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

NCT ID: NCT02964273

Last Updated: 2023-01-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 91 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-09-23
• Study Completion Date: 2021-11-17

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.

Conditions

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Phase A: Tolvaptan

Participants received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting doses based on their weight as per the following specifications: ≥20 to 45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; \>75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to \<45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; \>75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter participants continued the same dose for 12 months. Doses may be titrated down dependent upon participant tolerability.

Group Type: EXPERIMENTAL

Tolvaptan

Intervention Type: DRUG

Tolvaptan spray-dried, immediate release tablets

Phase A: Placebo

Participants received matching-placebo tablets, orally as a split-dose (with the first dose taken upon awakening and second dose taken approximately 8 hours later), and starting dose based on their weight as per the following specifications: ≥20 to \<45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; \>75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to \<45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; \>75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter participants continued the same dose for 12 months. Doses may be titrated down dependent upon participant tolerability.

Group Type: PLACEBO_COMPARATOR

Tolvaptan Matching-placebo

Intervention Type: DRUG

Tolvaptan matching-placebo tablets

Phase B: Prior Tolvaptan

Qualified participants (defined as those who were willing to continue in the trial and who did not have any adverse events \[AEs\] that would require investigational medicinal product \[IMP\] discontinuation) who received tolvaptan and completed Phase A were enrolled in Phase B and received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting dose based on their body weight as per following specifications: ≥20 to \<45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; \>75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to \<45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; \>75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter participants continued the same dose for 24 months. Doses may be titrated down dependent upon participant tolerability.

Group Type: EXPERIMENTAL

Tolvaptan

Intervention Type: DRUG

Tolvaptan spray-dried, immediate release tablets

Phase B: Prior Placebo

Qualified participants (defined as those who were willing to continue in the trial and who did not have any AEs that would require IMP discontinuation) who received matching-placebo and completed Phase A, were enrolled in Phase B and received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), based on their current body weight as per following specifications: ≥20 to \<45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; \>75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to \<45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; \>75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter participants continued the same dose for 24 months. Doses may be titrated down dependent upon participant tolerability.

Group Type: EXPERIMENTAL

Tolvaptan

Intervention Type: DRUG

Tolvaptan spray-dried, immediate release tablets

Interventions

Tolvaptan

Tolvaptan spray-dried, immediate release tablets

Intervention Type: DRUG

Tolvaptan Matching-placebo

Tolvaptan matching-placebo tablets

Intervention Type: DRUG

Other Intervention Names

OPC-41061

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 4 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Otsuka Pharmaceutical Development & Commercialization, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

Otsuka Pharmaceutical Development & Commercialization, Inc.

Locations

Ghent, Oost-Vlaanderen, Belgium

Leuven, Vlaams Brabant, Belgium

Brussels, , Belgium

Brussels, , Belgium

Montegnée, , Belgium

Cologne, , Germany

Hamburg, , Germany

Hanover, , Germany

Heidelberg, , Germany

Leipzig, , Germany

Tübingen, , Germany

Milan, , Italy

Napoli, , Italy

Napoli, , Italy

Pavia, , Italy

Birmingham, , United Kingdom

London, , United Kingdom

London, , United Kingdom

Manchester, , United Kingdom

Nottingham, , United Kingdom

Countries

Belgium; Germany; Italy; United Kingdom

References

St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.

Reference Type: DERIVED

PMID: 39356039 (View on PubMed)

Mekahli D, Guay-Woodford LM, Cadnapaphornchai MA, Greenbaum LA, Litwin M, Seeman T, Dandurand A, Shi L, Sikes K, Shoaf SE, Schaefer F. Tolvaptan for Children and Adolescents with Autosomal Dominant Polycystic Kidney Disease: Randomized Controlled Trial. Clin J Am Soc Nephrol. 2023 Jan 1;18(1):36-46. doi: 10.2215/CJN.0000000000000022.

Reference Type: DERIVED

PMID: 36719158 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34604341 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-000187-42

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

156-12-298

Identifier Type: -

Identifier Source: org_study_id