Randomized, Open-Label Study on Health-Related Quality of Life in Primary Adrenal Insufficiency: Comparison of Hydrocortisone (Plenadren) and Cortisone Therapy

The primary objective of this study is to evaluate the differences in **health-related quality of life (HRQoL)** scores in patients with newly diagnosed **primary adrenal insufficiency** (PAI) who are receiving Plenadren compared to those receiving conventional Cortisone. The assessment will be conducted at the time of diagnosis and subsequently at 1, 6, and 12 months. This objective is clinically relevant as it aims to determine the impact of different treatment regimens on the quality of life in patients with PAI, which is crucial for optimizing therapeutic strategies and improving patient outcomes.

The clinical trial involves participants diagnosed with **primary adrenal insufficiency (PAI)**, with an age range of 16 to 80 years. The study includes both male and female subjects, ensuring a diverse representation of the general population. Participants are required to be recently diagnosed and must have been on glucocorticoid replacement therapy for less than 31 days prior to inclusion, ensuring treatment naivety. Women of childbearing potential are included, provided they have a negative pregnancy test at the time of screening. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize the ability to provide informed consent, ensuring participants are capable of understanding the study's requirements and implications.

The clinical trial is designed as an **open-label**, randomized study to evaluate the quality of life in participants with newly diagnosed **primary adrenal insufficiency** (PAI). The trial will compare the effects of Plenadren 20 mg modified-release tablets and Cortison 25 mg tablets. The primary objective is to assess differences in health-related quality of life (HRQoL) scores at diagnosis and at 1, 6, and 12 months. Secondary endpoints include measurements of blood pressure, body weight, waist circumference, body mass index, cholesterol levels, glucose, insulin, HOMA index, hair cortisol levels, salivary cortisol day curves, 24-hour urine cortisol and metabolites, sleep patterns, cognitive testing, and bone mineral density, among others.

The trial will span from August 3, 2023, to February 28, 2027, with recruitment starting on August 3, 2023. Participants will be involved for a maximum treatment period of 12 months. The study includes several key visits: an initial screening visit to confirm eligibility, follow-up visits at 1, 6, and 12 months to monitor progress and collect data, and an end-of-study visit to conclude participation. Participants must be aged 16-80 years, have a recent diagnosis of PAI, and have been on glucocorticoid replacement therapy for less than 31 days prior to inclusion. Women of childbearing potential must have a negative pregnancy test at screening. Participants must also be capable of providing informed consent.

Involvement in the study may be terminated early if participants experience adverse events, serious adverse events, or symptoms of adrenal crisis that necessitate withdrawal. The trial is not categorized as low intervention and is classified as a Phase 4 clinical trial. The study aims to provide valuable insights into the management of PAI and the impact of different treatment regimens on patient quality of life.

The clinical trial involves the administration of **Plenadren 20 mg modified-release tablets**, which contain the active substance **hydrocortisone**. This pharmaceutical form is a modified-release tablet designed for oral administration. The dosage regimen allows for a maximum daily dose of 60 mg, with a total maximum dose of 21,900 mg over a treatment period of up to 12 months. The modified-release formulation is intended to provide a controlled release of hydrocortisone, optimizing therapeutic effects while minimizing potential side effects. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, the study includes a comparator treatment using **Cortison 25 mg tabletter**, which contains the active substance **cortisone**. This treatment is also administered orally in the form of standard tablets. The maximum daily dose for cortisone is set at 60 mg, with a total maximum dose of 60 mg over the same 12-month treatment period. The inclusion of cortisone as a comparator allows for the evaluation of differences in health-related quality of life (HRQoL) scores between participants receiving Plenadren and those receiving conventional cortisone therapy. Compliance with the cortisone dosing schedule will similarly be monitored to ensure accurate assessment of treatment effects.

The efficacy of the clinical trial will be assessed primarily through the evaluation of health-related quality of life (HRQoL) scores in patients receiving Plenadren compared to those receiving conventional Cortisone. These scores will be measured at the time of diagnosis and subsequently at 1, 6, and 12 months. The primary endpoint is the HRQoL score, which will provide insights into the differences in quality of life between the two treatment groups.

Secondary endpoints include a range of physiological and biochemical parameters. These encompass blood pressure, body weight, waist circumference, body mass index, cholesterol levels, glucose, insulin, and the Homeostatic Model Assessment (HOMA) index. Additionally, cortisol levels will be monitored through hair samples, salivary cortisol day curves, and 24-hour urine cortisol and metabolites. Sleep patterns will be assessed using a sleep diary, actigraphy, and sleep radar. Cognitive function and brain plasticity will be evaluated using cognitive testing and serum levels of brain-derived neurotrophic factor (BDNF). Bone health will be assessed through bone mineral density, body composition, and bone markers. Adverse events, serious adverse events, and symptoms and treatment of adrenal crisis will also be recorded.