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

Official title

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.

Overview

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.

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.

Interventions

• 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.
• 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.

Primary outcome measures

• ecological momentary assessments (EMA) of the Multidimensional Fatigue Inventory (MFI-20) General Fatigue scale, adjusted for EMA [Time frame: 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 (12)

• Daily 'end-of-day' app-facilitated patient reported outcome (PRO) assessments [Time frame: Patients are asked daily throughout the study period as 'end-of-day' assessments.]
• SF-36 [Time frame: At baseline, 3 months and 6 months]
• AddiQol-30 [Time frame: At baseline, 3 months and 6 months]
• PMR/GCA treatment characteristics -accumulated glucocorticoid dose [Time frame: Information from 6 months before baseline to end-of study]
• PMR/GCA treatment characteristics -prednisolone treatment duration [Time frame: Information from 6 months before baseline to end-of study]
• Number of 'sick days' [Time frame: Throughout study period (6 months)]
• Incidens of adrenal crises and hospitalisations [Time frame: Throughout study period (6 months)]
• Adrenal crises grading [Time frame: Throughout study period (6 months)]
• Body composition and muscle strength - DXA scan [Time frame: Baseline and 6 months]
• Body composition and muscle strength - Waist, hip, height [Time frame: Baseline and 6 months]
• Body composition and muscle strength -weight [Time frame: Baseline and 6 months]
• Body composition and muscle strength - body mass index (BMI) [Time frame: Baseline and 6 months]

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Denmark · 3 centers

• Department of Endocrinology, Aarhus University Hospital — Aarhus
• Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet — Copenhagen
• Department of Endocrinology, Odense University Hospital — Odense

Publications

• Borresen SW, Hansen SB, Al-Jorani H, Tei R, Dreyer AF, Boesen VB, Bislev LS, Jorgensen NT, Jensen RC, Bjergstrom MLL, Christensen LL, Frederiksen JSS, Glintborg D, Bjorner JB, Feldt-Rasmussen U, Jorgensen JOL, Andersen MS, Klose M. Effect of supplemental hydrocortisone during stress in prednisolone-induced adrenal insufficiency: a study protocol for a multicentre, randomised, double-blinded, place PMID 42276802

Identifiers

NCT: NCT05435781 · RESCUE · 2021-002528-18 · H-21041930 · 2024-518272-30-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗