Phase 3b Multicenter Open-label Study on Tolvaptan's Safety, Tolerability, and Efficacy in Infants with Autosomal Recessive Polycystic Kidney Disease

Trial ID: 2023-508217-17-00
Protocol: 156-12-204
Sponsor: Otsuka Pharmaceutical Development & Commercialization Inc.

Trial statistics

science

test molecule

location_city

research sites

public

countries

medical_information

disease

person_search

investigators

handshake

vendors

Diseases & Conditions

Congenital cystic kidney disease

Objectives

The primary objective of this study is to evaluate the effect of **tolvaptan** on the need for renal replacement therapy (RRT) in pediatric subjects with Autosomal Recessive Polycystic Kidney Disease (ARPKD). This is clinically relevant as it aims to determine the potential of tolvaptan to delay or reduce the necessity for RRT, which is a critical intervention in managing kidney failure in affected infants and children.

Secondary objectives include:

Evaluating changes in estimated glomerular filtration rate (eGFR) and assessing the palatability and acceptability of the formulation.
Assessing the pharmacodynamics, safety, tolerability, and efficacy of tolvaptan in pediatric subjects with ARPKD.

Participants

The clinical trial involves a total of **16 participants** diagnosed with **Autosomal Recessive Polycystic Kidney Disease (ARPKD)**. The study population consists of both male and female subjects, specifically infants aged between 28 days and less than 12 weeks. Participants were selected based on clinical and imaging features consistent with ARPKD, including nephromegaly, multiple renal cysts, and a history of oligohydramnios or anhydramnios. The trial includes a vulnerable population, as it involves pediatric subjects. The ability of the parent or legal guardian to provide informed consent and comply with trial requirements was also a consideration in participant selection. No specific lifestyle considerations such as diet or physical activity are mentioned for this trial.

Plans and Procedures

The clinical trial is designed to evaluate the **safety**, tolerability, and efficacy of **Tolvaptan** in infants and children aged 28 days to less than 12 weeks with **Autosomal Recessive Polycystic Kidney Disease** (ARPKD). This is a Phase 3b, multicenter, open-label trial. The primary objective is to assess the effect of Tolvaptan on the need for renal replacement therapy (RRT) in pediatric subjects with ARPKD. The trial is expected to run from July 2, 2023, to July 22, 2027, with a maximum treatment period of 36 months.

Participants will be required to attend several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age and clinical features consistent with ARPKD. Follow-up visits will occur at regular intervals to monitor the rate of change in estimated glomerular filtration rate (eGFR), changes in kidney size, and other secondary endpoints, including growth trajectories and laboratory values. The end-of-study visit will conclude the participant's involvement, summarizing the overall outcomes and any adverse events experienced.

The expected length of participant involvement is up to 24 months, with conditions for early termination including non-compliance with trial requirements or the occurrence of significant adverse events. The trial will utilize an oral suspension formulation of Tolvaptan, administered according to a specified dosing regimen. The study will not employ a randomized or double-blind design, as it is open-label, allowing for direct observation of the drug's effects. Participants' parents or legal guardians must provide informed consent prior to any trial-related procedures.

Treatment

The clinical trial involves the administration of **Tolvaptan**, an experimental medication, in the form of an **oral suspension**. The active substance, **tolvaptan**, is chemically derived and is provided by Otsuka Pharmaceutical Development & Commercialization, Inc. The pharmaceutical form is specifically designed for pediatric use, targeting infants and children aged 28 days to less than 12 weeks with Autosomal Recessive Polycystic Kidney Disease (ARPKD). The dosage is calculated based on body weight, with a maximum daily dose of 1 mg/kg and a total maximum dose of 36 mg/kg over the treatment period. The administration route is oral, and the treatment duration is capped at 36 weeks. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, participants may receive non-experimental treatments, including other diuretics and vasopressin antagonists, as part of the standard-of-care therapy. These treatments are not the primary focus of the study but may be used to manage symptoms or conditions associated with ARPKD. The trial does not include a placebo or comparator treatment, as the primary objective is to assess the safety, tolerability, and efficacy of **Tolvaptan** in the specified pediatric population. Monitoring of participant compliance with both experimental and non-experimental treatments is conducted to ensure accurate assessment of the trial outcomes.

Efficacy

The efficacy of Tolvaptan in the treatment of **Autosomal Recessive Polycystic Kidney Disease (ARPKD)** in infants and children aged 28 days to less than 12 weeks will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoint is the percentage of subjects requiring renal replacement therapy (RRT) by one year of age. This will provide a direct measure of the drug's impact on the progression of kidney disease.

Secondary efficacy endpoints include the rate of change in estimated glomerular filtration rate (eGFR) using the Schwartz formula over a two-year treatment period, which will be calculated from pretreatment to post-treatment. Additional assessments will involve age-appropriate evaluations of the palatability and acceptability of the suspension formulation, changes in serum sodium (sNa+) levels from baseline at each visit, and the percentage change in kidney size, specifically height-adjusted total kidney volume (TKV), at every time point from baseline to 24 months of treatment using ultrasound and ellipsoid methodology.

Further secondary endpoints include changes from baseline in growth percentile trajectories for height, weight, and head circumference at specified intervals (3, 6, 12, 18, and 24 months), a summary of vital signs data, and the incidence of adverse events, including aquaretic adverse events. Laboratory assessments will monitor changes from baseline in serum creatinine and liver function tests, including total bilirubin, ALT, AST, ALP, and GGT. These comprehensive measures will collectively evaluate the efficacy of Tolvaptan in managing ARPKD in the specified pediatric population.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

Male or female subjects between 28 days and < 12 weeks of age, inclusive.
Must have clinical and imaging features that are consistent with a diagnosis of ARPKD with all the following characteristics: Nephromegaly (> 2 standard deviations from age-appropriate standard via ultrasound) Multiple renal cysts History of oligohydramnios or anhydramnios.
Ability for parent/legal guardian to provide written, informed consent prior to initiation of any trial-related procedures, and ability, in the opinion of the principal investigator, to comply with all the requirements of the trial.

cancel

Exclusion Criteria

Premature birth (≤ 32 weeks gestational age).
Has or at risk of having significant hypovolemia (eg, subjects that lack free access to water, without adequate fluid monitoring and management) as determined by investigator.
Severe systolic dysfunction defined as ejection fraction < 14%.
Serum sodium levels < 130 mmol/L or >145 mmol/L (or the ULN of the local laboratory, whichever is lower).
Clinically significant anemia, as determined by investigator.
Anuria or RRT defined as intermittent or continuous hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration or history of kidney transplantation.
Evidence of syndromic conditions associated with renal cysts (other than ARPKD).
Abnormal liver function tests including ALT and AST, > 1.2 × ULN.
Parents with renal cystic disease.
Receiving chronic diuretic that could not be adjusted after tolvaptan initiation.
Cannot be monitored for fluid balance.
Has or at risk of having sodium and potassium electrolyte imbalances, as determined by the investigator.
Taking any other experimental medications.
Require ventilator support.
Taking medications known to induce CYP3A4.
Having an active infection including viral that would require therapy disruptive to IMP dosing.
Platelet count <50,000 µL.
Has findings consistent with clinically significant portal hypertension (eg, varices, variceal bleeding, hypersplenism indicated by thrombocytopenia).
Subjects who have bladder dysfunction and/or difficulty voiding.
Subjects taking a vasopressin agonist (eg, desmopressin).
Subjects having concomitant illnesses or taking medications likely to confound endpoint assessments, including taking approved (ie, marketed) therapies for the purpose of affecting PKD cysts such as tolvaptan, vasopressin antagonists, anti-sense RNA therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs (ie, octreotide, sandostatin).
History of cholangitis.
Received or are scheduled to receive a liver transplant.