Clinical trial NCT02964273: Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Keywords: Autosomal Dominant Polycystic Kidney Disease
ADPKD
Tolvaptan
Renal cysts
Chronic Kidney Disease
Genetic Kidney Disease
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
First posted: 2016-11-16
Enrollment: 91
Sex: ALL
Minimum age (years): 4
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)
timeFrame: Baseline, and Week 1 of Phase A
measure: Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)
timeFrame: Baseline, and Week 1 of Phase A
Secondary outcomes:
measure: Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI)
timeFrame: Baseline, and Month 12 of Phase A
measure: Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1
timeFrame: Prior to Week 1 in Phase A and B
measure: Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A
timeFrame: Phase A Baseline, Months 1, 6, and 12
measure: Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B
timeFrame: Phase B Baseline, Week 1, Months 1, 6, 12, 18, and 24
measure: Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24
timeFrame: Phase B Baseline, Months 12 and 24
measure: Phase A: 24-hour Urine Volume
timeFrame: 24 hours post dose after Month 1 on study medication in Phase A
measure: Phase A: 24-hour Fluid Intake
timeFrame: 24 hours post dose after Month 1 on study medication in Phase A
measure: Phase A: 24-hour Fluid Balance
timeFrame: 24 hours post dose after Month 1 on study medication in Phase A
measure: Phase A: 24-hour Sodium Clearance
timeFrame: 24 hours post dose after Month 1 on study medication in Phase A
measure: Phase A: 24-hour Creatinine Clearance
timeFrame: 24 hours post dose after Month 1 on study medication in Phase A
measure: Phase A: 24-hour Free Water Clearance
timeFrame: 24 hours post dose after Month 1 on study medication in Phase A
measure: Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations
timeFrame: At Baseline, Months 6 and 12 of Phase A
measure: Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations
timeFrame: At Baseline, Months 6, 12, 18, and 24 of Phase B
measure: Phase A: Change From Baseline in Growth Percentile by Gender and Age
timeFrame: At Baseline, Months 6 and 12 of Phase A
measure: Phase B: Change From Baseline in Growth Percentile by Gender and Age
timeFrame: At Baseline, Months 6, 12, 18, and 24 of Phase B
measure: Phase A: Change From Baseline in Creatinine Value
timeFrame: Baseline, Week 1, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, Follow Up Day 7, End of Treatment, and Last Visit
measure: Phase B: Change From Baseline in Creatinine Value
timeFrame: Baseline, Week 1, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, Follow Up Day 7, End of Treatment, and Last Visit
measure: Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Vital Signs
timeFrame: From first dose of study drug up to 14 days post last dose (up to approximately 37 months)
measure: Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs)
timeFrame: From first dose of study drug up to 14 days post last dose (up to approximately 37 months)
measure: Phase A and B: Percentage of Participants With Aquaretic Adverse Events (AEs)
timeFrame: From first dose of study drug up to 14 days post last dose (up to approximately 37 months)
Other outcomes:
Locations:
city: Gent
country: Belgium
state: Oost-Vlaanderen
city: Leuven
country: Belgium
state: Vlaams Brabant
city: Brussels
country: Belgium
city: Bruxelles
country: Belgium
city: Montegnee
country: Belgium
city: Cologne
country: Germany
city: Hamburg
country: Germany
city: Hannover
country: Germany
city: Heidelberg
country: Germany
city: Leipzig
country: Germany
city: Tuebingen
country: Germany
city: Milano
country: Italy
city: Napoli
country: Italy
city: Napoli
country: Italy
city: Pavia
country: Italy
city: Birmingham
country: United Kingdom
city: London
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Nottingham
country: United Kingdom
Study officials:
affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc.
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Liu F, Feng C, Shen H, Fu H, Mao J. Tolvaptan in Pediatric Autosomal Dominant Polycystic Kidney Disease: From Here to Where? Kidney Dis (Basel). 2021 Sep;7(5):343-349. doi: 10.1159/000517186. Epub 2021 Jul 2.