Evaluation of Dapagliflozin on Immunological Modulation in Patients with Membranous Nephropathy

The primary objective of this study is to evaluate the change in **anti-PLA2R1 antibody** titer, measured in ELISA titer (RU/mL), from baseline to six months following treatment with dapagliflozin in patients with **Membranous Nephropathy**. This objective is clinically relevant as it aims to assess the impact of dapagliflozin on the immunological activity associated with the disease, potentially offering insights into therapeutic efficacy and disease management.

Secondary objectives include:

• Measuring the change in proteinuria over the course of the study in patients undergoing an immunological relapse.
• Assessing the change in serum albumin levels during the study period.
• Evaluating the change in glomerular filtration rate in the same patient cohort.
• Monitoring the occurrence of clinical relapses throughout the study.
• Investigating the production of Th17, Th1, Th2, and Treg pathway cytokines before and after six months of dapagliflozin treatment.
• Assessing the safety of dapagliflozin treatment in these patients.

The clinical trial involves participants diagnosed with **Membranous Nephropathy** associated with anti-PLA2R1 autoantibodies. The study population includes both male and female subjects aged between 18 and 84 years. Participants are required to have a Urine Protein Creatinine Ratio (UPCR) between 0.5 g/g and 3.5 g/g and must be on antiproteinuric treatment at a maximal and stable dose. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include individuals experiencing an immunological relapse, defined by an increase in anti-PLA2R1 antibody concentration greater than 14 RU/mL following a phase of immunological and clinical remission. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations.

The clinical trial is designed to evaluate the impact of **dapagliflozin** on immunological activity in patients with **Membranous Nephropathy**. This study is a randomized, double-blind, controlled trial with an estimated duration from May 2025 to May 2027. The primary objective is to assess the change in anti-PLA2R1 antibody titer from baseline to six months post-treatment with dapagliflozin, compared to pretreatment levels. Secondary endpoints include changes in proteinuria, albumin levels, glomerular filtration rate, cytokine profile, and the need for Rituximab treatment, as well as the clinical and biological tolerance of dapagliflozin.

Participants eligible for inclusion are adults aged 18 to 84 years with Membranous Nephropathy associated with anti-PLA2R1 autoantibodies, a urine protein creatinine ratio between 0.5 g/g and 3.5 g/g, and an immunological relapse defined by an increase in anti-PLA2R1 antibody concentration. The trial involves several study visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria. Following randomization, participants will undergo regular follow-up visits to monitor treatment effects and safety, with assessments conducted at baseline and at six months. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any adverse events are addressed.

The expected length of participant involvement is approximately six months, corresponding to the maximum treatment period with dapagliflozin. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or any protocol violations that compromise the integrity of the trial. The trial is categorized as a low-intervention clinical trial, as dapagliflozin is administered according to national care recommendations for Membranous Nephropathy. The study aims to provide valuable insights into the therapeutic potential of dapagliflozin in managing this condition.

The clinical trial involves the administration of **Forxiga 10 mg film-coated tablets**, which contain the active substance **dapagliflozin**. Dapagliflozin is a chemical compound classified under the ATC code A10BK01. The pharmaceutical form of the medication is a film-coated tablet, designed for oral administration. Each tablet contains 10 mg of dapagliflozin, and the maximum daily dose is set at 10 mg. The total maximum dose over the course of the treatment period is 12,600 mg. The treatment duration is specified as six months. The medication is manufactured by AstraZeneca AB and is not a pediatric formulation. The primary objective of the trial is to assess the change in anti-PLA2R1 antibody titer from baseline to six months after dapagliflozin treatment.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The trial focuses solely on the effects of dapagliflozin in the context of Membranous Nephropathy. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen. The trial aims to provide insights into the immunological activity regulation by dapagliflozin, specifically targeting the change in antibody titers as a measure of efficacy.

Efficacy in the clinical trial titled "Impact of dapagliflozin for the regulation of immunological activity in Membranous Nephropathy" will be assessed using both primary and secondary endpoints. The primary endpoint is the change in **anti-PLA2R1 antibody titer** (measured in ELISA titer in RU/mL) from baseline to 6 months after treatment with dapagliflozin, compared with the pretreatment antibody titer. This endpoint will provide insight into the immunological response to the treatment.

Secondary endpoints include several parameters measured from baseline to 6 months post-treatment: change in proteinuria (in g/g), change in albumin levels (in g/L), and change in glomerular filtration rate (in ml/min/1.73m²), all under stable antiproteinuric treatment. Additionally, the need for Rituximab treatment for clinical relapse will be evaluated according to KDIGO 2021 guidelines and French 2022 guidelines. The trial will also assess changes in cytokine profiles, analyzing nine specific cytokines: IL-12p70, IL-17A, IL-4, IL-5, IL-1β, IL-10, IFNα, IL-6, and IFNγ. Clinical and biological tolerance of dapagliflozin treatment will also be monitored.