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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Intervention / Treatment
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* Drug: Tolvaptan
* Drug: Tolvaptan Matching-placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase A: Tolvaptan<br>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<br>* Tolvaptan spray-dried, immediate release tablets<br>* Other names: OPC-41061;|
| Placebo Comparator: Phase A: Placebo<br>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<br>* Tolvaptan matching-placebo tablets<br>|
| Experimental: Phase B: Prior Tolvaptan<br>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<br>* Tolvaptan spray-dried, immediate release tablets<br>* Other names: OPC-41061;|
| Experimental: Phase B: Prior Placebo<br>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<br>* Tolvaptan spray-dried, immediate release tablets<br>* Other names: OPC-41061;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, and Month 12 of Phase A | 
| 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. | 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 | 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 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 | 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 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 | htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency. | Phase B Baseline, Months 12 and 24 | 
| Phase A: 24-hour Urine Volume | Urine volume refers to the quantity of urine produced per unit of time. | 24 hours post dose after Month 1 on study medication in Phase A | 
| 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. | 24 hours post dose after Month 1 on study medication in Phase A | 
| 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. | 24 hours post dose after Month 1 on study medication in Phase A | 
| 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. | 24 hours post dose after Month 1 on study medication in Phase A | 
| 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. | 24 hours post dose after Month 1 on study medication in Phase A | 
| 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. | 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 | 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. | At Baseline, Months 6 and 12 of Phase A | 
| 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. | At Baseline, Months 6, 12, 18, and 24 of Phase B | 
| Phase A: Change From Baseline in Growth Percentile by Gender and Age | The growth percentile was based on the assessment of height and weight. | At Baseline, Months 6 and 12 of Phase A | 
| Phase B: Change From Baseline in Growth Percentile by Gender and Age | The growth percentile was based on the assessment of height and weight. | At Baseline, Months 6, 12, 18, and 24 of Phase B | 
| 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) | 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 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). | 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 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). | 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) | 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. | 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 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). | From first dose of study drug up to 14 days post last dose (up to approximately 37 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADPKD, Autosomal Dominant Polycystic Kidney Disease, Tolvaptan, Renal cysts, Chronic Kidney Disease, Genetic Kidney Disease