Evaluation of R3R01 on Albuminuria Reduction in Diabetic Kidney Disease: A Randomized, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of the ABCA1 inducer R3R01 in reducing **albuminuria** at 12 weeks (Day 84) when compared to placebo in patients with diabetic kidney disease. This is clinically relevant as albuminuria is a key marker of kidney damage and its reduction could indicate a potential therapeutic benefit in managing diabetic kidney disease.

Secondary objectives include:

• Evaluating the efficacy of R3R01 on estimated glomerular filtration rate (**eGFR**) at 12 weeks (Day 84) compared to placebo.
• Assessing the pharmacokinetics of R3R01 in subjects with diabetic kidney disease and comparing these pharmacokinetics to subjects with Alport syndrome (AS) or focal segmental glomerulosclerosis (FSGS).

The clinical trial focuses on evaluating the efficacy of R3R01 in reducing albuminuria in patients with **diabetic kidney disease**. The study population comprises both male and female adults over the age of 18, with type 2 diabetes controlled by a hemoglobin A1c level of less than 10.5%. Participants are required to maintain stable antihypertensive and lipid-lowering treatments, and those on SGLT2-Inhibitors must be on a stable dose for at least three months. The trial includes individuals with an eGFR greater than 30 ml/min/1.73 m² and a UACR between 30 mg/g and 5000 mg/g. Abdominal obesity is a consideration, with specific waist circumference criteria for men and women, or a fasting triglyceride level above 2.0 mmol/l. Systolic blood pressure must be between 110 mmHg and 160 mmHg. The trial does not involve a vulnerable population, and the sponsor has not provided the total number of participants.

The clinical trial is designed to evaluate the efficacy of **R3R01**, an **ATP-binding cassette transporter A1 (ABCA1) inducer**, in reducing albuminuria levels in patients with **diabetic kidney disease**. This is a Phase IV, randomized, double-blind, placebo-controlled study. The trial will span approximately 12 weeks, with an estimated recruitment start date of August 1, 2024, and an estimated end date of August 1, 2025. Participants will be randomly assigned to receive either the active treatment, R3R01, administered orally in tablet form, or a placebo. The primary endpoint is the change in urinary albumin-to-creatinine ratio (UACR) from randomization to the end of treatment at 3 months. Secondary endpoints include measured glomerular filtration rate (GFR) using plasma clearance of 99Tc-DTPA, 24-hour ambulatory blood pressure, and plasma pharmacokinetic parameters of R3R01.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, type 2 diabetes status, and stable antihypertensive treatment. Participants must have a UACR >30 mg/g and <5000 mg/g, an estimated GFR >30 ml/min/1.73 m², and meet specific blood pressure and metabolic criteria. Follow-up visits will occur at regular intervals to assess safety, efficacy, and adherence to the study protocol. The end-of-study visit will involve final assessments of the primary and secondary endpoints.

Participant involvement is expected to last for the full 12-week duration of the trial. However, conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial is not classified as low intervention, and all participants will be closely monitored throughout the study period to ensure their safety and the integrity of the trial data.

The clinical trial involves the administration of the experimental medication **R3R01**, an ATP-binding cassette transporter A1 (ABCA1) inducer, developed by River 3 Renal Corp. This medication is provided in the form of a **tablet** and is administered **orally**. The maximum daily dose is 400 mg, with a total maximum dose of 33,600 mg over a treatment period of 12 weeks. The trial aims to evaluate the efficacy of R3R01 in reducing albuminuria levels in patients with diabetic kidney disease. Participant compliance with the dosing schedule will be monitored throughout the study.

In addition to the experimental treatment, the study includes the use of **Technescan DTPA**, a radiopharmaceutical preparation containing **pentetic acid** as the active substance. This product is manufactured by Curium Netherlands B.V. and is administered as a **solution for injection** via direct intravenous injection. The maximum daily dose is 0.5 ml, with a total maximum dose of 1.0 ml over a treatment period of 2 days. This auxiliary treatment is used to support the study's objectives and is not the primary focus of the trial.

A **placebo** is also utilized in the study to serve as a comparator treatment. The placebo is designed to mimic the experimental medication in appearance but contains no active pharmaceutical ingredients. It is used to assess the efficacy of R3R01 by providing a baseline for comparison. The placebo administration follows the same schedule as the experimental treatment to ensure consistency in the trial design.

The efficacy of the investigational product R3R01 in the clinical trial will be assessed primarily by evaluating the change in the **urinary albumin-to-creatinine ratio (UACR)** from randomization to the end of treatment at 3 months. This primary endpoint is designed to measure the reduction in albuminuria levels in patients with diabetic kidney disease. Secondary endpoints include the measurement of glomerular filtration rate (GFR) using plasma clearance of 99Tc-DTPA or estimated GFR (eGFR) calculated with the CKD-EPI equation based on creatinine or cystatin C, 24-hour ambulatory blood pressure, and plasma pharmacokinetic (PK) parameters of R3R01.

The efficacy parameters will be collected and analyzed at specified timepoints, with the primary endpoint being assessed at the end of the 12-week treatment period. The trial will utilize validated laboratory tests and measurement techniques to ensure the accuracy and reliability of the data collected. The results will be compared between the treatment group receiving R3R01 and the placebo group to determine the efficacy of the investigational product in reducing albuminuria in the target patient population.