Evaluation of Corticosteroids, Dapagliflozin, and RASBs on Proteinuria in IgA Nephropathy Patients with Active and Chronic Renal Lesions

The primary objective of this study is to evaluate the **therapeutic effect** on proteinuria in patients with **Idiopathic IgA nephropathy (IgAN)**. This will be assessed by comparing early corticosteroid therapy administered after kidney biopsy in patients with active renal lesions against the standard care of renin-angiotensin system blockers (RASBs) alone followed by corticosteroids combined with RASBs. Additionally, the study aims to evaluate the effect of sodium-glucose cotransporter 2 inhibitor (SGLT2i), specifically Dapagliflozin, combined with RASBs on proteinuria, compared to corticosteroids combined with RASBs in patients with chronic or moderate renal lesions. This comparison is crucial to potentially avoid the side effects associated with corticosteroid therapy.

The secondary objectives include assessing the effect of study treatments on renal function and the progression of kidney damage in IgAN patients over a period of three years. Furthermore, the study seeks to determine whether personalized therapy, predicted through the IgAN Clinical Decision Support System (CDSS) tool, DialCheck, at the time of kidney biopsy, can delay the impairment of renal function.

The clinical trial focuses on patients diagnosed with **Idiopathic IgA nephropathy (IgAN)**, specifically targeting those with active or chronic renal lesions. The study population comprises both male and female participants aged between 18 to 75 years. Participants are required to have biopsy-proven idiopathic IgAN, with active lesions for the ACIgAN study or chronic/moderate lesions for the CHRONIgAN study. The trial includes individuals with an estimated glomerular filtration rate (eGFR) of at least 30 ml/min/1.73 m² and a 24-hour proteinuria level of 0.5 g or higher. All participants are either currently receiving or are candidates for treatment with renin-angiotensin system blockers (RASBs), such as ACE inhibitors or ARBs, in accordance with current KDIGO guidelines. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on these specific clinical criteria, ensuring a focus on individuals at high or very high risk of chronic kidney disease (CKD). The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating a careful selection process to ensure the safety and efficacy of the interventions being tested.

The clinical trial is designed to evaluate the therapeutic effects of early corticosteroid therapy versus standard care in patients with **Idiopathic IgA nephropathy (IgAN)**. This study is a multicenter, prospective, open-label, randomized clinical trial. The trial involves two distinct studies: one focusing on patients with active renal lesions and the other on those with chronic or moderate renal lesions. The trial is expected to last until March 2029, with recruitment having commenced in March 2023.

Participants will be randomly assigned to different treatment arms. The trial will assess the impact of early corticosteroid therapy on proteinuria in patients with active renal lesions compared to standard care, which involves renin-angiotensin system blockers (RASBs) followed by corticosteroids. Additionally, the trial will compare the effects of sodium-glucose cotransporter 2 inhibitors combined with RASBs against corticosteroids combined with RASBs in patients with chronic renal lesions.

The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age, biopsy-proven IgAN, and renal function. Follow-up visits will occur at regular intervals to monitor proteinuria levels, renal function, and any adverse events. The end-of-study visit will evaluate the primary and secondary endpoints, including proteinuria reduction and changes in estimated glomerular filtration rate (eGFR).

Participant involvement is expected to last up to three years, with conditions for early termination including significant adverse events or withdrawal of consent. The primary endpoints focus on the difference in proteinuria reduction between treatment arms within specified timeframes. Secondary endpoints include eGFR slope, composite renal outcomes, and remission of proteinuria. The trial aims to provide insights into the optimal therapeutic approach for managing proteinuria and preserving renal function in IgAN patients.

The clinical trial involves the administration of several treatments, including **Ramipril** combined with **Hydrochlorothiazide**. This experimental medication is provided in an oral pharmaceutical form, identified by the code PHF00245MIG. The maximum daily dose is 2.5 mg, with a total dose not exceeding 10 mg over a treatment period of up to 36 months. The administration route is oral, and participant compliance is monitored through regular assessments.

Another treatment used in the trial is **Solu Medrol**, which contains **Methylprednisolone Sodium Succinate**. This medication is provided as a solution for injection, with a maximum daily and total dose of 1000 mg. The administration route is intravenous, and the treatment period is limited to 3 days. Compliance is ensured by direct administration under clinical supervision.

The trial also includes **Losartan Potassium** combined with **Hydrochlorothiazide**. This medication is administered orally, with a pharmaceutical form identified by the code PHF00082MIG. The maximum daily dose is 12.5 mg, with a total dose not exceeding 100 mg over a treatment period of up to 36 months. Participant adherence is monitored through scheduled follow-ups.

**Dapagliflozin** is another treatment used in the study, provided as a film-coated tablet for oral administration. The maximum daily and total dose is 10 mg, with a treatment period extending up to 36 months. Compliance is tracked through regular patient visits and medication logs.

Lastly, **Prednisone** is administered in tablet form, with a maximum daily and total dose of 50 mg over a treatment period of 4 weeks. The administration route is oral, and adherence is monitored through patient diaries and periodic assessments.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints focused on evaluating the therapeutic effects on **proteinuria** and renal function in patients with Immunoglobulin A Nephropathy (IgAN). The primary endpoints include the between-arms difference in proteinuria reduction within 4 months and in nonresponders within 8 months for the ACIgAN study, and within 10 months for the CHRONIgAN study. Secondary endpoints will assess various aspects of renal function and proteinuria, including the eGFR slope calculated over three years, eGFR decline greater than 40% from baseline, and a composite endpoint involving GFR decline, end-stage kidney disease (ESKD), or death due to kidney disease. Additional secondary endpoints include the absolute difference between the last GFR value and baseline, stable renal function defined as a decline in GFR of 5 ml/min/1.73m² or less at the end of three years, and the mean annual change in the slope of the reciprocal of serum creatinine concentration.

Further assessments will include time-averaged proteinuria (TA-P), calculated as the weighted mean of all post-randomization measurements, and the proteinuria slope, calculated as the mean of individual slopes obtained from linear regression of daily proteinuria over time. Complete remission of proteinuria is defined as achieving a urinary protein level of 0.2 g/day or less, or a urinary protein-to-creatinine ratio of 0.2 g/g or less. Partial remission is defined as a urinary protein reduction of 50% or greater compared with baseline. These efficacy parameters will be measured and analyzed at specified intervals throughout the trial to determine the effectiveness of the interventions being tested.