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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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.

Conditions
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Adrenal Insufficiency, Polymyalgia Rheumatica, Giant Cell Arteritis

Intervention / Treatment
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* Drug: Hydrocortisone
* Drug: Placebo for hydrocortisone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blinded randomised placebo-controlled clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: RCT group - hydrocortisone<br>Patients with polymyalgia rheumatica/giant cell arteritis with glucocorticoid-induced adrenal insufficiency (Synacthen test response <420 nmol/l) that are randomised to receive hydrocortisone | Drug: Hydrocortisone<br>* 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.<br>|
| Placebo Comparator: RCT group - placebo<br>Patients with polymyalgia rheumatica/giant cell arteritis with glucocorticoid-induced adrenal insufficiency (Synacthen test response <420 nmol/l) that are randomised to receive placebo | Drug: Placebo for hydrocortisone<br>* 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.<br>|
| No Intervention: Control group<br>Patients with polymyalgia rheumatica/giant cell arteritis with normal adrenal function (Synacthen test response ≥420 nmol/l) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucocorticoid-induced adrenal insufficiency, Prednisolone, Glucocorticoids, Hypothalamic-pituitary-adrenal axis