Effect of Supplemental Hydrocortisone During Stress in Prednisolone-induced Adrenal Insufficiency
- Conditions
- Polymyalgia RheumaticaGiant Cell ArteritisAdrenal Insufficiency
- Interventions
- Registration Number
- NCT05435781
- Lead Sponsor
- Ulla Feldt-Rasmussen
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 250
- 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.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description RCT group - placebo Placebo for hydrocortisone Patients with polymyalgia rheumatica/giant cell arteritis with glucocorticoid-induced adrenal insufficiency (Synacthen test response \<420 nmol/l) that are randomised to receive placebo RCT group - hydrocortisone 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
- Primary Outcome Measures
Name Time Method ecological momentary assessments (EMA) of the Multidimensional Fatigue Inventory (MFI-20) General Fatigue scale, adjusted for EMA 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'. EMA in situations of stress. EMA reporting will be conducted electronically on a smartphone.
- Secondary Outcome Measures
Name Time Method Body composition and muscle strength - Waist, hip, height Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (Waist, hip, height)
Metabolic and cardiovascular risk - Automated office blood pressure Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (Automated office blood pressure)
Biological integrated cortisol status assessment - 24h urine At baseline, (3 months) and 6 months 24h urine for cortisol and metabolites.
Incidens of adrenal crises and hospitalisations Throughout study period (6 months) Incidence rate of adrenal crises and hospitalisations
Biological integrated cortisol status assessment - P-cortisol after 24 hours prednisolone pause. At baseline, (3 months) and 6 months P-cortisol after 24 hours prednisolone pause.
Daily 'end-of-day' app-facilitated patient reported outcome (PRO) assessments Patients are asked daily throughout the study period as 'end-of-day' 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.
Number of 'sick days' Throughout study period (6 months) Key secondary outcome
Body composition and muscle strength -weight Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (weight)
Body composition and muscle strength - Timed up and go Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (Timed up and go)
Body composition and muscle strength - Handgrip strength Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (Handgrip strength)
SF-36 At baseline, 3 months and 6 months Key secondary outcome
Body composition and muscle strength - DXA scan Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (Dual-energy X-ray absorptiometry (DXA) scan: fat percentage, body composition
Bone quality - Dual-energy X-ray absorptiometry (DXA) scan Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (DXA scan, vertebral and hip)
Metabolic and cardiovascular risk (Coagulation and Inflammation markers in blood) Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (Coagulation and Inflammation markers in blood)
Patient reported symptoms of hypercortisolism - Single item Sleep Quality Scale (SQS)) Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (Single item Sleep Quality Scale (SQS))
Biological integrated cortisol status assessment - ACTH test At baseline, (3 months) and 6 months ACTH test for normalization of adrenal function
Body composition and muscle strength - Short Physical Performance Battery Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (Short Physical Performance Battery)
Biological integrated cortisol status assessment - Salivary cortisol/cortisone At baseline, (3 months) and 6 months Salivary cortisol/cortisone
Biological integrated cortisol status assessment - Circulating biomarkers of glucocorticoid effects and adverse effects At baseline, (3 months) and 6 months Circulating biomarkers of glucocorticoid effects and adverse effects.
AddiQol-30 At baseline, 3 months and 6 months Key secondary outcome
PMR/GCA treatment characteristics -accumulated glucocorticoid dose Information from 6 months before baseline to end-of study Key secondary outcome. accumulated glucocorticoid dose
PMR/GCA treatment characteristics -prednisolone treatment duration Information from 6 months before baseline to end-of study Key secondary outcome. Duration of prednisolone treatment, duration of prednisolone tapering (5 mg - 0 mg)
Adrenal crises grading Throughout study period (6 months) Grade of adrenal crises.
Body composition and muscle strength - body mass index (BMI) Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (BMI)
Metabolic and cardiovascular risk - Metabolic and cardiovascular markers in blood and urine Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (Metabolic and cardiovascular markers in blood and urine)
Body composition and muscle strength - Chair rising test Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (Chair rising test)
Bone quality - bone markers in blood and urine Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (bone markers in blood and urine)
Patient reported symptoms of hypercortisolism - CushingQol Baseline and 6 months Safety outcome for exogenous Cushing's Syndrome (CushingQol)
ecological momentary assessments (EMA) of the Multidimensional Fatigue Inventory (MFI-20) General Fatigue scale, adjusted for EMA 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. EMA in situations without stress, key-secondary putcome: EMA reporting will be conducted electronically on a smartphone
Trial Locations
- Locations (3)
Department of Endocrinology, Aarhus University Hospital
🇩🇰Aarhus, Denmark
Department of Endocrinology, Odense University Hospital
🇩🇰Odense, Denmark
Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet
🇩🇰Copenhagen, Denmark