Clinical trial NCT05435781: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Adrenal Insufficiency
Polymyalgia Rheumatica
Giant Cell Arteritis
Keywords: Glucocorticoid-induced adrenal insufficiency
Prednisolone
Glucocorticoids
Hypothalamic-pituitary-adrenal axis
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
name: Odense University Hospital
First posted: 2022-06-28
Enrollment: 250
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-blinded randomised placebo-controlled clinical trial
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: ecological momentary assessments (EMA) of the Multidimensional Fatigue Inventory (MFI-20) General Fatigue scale, adjusted for EMA
timeFrame: 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 outcomes:
measure: Daily 'end-of-day' app-facilitated patient reported outcome (PRO) assessments
timeFrame: Patients are asked daily throughout the study period as 'end-of-day' assessments.
measure: SF-36
timeFrame: At baseline, 3 months and 6 months
measure: AddiQol-30
timeFrame: At baseline, 3 months and 6 months
measure: PMR/GCA treatment characteristics -accumulated glucocorticoid dose
timeFrame: Information from 6 months before baseline to end-of study
measure: PMR/GCA treatment characteristics -prednisolone treatment duration
timeFrame: Information from 6 months before baseline to end-of study
measure: Number of 'sick days'
timeFrame: Throughout study period (6 months)
measure: Incidens of adrenal crises and hospitalisations
timeFrame: Throughout study period (6 months)
measure: Adrenal crises grading
timeFrame: Throughout study period (6 months)
measure: Body composition and muscle strength - DXA scan
timeFrame: Baseline and 6 months
measure: Body composition and muscle strength - Waist, hip, height
timeFrame: Baseline and 6 months
measure: Body composition and muscle strength -weight
timeFrame: Baseline and 6 months
measure: Body composition and muscle strength - body mass index (BMI)
timeFrame: Baseline and 6 months
measure: Body composition and muscle strength - Timed up and go
timeFrame: Baseline and 6 months
measure: Body composition and muscle strength - Handgrip strength
timeFrame: Baseline and 6 months
measure: Body composition and muscle strength - Short Physical Performance Battery
timeFrame: Baseline and 6 months
measure: Body composition and muscle strength - Chair rising test
timeFrame: Baseline and 6 months
measure: Bone quality - Dual-energy X-ray absorptiometry (DXA) scan
timeFrame: Baseline and 6 months
measure: Bone quality - bone markers in blood and urine
timeFrame: Baseline and 6 months
measure: Metabolic and cardiovascular risk - Automated office blood pressure
timeFrame: Baseline and 6 months
measure: Metabolic and cardiovascular risk (Coagulation and Inflammation markers in blood)
timeFrame: Baseline and 6 months
measure: Metabolic and cardiovascular risk - Metabolic and cardiovascular markers in blood and urine
timeFrame: Baseline and 6 months
measure: Patient reported symptoms of hypercortisolism - CushingQol
timeFrame: Baseline and 6 months
measure: Patient reported symptoms of hypercortisolism - Single item Sleep Quality Scale (SQS))
timeFrame: Baseline and 6 months
measure: Biological integrated cortisol status assessment - ACTH test
timeFrame: At baseline, (3 months) and 6 months
measure: Biological integrated cortisol status assessment - 24h urine
timeFrame: At baseline, (3 months) and 6 months
measure: Biological integrated cortisol status assessment - Salivary cortisol/cortisone
timeFrame: At baseline, (3 months) and 6 months
measure: Biological integrated cortisol status assessment - Circulating biomarkers of glucocorticoid effects and adverse effects
timeFrame: At baseline, (3 months) and 6 months
measure: Biological integrated cortisol status assessment - P-cortisol after 24 hours prednisolone pause.
timeFrame: At baseline, (3 months) and 6 months
measure: ecological momentary assessments (EMA) of the Multidimensional Fatigue Inventory (MFI-20) General Fatigue scale, adjusted for EMA
timeFrame: 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.
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Department of Endocrinology, Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet
city: Odense
country: Denmark
facility: Department of Endocrinology, Odense University Hospital
Study officials:
affiliation: Rigshospitalet, Denmark
name: Ulla Feldt-Rasmussen, Professor
role: PRINCIPAL_INVESTIGATOR
References: