Evaluation of Hydrocortisone Supplementation on Quality of Life in Glucocorticoid-Induced Adrenal Insufficiency in Polymyalgia Rheumatica and Giant Cell Arteritis

The primary objective of this study is to evaluate the effect of supplemental **hydrocortisone** compared with placebo during mild to moderate physical or mental stress on health-related quality of life (HRQoL) in patients with polymyalgia rheumatica (PMR) and/or giant cell arteritis (GCA) who have been diagnosed with glucocorticoid-induced adrenal insufficiency while on ongoing low-dose prednisolone treatment. The main emphasis is on fatigue and its daily variation during periods of stress. This is clinically relevant as it aims to improve the management of glucocorticoid-induced adrenal insufficiency, potentially enhancing patient outcomes by addressing fatigue, a common and debilitating symptom.

Secondary objectives include:

• Determining the association between adrenal function and HRQoL at baseline.
• Assessing the effect of hydrocortisone stress doses on general daily symptom reporting and HRQoL over four-week periods.
• Exploring the relationship between HRQoL and the severity of glucocorticoid-induced adrenal insufficiency at baseline and during treatment with hydrocortisone stress doses compared to placebo.
• Evaluating the impact of hydrocortisone stress doses on the tapering of prednisolone treatment for PMR/GCA, including differences in glucocorticoid treatment doses, treatment duration, and disease activity.
• Investigating the safety of stress doses concerning hypo- and hypercortisolism, including adrenal crises, sick days, hospitalizations, and cushingoid symptoms.
• Examining the effect of prednisolone pause duration on ACTH test outcomes and the cross-reactivity of prednisolone in cortisol assays.
• Identifying biomarkers for the risk of adrenal insufficiency, adequacy of glucocorticoid replacement treatment, and glucocorticoid effects and adverse effects.

The clinical trial focuses on patients diagnosed with **glucocorticoid-induced adrenal insufficiency** in the context of polymyalgia rheumatica (PMR) and/or giant cell arteritis (GCA). The study population includes both male and female participants aged 50 years and older, with women required to be postmenopausal. Participants are currently undergoing treatment with prednisolone, having been on a stable low-dose regimen for at least two weeks prior to screening. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified, but the trial's focus on fatigue suggests that daily variations in these factors may be relevant. The selection criteria ensure that participants have been on prednisolone treatment for a minimum of 12 weeks, with a current daily dose between greater than 0 mg and up to 5 mg.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the effect of supplemental **hydrocortisone** on health-related quality of life in patients with **glucocorticoid-induced adrenal insufficiency**. The trial targets individuals diagnosed with polymyalgia rheumatica and/or giant cell arteritis who are undergoing low-dose prednisolone treatment. The primary focus is on assessing fatigue and its daily variation during periods of stress. The trial is expected to run until December 31, 2026, with recruitment having commenced on June 1, 2022.

Participants will be involved in the study for a maximum treatment period of nine months. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress, and an end-of-study visit to conclude participation. The inclusion criteria require participants to be aged 50 years or older, with women being postmenopausal, and to have been on prednisolone treatment for at least 12 weeks. The current daily prednisolone dose must be greater than 0 mg and less than or equal to 5 mg, maintained for a minimum of two weeks prior to the screening visit.

Study visits are structured to ensure comprehensive data collection and participant safety. The screening visit will assess eligibility based on the inclusion criteria. Follow-up visits will occur at regular intervals to monitor the primary and secondary endpoints, including ecological momentary assessments of fatigue using the Multidimensional Fatigue Inventory and other health-related quality of life measures. The end-of-study visit will involve a final assessment of the participant's condition and the collection of any remaining data.

Participants may be withdrawn from the study if they experience adverse events that compromise their safety, if they fail to adhere to the study protocol, or if they choose to withdraw consent. The trial's primary endpoint focuses on fatigue assessments during stress, while secondary endpoints include various health-related quality of life measures and safety outcomes. The study employs a smartphone application for data collection, with a paper version available for those unable to use the app. The trial aims to provide valuable insights into the management of glucocorticoid-induced adrenal insufficiency and its impact on patients' quality of life.

The clinical trial involves the administration of **Hydrocortisone** Orion 10 mg tablets, which serve as the experimental medication. The pharmaceutical form of this medication is a tablet, and it is administered orally. The active substance in the tablet is hydrocortisone, a chemical compound, with an ATC code of H02AB09. The maximum daily dose of hydrocortisone is 100 mg, and the total maximum dose over the treatment period is 27.4 grams. The treatment period is limited to a maximum of 9 days. The medication is manufactured by Orion Corporation and is not a paediatric formulation. The trial aims to assess the effect of supplemental hydrocortisone during mild to moderate physical or mental stress in patients with polymyalgia rheumatica or giant cell arteritis who are experiencing glucocorticoid-induced adrenal insufficiency while on low-dose prednisolone treatment.

The study also includes a **placebo** for hydrocortisone, which is used as a comparator treatment. The placebo is designed to mimic the hydrocortisone tablets in appearance and is administered orally. It is manufactured by Glostrup Apotek according to good manufacturing practice for medicinal products. The placebo does not contain any active substance and serves to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. This allows for an unbiased comparison of the effects of hydrocortisone versus placebo on health-related quality of life, with a primary focus on fatigue and its daily variation during stress periods.

Efficacy in this clinical trial will be assessed primarily through the use of **Ecological Momentary Assessments (EMA)** of the Multidimensional Fatigue Inventory (MFI-20), specifically focusing on the General Fatigue scale during situations of stress. Participants will report stress using a study smartphone application, which will prompt them to answer four momentary MFI-20 General Fatigue questions five times daily at semi-randomized timepoints over a three-day period. A paper version of the assessment is available for participants unable to use a smartphone.

Secondary efficacy endpoints include several key measures: the EMA version of the MFI-20 General Fatigue scale at baseline and at fixed monthly timepoints, the SF-36v2 questionnaire, and daily 'end-of-day' patient-reported symptoms of adrenal insufficiency and intercurrent illness and stress, facilitated by a smartphone app. Additional secondary outcomes involve the AddiQol-30 questionnaire, PMR/GCA treatment characteristics, and the number of 'sick days'. The trial will also assess ACTH test results, including basal and stimulated plasma cortisol levels after varying durations of prednisolone pause, and prednisolone cross-reactivity in the Roche Elecsys cortisol II immunoassay.