Adrenal Insufficiency, Giant Cell Arteritis, Polymyalgia Rheumatica
Conditions
Keywords
Glucocorticoid-induced adrenal insufficiency, Prednisolone, Glucocorticoids, Hypothalamic-pituitary-adrenal axis
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. 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
DRUGHydrocortisone
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.
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.
Sponsors
Marianne Christina Klose
Aarhus University Hospital
Odense University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Patients and all study personnel are blinded for study medication (hydrocortisone or placebo)
Intervention model description
Double-blinded randomised placebo-controlled clinical trial
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Body composition and muscle strength - Handgrip strength | Baseline and 6 months | Safety outcome for exogenous Cushing's Syndrome (Handgrip strength) |
| 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. |
| SF-36 | At baseline, 3 months and 6 months | Key secondary outcome |
| 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) |
| Number of 'sick days' | Throughout study period (6 months) | Key secondary outcome |
| Incidens of adrenal crises and hospitalisations | Throughout study period (6 months) | Incidence rate of adrenal crises and hospitalisations |
| Adrenal crises grading | Throughout study period (6 months) | Grade of adrenal crises. |
| 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 |
| Body composition and muscle strength - Waist, hip, height | Baseline and 6 months | Safety outcome for exogenous Cushing's Syndrome (Waist, hip, height) |
| Body composition and muscle strength -weight | Baseline and 6 months | Safety outcome for exogenous Cushing's Syndrome (weight) |
| Body composition and muscle strength - body mass index (BMI) | Baseline and 6 months | Safety outcome for exogenous Cushing's Syndrome (BMI) |
| Body composition and muscle strength - Short Physical Performance Battery | Baseline and 6 months | Safety outcome for exogenous Cushing's Syndrome (Short Physical Performance Battery) |
| Body composition and muscle strength - Chair rising test | Baseline and 6 months | Safety outcome for exogenous Cushing's Syndrome (Chair rising test) |
| 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) |
| 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) |
| Metabolic and cardiovascular risk - Automated office blood pressure | Baseline and 6 months | Safety outcome for exogenous Cushing's Syndrome (Automated office blood pressure) |
| 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) |
| 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) |
| Patient reported symptoms of hypercortisolism - CushingQol | Baseline and 6 months | Safety outcome for exogenous Cushing's Syndrome (CushingQol) |
| 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 |
| Biological integrated cortisol status assessment - 24h urine | At baseline, (3 months) and 6 months | 24h urine for cortisol and metabolites. |
| 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. |
| 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. |
| 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 |
| Influence of the length of the prednisolone pause (0 vs. 1 vs. 2 days) on ACTH test outcome | The ACTH tests are performed at screening (1 day pause) and two extra ACTH tests in the following weeks, every second patient starting with the 2 days pause and every second with the 0 day pause. | Forty patients (all on 5 mg prednisolone/day) will undergo two extra ACTH tests after 0 and 2 days of prednisolone pause, meaning last prednisolone dose taken on the day of the test or 2 days before the test, respectively. The exact number of hours of prednisolone pause is registered for each visit. For these patients, samples for ACTH measurements are drawn at each ACTH test, before ACTH injection. |
| Body composition and muscle strength - Timed up and go | Baseline and 6 months | Safety outcome for exogenous Cushing's Syndrome (Timed up and go) |
| Prednisolone cross reactivity in the Roche Elecsys cortisol II immunoassay | Blood samples are drawn at the screening, baseline and at the two extra ACTH test visits (0 and 2 days prednisolone pause) | Prednisolone cross reactivity in the Roche Elecsys cortisol II immunoassay at different timepoints (hours) since last prednisolone dose is determined in fourty consecutive patients by measuring plasma prednisolone concentrations with LC-MS and cortisol concentrations with both LC-MS and Roche Elecsys cortisol II immunoassay. Blood samples will be collected at 2 and 4 hours plus 1 and 2 days after the last prednisolone dose. |
Countries
Denmark
Contacts
CONTACTMarianne Klose, MD, PhD
CONTACTStina W. Borresen, MD, PhD
PRINCIPAL_INVESTIGATORUlla Feldt-Rasmussen, Professor
Rigshospitalet, Denmark
PRINCIPAL_INVESTIGATORMarianne Klose, MD, PhD
Rigshospitalet, Denmark
Outcome results
None listed