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

NCT02964273 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 156-12-2982016-000187-42
• Study Type: interventional
• Target: 91
• Locations: 4 countries
• Sites: 20

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.

Conditions

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Keywords

Autosomal Dominant Polycystic Kidney Disease; ADPKD; Tolvaptan; Renal cysts; Chronic Kidney Disease; Genetic Kidney Disease

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  Baseline, and Week 1 of Phase A

Secondary Outcomes (20)

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

  Baseline, and Month 12 of Phase A

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

  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

  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

  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

  Phase B Baseline, Months 12 and 24

Study Arms (4)

Phase A: Tolvaptan

EXPERIMENTAL

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.

Drug: Tolvaptan

Phase A: Placebo

PLACEBO COMPARATOR

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.

Drug: Tolvaptan Matching-placebo

Phase B: Prior Tolvaptan

EXPERIMENTAL

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.

Drug: Tolvaptan

Phase B: Prior Placebo

EXPERIMENTAL

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.

Drug: Tolvaptan

Interventions

Tolvaptan DRUG

Tolvaptan spray-dried, immediate release tablets

Also known as: OPC-41061

Phase A: Tolvaptan; Phase B: Prior Placebo; Phase B: Prior Tolvaptan

Tolvaptan Matching-placebo DRUG

Tolvaptan matching-placebo tablets

Phase A: Placebo

Eligibility Criteria

• Age: 4 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (20)

Unknown Facility

Ghent, Oost-Vlaanderen, 9000, Belgium

Location

Unknown Facility

Leuven, Vlaams Brabant, 3000, Belgium

Location

Unknown Facility

Brussels, 1020, Belgium

Location

Unknown Facility

Brussels, 1200, Belgium

Location

Unknown Facility

Montegnée, 4420, Belgium

Location

Unknown Facility

Cologne, 50937, Germany

Location

Unknown Facility

Hamburg, 20246, Germany

Location

Unknown Facility

Hanover, 30625, Germany

Location

Unknown Facility

Heidelberg, 69120, Germany

Location

Unknown Facility

Leipzig, 04103, Germany

Location

Unknown Facility

Tübingen, 72076, Germany

Location

Unknown Facility

Milan, 20122, Italy

Location

Unknown Facility

Napoli, 80129, Italy

Location

Unknown Facility

Napoli, 80131, Italy

Location

Unknown Facility

Pavia, 27100, Italy

Location

Unknown Facility

Birmingham, B4 6NH, United Kingdom

Location

Unknown Facility

London, SE1 7EH, United Kingdom

Location

Unknown Facility

London, WC1N 3JH, United Kingdom

Location

Unknown Facility

Manchester, M13 9WL, United Kingdom

Location

Unknown Facility

Nottingham, NG7 2UH, United Kingdom

Location

Related Publications (4)

• Shoaf SE, Sikes K. Tolvaptan pharmacokinetics and pharmacodynamics in adolescents with autosomal dominant polycystic kidney disease. Eur J Pediatr. 2025 Dec 18;185(1):26. doi: 10.1007/s00431-025-06689-2.

  PMID: 41407907 DERIVED

• 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.

  PMID: 39356039 DERIVED

• 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.

  PMID: 36719158 DERIVED

• 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.

  PMID: 34604341 DERIVED

MeSH Terms

Conditions

Polycystic Kidney, Autosomal Dominant; Renal Insufficiency, Chronic

Interventions

Tolvaptan

Condition Hierarchy (Ancestors)

Polycystic Kidney Diseases; Kidney Diseases, Cystic; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Ciliopathies; Genetic Diseases, Inborn; Renal Insufficiency; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Global Clinical Development
• Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.

clinicaltransparency@otsuka-us.com

+1-609-524-6788

Study Officials

• Study Director

  Otsuka Pharmaceutical Development & Commercialization, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 15, 2016
• First Posted: November 16, 2016
• Study Start: September 23, 2016
• Primary Completion: November 17, 2021
• Study Completion: November 17, 2021
• Last Updated: January 3, 2023
• Results First Posted: January 3, 2023

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
• Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/

Locations

BE (5); DE (6); IT (4); GB (5)