Evaluation of Obinutuzumab Efficacy, Safety, and Pharmacokinetics in Adolescents with Class III/IV Lupus Nephritis and Pediatric Safety and PK Analysis

The primary objective of this study is to evaluate the **efficacy** of obinutuzumab compared with placebo in adolescent participants with active Class III or IV **Lupus Nephritis** (LN). Additionally, the study aims to assess the safety of obinutuzumab and characterize its pharmacokinetic (PK) profile in pediatric patients aged 5 to less than 12 years with LN. This is clinically relevant as it addresses the need for effective and safe treatment options for young patients suffering from this severe form of lupus, which can lead to significant kidney damage.

Secondary objectives include:

• Evaluating the efficacy of obinutuzumab compared with placebo.
• Assessing the safety of obinutuzumab compared with placebo.
• Characterizing the pharmacokinetic profile of obinutuzumab.
• Characterizing the pharmacodynamic profile of obinutuzumab.
• Evaluating changes in fatigue of participants treated with obinutuzumab compared with placebo.
• Assessing changes in SLE disease activity of participants treated with obinutuzumab compared with placebo.
• Evaluating changes in the quality of life of participants treated with obinutuzumab compared with placebo.
• Evaluating the efficacy of obinutuzumab.
• Assessing the immune response to obinutuzumab.
• Evaluating autoantibodies over time.

These secondary objectives aim to provide a comprehensive understanding of the therapeutic potential and safety profile of obinutuzumab, as well as its impact on various clinical and patient-reported outcomes in the context of lupus nephritis.

The clinical trial involves a total of **30 participants** diagnosed with **Lupus Nephritis (LN)**. The study population includes both male and female subjects, with an age range of 5 to less than 18 years. Participants were selected based on specific criteria, including a diagnosis of Class III or IV active LN as per the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification, confirmed by renal biopsy within the last 12 months. The trial includes adolescents aged 12 to less than 18 years and a younger cohort aged 5 to less than 12 years. All participants must have a positive test for antinuclear antibody (ANA) and/or antibodies to double-stranded DNA (dsDNA). Additionally, significant proteinuria, defined by a urine protein-to-creatinine ratio (UPCR) above 0.5 g/g, is required. Participants must have received at least one dose of pulse-range IV methylprednisolone or equivalent for the treatment of the current episode of active LN within the past year. The trial population is considered vulnerable, and the study aims to evaluate the efficacy and safety of obinutuzumab compared to placebo in this demographic.

The clinical trial is a **Phase II**, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of **obinutuzumab** in adolescent patients with active Class III or IV **lupus nephritis**. The trial also includes an evaluation of open-label safety and pharmacokinetics in a cohort of pediatric patients aged 5 to less than 12 years. The study is expected to last for approximately 76 weeks, with participant involvement beginning from the screening visit and continuing through to the end-of-study visit.

Participants will undergo a series of study visits, starting with an inclusion (screening) visit to assess eligibility based on criteria such as age, renal biopsy results, and serological markers. Following randomization, participants will receive either obinutuzumab or placebo, with obinutuzumab administered as a concentrate for solution for infusion and placebo as a matching formulation. The trial includes multiple follow-up visits to monitor the participants' response to treatment, assess safety, and collect pharmacokinetic data. These visits will occur at specified intervals throughout the study duration, with key assessments at Weeks 24, 52, and 76.

The primary endpoint is the proportion of participants achieving a complete renal response at Week 76. Secondary endpoints include the incidence and severity of adverse events, changes in laboratory parameters, and pharmacokinetic measurements. Participants are expected to remain in the study for the full duration unless they meet predefined criteria for early termination, such as significant adverse events or withdrawal of consent. The trial aims to provide comprehensive data on the efficacy and safety of obinutuzumab in this patient population, contributing to the understanding of its potential therapeutic role in lupus nephritis.

The clinical trial involves the administration of **Gazyvaro** (obinutuzumab), a **concentrate for solution for infusion**. This experimental medication is provided in a pharmaceutical form suitable for intravenous administration. Each dose contains 1,000 mg of obinutuzumab, with a maximum daily dose of 1,000 mg and a total maximum dose of 5 g over the treatment period. The treatment is administered intravenously, and the maximum treatment period is 76 weeks. The product has been relabeled and repackaged specifically for clinical trial use. Participant compliance with the dosing schedule will be monitored throughout the study.

In addition to the experimental treatment, participants may receive **Myfenax** (mycophenolate mofetil), which is provided as 500 mg film-coated tablets. This medication is administered orally, with a maximum daily dose of 2.5 g and a total maximum dose of 12.5 g over the treatment period. Myfenax is classified as an immunosuppressive agent and has also been relabeled and repackaged for the clinical trial. The administration schedule and participant adherence will be closely monitored.

The study also includes the use of **CellCept** (mycophenolate mofetil) in the form of a powder for oral suspension, with a concentration of 1 g/5 ml. This formulation is administered orally, with the same dosing limits as Myfenax: a maximum daily dose of 2.5 g and a total maximum dose of 12.5 g over the treatment period. CellCept is also categorized as an immunosuppressive agent and has been prepared for clinical trial use. Compliance with the dosing regimen will be assessed throughout the study.

A **placebo** for Gazyvaro is included in the trial to maintain the double-blind design. The placebo is administered in a manner consistent with the experimental treatment to ensure blinding. The placebo does not contain any active substance and is used to evaluate the efficacy and safety of the experimental medication in comparison to a non-active control.

The efficacy of **obinutuzumab** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the proportion of participants achieving a complete renal response (CRR) at Week 76. Secondary endpoints include the proportion of adolescent participants achieving CRR at Weeks 24 and 52, the proportion achieving CRR with successful prednisone taper at Week 76, and the proportion achieving a partial renal response (PRR) at Week 76. Additional secondary endpoints involve changes in urinary protein-to-creatinine ratio (UPCR), estimated glomerular filtration rate (eGFR), anti-dsDNA titers, and complement levels (C3 and C4) from baseline to Week 76. The time to onset of CRR, incidence of treatment failure, and changes in quality of life and disease activity scores will also be evaluated.

Measurements will be collected at specified timepoints, including Weeks 24, 52, and 76, using validated scales and laboratory tests. The trial will also assess the incidence, nature, and severity of adverse events, as well as laboratory or vital sign abnormalities from baseline to Week 76. Serum concentrations of obinutuzumab and the presence of anti-drug antibodies (ADA) will be monitored at specified intervals. The relationship between ADA status and efficacy, safety, pharmacodynamic, or pharmacokinetic endpoints will be explored. The trial is designed to provide comprehensive data on the efficacy and safety of obinutuzumab in adolescent patients with active Class III or IV lupus nephritis over a 76-week period.