Randomized Controlled Trial on the Efficacy of Prednisone Tapering Versus Abrupt Discontinuation in Patients with Inflammatory or Autoimmune Disorders

The primary objective of this study is to conduct a randomized, placebo-controlled, multicenter noninferiority trial to compare the clinical outcomes of immediate termination versus a tapering regime over four weeks of systemic **glucocorticoid** treatment in patients with inflammatory or autoimmune disorders. This objective is clinically relevant as it aims to determine whether rapid cessation of glucocorticoid therapy results in comparable clinical outcomes to a gradual tapering approach, potentially impacting treatment protocols for these conditions.

Secondary objectives include:

• Testing whether the 250 mcg ACTH test can predict the need for unplanned glucocorticoid treatment during a six-month follow-up period.
• Evaluating the correlation between clinical signs and symptoms of hypocortisolism and biochemical adrenocortical performance as assessed with the 250 mcg ACTH test.

The clinical trial involves a total of **493 participants** diagnosed with various **inflammatory or autoimmune disorders**. The study population includes both male and female subjects, aged 18 years and older, who are currently undergoing systemic glucocorticoid treatment. Participants were selected based on specific criteria, including a daily glucocorticoid dose of at least 7.5 mg prednisone-equivalent and a cumulative dose of at least 420 mg prednisone-equivalent prior to inclusion. The trial does not restrict participation based on lifestyle factors such as diet or physical activity. The study includes a vulnerable population, ensuring that all participants have provided informed consent. The trial aims to compare the effects of immediate termination of glucocorticoid treatment with a tapering regime over four weeks, hypothesizing that rapid termination will not result in worse clinical outcomes.

The clinical trial is designed as a **randomized**, **controlled**, multicenter study to evaluate the effects of glucocorticoid withdrawal in patients with inflammatory or autoimmune disorders. The primary objective is to compare the clinical outcomes of immediate termination of systemic glucocorticoid treatment with a tapering regime over four weeks. The trial will assess whether rapid termination results in a non-inferior clinical outcome compared to a tapering approach. The study will utilize a double-blind methodology to ensure unbiased results, with participants receiving either **prednisone** or a placebo. The trial is expected to run from March 2022 to December 2025, with participant involvement lasting up to 28 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥ 18 years), a daily glucocorticoid dose of ≥ 7.5 mg prednisone-equivalent, and a cumulative dose of ≥ 420 mg prednisone-equivalent prior to inclusion. Follow-up visits will be scheduled to monitor the primary endpoint, which includes the time to first occurrence of hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary endpoints will evaluate individual components of the primary outcome, cumulative glucocorticoid doses, general health status, and performance in the 250 mcg ACTH test. The end-of-study visit will conclude the participant's involvement, assessing overall health and any adverse events.

Participants may be withdrawn from the study if they experience significant adverse effects, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial's design ensures rigorous monitoring and data collection to provide robust evidence on the safety and efficacy of glucocorticoid withdrawal strategies in the specified patient population.

The clinical trial involves the administration of **Prednisone**, a synthetic glucocorticoid, as the experimental medication. Prednisone is provided in the form of tablets, with each tablet containing the active substance **prednisone**. The tablets are administered orally. The maximum daily dose is 7.5 mg, with a total maximum dose of 115 mg over the treatment period. The treatment duration is set for a maximum of 28 days. To maintain the blinding of the trial, the Prednisone tablets are deblistered and repacked into glass bottles containing 30 tablets each. This ensures that neither the participants nor the investigators are aware of the treatment allocation. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a non-experimental treatment, which serves as a comparator. This is a placebo, identified as "P-Tabletten weiß 7 mm Lichtenstein," with a marketing authorization number of 6866372.00.00 and an ATC code of V03AX10. The placebo is designed to match the experimental medication in appearance and administration route to maintain the integrity of the double-blind study design. The placebo tablets are administered orally, similar to the Prednisone tablets, to ensure consistency in the administration process. The placebo is used to evaluate the efficacy and safety of the experimental treatment by providing a baseline for comparison.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the time to the first occurrence of hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or **adrenal crisis**. An adrenal crisis is defined as glucocorticoid-responsive hypotension or shock, with or without accompanying symptoms such as weakness, apathy, nausea, vomiting, abdominal pain, hypothermia, hyponatremia, hyperkalemia, and hypoglycemia. This endpoint will be measured to determine the noninferiority of immediate termination of systemic glucocorticoid treatment compared to a tapering regime over four weeks.

Secondary endpoints include the time to the first occurrence of individual components of the primary outcome, cumulative overall systemic glucocorticoid dose, and cumulative doses administered to treat or prevent adrenal failure or disease relapse. Additional assessments involve the general health status as self-assessed by participants using a visual analog scale (VAS) from 0 to 100, and a score of symptoms and signs of hypocortisolism, including weakness, hypothermia, nausea, vomiting, abdominal pain, fatigue, dizziness, and blood pressure. Performance in the 250 mcg ACTH (Synacthen®) test will also be evaluated. For patients hospitalized at study entry, the length of hospital stay will be recorded. These efficacy parameters will be collected and analyzed to provide comprehensive insights into the clinical outcomes associated with the treatment strategies under investigation.