Efficacy and Safety Evaluation of BI 764198 in Patients with Focal Segmental Glomerulosclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to explore the **efficacy** of BI 764198 in lowering **proteinuria** in patients with focal segmental glomerulosclerosis. Proteinuria is a significant clinical marker of kidney damage, and its reduction is crucial in managing the progression of this kidney disease. The secondary objective is to investigate the **pharmacokinetic** profile of BI 764198, which is essential for understanding the drug's absorption, distribution, metabolism, and excretion, thereby informing dosing regimens and optimizing therapeutic outcomes.

The clinical trial involves a total of **32 participants** diagnosed with **focal segmental glomerulosclerosis** (FSGS), a condition confirmed through biopsy or a documented TRPC6 gene mutation. The study population includes both male and female subjects aged between 18 and 75 years. Participants are required to have a urine protein-creatinine ratio of at least 1000 mg/g, indicating significant proteinuria. The trial population was selected based on specific inclusion criteria, including stable treatment with corticosteroids or other relevant medications such as ACE inhibitors, ARBs, finerenone, aldosterone inhibitors, or SGLT2 inhibitors for at least four weeks prior to the screening. Participants must have a **Body Mass Index (BMI)** of 40 kg/m² or less. Women of childbearing potential are required to use highly effective contraception methods. The study does not include a vulnerable population, and participants are expected to maintain their current medication regimen throughout the trial duration.

The clinical trial is designed as a **randomized**, **double-blind**, parallel group, **placebo-controlled** study to evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 764198. This investigational drug is administered orally once daily for a duration of 12 weeks in patients diagnosed with **focal segmental glomerulosclerosis**. The trial is structured to include a series of study visits, beginning with an inclusion (screening) visit, followed by regular follow-up visits, and concluding with an end-of-study visit. The primary objective is to explore the efficacy of BI 764198 in lowering proteinuria, with the primary endpoint being the number of patients achieving at least a 25% reduction in 24-hour urine protein-creatinine ratio (UPCR) relative to baseline at week 12.

Participants are expected to be involved in the study for approximately 12 weeks, with the possibility of early termination if specific conditions arise, such as adverse events or non-compliance with the study protocol. The inclusion criteria require participants to be between 18 and 75 years of age, with a biopsy-proven diagnosis of primary focal segmental glomerulosclerosis or a documented TRPC6 gene mutation causing the condition. Additionally, participants must have a urine protein-creatinine ratio of at least 1000 mg/g and be on stable doses of corticosteroids or other specified medications for at least four weeks prior to the screening visit. The study will also monitor secondary endpoints, including changes in 24-hour UPCR and urinary protein excretion at various time points, as well as pre-dose plasma concentrations of BI 764198 at weeks 4 and 12.

The clinical trial involves the administration of **BI 764198**, an investigational medication, in the form of a capsule. The active substance in BI 764198 is **[4-(6-aminopyridazin-3-yl)piperidin-1-yl][5-(4-fluorophenoxy)-4-methoxypyridin-2-yl]methanone**, a chemical compound developed by Boehringer Ingelheim International. The medication is administered orally once daily for a period of 12 weeks. The maximum daily and total dose amounts are not specified, indicating a flexible dosing regimen within the trial parameters. The pharmaceutical form of the medication is a capsule, ensuring ease of administration and compliance monitoring. The trial aims to assess the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 764198 in patients with focal segmental glomerulosclerosis.

A placebo, designed to match BI 764198, is utilized as a comparator treatment in this double-blind, placebo-controlled study. The placebo is intended to mimic the appearance and administration route of the active medication, ensuring the integrity of the blinding process. The placebo does not contain any active pharmaceutical ingredients and serves as a control to evaluate the true effects of BI 764198 on the study population. The use of a placebo is critical in determining the efficacy of the investigational drug by providing a baseline for comparison.

The efficacy of the investigational product BI 764198 in the clinical trial will be assessed primarily by evaluating the number of patients achieving at least a 25% reduction in the 24-hour urine protein-creatinine ratio (UPCR) relative to baseline at week 12. This primary endpoint is designed to measure the drug's effectiveness in lowering proteinuria in patients with **focal segmental glomerulosclerosis** (FSGS). Secondary endpoints include changes in the 24-hour UPCR relative to visit 3 at week 12, changes in 24-hour UPCR relative to baseline at week 13, and changes in 24-hour urinary protein excretion relative to baseline at week 12. Additionally, pre-dose plasma concentration at steady state (Cpre,ss) of BI 764198 will be measured at weeks 4 and 12 to assess pharmacokinetics.

These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial, with the primary endpoint being assessed at week 12. The trial is structured as a multicenter, randomized, double-blind, parallel group, placebo-controlled study, ensuring rigorous evaluation of the investigational product's efficacy. The study will involve the administration of BI 764198 orally once daily for a period of 12 weeks. The trial's design and endpoints are aligned with the main objective of exploring the efficacy of BI 764198 in reducing proteinuria in patients with FSGS.