Back to resultsSafety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease)
Primary Purpose
Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Tolvaptan
Tolvaptan Matching-placebo
Sponsored by
About this trial
This is an interventional treatment trial for Autosomal Dominant Polycystic Kidney Disease (ADPKD) focused on measuring Autosomal Dominant Polycystic Kidney Disease, ADPKD, Tolvaptan, Renal cysts, Chronic Kidney Disease, Genetic Kidney Disease
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.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Placebo Comparator
Experimental
Experimental
Arm Label
Phase A: Tolvaptan
Phase A: Placebo
Phase B: Prior Tolvaptan
Phase B: Prior Placebo
Arm Description
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.
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.
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.
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.
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI)
htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency.
Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1
Participants were instructed to record all fluid taken and all urine output for the 24-hour period.
Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A
Renal function was assessed by estimated eGFR calculated by the Schwartz formula (eGFR = 0.413 × height [cm] /serum creatinine mg/dL), expressed as mean change in eGFR at the specified time points. The units for the data reported are milliliter per minute per 1.73 meter square (mL/min/1.73 m^2). The baseline was the evaluation done at Week 1 in Phase A for this outcome measure.
Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B
Renal function was assessed by estimated eGFR calculated by the Schwartz formula (eGFR = 0.413 × height [cm] /serum creatinine mg/dL), expressed as mean change in eGFR at the specified time points.
Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24
htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency.
Phase A: 24-hour Urine Volume
Urine volume refers to the quantity of urine produced per unit of time.
Phase A: 24-hour Fluid Intake
Daily fluid intake (total water) is defined as the amount of water consumed from foods, plain drinking water, and other beverages.
Phase A: 24-hour Fluid Balance
Fluid balance is a term used to describe the balance of the input and output of fluids in the body to allow metabolic processes to function correctly.
Phase A: 24-hour Sodium Clearance
Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.
Phase A: 24-hour Creatinine Clearance
Creatinine is produced from the metabolism of protein, when muscles burn energy. Most creatinine is filtered out of the blood by the kidneys and excreted in urine. The creatinine clearance value is determined by measuring the concentration of endogenous creatinine (that which is produced by the body) in both plasma and urine. Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.
Phase A: 24-hour Free Water Clearance
Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.
Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations
Tanner stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Only those categories with at least one participant with event are reported.
Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations
Tanner stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Only those categories with at least one participant with event are reported.
Phase A: Change From Baseline in Growth Percentile by Gender and Age
The growth percentile was based on the assessment of height and weight.
Phase B: Change From Baseline in Growth Percentile by Gender and Age
The growth percentile was based on the assessment of height and weight.
Phase A: Change From Baseline in Creatinine Value
Phase A Baseline is the last pre-dose evaluation. The Last Visit is the last available post-baseline evaluation including early term. As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan and Phase A: Placebo)
Phase B: Change From Baseline in Creatinine Value
Phase B Baseline is the last evaluation prior to the first dose in Phase B. The Last Visit is the last available post-baseline evaluation including early term. As prespecified in the protocol, data for safety is reported by the treatment group (Phase B: Prior Tolvaptan and Phase B: Prior Placebo).
Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Vital Signs
Vital sign measurements included measurements of respiratory rate, blood pressure, body temperature and pulse. Any value outside the normal range was flagged for the attention of the investigator who assessed whether or not a flagged value is of clinical significance. Only those categories with at least one participant with event are reported. As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan, Phase A: Placebo, Phase B: Prior Tolvaptan and Phase B: Prior Placebo).
Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs)
Laboratory parameters=haematology,chemistry,urinalysis,& LFTs.Criteria for laboratory abnormalities along with their test result grade=Increased creatinine level: Baseline(BSL):Grade 0,>BSL-1.5xBSL:1,>1.5-3xBSL:2,>3-6xBSL:3,>6xBSL:4.Decreased glucose level: <30:-4,30-<40:-3, 40-<55:-2, 55-<65:-1,>=65:0; Increased:<=115:0,>115-160:1,>160-250:2,>250-500:3,>500:4.Decreased potassium level: <2.5:-4,2.5-<3:-3,3-<lower limit of normal(LLN):-1,LLN:0; Increased:upper limit of normal(ULN):0,>ULN-5.5:1,>5.5-6:2,>6-7:3,>7:4.Decreased sodium level: <120:-4,120-124:-3,125-129:-2,130-135:-1,>=136:0; Increased:<=145:0,146-150:1,151-155:2,156-160:3,>160:4. Increased triglyceride level:ULN:0,>ULN-2.5xULN:1,>2.5-5xULN:2,>5-6xULN:3,>6xULN:4. Decreased Neutrophils:<0.5:-4,0.5-<1:-3,1-<1.5:-2,1.5-<LLN:-1,LLN:0. Potentially clinically significant increase or decrease was defined as Baseline grade 0,1,-1 and post-baseline grade >1, <-1 or Baseline grade >1,<-1 and post-baseline grade >or<Baseline grade.
Phase A and B: Percentage of Participants With Aquaretic Adverse Events (AEs)
An AE was defined as any untoward medical occurrence in a participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Aquaretic AEs included Medical Dictionary for Regulatory Activities [MedDRA] preferred terms of thirst, polyuria (production of large volumes of dilute urine), nocturia (need to wake up to urinate at night), pollakiuria (abnormally frequent urination), and polydipsia (excessive thirst). As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan, Phase A: Placebo, Phase B: Prior Tolvaptan and Phase B: Prior Placebo).
Full Information
NCT ID
NCT02964273
First Posted
September 15, 2016
Last Updated
December 7, 2022
Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT02964273
Brief Title
Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease)
Official Title
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)
Study Type
Interventional
2. Study Status
Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
September 23, 2016 (Actual)
Primary Completion Date
November 17, 2021 (Actual)
Study Completion Date
November 17, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Keywords
Autosomal Dominant Polycystic Kidney Disease, ADPKD, Tolvaptan, Renal cysts, Chronic Kidney Disease, Genetic Kidney Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
91 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Phase A: Tolvaptan
Arm Type
Experimental
Arm Description
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.
Arm Title
Phase A: Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Phase B: Prior Tolvaptan
Arm Type
Experimental
Arm Description
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.
Arm Title
Phase B: Prior Placebo
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
Tolvaptan
Other Intervention Name(s)
OPC-41061
Intervention Description
Tolvaptan spray-dried, immediate release tablets
Intervention Type
Drug
Intervention Name(s)
Tolvaptan Matching-placebo
Intervention Description
Tolvaptan matching-placebo tablets
Primary Outcome Measure Information:
Title
Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)
Description
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.
Time Frame
Baseline, and Week 1 of Phase A
Title
Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)
Description
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.
Time Frame
Baseline, and Week 1 of Phase A
Secondary Outcome Measure Information:
Title
Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI)
Description
htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency.
Time Frame
Baseline, and Month 12 of Phase A
Title
Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1
Description
Participants were instructed to record all fluid taken and all urine output for the 24-hour period.
Time Frame
Prior to Week 1 in Phase A and B
Title
Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A
Description
Renal function was assessed by estimated eGFR calculated by the Schwartz formula (eGFR = 0.413 × height [cm] /serum creatinine mg/dL), expressed as mean change in eGFR at the specified time points. The units for the data reported are milliliter per minute per 1.73 meter square (mL/min/1.73 m^2). The baseline was the evaluation done at Week 1 in Phase A for this outcome measure.
Time Frame
Phase A Baseline, Months 1, 6, and 12
Title
Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B
Description
Renal function was assessed by estimated eGFR calculated by the Schwartz formula (eGFR = 0.413 × height [cm] /serum creatinine mg/dL), expressed as mean change in eGFR at the specified time points.
Time Frame
Phase B Baseline, Week 1, Months 1, 6, 12, 18, and 24
Title
Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24
Description
htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency.
Time Frame
Phase B Baseline, Months 12 and 24
Title
Phase A: 24-hour Urine Volume
Description
Urine volume refers to the quantity of urine produced per unit of time.
Time Frame
24 hours post dose after Month 1 on study medication in Phase A
Title
Phase A: 24-hour Fluid Intake
Description
Daily fluid intake (total water) is defined as the amount of water consumed from foods, plain drinking water, and other beverages.
Time Frame
24 hours post dose after Month 1 on study medication in Phase A
Title
Phase A: 24-hour Fluid Balance
Description
Fluid balance is a term used to describe the balance of the input and output of fluids in the body to allow metabolic processes to function correctly.
Time Frame
24 hours post dose after Month 1 on study medication in Phase A
Title
Phase A: 24-hour Sodium Clearance
Description
Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.
Time Frame
24 hours post dose after Month 1 on study medication in Phase A
Title
Phase A: 24-hour Creatinine Clearance
Description
Creatinine is produced from the metabolism of protein, when muscles burn energy. Most creatinine is filtered out of the blood by the kidneys and excreted in urine. The creatinine clearance value is determined by measuring the concentration of endogenous creatinine (that which is produced by the body) in both plasma and urine. Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.
Time Frame
24 hours post dose after Month 1 on study medication in Phase A
Title
Phase A: 24-hour Free Water Clearance
Description
Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.
Time Frame
24 hours post dose after Month 1 on study medication in Phase A
Title
Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations
Description
Tanner stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Only those categories with at least one participant with event are reported.
Time Frame
At Baseline, Months 6 and 12 of Phase A
Title
Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations
Description
Tanner stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Only those categories with at least one participant with event are reported.
Time Frame
At Baseline, Months 6, 12, 18, and 24 of Phase B
Title
Phase A: Change From Baseline in Growth Percentile by Gender and Age
Description
The growth percentile was based on the assessment of height and weight.
Time Frame
At Baseline, Months 6 and 12 of Phase A
Title
Phase B: Change From Baseline in Growth Percentile by Gender and Age
Description
The growth percentile was based on the assessment of height and weight.
Time Frame
At Baseline, Months 6, 12, 18, and 24 of Phase B
Title
Phase A: Change From Baseline in Creatinine Value
Description
Phase A Baseline is the last pre-dose evaluation. The Last Visit is the last available post-baseline evaluation including early term. As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan and Phase A: Placebo)
Time Frame
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
Title
Phase B: Change From Baseline in Creatinine Value
Description
Phase B Baseline is the last evaluation prior to the first dose in Phase B. The Last Visit is the last available post-baseline evaluation including early term. As prespecified in the protocol, data for safety is reported by the treatment group (Phase B: Prior Tolvaptan and Phase B: Prior Placebo).
Time Frame
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
Title
Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Vital Signs
Description
Vital sign measurements included measurements of respiratory rate, blood pressure, body temperature and pulse. Any value outside the normal range was flagged for the attention of the investigator who assessed whether or not a flagged value is of clinical significance. Only those categories with at least one participant with event are reported. As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan, Phase A: Placebo, Phase B: Prior Tolvaptan and Phase B: Prior Placebo).
Time Frame
From first dose of study drug up to 14 days post last dose (up to approximately 37 months)
Title
Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs)
Description
Laboratory parameters=haematology,chemistry,urinalysis,& LFTs.Criteria for laboratory abnormalities along with their test result grade=Increased creatinine level: Baseline(BSL):Grade 0,>BSL-1.5xBSL:1,>1.5-3xBSL:2,>3-6xBSL:3,>6xBSL:4.Decreased glucose level: <30:-4,30-<40:-3, 40-<55:-2, 55-<65:-1,>=65:0; Increased:<=115:0,>115-160:1,>160-250:2,>250-500:3,>500:4.Decreased potassium level: <2.5:-4,2.5-<3:-3,3-<lower limit of normal(LLN):-1,LLN:0; Increased:upper limit of normal(ULN):0,>ULN-5.5:1,>5.5-6:2,>6-7:3,>7:4.Decreased sodium level: <120:-4,120-124:-3,125-129:-2,130-135:-1,>=136:0; Increased:<=145:0,146-150:1,151-155:2,156-160:3,>160:4. Increased triglyceride level:ULN:0,>ULN-2.5xULN:1,>2.5-5xULN:2,>5-6xULN:3,>6xULN:4. Decreased Neutrophils:<0.5:-4,0.5-<1:-3,1-<1.5:-2,1.5-<LLN:-1,LLN:0. Potentially clinically significant increase or decrease was defined as Baseline grade 0,1,-1 and post-baseline grade >1, <-1 or Baseline grade >1,<-1 and post-baseline grade >or<Baseline grade.
Time Frame
From first dose of study drug up to 14 days post last dose (up to approximately 37 months)
Title
Phase A and B: Percentage of Participants With Aquaretic Adverse Events (AEs)
Description
An AE was defined as any untoward medical occurrence in a participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Aquaretic AEs included Medical Dictionary for Regulatory Activities [MedDRA] preferred terms of thirst, polyuria (production of large volumes of dilute urine), nocturia (need to wake up to urinate at night), pollakiuria (abnormally frequent urination), and polydipsia (excessive thirst). As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan, Phase A: Placebo, Phase B: Prior Tolvaptan and Phase B: Prior Placebo).
Time Frame
From first dose of study drug up to 14 days post last dose (up to approximately 37 months)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Otsuka Pharmaceutical Development & Commercialization, Inc.
Official's Role
Study Director
Facility Information:
City
Gent
State/Province
Oost-Vlaanderen
ZIP/Postal Code
9000
Country
Belgium
City
Leuven
State/Province
Vlaams Brabant
ZIP/Postal Code
3000
Country
Belgium
City
Brussels
ZIP/Postal Code
1200
Country
Belgium
City
Bruxelles
ZIP/Postal Code
1020
Country
Belgium
City
Montegnee
ZIP/Postal Code
4420
Country
Belgium
City
Cologne
ZIP/Postal Code
50937
Country
Germany
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
City
Hannover
ZIP/Postal Code
30625
Country
Germany
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
City
Tuebingen
ZIP/Postal Code
72076
Country
Germany
City
Milano
ZIP/Postal Code
20122
Country
Italy
City
Napoli
ZIP/Postal Code
80129
Country
Italy
City
Napoli
ZIP/Postal Code
80131
Country
Italy
City
Pavia
ZIP/Postal Code
27100
Country
Italy
City
Birmingham
ZIP/Postal Code
B4 6NH
Country
United Kingdom
City
London
ZIP/Postal Code
SE1 7EH
Country
United Kingdom
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom
City
Nottingham
ZIP/Postal Code
NG7 2UH
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
IPD Sharing 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.
IPD Sharing Access Criteria
Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/
IPD Sharing URL
https://clinical-trials.otsuka.com
Citations:
PubMed Identifier
34604341
Citation
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.
Results Reference
derived
Learn more about this trial
Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents With ADPKD (Autosomal Dominant Polycystic Kidney Disease)
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