Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease)

A Phase 3b, Two-part, Multicenter, One Year Randomized, Double-blind, Placebo-controlled Trial of the Safety, Pharmacokinetics, Tolerability, and Efficacy of Tolvaptan Followed by a Two Year Open-label Extension in Children and Adolescent Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

The primary objective of the study is to assess the long term safety of treatment with tolvaptan in children and adolescents with autosomal dominant polycystic kidney disease (ADPKD). The secondary objective is to assess the pharmacodynamics, pharmacokinetics, and efficacy of tolvaptan in the same participant population.

Tolvaptan has been demonstrated to delay the decline of kidney function in adults with rapidly progressing ADPKD (chronic kidney disease [CKD] stages 1 to 3) as measured by estimated glomerular filtration rate (eGFR) and Total Kidney Volume (TKV).

This trial will be the first trial of tolvaptan in children and adolescents with ADPKD.

Participants in this study will be randomly assigned to one of two groups in Phase A; tolvaptan or placebo. Participants will have an equal chance of being assigned to either treatment group and will be stratified by age and gender into the following cohorts:

• Female participant ages 12 to 14 years, inclusive
• Female participant ages 15 to 17 years, inclusive
• Male participant ages 12 to 14 years, inclusive
• Male participant ages 15 to 17 years, inclusive

Phase (A) of this study will last 12 months. After that time, all participants who qualify will be assigned tolvaptan and will be treated with tolvaptan for 24 months (Phase B).

A qualified participant is defined as one who has completed Phase A on investigational medicinal product (IMP), is willing to continue in the trial, and who does not have any adverse events (AEs), which would require IMP discontinuation.

Participants in this study will be required to make monthly visits to the study clinic and will be closely monitored over the course of the study.

Key Inclusion Criteria:

• Male and female participants aged 4 to 17 years (inclusive) with a diagnosis of ADPKD as defined by the presence of family history and/or genetic criteria AND who have at least 10 renal cysts, each of which measure at least 0.5 cm, confirmed upon magnetic resonance imaging (MRI) inspection; participants under the age of 12 years must have at least 4 cysts that are at least 1 cm in size, confirmed by ultrasound.
• Weight ≥20 kg.
• Participants with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m^2 within 31 days prior to randomization (using the Schwartz formula, eGFR = 0.413 × height [cm]/serum creatinine milligrams per deciliter [mg/dL]).
• Independent in toileting.
• Ability to swallow a tablet.

Key Exclusion Criteria:

• Liver function tests including aspartate aminotransferase (AST), alanine aminotransferase (ALT) > 1.5 × the upper limit of normal (ULN).
• Nocturnal enuresis.
• Need for chronic diuretic use.
• Participants with advanced diabetes (e.g., glycosylated hemoglobin >7.5, and/or glycosuria by dipstick, significant proteinuria, retinopathy), evidence of additional significant renal disease(s) (i.e., currently active glomerular nephritides), renal cancer, single kidney, or recent (within 6 months of screening) renal surgery or acute kidney injury.
• Participants having disorders in thirst recognition or inability to access fluids.
• Participants with critical electrolyte imbalances, as determined by the investigator.
• Participants with, or at risk of, significant hypovolemia as determined by investigator.
• Participants with clinically significant anemia, as determined by investigator.
• Participants 12 years of age and older having contraindications to, or interference with MRI assessments (e.g., ferro-magnetic prostheses, aneurysm clips, severe claustrophobia).
• Participants with a history of taking a vasopressin agonist/antagonist.
• Participants taking medications or having concomitant illnesses likely to confound endpoint assessments, including taking approved (i.e., marketed) therapies for the purpose of affecting polycystic kidney disease (PKD) cysts such as tolvaptan, vasopressin antagonists, anti-sense ribonucleic acid (RNA) therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs (i.e., octreotide, sandostatin).
• Participants who have had cyst reduction surgery within 6 weeks of the screening visit.