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)

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

Sponsors

Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Source Otsuka Pharmaceutical Development & Commercialization, Inc.
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 subject population.

Detailed Description

Tolvaptan has been demonstrated to delay the decline of kidney function in adults with rapidly progressing ADPKD (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.

Subjects 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 subjects ages 12 to 14 years, inclusive

- Female subjects ages 15 to 17 years, inclusive

- Male subjects ages 12 to 14 years, inclusive

- Male subjects ages 15 to 17 years, inclusive

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

A qualified subject 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.

Overall Status Active, not recruiting
Start Date September 2016
Completion Date December 2021
Primary Completion Date December 2, 2019
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Change from baseline in spot urine osmolality (pre-morning dose) After 1 week of daily dosing during Phase A
Change from baseline in specific gravity (pre-morning dose) After 1 week of daily dosing during Phase A
Secondary Outcome
Measure Time Frame
Percent change from Phase A baseline in height-adjusted total kidney volume (htTKV) as measured by MRI at 12 months
24-hour urine volume in mL After at least 1 month on study medication during Phase A
24-hour fluid intake in mL After at least 1 month on study medication during Phase A
24-hour fluid balance in mL After at least 1 month on study medication during Phase A
24-hour fluid balance in mL At Week 1 during Phase A and Phase B
Change from baseline in renal function (eGFR by Schwartz formula) at each visit in Phase A At Week 1, Month 1, Month 6, Month 12
Change from Phase B baseline in renal function (eGFR by Schwartz formula) At Week 1, Months 1, 6, 12, 18, 24
Percent change from Phase B baseline in htTKV as measured by MRI at 12 months
Percent change from Phase B baseline in htTKV as measured by MRI at 24 months
Proportions of each Tanner Stage by gender compared to normative populations At baseline, 6 and 12 months during the placebo-controlled phase (Phase A) and every 6 months (up to 26, 52, 78 and 104 weeks) during the open-label extension (Phase B)
Proportions of each Tanner Stage by age compared to normative populations At baseline, 6 and 12 months during the placebo-controlled phase (Phase A) and every 6 months (up to 26, 52, 78 and 104 weeks) during the open-label extension (Phase B)
Description of changes from baseline for height in cm by gender and age at baseline, 6 and 12 months during the placebo-controlled phase (Phase A) and every 6 months (up to 26, 52, 78 and 104 weeks) during the open-label extension (Phase B)
Description of changes from baseline for weight in kilograms by gender and age at baseline, 6 and 12 months during the placebo-controlled phase (Phase A) and every 6 months (up to 26, 52, 78 and 104 weeks) during the open-label extension (Phase B)
Changes from baseline in creatinine up thru 14 days post last dose in Phase A or B, whichever completion is latter.
Changes from baseline in vital signs up thru 14 days post last dose in Phase A or B, whichever completion is latter.
Changes from baseline in liver function tests (LFTs) up thru 14 days post last dose in Phase A or B, whichever completion is latter.
Changes from baseline in rate of aquaretic AEs in placebo and tolvaptan up thru 14 days post last dose in Phase A or B, whichever completion is latter.
Pharmacodynamic (PD) endpoints of sodium, creatinine and free water clearances in mL/min After at least 1 month on study medication in Phase A
Enrollment 91
Condition
Intervention

Intervention type: Drug

Intervention name: Tolvaptan

Description: Tolvaptan 7.5, 15, and 30 mg spray-dried, immediate release tablets with matching placebo. Subjects will be randomized to receive either active tolvaptan or matching placebo for 12 months in Phase A, followed by open-label tolvaptan for 24 months in Phase B. Study medication will be administered orally as a split-dose, with the first dose taken upon awakening and the second dose taken approximately 8 hours later. Phase A and Phase B starting doses will be based on weight. After 1 week, subjects will be asked to up-titrate once from their starting dose. Subjects may down-titrate at any time during the trial; however, subjects will be asked to stay on the highest tolerable dose (by weight group) if possible. The titration schedules for Phase A and Phase B are similar. Frequency: Twice daily.

Arm group label: Active Tolvaptan

Other name: JINARC®

Intervention type: Drug

Intervention name: Matching Placebo

Description: Placebo matching Tolvaptan 7.5, 15, and 30 mg spray-dried, immediate release tablets. Subjects will be randomized to receive either active tolvaptan or matching placebo for 12 months in Phase A, followed by open-label tolvaptan for 24 months in Phase B. Study medication will be administered orally as a split-dose, with the first dose taken upon awakening and the second dose taken approximately 8 hours later. Phase A and Phase B starting doses will be based on weight. After 1 week, subjects will be asked to up-titrate once from their starting dose. Subjects may down-titrate at any time during the trial; however, subjects will be asked to stay on the highest tolerable dose (by weight group) if possible. The titration schedules for Phase A and Phase B are similar. Frequency: Twice daily.

Arm group label: Matching Placebo

Eligibility

Criteria:

Key Inclusion Criteria:

- Male and female subjects 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; subjects 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.

- Subjects with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2 within 31 days prior to randomization (using the Schwartz formula, eGFR = 0.413 × height [cm]/serum creatinine mg/dL).

- Independent in toileting.

- Ability to swallow a tablet.

Key Exclusion Criteria:

- Liver function tests including AST (aspartate aminotransferase), ALT (alanine aminotransferase) > 1.5 × the upper limit of normal (ULN).

- Nocturnal enuresis.

- Need for chronic diuretic use.

- Subjects with advanced diabetes (eg, glycosylated hemoglobin > 7.5, and/or glycosuria by dipstick, significant proteinuria, retinopathy), evidence of additional significant renal disease(s) (ie, currently active glomerular nephritides), renal cancer, single kidney, or recent (within 6 months of screening) renal surgery or acute kidney injury.

- Subjects having disorders in thirst recognition or inability to access fluids.

- Subjects with critical electrolyte imbalances, as determined by the investigator.

- Subjects with, or at risk of, significant hypovolemia as determined by investigator.

- Subjects with clinically significant anemia, as determined by investigator.

- Subjects 12 years of age and older having contraindications to, or interference with MRI assessments (eg, ferro-magnetic prostheses, aneurysm clips, severe claustrophobia).

- Subjects with a history of taking a vasopressin agonist/antagonist.

- Subjects taking medications or having concomitant illnesses likely to confound endpoint assessments, including taking approved (ie, 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 (ie, octreotide, sandostatin).

- Subjects who have had cyst reduction surgery within 6 weeks of the screening visit.

Gender: All

Minimum age: 4 Years

Maximum age: 17 Years

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Ann Dandurand, MD Study Director Otsuka Pharmaceutical Development & Commercialization, Inc.
Location
facility
| Gent, Oost-Vlaanderen, 9000, Belgium
| Leuven, Vlaams Brabant, 3000, Belgium
| Brussels, 1200, Belgium
| Bruxelles, 1020, Belgium
| Montegnee, 4420, Belgium
| Cologne, 50937, Germany
| Hamburg, 20246, Germany
| Hannover, 30625, Germany
| Heidelberg, 69120, Germany
| Leipzig, 04103, Germany
| Tuebingen, 72076, Germany
| Milano, 20122, Italy
| Napoli, 80129, Italy
| Napoli, 80131, Italy
| Pavia, 27100, Italy
| Birmingham, B4 6NH, United Kingdom
| London, SE1 7EH, United Kingdom
| London, WC1N 3JH, United Kingdom
| Manchester, M13 9WL, United Kingdom
| Nottingham, NG7 2UH, United Kingdom
Location Countries

Belgium

Germany

Italy

United Kingdom

Verification Date

May 2020

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Arm group label: Active Tolvaptan

Arm group type: Experimental

Description: In Phase A, subjects will be randomized in a 1:1 ratio to receive IMP (active tolvaptan or matching placebo) for 12 months. Starting doses, if receiving active tolvaptan, are based on weight: ≥ 20 kg to < 45 kg, 15/7.5 mg tolvaptan (TLV) split-dose ≥ 45 kg to ≤ 75 kg, 30/15 mg TLV split-dose > 75 kg, 45/15 mg TLV split-dose After 1 week, subjects will be asked to uptitrate once from their starting dose of active tolvaptan. ≥ 20 kg to < 45 kg, 30/15 mg TLV split-dose ≥ 45 kg to ≤ 75 kg, 45/15 mg TLV split-dose > 75 kg, 60/30 mg TLV split-dose Qualified subjects who Complete Phase A are eligible to participate in Phase B.

Arm group label: Matching Placebo

Arm group type: Placebo Comparator

Description: In Phase A, subjects will be randomized in a 1:1 ratio to receive IMP (active tolvaptan or matching placebo) for 12 months. Starting doses are based on weight: ≥ 20 kg to < 45 kg, 15/7.5 mg matching placebo split-dose ≥ 45 kg to ≤ 75 kg, 30/15 mg matching placebo split-dose > 75 kg, 45/15 mg matching placebo split-dose After 1 week, subjects will be asked to uptitrate once from their starting dose of matching placebo. ≥ 20 kg to < 45 kg, 30/15 mg matching placebo split-dose ≥ 45 kg to ≤ 75 kg, 45/15 mg matching placebo split-dose > 75 kg, 60/30 mg matching placebo split-dose Qualified subjects who Complete Phase A are eligible to participate in Phase B.

Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: Triple (Participant, Care Provider, Investigator)

Source: ClinicalTrials.gov