Efficacy of Hydroxychloroquine Sulfate in Reducing GFR Decline in Biopsy-Proven IgA Nephropathy with Albuminuria Despite RAAS Inhibitor Therapy

The primary objective of this study is to demonstrate the efficacy of **hydroxychloroquine** versus placebo over a period of three years in improving the decrease in glomerular filtration rate (GFR) in patients with biopsy-proven IgA nephropathy. These patients exhibit albuminuria greater than 300 mg/g despite optimized nephroprotective treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors and have at least one Oxford lesion. This objective is clinically relevant as it addresses the potential of hydroxychloroquine to slow the progression of renal impairment in IgA nephropathy, a condition that can lead to chronic kidney disease and end-stage renal disease.

Secondary objectives include:

• Evaluating the effects of hydroxychloroquine on routine nephrologic evaluations annually, including proteinuria, albuminuria, GFR, and hematuria.
• Assessing the effects of hydroxychloroquine on the progression to end-stage renal disease (ESRD) and mortality.
• Evaluating the safety profile of hydroxychloroquine.
• Investigating the impact of hydroxychloroquine blood concentrations on therapeutic effects and adverse events.
• Constituting a biocollection to explore further research hypotheses, such as immune system monitoring and cystatin C levels.

The clinical trial focuses on patients diagnosed with **IgA nephropathy**, specifically targeting individuals with biopsy-proven cases and albuminuria greater than 300 mg/g, despite optimized nephroprotective treatment with RAAS inhibitors. The study population includes both male and female participants over the age of 18, with no vulnerable populations selected. Participants are required to have an estimated glomerular filtration rate (eGFR) above 15 mL/min/1.73m², as calculated by the CKD-EPI formula, and must have at least one Oxford lesion on their most recent kidney biopsy. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants must have been treated with dual SGLT2i and RAAS therapy prior to inclusion and must adhere to lifestyle considerations such as maintaining a highly effective contraceptive method for women of childbearing age. The trial population was selected based on specific inclusion criteria, including social security affiliation and the ability to provide signed informed consent.

The clinical trial is designed to evaluate the **therapeutic effect** of **hydroxychloroquine** on the progression of **IgA nephropathy**. This study is a randomized, double-blind, placebo-controlled trial, aiming to demonstrate the efficacy of hydroxychloroquine in improving the glomerular filtration rate (GFR) over a period of three years. Participants will be randomly assigned to receive either hydroxychloroquine or a placebo, with the primary endpoint being the GFR slope from inclusion to three years. Secondary endpoints include differences in routine nephrological clinical follow-up parameters, the proportion of end-stage renal disease and deaths, and the incidence of adverse events.

The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as biopsy-proven IgA nephropathy, urine albumin/creatinine ratio greater than 300 mg/g, and treatment with dual SGLT2i and RAAS therapy. Participants must also have an estimated GFR above 15 mL/min/1.73m² and at least one Oxford lesion on the last available kidney biopsy. Following successful screening, participants will be enrolled and randomized into the study.

Study visits will occur at regular intervals, including follow-up visits at one, two, and three years to assess the primary and secondary endpoints. These visits will involve routine nephrological assessments, monitoring of adverse events, and collection of biological samples for biocollection purposes. The end-of-study visit will mark the conclusion of the participant's involvement, with a comprehensive evaluation of the study outcomes.

The expected duration of participant involvement is up to 36 months, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial is anticipated to start recruitment in June 2024 and is estimated to conclude by December 2030, contingent upon the successful enrollment and retention of participants.

The clinical trial involves the administration of **hydroxychloroquine sulfate** as the experimental medication. The product used is marketed under the name PLAQUENIL, which is formulated as a **film-coated tablet**. Each tablet contains 200 mg of hydroxychloroquine sulfate. The medication is administered orally, with a maximum daily dose of 400 mg. The treatment period extends up to 36 months. The active substance, hydroxychloroquine sulfate, is of chemical origin and is classified under the ATC code P01BA02. The product is manufactured by Sanofi Belgium and is authorized for use in the trial, although it is being used off-label for the population with IgA nephropathy.

The study also includes a **placebo** group for comparison. The placebo is designed to mimic the appearance of the PLAQUENIL tablets but contains no active substance. The placebo tablets are administered in the same manner as the experimental medication, ensuring blinding of the study participants and investigators. The placebo serves as a control to evaluate the efficacy of hydroxychloroquine in improving the course of IgA nephropathy. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of Hydroxychloroquine in the treatment of **IgA Nephropathy** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the evaluation of the GFR (glomerular filtration rate) slope from inclusion to 3 years. This will provide a measure of the drug's impact on kidney function over the trial period. Secondary endpoints include the difference between treatment groups in routine nephrological clinical follow-up parameters such as proteinuria, albuminuria, GFR, hematuria, and blood pressure at 1, 2, and 3 years. Additionally, the trial will assess the difference in the proportion of patients reaching end-stage renal disease (GFR < 15 mL/min/1.73m²) and mortality rates.

Further secondary endpoints involve the proportion of adverse events, including pruritus and gastrointestinal disorders, and serious adverse events such as QT enlargement, cardiomyopathy, ophthalmologic disorders, neuromyopathy, and cytopenia. Correlations between hydroxychloroquine trough levels and the evolution of proteinuria, eGFR, blood pressure, as well as adverse events, will also be analyzed. The study will include a biocollection of plasma, serum, urine, and DNA samples to support these analyses. Efficacy assessments will be conducted at specified intervals throughout the trial, ensuring comprehensive data collection and analysis to determine the therapeutic effect of Hydroxychloroquine in this patient population.