Evaluation of Rituximab Efficacy in Inducing Remission in Pediatric Idiopathic Nephrotic Syndrome: A Randomized, Placebo-Controlled Trial

The primary objective of this study is the **assessment of the duration of disease remission** in children with idiopathic **nephrotic syndrome** treated with rituximab compared to placebo. This is clinically relevant as it aims to determine the efficacy of rituximab in prolonging remission periods, which is crucial for improving patient outcomes and reducing the frequency of relapses in this population.

Secondary objectives include:

• Assessment of treatment failure in the study group compared to placebo.
• Evaluation of the total dose of steroids administered in the test group compared to placebo.
• Assessment of B-cell depletion as an indicator of the risk of recurrence in the study group compared to placebo.
• Evaluation of the duration of remission in the unblinded phase of the study.
• Optimization of rituximab dosing.
• Assessment of the impact of the presence of anti-rituximab antibodies on the effectiveness and presence of allergic reactions.
• Evaluation of the effect of hypogammaglobulinemia on the duration of remission in the study group compared to placebo.
• Understanding the risk factors for the disease and how to respond to treatment with steroid-dependent nephrotic syndrome.

The clinical trial focuses on **nephrotic syndrome**, specifically targeting a pediatric population aged over 2 years and under 16 years. Both male and female participants are included, and the study involves a vulnerable population. The trial aims to assess the duration of disease remission in the study group compared to a placebo. Participants are required to have a diagnosis of idiopathic steroid-dependent nephrotic syndrome or nephrotic syndrome with frequent relapses, and must be in remission immediately prior to study entry. The sponsor has not provided information regarding the total number of participants. Relevant lifestyle considerations include the commitment of patients of childbearing age to abstinence or effective contraception during the study and up to 12 months after stopping RTX treatment. The trial population was selected based on specific inclusion criteria, including age and health status related to nephrotic syndrome.

The clinical trial is designed to evaluate the efficacy of early **rituximab** treatment in children diagnosed with idiopathic nephrotic syndrome. This study is structured as a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thus minimizing bias. The trial is set to span from December 2021 to July 2027, with the primary objective being the assessment of the duration of disease remission in the study group compared to the placebo group.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age between 2 and 16 years and a diagnosis of idiopathic steroid-dependent nephrotic syndrome. Following the screening, eligible participants will be randomized to receive either the investigational drug, MabThera (rituximab), or a placebo. The investigational drug is administered intravenously as a concentrate for solution for infusion. The primary endpoint is relapse-free survival, defined as the absence of proteinuria persisting for three or more days during the blinded phase, which lasts from day 1 to day 365.

Throughout the trial, participants will attend regular follow-up visits to monitor their health status and treatment response. These visits will include assessments of relapse-free survival, time to treatment failure, and the total dose of administered steroids. The study will conclude with an end-of-study visit, where final evaluations will be conducted to gather comprehensive data on the trial's outcomes. The expected length of participant involvement is approximately 21 days for the treatment period, with follow-up extending to one year post-treatment.

Participants may be subject to early termination from the study if they experience significant adverse events, fail to adhere to the study protocol, or withdraw consent. The trial's design and procedures are meticulously crafted to ensure the collection of robust and reliable data, contributing to the understanding of rituximab's role in managing nephrotic syndrome in pediatric patients.

The clinical trial involves the administration of **MabThera 100 mg concentrate for solution for infusion**, which contains the active substance **rituximab**. Rituximab is a monoclonal antibody classified under the ATC code L01XC02. The pharmaceutical form of MabThera is a concentrate for solution for infusion, intended for intravenous administration. The dosing regimen specifies a maximum daily dose of 375 mg/m² and a maximum total dose of 750 mg/m², with a treatment period not exceeding 21 days. The product is manufactured by Roche Registration GmbH and is authorized under the marketing authorization number EU/1/98/067/001. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the study utilizes **saline** as a placebo. Saline is administered in a manner consistent with standard clinical practice for placebo-controlled trials. The pharmaceutical form, dosage, and route of administration for saline are not specified in the trial documentation. The use of saline as a placebo is intended to provide a control for evaluating the efficacy of rituximab in achieving disease remission in children with idiopathic nephrotic syndrome. Participant compliance with the administration of saline is also monitored to maintain the integrity of the trial results.

The clinical trial aims to assess the efficacy of early **rituximab** treatment in children with idiopathic nephrotic syndrome. The primary endpoint for evaluating efficacy is relapse-free survival, defined as the absence of proteinuria persisting for three or more days during the blinded phase, which spans from day 1 to day 365. Secondary endpoints include the time to treatment failure, the percentage of failures in the experimental and placebo groups, the total dose of administered steroids, the time from depletion resolution to relapse, and relapse-free survival during the open-label phase from the day of investigational drug administration to day 365 of observation.

Efficacy parameters will be measured and collected at specified timepoints throughout the trial. The assessment of proteinuria, a key indicator of relapse, will be conducted using urinalysis to determine the presence or trace of protein, with a urine protein-to-creatinine ratio (uPCR) of less than 0.2 mg protein/mg creatinine or less than 1+ on a test strip for three consecutive days indicating remission. The trial will compare the duration of disease remission in the study group receiving rituximab against a placebo group. The analysis will focus on the duration of relapse-free survival and other secondary endpoints to determine the treatment's efficacy.