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

Adrenal Insufficiency Clinical Trial

— RESCUE  

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05435781
• Other study ID #: RESCUE
• Secondary ID: 2021-002528-18H-
• Status: Recruiting
• Phase: Phase 4
• Start date: June 7, 2022
• Est. completion date: March 1, 2028

Study information

• Verified date: June 2022
• Source: Rigshospitalet, Denmark
• Contact: Ulla Feldt-Rasmussen, Professor
• Phone: +4523829869
• Email: ufeldt[@]rh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 250
• Est. completion date: March 1, 2028
• Est. primary completion date: March 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Adrenal Insufficiency
• Arteritis
• Giant Cell Arteritis
• Polymyalgia Rheumatica

Intervention

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 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.

Locations

Country	Name	City	State
Denmark	Department of Endocrinology, Aarhus University Hospital	Aarhus
Denmark	Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet	Copenhagen
Denmark	Department of Endocrinology, Odense University Hospital	Odense

Sponsors (3)

Lead Sponsor	Collaborator
Ulla Feldt-Rasmussen	Aarhus University Hospital, Odense University Hospital

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	SF-36	Key secondary outcome	At baseline, 3 months and 6 months
Secondary	AddiQol-30	Key secondary outcome	At baseline, 3 months and 6 months
Secondary	PMR/GCA treatment characteristics -accumulated glucocorticoid dose	Key secondary outcome. accumulated glucocorticoid dose	Information from 6 months before baseline to end-of study
Secondary	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
Secondary	Number of 'sick days'	Key secondary outcome	Throughout study period (6 months)
Secondary	Incidens of adrenal crises and hospitalisations	Incidence rate of adrenal crises and hospitalisations	Throughout study period (6 months)
Secondary	Adrenal crises grading	Grade of adrenal crises.	Throughout study period (6 months)
Secondary	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
Secondary	Body composition and muscle strength - Waist, hip, height	Safety outcome for exogenous Cushing's Syndrome (Waist, hip, height)	Baseline and 6 months
Secondary	Body composition and muscle strength -weight	Safety outcome for exogenous Cushing's Syndrome (weight)	Baseline and 6 months
Secondary	Body composition and muscle strength - body mass index (BMI)	Safety outcome for exogenous Cushing's Syndrome (BMI)	Baseline and 6 months
Secondary	Body composition and muscle strength - Timed up and go	Safety outcome for exogenous Cushing's Syndrome (Timed up and go)	Baseline and 6 months
Secondary	Body composition and muscle strength - Handgrip strength	Safety outcome for exogenous Cushing's Syndrome (Handgrip strength)	Baseline and 6 months
Secondary	Body composition and muscle strength - Short Physical Performance Battery	Safety outcome for exogenous Cushing's Syndrome (Short Physical Performance Battery)	Baseline and 6 months
Secondary	Body composition and muscle strength - Chair rising test	Safety outcome for exogenous Cushing's Syndrome (Chair rising test)	Baseline and 6 months
Secondary	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
Secondary	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
Secondary	Metabolic and cardiovascular risk - Automated office blood pressure	Safety outcome for exogenous Cushing's Syndrome (Automated office blood pressure)	Baseline and 6 months
Secondary	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
Secondary	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
Secondary	Patient reported symptoms of hypercortisolism - CushingQol	Safety outcome for exogenous Cushing's Syndrome (CushingQol)	Baseline and 6 months
Secondary	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
Secondary	Biological integrated cortisol status assessment - ACTH test	ACTH test for normalization of adrenal function	At baseline, (3 months) and 6 months
Secondary	Biological integrated cortisol status assessment - 24h urine	24h urine for cortisol and metabolites.	At baseline, (3 months) and 6 months
Secondary	Biological integrated cortisol status assessment - Salivary cortisol/cortisone	Salivary cortisol/cortisone	At baseline, (3 months) and 6 months
Secondary	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
Secondary	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
Secondary	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.