Efficacy and Safety Evaluation of Obinutuzumab Versus Mycophenolate Mofetil in Pediatric Idiopathic Nephrotic Syndrome: A Phase III Randomized Study

The primary objective of this Phase III, international, multicenter, randomized open-label study is to evaluate the **efficacy** of obinutuzumab compared with mycophenolate mofetil (MMF) in patients with childhood onset idiopathic nephrotic syndrome. This objective is clinically relevant as it aims to determine the potential of obinutuzumab as an effective treatment option, which could lead to improved management of this condition in pediatric patients.

Secondary objectives include:

• To evaluate the efficacy of obinutuzumab compared with MMF.
• To evaluate changes in fatigue of participants treated with obinutuzumab compared with MMF.
• To evaluate changes in the quality of life of participants treated with obinutuzumab compared with MMF.
• To evaluate edema over time.
• To evaluate the safety of obinutuzumab compared with MMF.
• To characterize the obinutuzumab pharmacokinetic (PK) profile.
• To characterize obinutuzumab-induced pharmacodynamic (PD) changes.

These secondary objectives are crucial for understanding the broader impact of obinutuzumab on patient well-being, safety, and its pharmacological characteristics, which are essential for comprehensive treatment evaluation.

The clinical trial involves a total of **54 participants** diagnosed with **Childhood Idiopathic Nephrotic Syndrome**. The study population includes both male and female subjects, categorized within age ranges 2 and 3, indicating a pediatric cohort. Participants were selected based on specific criteria, including a diagnosis of frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS) before the age of 18 years. All participants must be in complete remission, characterized by the absence of edema and specific urine protein levels at screening. Additionally, they must have experienced at least one relapse in the six months prior to screening, either after discontinuation of or while receiving oral corticosteroids and/or immunosuppressive therapy. The trial also includes individuals who have received cyclophosphamide in the six months prior to randomization, provided they have experienced at least one relapse after its discontinuation. The estimated glomerular filtration rate (eGFR) of participants is required to be within the normal range for their age. The trial population is considered vulnerable, given the pediatric nature of the study and the specific health conditions being addressed.

The clinical trial is designed to evaluate the efficacy and safety of **obinutuzumab** compared to **mycophenolate mofetil** (MMF) in patients with childhood onset idiopathic nephrotic syndrome. This is a Phase III, international, multicenter, randomized, open-label study. The trial is expected to last until August 2026, with recruitment starting in August 2023. Participants will be randomly assigned to receive either obinutuzumab or MMF, with obinutuzumab administered as a concentrate for solution for infusion and MMF provided in various oral formulations, including film-coated tablets and powder for oral suspension.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome before the age of 18, complete remission at screening, and a history of relapse. Follow-up visits will occur throughout the 52-week treatment period to monitor primary and secondary endpoints, including sustained complete remission, overall relapse-free survival, and incidence of adverse events. The end-of-study visit will assess the long-term outcomes and safety of the treatments.

Participant involvement is expected to last up to 76 weeks, including the treatment and follow-up periods. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial aims to provide comprehensive data on the comparative effectiveness of obinutuzumab and MMF, contributing to the understanding of treatment options for childhood idiopathic nephrotic syndrome.

The clinical trial involves the administration of **CellCept 500 mg film-coated tablets**, which contain the active substance **mycophenolate mofetil**. This pharmaceutical form is a film-coated tablet intended for oral administration. The maximum daily dose is 2000 mg, with a total maximum dose of 896 g over a treatment period of up to 64 weeks. Mycophenolate mofetil acts as a prodrug of mycophenolic acid (MPA), an inhibitor of inosine-5'-monophosphate dehydrogenase, and is chemically derived. The tablets have been relabeled and repackaged specifically for clinical trial use.

Another formulation of **CellCept** used in the trial is the **1 g/5 ml powder for oral suspension**, also containing **mycophenolate mofetil**. This oral suspension is administered similarly to the film-coated tablets, with a maximum daily dose of 2000 mg and a total maximum dose of 896 g over a 64-week period. The suspension is also relabeled and repackaged for the trial, maintaining the same chemical origin and mechanism of action as the tablet form.

The trial also includes the administration of **Gazyvaro 1,000 mg concentrate for solution for infusion**, which contains the active substance **obinutuzumab**. This pharmaceutical form is a solution for infusion, administered via intravenous infusion. The maximum daily dose is 1000 mg, with a total maximum dose of 4000 mg over a treatment period of up to 26 weeks. Obinutuzumab is a protein-based substance, and the concentrate has been relabeled and repackaged for clinical trial use.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the prescribed treatment regimens. The study aims to evaluate the efficacy and safety of obinutuzumab compared to mycophenolate mofetil in patients with childhood-onset idiopathic nephrotic syndrome.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the percentage of participants with sustained complete remission at one year. Secondary endpoints include overall relapse-free survival (RFS), probability of RFS at Week 52, cumulative corticosteroid dose, number of relapses, and the proportion of participants experiencing edema-associated relapse during the 52-week treatment period. Additional secondary endpoints involve the proportion of patients with sustained complete remission at Week 76, mean changes in the "General Fatigue" domain of the PedsQL-Multidimensional Fatigue scale, and the "Physical Functioning" domain of the PedsQL-Quality of Life Inventory from baseline to Week 52. The CureGN Edema Scale will also be used to measure changes from baseline to Week 52.

Further assessments include the incidence, nature, and severity of adverse events, with severity determined according to AE intensity and NCI CTCAE grading from baseline to Week 52. Laboratory or vital sign abnormalities will be monitored, and serum concentrations of **obinutuzumab** will be measured at specified timepoints. The proportion of participants achieving B-cell depletion (HSFC) and total peripheral B cell and B cell subsets counts, including changes from baseline, will be evaluated at specified timepoints. These efficacy parameters will be collected and analyzed using validated scales and laboratory tests at designated intervals throughout the trial duration.