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)
Overview
- Phase
- Phase 3
- Intervention
- Tolvaptan
- Conditions
- Autosomal Dominant Polycystic Kidney Disease (ADPKD)
- Sponsor
- Otsuka Pharmaceutical Development & Commercialization, Inc.
- Enrollment
- 91
- Primary Endpoint
- Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
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.
Investigators
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.
Arms & Interventions
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.
Intervention: Tolvaptan
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.
Intervention: Tolvaptan Matching-placebo
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.
Intervention: Tolvaptan
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.
Intervention: Tolvaptan
Outcomes
Primary Outcomes
Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)
Time Frame: Baseline, and Week 1 of Phase A
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.
Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)
Time Frame: Baseline, and Week 1 of Phase A
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.
Secondary Outcomes
- Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations(At Baseline, Months 6, 12, 18, and 24 of Phase B)
- Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1(Prior to Week 1 in Phase A and B)
- Phase A: 24-hour Urine Volume(24 hours post dose after Month 1 on study medication in Phase A)
- 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 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)
- Phase A: 24-hour Creatinine Clearance(24 hours post dose after Month 1 on study medication in Phase A)
- Phase A: Change From Baseline in Creatinine Value(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)
- Phase A: 24-hour Sodium Clearance(24 hours post dose after Month 1 on study medication in Phase A)
- Phase A: 24-hour Free Water Clearance(24 hours post dose after Month 1 on study medication in Phase A)
- Phase B: Change From Baseline in Creatinine Value(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)
- Phase A and B: Percentage of Participants With Aquaretic Adverse Events (AEs)(From first dose of study drug up to 14 days post last dose (up to approximately 37 months))
- Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs)(From first dose of study drug up to 14 days post last dose (up to approximately 37 months))
- 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 A: 24-hour Fluid Intake(24 hours post dose after Month 1 on study medication in Phase A)
- Phase A: 24-hour Fluid Balance(24 hours post dose after Month 1 on study medication in Phase A)
- Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations(At Baseline, Months 6 and 12 of Phase A)
- Phase A: Change From Baseline in Growth Percentile by Gender and Age(At Baseline, Months 6 and 12 of Phase A)
- Phase B: Change From Baseline in Growth Percentile by Gender and Age(At Baseline, Months 6, 12, 18, and 24 of Phase B)
- Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Vital Signs(From first dose of study drug up to 14 days post last dose (up to approximately 37 months))