Efficacy and Safety of Prolonged-Release Budesonide Versus Prednisone in Pediatric Primary IgA Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the efficacy of **Budesonide** delayed-release (DR) in combination with angiotensin-converting enzyme inhibitors (ACEI) compared to placebo in reducing proteinuria in children with primary IgA nephropathy. Additionally, the study aims to assess whether treatment with Budesonide DR is superior to Prednisone in reducing proteinuria within the same population. Proteinuria is a significant clinical marker in IgA nephropathy, and its reduction is crucial for improving renal outcomes and delaying disease progression.

Secondary objectives include:

• Assessment of the safety profile of Budesonide DR in the pediatric population with IgA nephropathy compared to standard of care (SoC) and Prednisone.
• Confirmation of the effectiveness of the used dose of Budesonide DR in the pediatric population with IgA nephropathy.

The clinical trial involves a study population of children aged 8 to 17 years diagnosed with **primary IgA nephropathy**. The trial includes both male and female participants, and the population is considered vulnerable due to the age group involved. Participants were selected based on specific criteria, including a confirmed diagnosis through kidney biopsy and a history of either no treatment or treatment with ACE inhibitors (ACEI) or angiotensin receptor blockers (ARB). The trial also requires that any previous steroid or immunosuppressive treatment was completed at least two months prior to participation. Additionally, participants must exhibit proteinuria greater than 200 mg/day or a protein-creatinine ratio (UPR) exceeding 0.2 g/g in three tests. A negative pregnancy test is required for qualification. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the **efficacy** and safety of prolonged-release **budesonide** in children diagnosed with primary IgA nephropathy. This is a multicenter, interventional phase III study that employs a randomized, placebo-controlled, double-blind methodology. The trial aims to compare the effectiveness of budesonide in combination with ACE inhibitors (ACEI) against a placebo in reducing proteinuria, as well as to assess its efficacy relative to **prednisone**. The study is expected to commence recruitment on January 1, 2025, and conclude by March 31, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (8-17 years), a confirmed diagnosis of primary IgA nephropathy via kidney biopsy, and specific proteinuria levels. The trial will include follow-up visits to monitor the primary endpoint, which is the reduction of the urine protein-creatinine ratio (UPCR) after 24 weeks of treatment. Secondary endpoints include the number of side effects and changes in glomerular filtration rate (GFR) during treatment. The end-of-study visit will assess the percentage change in proteinuria compared to baseline.

Participant involvement is anticipated to last up to 24 weeks, with conditions for early termination including non-compliance with the study protocol or the occurrence of adverse events that compromise participant safety. The trial will utilize three products: a placebo, Encorton (1 mg prednisone tablets), and Entocort (3 mg prolonged-release budesonide capsules). Both active treatments are administered orally, with a maximum daily dose of 1 mg for prednisone and 9 mg for budesonide. The study is not classified as a low-intervention trial and is categorized under therapeutic exploratory and confirmatory clinical trials.

The clinical trial involves the administration of **Entocort**, a prolonged-release capsule containing **budesonide** as the active substance. Each capsule contains 3 mg of budesonide and is manufactured by Tillotts Pharma GmbH. The pharmaceutical form is a hard capsule designed for prolonged release, ensuring a controlled delivery of the active ingredient. The route of administration is oral, with a maximum daily dose of 9 mg. The treatment period is set for a maximum of 24 weeks. Budesonide is classified under the ATC code A07EA06 and is categorized as a glucocorticoid. Participant compliance with the dosing schedule will be monitored throughout the study.

**Encorton** is used as a comparator treatment in this trial. It is a tablet formulation containing **prednisone** as the active substance, with each tablet providing 1 mg of prednisone. Manufactured by Adamed Pharma S.A., this medication is also administered orally. The maximum daily dose is 1 mg/kg, with a treatment duration of up to 24 weeks. Prednisone is classified under the ATC code H02AB07 and is also a glucocorticoid. Compliance with the dosing regimen will be closely monitored to ensure adherence to the study protocol.

A **placebo** is utilized in this study to serve as a control for evaluating the efficacy of the experimental treatments. The placebo is designed to mimic the appearance and administration route of the active treatments, ensuring blinding in the study. It is administered orally, with the same frequency and duration as the active treatments, to maintain consistency in the trial design. Participant adherence to the placebo regimen will be monitored to ensure the integrity of the study results.

Efficacy in this clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the reduction of the urine protein-creatinine ratio (UPCR) after 24 weeks of treatment and the assessment of the percentage change in **proteinuria** at the end of treatment compared to the beginning. Secondary endpoints will evaluate the number of side effects, reduction in glomerular filtration rate (GFR) during treatment, and the reduction of UPCR after 24 weeks of treatment in relation to the beginning of treatment (deltaUPCR).

The trial aims to demonstrate that Budesonide delayed-release (DR) in combination with angiotensin-converting enzyme inhibitors (ACEI) is more effective than placebo in reducing proteinuria. Additionally, it will assess whether treatment with Budesonide DR is superior to treatment with Prednisone in reducing proteinuria in the study population. The efficacy parameters will be measured and collected at specified timepoints, including the end of the 24-week treatment period. The analysis will focus on comparing the changes in UPCR and proteinuria levels from baseline to the end of the treatment period.