Efficacy and Safety Evaluation of Obinutuzumab in ISN/RPS 2003 Class III/IV Lupus Nephritis: A Phase III Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of obinutuzumab, in comparison to placebo, by assessing the proportion of patients with **Lupus Nephritis** who achieve a complete renal response (CRR) at Week 76. This is clinically relevant as achieving CRR is indicative of significant improvement in renal function, which is a critical outcome for patients with this condition.

Secondary objectives include:

• Evaluating the efficacy of obinutuzumab compared with placebo based on various parameters such as proteinuric response, CRR with successful prednisone taper, overall renal response (ORR), and changes in estimated glomerular filtration rate (eGFR), anti-double stranded deoxyribonucleic acid (anti-dsDNA) titer, C3 levels, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI2K), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale.
• Assessing the safety profile of obinutuzumab compared with placebo.
• Characterizing the pharmacokinetic profile of obinutuzumab.
• Evaluating the immune response to obinutuzumab.
• Characterizing obinutuzumab-induced changes in circulating B cells.

The clinical trial involves a total of **219 participants** diagnosed with **Lupus Nephritis (LN)**. The study population includes both male and female subjects, with an age range that encompasses both adults and adolescents. Participants were selected based on specific criteria, including a diagnosis of active or active/chronic Class III or IV proliferative LN as per the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification, confirmed by renal biopsy within six months prior to or during screening. Additionally, participants must have systemic lupus erythematosus (SLE) according to the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) Classification Criteria. The trial population includes individuals with a urinary protein-to-creatinine ratio (UPCR) of at least 1 g/g on a 24-hour collection at screening. Participants are required to have received at least one dose of pulse methylprednisolone IV or equivalent for the treatment of the current episode of active LN within the six months prior to screening or during screening. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy across diverse patient groups.

The clinical trial is designed to evaluate the efficacy and safety of **obinutuzumab** in patients with ISN/RPS 2003 Class III or IV **lupus nephritis**. This is a Phase III, randomized, double-blind, placebo-controlled, multicenter study. The trial aims to assess the proportion of patients achieving a complete renal response (CRR) at Week 76. The study is expected to run from November 10, 2020, to February 28, 2029, with participant involvement lasting up to 76 weeks.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a recent renal biopsy and specific laboratory markers. Following randomization, participants will receive either obinutuzumab or a placebo, administered via intravenous infusion. The trial includes several follow-up visits to monitor safety and efficacy, with assessments of renal function, proteinuria, and other clinical parameters. The end-of-study visit will occur at Week 76, where final evaluations will be conducted to determine the primary and secondary endpoints.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial will adhere to rigorous safety monitoring, with adverse events assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The study's design ensures that data collected will contribute to understanding the therapeutic potential of obinutuzumab in treating lupus nephritis.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Methylprednisolone acetate** is administered as an intravenous glucocorticoid. The pharmaceutical form is coded as PHF00243MIG, with a maximum daily dose of 80 mg and a total dose not exceeding 480 mg over a treatment period of 80 days. This medication is used as an auxiliary treatment in the trial.

**Obinutuzumab**, marketed as Gazyvaro, is provided as a 1,000 mg concentrate for solution for infusion. It is administered via intravenous infusion, with a maximum daily dose of 1,000 mg and a total dose of up to 6,000 mg over 72 days. This drug is relabeled and repackaged specifically for clinical trial use and serves as a test treatment in the study.

The trial also includes a combination of **buclizine hydrochloride, paracetamol, and codeine phosphate**. This oral medication is categorized under other analgesics and antipyretics, with a maximum daily dose of 1,000 mg and a total dose of 6,000 mg over 80 days. It is used as an auxiliary treatment.

**Prednisolone** is administered orally as a corticosteroid, with a maximum daily dose of 60 mg and a total dose of 5,330 mg over 80 days. This medication is also used as an auxiliary treatment in the trial.

**Diphenhydramine** is available for both intravenous and oral use, classified as an antihistamine for systemic use. The maximum daily dose is 50 mg, with a total dose of 300 mg over 80 days. It serves as an auxiliary treatment in the study.

The trial includes a placebo for **obinutuzumab**, which is used as a comparator treatment. The placebo is not associated with any active substance and is administered to maintain the double-blind nature of the study.

**Mycophenolate mofetil**, marketed as Myfenax, is provided as 500 mg film-coated tablets for oral administration. It is used as a test treatment, with a maximum daily dose of 2,500 mg and a total dose of 1,330 g over 76 days. This medication is relabeled and repackaged for clinical trial use.

The efficacy of the clinical trial will be assessed by evaluating the proportion of patients who achieve a **Complete Renal Response (CRR)** at Week 76. This primary endpoint will be measured to determine the effectiveness of obinutuzumab compared to placebo in patients with ISN/RPS 2003 Class III or IV Lupus Nephritis. Secondary endpoints include the proportion of patients achieving a proteinuric response at Week 76, CRR with successful prednisone taper at Week 76, and Overall Renal Response (ORR) evaluated at Week 50. Additional secondary endpoints involve the proportion of patients experiencing death or renal-related events through Week 76, mean change in estimated Glomerular Filtration Rate (eGFR) from baseline to Week 76, and changes in anti-dsDNA titer, C3, and SLEDAI-2K from baseline to specified timepoints.

Other secondary endpoints include the time to onset of CRR over 76 weeks, change in FACIT-F scale from baseline to Week 76, and the proportion of patients achieving CRR with serum creatinine criteria at Week 76. The incidence and severity of adverse events will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0). Pharmacokinetic parameters such as maximum observed concentration (Cmax), minimum observed concentration (Cmin), area under the concentration-time curve (AUC), and clearance (CL) of obinutuzumab will also be evaluated. The prevalence of anti-drug antibodies (ADAs) at baseline and incidence post-treatment, as well as total peripheral B-cell count at specified timepoints, will be monitored to further assess efficacy and safety.