Phase 3
N=91
Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease)
Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Bottom Line
View on ClinicalTrials.gov: NCT02964273 ↗Enrolled (actual)
91
Serious AEs
12.8%
Results posted
Jan 2023
Primary outcome: Primary: Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose) — 635; 646; -386; -93 milliosmoles per kilogram (mOsm/kg)
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 3
- Interventions
- Tolvaptan (Drug); Tolvaptan Matching-placebo (Drug)
- Age
- Pediatric · 4+ yrs
- Sex
- All
- Sponsor
- Otsuka Pharmaceutical Development & Commercialization, Inc.
- Primary completion
- Nov 2021
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose) |
635; 646; -386; -93 | — |
| PRIMARY Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose) |
1.017; 1.017; -0.009; -0.002 | — |
| SECONDARY Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI) |
2.28; 6.11 | — |
| SECONDARY Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1 |
31; 241; 138; 207 | — |
| SECONDARY Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A |
93.9; 102.1; 2.8; -1.9; 4.6; -2.5 | — |
| SECONDARY Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B |
97.0; 98.5; -1.7; -6.7; -0.9; -4.8 | — |
| SECONDARY Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24 |
7.68; 3.09; 13.55; 7.35 | — |
| SECONDARY Phase A: 24-hour Urine Volume |
7171; 2529 | — |
| SECONDARY Phase A: 24-hour Fluid Intake |
7486; 3156 | — |
| SECONDARY Phase A: 24-hour Fluid Balance |
53; 230 | — |
| SECONDARY Phase A: 24-hour Sodium Clearance |
0.8; 0.7; 0.9; 0.7 | — |
| SECONDARY Phase A: 24-hour Creatinine Clearance |
124.6; 148.5; 95.0; 123.7; 105.1 | — |
| SECONDARY Phase A: 24-hour Free Water Clearance |
2.3; 2.6; 3.0; 0.1 | — |
| SECONDARY Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations |
6.3; 11.6; 0.0; 2.3; 6.3; 9.3 | — |
| SECONDARY Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations |
7.1; 10.3; 0.0; 2.6; 0.0; 2.6 | — |
| SECONDARY Phase A: Change From Baseline in Growth Percentile by Gender and Age |
62; 60; 2; -2; 7; -5 | — |
| SECONDARY Phase B: Change From Baseline in Growth Percentile by Gender and Age |
69; 46; -7; 12; 0; 20 | — |
| SECONDARY Phase A: Change From Baseline in Creatinine Value |
0.70; 0.67; 0.04; -0.01; 0.01; 0.01 | — |
| SECONDARY Phase B: Change From Baseline in Creatinine Value |
0.73; 0.69; 0.01; 0.04; 0.01; 0.04 | — |
| SECONDARY Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Vital Signs |
0.0; 2.3; 0.0; 5.3; 2.1; 0.0 | — |
| SECONDARY Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs) |
8.3; 0.0; 7.1; 7.7; 0.0; 2.6 | — |
| SECONDARY Phase A and B: Percentage of Participants With Aquaretic Adverse Events (AEs) |
64.6; 16.3; 14.3; 48.7 | — |
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.
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.
Data sourced from ClinicalTrials.gov (NCT02964273). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.