Safety, Tolerability, and Efficacy of Tolvaptan in Pediatric Patients with Autosomal Recessive Polycystic Kidney Disease: A Phase 3b Multicenter Open-label Trial

The primary objective of this study is to evaluate the **safety** of tolvaptan in pediatric subjects with Autosomal Recessive Polycystic Kidney Disease (ARPKD). This is clinically relevant as ensuring the safety of tolvaptan in this population is crucial for its potential therapeutic use in managing ARPKD, a condition characterized by the development of numerous cysts in the kidneys, leading to renal dysfunction.

Secondary objectives include:

• Evaluating the effect of tolvaptan on the need for renal replacement therapy (RRT) in pediatric subjects with ARPKD. This is important for understanding the potential of tolvaptan to delay or reduce the necessity for RRT, which is a significant intervention in managing kidney failure.
• Assessing the pharmacodynamics, safety, tolerability, and efficacy of tolvaptan in this patient group. These evaluations are essential for determining the overall therapeutic profile of tolvaptan, including its mechanism of action, side effect profile, patient tolerance, and effectiveness in treating ARPKD.

The clinical trial involves a total of **three participants** diagnosed with **Autosomal Recessive Polycystic Kidney Disease (ARPKD)**. The study population includes both male and female subjects ranging from 28 days to less than 18 years of age. Participants were selected based on clinical features consistent with a diagnosis of ARPKD. The trial population is characterized by its inclusion of a vulnerable group, given the pediatric nature of the participants. The health status of the participants is defined by their diagnosis, and no specific lifestyle considerations such as diet or physical activity are highlighted. The selection process required the ability of the parent or legal guardian to provide written, informed consent, and for subjects old enough, the ability to provide written informed assent in accordance with local laws.

The clinical trial is designed to evaluate the **safety** and efficacy of **tolvaptan** in pediatric subjects diagnosed with **Autosomal Recessive Polycystic Kidney Disease (ARPKD)**. This is a Phase 3b, multicenter, open-label trial involving infants and children aged 28 days to less than 18 years. The trial will assess the safety of tolvaptan through various endpoints, including adverse events, vital signs, and clinical laboratory assessments. The trial is expected to last for approximately 18 months, with the estimated end date being December 17, 2025.

The trial design includes a sequence of study visits, starting with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria. These criteria require participants to be within the specified age range and to have clinical features consistent with a diagnosis of ARPKD. Written informed consent from a parent or legal guardian is mandatory, along with assent from subjects old enough to provide it per local laws. Follow-up visits will occur at regular intervals, including assessments at Months 1, 6, 12, and 18, to monitor changes in eGFR, kidney size, and growth percentiles. The end-of-study visit will conclude the trial, summarizing the safety and efficacy data collected.

Participants are expected to be involved in the trial for the full 18-month duration unless conditions arise that necessitate early termination. Such conditions may include significant adverse events or non-compliance with trial protocols. The trial will utilize **tolvaptan** in both oral suspension and tablet forms, with a maximum daily dose of 90 mg and a total dose not exceeding 1620 mg over the treatment period. The primary endpoints focus on safety assessments, while secondary endpoints include the annual rate of change of eGFR, time to renal replacement therapy (RRT), and changes in kidney size and growth trajectories.

The clinical trial involves the administration of **Tolvaptan**, an experimental medication, in various pharmaceutical forms. The primary formulation is an **oral suspension** developed by Otsuka Pharmaceutical Development & Commercialization, Inc. This formulation is designed for pediatric use and is administered orally. The maximum daily dose is 90 mg, with a total maximum dose of 1620 mg over a treatment period of up to 18 months. The suspension is intended to be used in the treatment of Autosomal Recessive Polycystic Kidney Disease (ARPKD) in infants and children aged 28 days to less than 18 years.

In addition to the oral suspension, the trial also includes the use of **Jinarc 15 mg tablets**. These tablets are blue, triangular, shallow-convex, and debossed with "Otsuka" and "15" on one side. They are produced by Otsuka Pharmaceutical Netherlands B.V. and are also administered orally. The dosing regimen for Jinarc 15 mg tablets aligns with the maximum daily dose of 90 mg and a total maximum dose of 1620 mg over the same treatment period.

Another formulation used in the trial is **Samsca 7.5 mg tablets**, which are blue, rectangular, shallow-convex, and debossed with "Otsuka" and "7.5" on one side. These tablets are also manufactured by Otsuka Pharmaceutical Netherlands B.V. and are administered orally. The dosing schedule for Samsca 7.5 mg tablets is consistent with the other formulations, maintaining the same maximum daily and total dose limits.

Additionally, the trial includes **Jinarc 30 mg tablets**, which are blue, round, shallow-convex, and debossed with "Otsuka" and "30" on one side. These tablets are also produced by Otsuka Pharmaceutical Netherlands B.V. and administered orally. The dosing regimen for Jinarc 30 mg tablets follows the same guidelines as the other formulations, with a maximum daily dose of 90 mg and a total maximum dose of 1620 mg over the treatment period.

Throughout the trial, participant compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol. The trial also considers the use of non-experimental treatments, such as other diuretics and vasopressin antagonists, as part of the standard-of-care therapy. These additional treatments are evaluated to assess their impact on the safety and efficacy of Tolvaptan in the pediatric population with ARPKD.

The efficacy of **Tolvaptan** in the clinical trial will be assessed through several secondary endpoints. These include the annual rate of change of estimated Glomerular Filtration Rate (eGFR) using the Schwartz formula, which is calculated as 0.413 multiplied by height (or length, in cm) divided by serum creatinine (mg/dL). This will be measured from baseline to post-treatment after 18 months of treatment. Additionally, changes from baseline in eGFR will be evaluated at Months 1, 6, 12, and 18 while on treatment.

Other efficacy parameters include the time to renal replacement therapy (RRT) and the percentage of subjects who receive RRT. The percentage change in kidney size, adjusted for height, will be assessed at every time point from baseline to 18 months on treatment using ultrasound and the ellipsoid methodology. Growth percentile trajectories for height, weight, and head circumference (for subjects ≤ 2 years of age) will be monitored at 3, 6, 12, and 18 months. The palatability and acceptability of the suspension formulation will be assessed in an age-appropriate manner for applicable subjects. Additionally, the proportions of each Tanner Staging by gender and age will be recorded at baseline and every 6 months until Month 18 or the end of treatment.