Metabolic and cardiovascular markers in blood and urine)	Baseline and 6 months
Patient reported symptoms of hypercortisolism - CushingQol	Safety outcome for exogenous Cushing's Syndrome (CushingQol)	Baseline and 6 months
Patient reported symptoms of hypercortisolism - Single item Sleep Quality Scale (SQS))	Safety outcome for exogenous Cushing's Syndrome (Single item Sleep Quality Scale (SQS))	Baseline and 6 months
Biological integrated cortisol status assessment - ACTH test	ACTH test for normalization of adrenal function	At baseline, (3 months) and 6 months
Biological integrated cortisol status assessment - 24h urine	24h urine for cortisol and metabolites.	At baseline, (3 months) and 6 months
Biological integrated cortisol status assessment - Salivary cortisol/cortisone	Salivary cortisol/cortisone	At baseline, (3 months) and 6 months
Biological integrated cortisol status assessment - Circulating biomarkers of glucocorticoid effects and adverse effects	Circulating biomarkers of glucocorticoid effects and adverse effects.	At baseline, (3 months) and 6 months
Biological integrated cortisol status assessment - P-cortisol after 24 hours prednisolone pause.	P-cortisol after 24 hours prednisolone pause.	At baseline, (3 months) and 6 months
ecological momentary assessments (EMA) of the Multidimensional Fatigue Inventory (MFI-20) General Fatigue scale, adjusted for EMA	EMA in situations without stress, key-secondary putcome: EMA reporting will be conducted electronically on a smartphone	EMA is used at fixed time points monthly. Participants are asked to answer the EMA items 5 times daily at semi-randomised time points, for 3 days. Diurnal profiles are generated and one diurnal profile summarizes responses during the day across all days.
Influence of the length of the prednisolone pause (0 vs. 1 vs. 2 days) on ACTH test outcome	Forty patients (all on 5 mg prednisolone/day) will undergo two extra ACTH tests after 0 and 2 days of prednisolone pause, meaning last prednisolone dose taken on the day of the test or 2 days before the test, respectively. The exact number of hours of prednisolone pause is registered for each visit. For these patients, samples for ACTH measurements are drawn at each ACTH test, before ACTH injection.	The ACTH tests are performed at screening (1 day pause) and two extra ACTH tests in the following weeks, every second patient starting with the 2 days pause and every second with the 0 day pause.
Prednisolone cross reactivity in the Roche Elecsys cortisol II immunoassay	Prednisolone cross reactivity in the Roche Elecsys cortisol II immunoassay at different timepoints (hours) since last prednisolone dose is determined in fourty consecutive patients by measuring plasma prednisolone concentrations with LC-MS and cortisol concentrations with both LC-MS and Roche Elecsys cortisol II immunoassay. Blood samples will be collected at 2 and 4 hours plus 1 and 2 days after the last prednisolone dose.	Blood samples are drawn at the screening, baseline and at the two extra ACTH test visits (0 and 2 days prednisolone pause)

Collaborators and Investigators

• Sponsor: Marianne Christina Klose
• Collaborators: Odense University Hospital; Aarhus University Hospital
• Investigators: Principal Investigator: Ulla Feldt-Rasmussen, Professor, Rigshospitalet, Denmark; Principal Investigator: Marianne Klose, MD, PhD, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2022
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: June 13, 2022
• First Submitted That Met QC Criteria: June 23, 2022
• First Posted (Actual): June 28, 2022

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Prednisolone; Glucocorticoids; Hypothalamic-pituitary-adrenal axis; Glucocorticoid-induced adrenal insufficiency
• Additional Relevant MeSH Terms: Endocrine System Diseases; Musculoskeletal Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Muscular Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Autoimmune Diseases of the Nervous System; Skin Diseases; Skin Diseases, Vascular; Adrenal Gland Diseases; Vasculitis; Vasculitis, Central Nervous System; Arteritis; Skin and Connective Tissue Diseases; Adrenal Insufficiency; Polymyalgia Rheumatica; Giant Cell Arteritis; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Pregnanes; Steroids; Fused-Ring Compounds; Pregnenediones; Pregnenes; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; 17-Hydroxycorticosteroids; Hydrocortisone
• Other Study ID Numbers: RESCUE; 2021-002528-18 (EudraCT Number); H-21041930 (Other Identifier: The Committees of Health Research Ethics in the Capital Region of Denmark); 2024-518272-30-00 (Other Identifier: CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified patient data will be made available after completion of the study and publication of the main results, upon reasonable request. Data sharing will comply with GDPR and national data protection regulations.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No