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

NCT ID: NCT05435781

Last Updated: 2025-05-02

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 250 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-07
• Study Completion Date: 2028-03-01

Brief Summary

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.

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.

Seventy-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.

Conditions

Adrenal Insufficiency; Polymyalgia Rheumatica; Giant Cell Arteritis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

Hydrocortisone

Intervention Type: DRUG

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.

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

Group Type: PLACEBO_COMPARATOR

Placebo for hydrocortisone

Intervention Type: DRUG

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.

Control group

Patients with polymyalgia rheumatica/giant cell arteritis with normal adrenal function (Synacthen test response ≥420 nmol/l)

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aarhus University Hospital

OTHER

Sponsor Role: collaborator

Odense University Hospital

OTHER

Sponsor Role: collaborator

Ulla Feldt-Rasmussen

OTHER

Sponsor Role: lead

Responsible Party

Ulla Feldt-Rasmussen

Professor, Senior Consultant Ulla Feldt-Rasmussen

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Ulla Feldt-Rasmussen, Professor

Role: PRINCIPAL_INVESTIGATOR

Rigshospitalet, Denmark

Locations

Department of Endocrinology, Aarhus University Hospital

Aarhus, , Denmark

Site Status: NOT_YET_RECRUITING

Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet

Copenhagen, , Denmark

Site Status: RECRUITING

Department of Endocrinology, Odense University Hospital

Odense, , Denmark

Site Status: NOT_YET_RECRUITING

Countries

Denmark

Central Contacts

Ulla Feldt-Rasmussen, Professor

Role: CONTACT

ufeldt@rh.dk

+4523829869

Stina W. Borresen, MD, PhD

Role: CONTACT

stina.borresen@regionh.dk

+4525347551

Facility Contacts

Jens Otto L. Jørgensen, Professor

Role: primary

Ulla Feldt-Rasmussen, Professor

Role: primary

ufeldt@rh.dk

Stina W. Borresen, MD, PhD

Role: backup

Marianne S. Andersen, professor

Role: primary

Other Identifiers

2021-002528-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

H-21041930

Identifier Type: OTHER

Identifier Source: secondary_id

RESCUE

Identifier Type: -

Identifier Source: org_study_id