A Phase 3a Randomized Controlled Trial Comparing Metformin and Tolvaptan in Adults with Autosomal Dominant Polycystic Kidney Disease

The primary objective of this study is to evaluate whether a two-year course of 1500 mg daily of **metformin** is equivalent or not inferior to **tolvaptan** in reducing the decline of estimated glomerular filtration rate (eGFR) in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). This is clinically relevant as eGFR decline is a critical marker of kidney function deterioration in ADPKD, and finding an effective treatment could significantly impact patient outcomes.

Secondary objectives include assessing the safety and efficacy of **metformin** in reducing kidney volume enlargement and alleviating symptoms associated with ADPKD. These objectives aim to provide a comprehensive understanding of the potential benefits of **metformin** beyond eGFR stabilization, addressing both structural and symptomatic aspects of the disease.

The clinical trial involves participants diagnosed with **Autosomal Dominant Polycystic Kidney Disease** (ADPKD). The study population comprises both male and female subjects aged between 18 and 55 years. Participants are required to have a mean estimated glomerular filtration rate (eGFR) of at least 45 ml/min/1.73 m², as measured by the CKD-EPI formula, and a genetic diagnosis of Type I ADPKD with a truncating mutation. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants must have signed and dated informed consent to be included in the study. No specific lifestyle considerations such as diet or physical activity are mentioned as part of the trial's criteria.

The clinical trial is designed as a **randomized**, controlled study with two parallel arms, focusing on the efficacy and safety of **metformin** versus **tolvaptan** in adults with **Autosomal Dominant Polycystic Kidney Disease (ADPKD)**. The trial aims to determine if a two-year course of 1500 mg per day of metformin is equivalent or not inferior to tolvaptan in reducing the decline of estimated glomerular filtration rate (eGFR) in affected patients. The study is expected to run from April 2021 to June 2026, with a maximum treatment period of 24 months for each participant.

Participants will be randomly assigned to receive either metformin or tolvaptan, both administered orally in tablet form. The primary endpoint is the difference in the annualized slope of eGFR between the two treatments, while a key secondary endpoint is the percent change from baseline in height-adjusted total kidney volume (htTKV) as measured by CT-scan at 12 and 24 months. The trial includes an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor treatment effects and safety. The end-of-study visit will assess the final outcomes and any adverse events.

Inclusion criteria require participants to be men or women aged 18 to 55 years, with a mean eGFR (CKD-EPI) of at least 45 ml/min/1.73 m², a genetic diagnosis of Type I ADPKD truncating mutation, and signed informed consent. The expected length of participant involvement is up to 24 months, with conditions for early termination including significant adverse events or withdrawal of consent. The trial is not categorized as low intervention and is conducted under the authorization of Otsuka Pharmaceutical Netherlands B.V.

The clinical trial involves the administration of **Jinarc** tablets, which are available in three different dosage combinations: 15 mg + 45 mg, 30 mg + 60 mg, and 30 mg + 90 mg. These tablets contain the active substance **tolvaptan** and are manufactured by Otsuka Pharmaceutical Netherlands B.V. The pharmaceutical form is a tablet, and the route of administration is oral. The maximum daily dose for each combination is 120 mg, with a total treatment period of 24 months. The tablets are not formulated for pediatric use and are classified under the ATC code C03XA01. Compliance with the dosing schedule is monitored throughout the trial.

**Metformin** is used as a comparator treatment in this study. It is administered in the form of coated tablets, with a maximum daily dose of 1500 mg. The treatment period for metformin is also 24 months, and it is administered orally. The active substance, metformin, is of chemical origin. The trial aims to evaluate the efficacy of metformin in comparison to tolvaptan in reducing the decline of estimated glomerular filtration rate (eGFR) in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Compliance with the dosing regimen is closely monitored to ensure accurate assessment of treatment outcomes.

Efficacy in this clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the difference in the annualized slope of estimated glomerular filtration rate (**eGFR**) using the CKD-EPI formula between the two treatment groups, Metformin and Tolvaptan, in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). This will involve calculating the slope from baseline and post-randomization assessments. The key secondary endpoint is the percent change from baseline in height-adjusted total kidney volume (htTKV), which will be measured by CT-scan at 12 and 24 months. These efficacy parameters will be collected and analyzed at specified timepoints to determine the comparative effectiveness of the treatments over the course of the study.