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

• ClinicalTrials.gov Identifier: NCT02964273
• Recruitment Status: Completed
• First Posted: November 16, 2016
• Results First Posted: January 3, 2023
• Last Update Posted: January 3, 2023
• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Information provided by (Responsible Party): Otsuka Pharmaceutical Development & Commercialization, Inc.

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.

Condition or disease	Intervention/treatment	Phase
Autosomal Dominant Polycystic Kidney Disease (ADPKD)	Drug: Tolvaptan; Drug: Tolvaptan Matching-placebo	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 91 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: September 23, 2016
• Actual Primary Completion Date: November 17, 2021
• Actual Study Completion Date: November 17, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: Tolvaptan; Tolvaptan spray-dried, immediate release tablets; Other Name: OPC-41061
Placebo Comparator: 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.	Drug: Tolvaptan Matching-placebo; Tolvaptan matching-placebo tablets
Experimental: 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.	Drug: Tolvaptan; Tolvaptan spray-dried, immediate release tablets; Other Name: OPC-41061
Experimental: 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.	Drug: Tolvaptan; Tolvaptan spray-dried, immediate release tablets; Other Name: OPC-41061

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.

Secondary Outcome Measures :

1. Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline, and Month 12 of Phase A ]
   htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency.
2. Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1 [ Time Frame: Prior to Week 1 in Phase A and B ]
   Participants were instructed to record all fluid taken and all urine output for the 24-hour period.
3. Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A [ Time Frame: Phase A Baseline, Months 1, 6, and 12 ]
   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.
4. Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B [ Time Frame: Phase B Baseline, Week 1, Months 1, 6, 12, 18, and 24 ]
   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.
5. Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24 [ Time Frame: Phase B Baseline, Months 12 and 24 ]
   htTKV is used in participants with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency.
6. Phase A: 24-hour Urine Volume [ Time Frame: 24 hours post dose after Month 1 on study medication in Phase A ]
   Urine volume refers to the quantity of urine produced per unit of time.
7. Phase A: 24-hour Fluid Intake [ Time Frame: 24 hours post dose after Month 1 on study medication in Phase A ]
   Daily fluid intake (total water) is defined as the amount of water consumed from foods, plain drinking water, and other beverages.
8. Phase A: 24-hour Fluid Balance [ Time Frame: 24 hours post dose after Month 1 on study medication in Phase A ]
   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.
9. Phase A: 24-hour Sodium Clearance [ Time Frame: 24 hours post dose after Month 1 on study medication in Phase A ]
   Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.
10. Phase A: 24-hour Creatinine Clearance [ Time Frame: 24 hours post dose after Month 1 on study medication in Phase A ]
    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.
11. Phase A: 24-hour Free Water Clearance [ Time Frame: 24 hours post dose after Month 1 on study medication in Phase A ]
    Data was categorized and reported based on the total daily dose for the given time point of 0-24 hours.
12. Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations [ Time Frame: At Baseline, Months 6 and 12 of Phase A ]
    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.
13. Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations [ Time Frame: At Baseline, Months 6, 12, 18, and 24 of Phase B ]
    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.
14. Phase A: Change From Baseline in Growth Percentile by Gender and Age [ Time Frame: At Baseline, Months 6 and 12 of Phase A ]
    The growth percentile was based on the assessment of height and weight.
15. Phase B: Change From Baseline in Growth Percentile by Gender and Age [ Time Frame: At Baseline, Months 6, 12, 18, and 24 of Phase B ]
    The growth percentile was based on the assessment of height and weight.
16. Phase A: Change From Baseline in Creatinine Value [ 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 ]
    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)
17. Phase B: Change From Baseline in Creatinine Value [ 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 ]
    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).
18. Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Vital Signs [ Time Frame: From first dose of study drug up to 14 days post last dose (up to approximately 37 months) ]
    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).
19. Phase A and B: Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs) [ Time Frame: From first dose of study drug up to 14 days post last dose (up to approximately 37 months) ]
    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.
20. Phase A and B: Percentage of Participants With Aquaretic Adverse Events (AEs) [ Time Frame: From first dose of study drug up to 14 days post last dose (up to approximately 37 months) ]
    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).

Eligibility Criteria

• Ages Eligible for Study: 4 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Belgium

Gent, Oost-Vlaanderen, Belgium, 9000

Leuven, Vlaams Brabant, Belgium, 3000

Brussels, Belgium, 1200

Bruxelles, Belgium, 1020

Montegnee, Belgium, 4420

Germany

Cologne, Germany, 50937

Hamburg, Germany, 20246

Hannover, Germany, 30625

Heidelberg, Germany, 69120

Leipzig, Germany, 04103

Tuebingen, Germany, 72076

Italy

Milano, Italy, 20122

Napoli, Italy, 80129

Napoli, Italy, 80131

Pavia, Italy, 27100

United Kingdom

Birmingham, United Kingdom, B4 6NH

London, United Kingdom, SE1 7EH

London, United Kingdom, WC1N 3JH

Manchester, United Kingdom, M13 9WL

Nottingham, United Kingdom, NG7 2UH

Sponsors and Collaborators

Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

• Study Director: Study Director; Otsuka Pharmaceutical Development & Commercialization, Inc.

  Study Documents (Full-Text)

Documents provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Study Protocol  [PDF] July 29, 2020

Statistical Analysis Plan  [PDF] November 30, 2021

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT02964273
• Other Study ID Numbers: 156-12-298; 2016-000187-42 ( EudraCT Number )
• First Posted: November 16, 2016
• Results First Posted: January 3, 2023
• Last Update Posted: January 3, 2023
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• 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.
• Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/
• URL: https://clinical-trials.otsuka.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Autosomal Dominant Polycystic Kidney Disease; ADPKD; Tolvaptan; Renal cysts; Chronic Kidney Disease; Genetic Kidney Disease

Additional relevant MeSH terms:

Arthrogryposis; Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Musculoskeletal Abnormalities; Congenital Abnormalities; Kidney Diseases, Cystic; Abnormalities, Multiple; Ciliopathies; Genetic Diseases, Inborn; Tolvaptan; Antidiuretic Hormone Receptor Antagonists; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Physiological Effects of Drugs