Efficacy and Safety Evaluation of Obinutuzumab Versus Tacrolimus in Primary Membranous Nephropathy: A Phase III Randomized Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of obinutuzumab compared with tacrolimus in patients with **Primary Membranous Nephropathy (pMN)**, specifically focusing on the proportion of patients achieving a complete remission (CR) at Week 104. This is clinically relevant as achieving CR is a critical endpoint in the management of pMN, potentially leading to improved renal outcomes and quality of life for patients.

Secondary objectives include:

• Evaluating the efficacy of obinutuzumab compared with tacrolimus based on several parameters: achievement of overall remission at Week 104, achievement of CR at Week 76, time to treatment failure, meeting escape criteria, or relapse after complete or partial remission, time to a sustained reduction of eGFR ≥30% from baseline, mean change in T-score from baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue scale at Week 104, duration of CR, change in anti-PLA2R autoantibody titer from baseline to Week 52, and mean change from baseline in PROMIS Global Assessment of Physical Health scale at Week 104.
• Evaluating the safety of obinutuzumab compared with tacrolimus.
• Characterizing the pharmacodynamic effects of obinutuzumab in pMN patients.
• Characterizing the pharmacokinetics of obinutuzumab in the pMN population.
• Evaluating the immune response to obinutuzumab.

The clinical trial involves a total of **88 participants** diagnosed with **Primary Membranous Nephropathy (pMN)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults. Participants were selected based on their ability to comply with the study protocol and a confirmed diagnosis of pMN via renal biopsy. The trial includes individuals with a screening urinary protein-to-creatinine ratio (UPCR) meeting specific thresholds after best supportive care, and an estimated glomerular filtration rate (eGFR) or qualified endogenous creatinine clearance of at least 40 mL/min/1.73m². The population also comprises individuals who have previously responded to certain treatments and subsequently relapsed, provided they meet the required discontinuation periods for these therapies. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified. Participants from mainland China of Chinese ancestry are included in an extended enrollment phase. The selection criteria ensure a focused study on the efficacy of obinutuzumab compared with tacrolimus in achieving complete remission at Week 104.

The clinical trial is a **Phase III**, randomized, open-label, active comparator-controlled, multicenter study designed to evaluate the efficacy and safety of **obinutuzumab** in patients with **primary membranous nephropathy**. The trial aims to compare obinutuzumab with **tacrolimus** based on the proportion of patients achieving complete remission at Week 104. The study is expected to conclude by June 2028, with recruitment having commenced in August 2021. Participants will be involved in the study for a maximum treatment period of 104 weeks.

The trial includes several key study visits. The initial visit is the inclusion (screening) visit, where eligibility is assessed based on criteria such as a diagnosis of primary membranous nephropathy confirmed by renal biopsy, a specific urinary protein-to-creatinine ratio, and adequate renal function. Following the screening, eligible participants will be randomized to receive either obinutuzumab via intravenous infusion or tacrolimus orally. The study involves regular follow-up visits to monitor efficacy and safety, with assessments including the measurement of urinary protein levels, renal function, and adverse events. The end-of-study visit will occur at Week 104, where the primary endpoint of complete remission will be evaluated.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include the inability to comply with the study protocol, significant adverse events, or meeting predefined escape criteria. The trial's design ensures rigorous monitoring and data collection to assess both primary and secondary endpoints, including overall remission rates, time to treatment failure, and changes in patient-reported outcomes. The study's methodology and procedures are structured to provide comprehensive data on the comparative efficacy and safety of the investigational and comparator treatments in this patient population.

The clinical trial involves the administration of **obinutuzumab**, marketed as Gazyvaro, which is provided as a 1,000 mg concentrate for solution for infusion. This pharmaceutical form is a **solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 1,000 mg, with a total maximum dose of 4 g over the course of the study. The treatment period for obinutuzumab extends up to 104 weeks. The product is manufactured by Roche Registration GmbH and is not a pediatric formulation. The secondary packaging and labeling are specifically designed for clinical trial studies.

In addition to obinutuzumab, the trial includes the use of **tacrolimus**, marketed under the name Prograf, in three different dosages: 0.5 mg, 1 mg, and 5 mg hard capsules. These capsules are administered **orally**. The maximum daily dose for tacrolimus is 0.05 mg/kg, with a total maximum dose of 21 mg/kg over the treatment period. The treatment period for tacrolimus is up to 60 weeks. The capsules are produced by Astellas Pharma GmbH and are not formulated for pediatric use. Similar to obinutuzumab, the tacrolimus products are also subject to secondary packaging and labeling for the purposes of the clinical trial.

Throughout the study, participant compliance with the dosing schedules will be monitored to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the efficacy of obinutuzumab compared to tacrolimus in achieving complete remission in patients with primary membranous nephropathy by Week 104.

The efficacy of **obinutuzumab** in patients with primary membranous nephropathy will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients achieving a complete remission (CR) at Week 104. Secondary endpoints include the proportion of patients achieving overall remission at Week 104, CR at Week 76, and the time to treatment failure, meeting escape criteria, or relapse after complete or partial remission. Additional secondary endpoints involve the time to a sustained reduction of eGFR by 30% or more from baseline, mean change in T-score from baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue scale at Week 104, and the duration of CR.

Further secondary endpoints include changes in anti-PLA2R autoantibody titer from baseline to Week 52, mean change from baseline in the PROMIS Global Assessment of Physical Health scale at Week 104, and the incidence and severity of adverse events, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The study will also assess the characterization of adverse events of special interest, changes from baseline in targeted vital signs and clinical laboratory test results, serum concentrations of obinutuzumab at specified timepoints, peripheral B-cell counts at specified timepoints, and the prevalence and incidence of anti-drug antibodies (ADAs) to obinutuzumab.