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

Otsuka Pharmaceutical Development & Commercialization, Inc.91 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Interventions

TolvaptanDRUG

Tolvaptan spray-dried, immediate release tablets

Tolvaptan Matching-placeboDRUG

Tolvaptan matching-placebo tablets

Eligibility

Sex: ALLMin age: 4 YearsMax age: 17 Years

Medical Language ↔ Plain English

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.

Locations (20)

Unnamed facility

Ghent, Oost-Vlaanderen, Belgium

Unnamed facility

Leuven, Vlaams Brabant, Belgium

Unnamed facility

Brussels, Belgium

Outcomes

Primary Outcomes

Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)

Urine osmolality is a measure of urine concentration, measured by osmometer, which evaluates the freezing point depression of a solution and supplies results as milliosmoles per kilogram of water. Spot urine osmolality was determined for urine samples collected immediately prior to morning dosing for Day 1 (Baseline), and Week 1 for all participants. Sample was taken after the first morning's void and was provided as a mid-stream, clean catch sample. All participants were fasting.

Time frame: Baseline, and Week 1 of Phase A

Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)

Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. Spot urine sample for determination of specific gravity was collected immediately prior to morning dosing for Day 1 (Baseline), and Week 1 for all participants. Sample was taken after the first morning's void and was provided as a mid-stream, clean catch sample. All participants were fasting.

Time frame: Baseline, and Week 1 of Phase A

Secondary Outcomes

Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI)

htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency.

Time frame: Baseline, and Month 12 of Phase A

Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1

Participants were instructed to record all fluid taken and all urine output for the 24-hour period.

Time frame: Prior to Week 1 in Phase A and B

Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A

Data from ClinicalTrials.gov

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Unnamed facility

Brussels, Belgium

Unnamed facility

Montegnée, Belgium

Unnamed facility

Cologne, Germany

Unnamed facility

Hamburg, Germany

Unnamed facility

Hanover, Germany

Unnamed facility

Heidelberg, Germany

Unnamed facility

Leipzig, Germany

...and 10 more locations

Renal function was assessed by estimated eGFR calculated by the Schwartz formula (eGFR = 0.413 × height \[cm\] /serum creatinine mg/dL), expressed as mean change in eGFR at the specified time points. The units for the data reported are milliliter per minute per 1.73 meter square (mL/min/1.73 m\^2). The baseline was the evaluation done at Week 1 in Phase A for this outcome measure.

Time frame: Phase A Baseline, Months 1, 6, and 12

Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B

Time frame: Phase B Baseline, Week 1, Months 1, 6, 12, 18, and 24

Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24

htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency.

Time frame: Phase B Baseline, Months 12 and 24

Phase A: 24-hour Urine Volume

Urine volume refers to the quantity of urine produced per unit of time.