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

Phase 4RecruitingNCT05435781

Ulla Feldt-Rasmussen250 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Interventions

HydrocortisoneDRUG

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 hydrocortisoneDRUG

Eligibility

Sex: ALLMin age: 50 Years

Medical Language ↔ Plain English

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.

Locations (3)

Department of Endocrinology, Aarhus University Hospital

Aarhus, Denmark

NOT_YET_RECRUITING

Department of Medical Endocrinology, Copenhagen University Hospital, Rigshospitalet

Copenhagen, Denmark

RECRUITING

Department of Endocrinology, Odense University Hospital

Odense, Denmark

NOT_YET_RECRUITING

Outcomes

Primary Outcomes

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.

Time frame: 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

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.

Time frame: Patients are asked daily throughout the study period as 'end-of-day' assessments.

SF-36

Key secondary outcome

Time frame: At baseline, 3 months and 6 months

AddiQol-30

Key secondary outcome

Time frame: At baseline, 3 months and 6 months

PMR/GCA treatment characteristics -accumulated glucocorticoid dose

Key secondary outcome. accumulated glucocorticoid dose

Time frame: 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)

Time frame: Information from 6 months before baseline to end-of study

Number of 'sick days'

Key secondary outcome

Time frame: Throughout study period (6 months)

Incidens of adrenal crises and hospitalisations

Incidence rate of adrenal crises and hospitalisations

Time frame: Throughout study period (6 months)

Adrenal crises grading

Grade of adrenal crises.

Time frame: 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