Randomized Controlled Trial of Obinutuzumab and Mycophenolate Mofetil Versus Corticosteroids and Mycophenolate Mofetil in Induction Therapy for Lupus Nephritis

The primary objective of this study is to demonstrate that a regimen free of additional oral corticosteroids, incorporating **obinutuzumab** and mycophenolate mofetil (MMF), is non-inferior to a regimen based on oral corticosteroids and MMF in achieving the primary outcome of complete renal response at week 52 without exceeding a prespecified dose of corticosteroids. This is clinically relevant as it aims to reduce the potential side effects associated with long-term corticosteroid use in patients with **lupus nephritis**, while maintaining therapeutic efficacy.

Secondary objectives include:

• Comparing the efficacy of the treatment in both arms by analyzing the number of patients with partial plus complete renal response at week 52, proteinuria less than 0.8g/g at week 52, extrarenal flares, and a response defined by a greater than 4 points reduction in the SELENA-SLEDAI score at week 52.
• Comparing the safety of the treatments in both arms in terms of the occurrence of corticosteroid toxicity, serious adverse events, serious infectious episodes, and new damage.
• Comparing the number of patients with non-adherence to treatment in both arms.
• Estimating the efficiency of obinutuzumab in this indication.

The clinical trial focuses on individuals diagnosed with **lupus nephritis**, specifically targeting a population that includes both male and female participants. The study encompasses a broad age range, including children aged 14-17 years and adults up to 75 years old. Participants are required to have active lupus nephritis, confirmed by a kidney biopsy within the preceding 8 weeks, and must meet specific criteria such as a urine protein-to-creatinine ratio of at least 0.5 g/g. The trial does not involve a vulnerable population, and participants must be able to provide informed consent. Additionally, women of childbearing age are required to use effective contraception. The sponsor has not provided information regarding the total number of participants in the trial. The selection process ensures that participants are affiliated with a French social security system. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations.

The clinical trial is designed as an open-label, randomized, multicenter, controlled phase III study aimed at evaluating the efficacy of a regimen free of additional oral corticosteroids, incorporating **obinutuzumab** and **mycophenolate mofetil** (MMF), compared to a regimen based on oral corticosteroids and MMF in patients with **lupus nephritis**. The primary objective is to demonstrate non-inferiority in achieving complete renal response (CR) at week 52 without exceeding a prespecified corticosteroid dose. The trial is expected to conclude by December 31, 2026, with recruitment having commenced on December 9, 2021.

Participants will be randomly assigned to one of the two treatment arms. The study will involve several key visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as age, active lupus nephritis status, and urine protein-to-creatinine ratio. Follow-up visits will be scheduled to monitor treatment efficacy and safety, with assessments including urine PCR, estimated glomerular filtration rate (eGFR), and adherence to treatment. The end-of-study visit will evaluate the primary and secondary endpoints, including complete and partial renal responses, safety, and treatment adherence.

The expected duration of participant involvement is up to 52 weeks, with conditions for early termination including significant adverse events or non-compliance with the study protocol. The trial will adhere to rigorous scientific standards, ensuring that data collected is robust and reliable for evaluating the treatment regimens' efficacy and safety. Participants will be monitored closely throughout the study to ensure their well-being and the integrity of the trial data.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Azathioprine** is utilized in the study as a **film-coated tablet**. It is administered orally with a maximum daily dose of 150 mg and a total maximum dose of 25,200 mg over a treatment period of up to 6 months. This medication is used as a comparator in the trial.

**Mycophenolate mofetil** is another treatment used in the trial, provided in the form of a **film-coated tablet**. It is administered orally with a maximum daily dose of 3 g and a total maximum dose of 1,008 g over a treatment period of up to 12 months. This medication is part of both the test and comparator regimens.

**Obinutuzumab**, marketed as Gazyvaro, is administered as a **concentrate for solution for infusion**. It is given via intravenous infusion with a maximum daily dose of 1,000 mg and a total maximum dose of 2,000 mg over a treatment period of up to 15 weeks. This medication is part of the test regimen and is classified as an orphan drug.

**Betamethasone sodium phosphate**, referred to as **Prednisolone** in the trial, is administered orally. It is provided in a pharmaceutical form coded as PHF00059MIG, with a maximum daily dose of 60 mg and a total maximum dose of 2,625 mg over a treatment period of up to 12 months. This medication is part of the comparator regimen.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed regimens. The trial aims to compare the efficacy of a regimen free of additional oral corticosteroids, including obinutuzumab and mycophenolate mofetil, against a regimen based on oral corticosteroids and mycophenolate mofetil in achieving complete renal response in patients with lupus nephritis.

Efficacy in this clinical trial will be assessed primarily through the achievement of a **Complete Renal Response (CR)** at week 52. The CR is defined by a urine protein-to-creatinine ratio (uPCR) of less than 0.5 g/g, an estimated glomerular filtration rate (eGFR) of at least 60 ml/min, or if below 60 ml/min at screening, no decline greater than 20% compared to screening or randomization. In the obinutuzumab arm, CR must be achieved without the use of oral corticosteroids exceeding 10 mg/day within the first six months, and not more than 7.5 mg/day between six months and the end of the trial.

Secondary efficacy endpoints include the **Partial Renal Response (PR)**, defined as a 50% improvement in spot uPCR, a uPCR between 0.5 and 3 g/g, and an eGFR of at least 60 ml/min, or if below 60 ml/min at screening, no decline greater than 20% compared to screening or randomization. Additional assessments involve proteinuria measurement and extrarenal flare evaluation according to the SELENA-SLEDAI criteria. Safety will be monitored through the Glucocorticoid Toxicity Index (GTI) and the number of serious adverse events, measured per patient according to the CTCAE version 5.0 toxicity grading system. Non-adherence to treatment will be assessed using hydroxychloroquine blood levels and questionnaires. Efficiency will be evaluated through the incremental cost-effectiveness ratio in cost per QALY.