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

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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)

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 (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 Phase

Phase 3

Study Type

Interventional


Primary Outcome

Change from baseline in spot urine osmolality (pre-morning dose)

Secondary Outcome

 Percent change from Phase A baseline in height-adjusted total kidney volume (htTKV) as measured by MRI

Condition

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Intervention

Phase A Tolvaptan

Study Arms / Comparison Groups

 Phase A Tolvaptan
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

91

Start Date

September 2016

Completion Date

December 2021

Primary Completion Date

December 2, 2019

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/1.73m2
             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.
      

Gender

All

Ages

4 Years - 17 Years

Accepts Healthy Volunteers

No

Contacts

Rosa Real, MD, , 

Location Countries

Belgium

Location Countries

Belgium

Administrative Informations


NCT ID

NCT02964273

Organization ID

156-12-298


Responsible Party

Sponsor

Study Sponsor

Otsuka Pharmaceutical Development & Commercialization, Inc.


Study Sponsor

Rosa Real, MD, Study Director, Otsuka Pharmaceutical Development & Commercialization, Inc.


Verification Date

January 2021