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

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ClinicalTrials.gov Identifier: NCT02964273
Recruitment Status : Active, not recruiting
First Posted : November 16, 2016
Last Update Posted : February 25, 2021
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

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: Phase A Tolvaptan Drug: Placebo Phase A Drug: Phase B Tolvaptan Phase 3

Detailed Description:

Tolvaptan has been demonstrated to delay the decline of kidney function in adults with rapidly progressing ADPKD (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.

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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)
Study Start Date : September 2016
Actual Primary Completion Date : December 2, 2019
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
Active Comparator: Phase A Tolvaptan
Participants will be randomized to receive active tolvaptan for 12 months. Study medication will be administered orally as a split dose, with the first dose taken upon awakening and the second dose taken approximately 8 hours later. The starting dose is based on weight.
Drug: Phase A Tolvaptan
Tolvaptan 7.5, 15, and 30 mg spray-dried, immediate release tablets Frequency: Twice daily.
Other Name: JINARC®

Placebo Comparator: Phase A Placebo
Participants receive matching-placebo spray dried, immediate release tablets orally as a split-dose, with first dose taken upon awakening and second dose taken approximately 8 hours later.
Drug: Placebo Phase A
Frequency: Twice daily.

Active Comparator: Phase B Tolvaptan
Participants will receive open-label tolvaptan for 24 months. Study medication will be administered orally as a split dose, with the first dose taken upon awakening and the second dose taken approximately 8 hours later. The starting dose is weight based.
Drug: Phase B Tolvaptan
Tolvaptan 7.5, 15, and 30 mg spray-dried, immediate release tablets Frequency: Twice daily.
Other Name: JINARC®




Primary Outcome Measures :
  1. Change from baseline in spot urine osmolality (pre-morning dose) [ Time Frame: After 1 week of daily dosing during Phase A ]
  2. Change from baseline in specific gravity (pre-morning dose) [ Time Frame: After 1 week of daily dosing during Phase A ]

Secondary Outcome Measures :
  1. Percent change from Phase A baseline in height-adjusted total kidney volume (htTKV) as measured by MRI [ Time Frame: at 12 months ]
  2. 24-hour urine volume in mL [ Time Frame: After at least 1 month on study medication during Phase A ]
  3. 24-hour fluid intake in mL [ Time Frame: After at least 1 month on study medication during Phase A ]
  4. 24-hour fluid balance in mL [ Time Frame: After at least 1 month on study medication during Phase A ]
  5. 24-hour fluid balance in mL [ Time Frame: At Week 1 during Phase A and Phase B ]
  6. Change from baseline in renal function (eGFR by Schwartz formula) at each visit in Phase A [ Time Frame: At Week 1, Month 1, Month 6, Month 12 ]
  7. Change from Phase B baseline in renal function (eGFR by Schwartz formula) [ Time Frame: At Week 1, Months 1, 6, 12, 18, 24 ]
  8. Percent change from Phase B baseline in htTKV as measured by MRI [ Time Frame: at 12 months ]
  9. Percent change from Phase B baseline in htTKV as measured by MRI [ Time Frame: at 24 months ]
  10. Proportions of each Tanner Stage by gender compared to normative populations [ Time Frame: At baseline, 6 and 12 months during the placebo-controlled phase (Phase A) and every 6 months (up to 26, 52, 78 and 104 weeks) during the open-label extension (Phase B) ]
  11. Proportions of each Tanner Stage by age compared to normative populations [ Time Frame: At baseline, 6 and 12 months during the placebo-controlled phase (Phase A) and every 6 months (up to 26, 52, 78 and 104 weeks) during the open-label extension (Phase B) ]
  12. Description of changes from baseline for height in cm by gender and age [ Time Frame: at baseline, 6 and 12 months during the placebo-controlled phase (Phase A) and every 6 months (up to 26, 52, 78 and 104 weeks) during the open-label extension (Phase B) ]
  13. Description of changes from baseline for weight in kilograms by gender and age [ Time Frame: at baseline, 6 and 12 months during the placebo-controlled phase (Phase A) and every 6 months (up to 26, 52, 78 and 104 weeks) during the open-label extension (Phase B) ]
  14. Changes from baseline in creatinine [ Time Frame: up thru 14 days post last dose in Phase A or B, whichever completion is latter. ]
  15. Changes from baseline in vital signs [ Time Frame: up thru 14 days post last dose in Phase A or B, whichever completion is latter. ]
  16. Changes from baseline in liver function tests (LFTs) [ Time Frame: up thru 14 days post last dose in Phase A or B, whichever completion is latter. ]
  17. Changes from baseline in rate of aquaretic AEs in placebo and tolvaptan [ Time Frame: up thru 14 days post last dose in Phase A or B, whichever completion is latter. ]
  18. Pharmacodynamic (PD) endpoints of sodium, creatinine and free water clearances in mL/min [ Time Frame: After at least 1 month on study medication in Phase A ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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/1.73m2 within 31 days prior to randomization (using the Schwartz formula, eGFR = 0.413 × height [cm]/serum creatinine 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 (eg, glycosylated hemoglobin > 7.5, and/or glycosuria by dipstick, significant proteinuria, retinopathy), evidence of additional significant renal disease(s) (ie, 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 (eg, 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 (ie, 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 (ie, octreotide, sandostatin).
  • Participants who have had cyst reduction surgery within 6 weeks of the screening visit.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02964273


Locations
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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
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Study Director: Rosa Real, MD Otsuka Pharmaceutical Development & Commercialization, Inc.
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Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT02964273    
Other Study ID Numbers: 156-12-298
First Posted: November 16, 2016    Key Record Dates
Last Update Posted: February 25, 2021
Last Verified: January 2021
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 an Otsuka-owned remotely accessible data sharing platform with Python and R analytical software. Research requests should be directed to clinicaltransparency@Otsuka-us.com
URL: https://clinical-trials.otsuka.com
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:
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Arthrogryposis
Kidney Diseases
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant
Urologic 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