Randomized, Double-Blind, Placebo-Controlled Study of Hydrocortisone in Patients with Giant Cell Arteritis/Polymyalgia Rheumatica and Adrenal Insufficiency

The primary objective of this study is to conduct the first placebo-controlled randomized controlled trial (RCT) in patients with **Polymyalgia Rheumatica** and **Giant Cell Arteritis** following the planned cessation of glucocorticoid treatment. This trial aims to provide evidence-based guidance for managing glucocorticoid-induced **adrenal insufficiency**, addressing a significant clinical need for numerous patients. The study evaluates the effects of hydrocortisone compared to a placebo over a 16-week period, focusing on patient-reported symptoms of adrenal insufficiency. The clinical relevance of this objective lies in its potential to improve treatment protocols and patient outcomes by offering a scientifically validated approach to managing adrenal insufficiency post-glucocorticoid therapy.

The clinical trial focuses on patients with **tertiary adrenal insufficiency** following glucocorticoid treatment cessation. The study population includes both male and female participants aged 50 years and older. Participants must have a diagnosis of polymyalgia rheumatica or giant cell arteritis and must be in glucocorticoid-free remission for more than two weeks but less than twelve weeks after treatment with prednisolone for at least twelve weeks. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the effects of **hydrocortisone** compared to placebo in patients with **Giant Cell Arteritis** or **Polymyalgia Rheumatica** who report symptoms of **adrenal insufficiency** following the cessation of glucocorticoid treatment. The trial will span a period of 16 weeks, with the primary objective of providing evidence-based guidance for managing glucocorticoid-induced adrenal insufficiency. Participants will be randomly assigned to receive either hydrocortisone or placebo, administered orally in tablet form. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and collect data, and a final end-of-study visit to assess outcomes.

Inclusion criteria require participants to be aged 50 years or older, with a confirmed diagnosis of polymyalgia rheumatica or giant cell arteritis, and in glucocorticoid-free remission for more than two weeks but less than 12 weeks after treatment with prednisolone. The primary endpoint will focus on symptoms of adrenal insufficiency, assessed using the AddiQoL-30 questionnaire. Secondary endpoints will include patient-reported symptoms of fatigue, health-related quality of life, incidence of adrenal crises, hospitalizations, blood pressure, arterial stiffness, body composition, muscle strength, metabolic and cardiovascular risk, bone status, and cortisol status assessment.

The expected duration of participant involvement is 16 weeks, aligning with the trial's overall duration. Conditions that may lead to early termination from the study include adverse reactions to the study medication, withdrawal of consent, or any significant protocol deviations. The trial aims to recruit participants starting from March 2022, with an estimated completion date in September 2031. The study is not classified as low intervention, as it explores the risks, benefits, and indications of a study drug that is in routine medical use.

The clinical trial involves the administration of **Hydrocortisone**, marketed as "Hydrokortison 'Orion', tabletter," which is a chemically derived active substance. The pharmaceutical form of this medication is a tablet, and it is administered orally. The maximum daily dose of hydrocortisone is 40 mg, with a total maximum dose of 4480 mg over the course of the study. The treatment period is set for a maximum of 16 weeks. The hydrocortisone tablets are produced by Orion Corporation and are not formulated for pediatric use. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a **placebo** control, which is administered in the form of a tablet identical in appearance to the hydrocortisone tablets. The placebo is chemically inert and serves as a comparator to evaluate the efficacy of hydrocortisone in the treatment of patients with Giant Cell Arteritis (GCA) and Polymyalgia Rheumatica (PMR) who report symptoms of adrenal insufficiency following the cessation of glucocorticoid treatment. The placebo is administered orally, with a dosing schedule that mirrors that of the hydrocortisone group, ensuring that the study remains double-blinded. The placebo tablets are not intended for pediatric use, and participant adherence to the placebo regimen will be similarly monitored to maintain the integrity of the trial results.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint focuses on the evaluation of **adrenal insufficiency symptoms** using the AddiQoL-30, a validated patient-reported outcome measure. Secondary endpoints include a range of patient-reported and physiological parameters: symptoms of fatigue, health-related quality of life (HRQoL) assessed through questionnaires other than AddiQoL-30, incidence of adrenal crises, hospitalizations, and sick days. Additionally, physiological assessments will be conducted to measure blood pressure, arterial stiffness, body composition, muscle strength, metabolic and cardiovascular risk, bone status, and biological integrated cortisol status.

The trial is designed as a multi-centre, randomized, double-blinded, placebo-controlled study over a 16-week period. Efficacy parameters will be collected at specified timepoints throughout the study duration. The use of validated scales and questionnaires ensures the reliability and accuracy of patient-reported outcomes. Laboratory tests and clinical assessments will be employed to gather data on physiological endpoints. The analysis of these parameters will provide comprehensive insights into the efficacy of hydrocortisone compared to placebo in patients with Giant Cell Arteritis and Polymyalgia Rheumatica who have ceased glucocorticoid treatment.