A Study to See if Tolvaptan is Safe in Infants and Children Who at Enrollment Are 28 Days to Less Than 18 Years Old With Autosomal Recessive Polycystic Kidney Disease (ARPKD)

A Phase 3b Multicenter Open-label Trial of the Safety, Tolerability, and Efficacy of Tolvaptan in Infants and Children 28 Days to Less Than 18 Years of Age With Autosomal Recessive Polycystic Kidney Disease (ARPKD)

The primary objective of this study is to evaluate the safety of tolvaptan in pediatric subjects with autosomal recessive polycystic kidney disease (ARPKD)

Study Overview

• Status: Recruiting
• Conditions: Autosomal Recessive Polycystic Kidney (ARPKD)
• Intervention / Treatment: Drug: Tolvaptan Suspension; Drug: Tolvaptan Tablets

Detailed Description

This study is a multinational, multicenter, open-label, non-randomized trial. The study consist of three periods: Screening Period, Treatment period and Follow-up period.

Tolvaptan has been demonstrated to delay the decline of kidney function in adults with rapidly progressing ADPKD (CKD stages 1 to 4), a closely related indication to ARPKD, as measured by estimated glomerular filtration rate (eGFR) and Total Kidney Volume (TKV).

Participants in this study will be assigned to tolvaptan and followed for 18 months over the course of the study.

The overall trial duration is expected to be approximately 3.5 years.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Leslyn Hermonstine; Phone Number: 240.683.3157; Email: Leslyn.Hermonstine@otsuka-us.com
• Study Contact Backup: Name: Linda Cappiello; Phone Number: +1 (609) 6084545; Email: linda.cappiello-cw@otsuka-us.com

Study Locations

• Belgium
  • Brussels Capital Region
    • Brussels, Brussels Capital Region, Belgium, 1200
      • Not yet recruiting
      • Université Catholique De Louvain And Cliniques St Luc
  • Vlaams Brabant
    • Leuven, Vlaams Brabant, Belgium, 3000
      • Not yet recruiting
      • UZ Leuven
• France
  • Bordeaux, France, 33000
    • Withdrawn
    • Centre Hospitalier Universitaire de Bordeaux (CHU) - Groupe
• Germany
  • Nordrhein-Westfalen
    • Cologne, Nordrhein-Westfalen, Germany, 50937
      • Not yet recruiting
      • University Hospital Cologne AöR
• Italy
  • Milano, Italy, 20122
    • Not yet recruiting
    • Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico - Clinica De Marchi
  • Liguria
    • Genova, Liguria, Italy, 16147
      • Not yet recruiting
      • Istituto G.Gaslini, Istituto Pediatrico di Ricovero e Cura a
• Poland
  • Bialystok, Poland, 15-274
    • Not yet recruiting
    • Uniwersytecki Dzieciecy Szpital Kliniczny im. L. Zamenhofa
• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Not yet recruiting
    • Great Ormond Street Hospital for Children NHS Trust
  • Manchester, United Kingdom, M13 9WL
    • Withdrawn
    • Central Manchester University Hospitals NHS Foundation Trust
• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • Children's National Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Not yet recruiting
      • Emory University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Not yet recruiting
      • Northwestern University Feinberg School of Medicine - Ann & Robert H. Lurie Children's Hospital of Chicago - Neonatology
  • Louisiana
    • New Orleans, Louisiana, United States, 70118
      • Completed
      • Children's Hospital - New Orleans
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Not yet recruiting
      • Mayo Clinic - Rochester
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Not yet recruiting
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Not yet recruiting
      • The Children's Hospital of Philadelphia (CHOP)
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • Children's Hospital of Pittsburgh of UPMC
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Not yet recruiting
      • Primary Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female subjects between 28 days and less than 18 years of age, with clinical features that are consistent with a diagnosis of ARPKD.
2. Ability for parent/legal guardian to provide written, informed consent prior to initiation of any trial-related procedures, and ability, in the opinion of the principal investigator, to comply with all the requirements of the trial. Ability to provide written informed assent from all subjects old enough per local laws to provide assent.

Exclusion Criteria:

1. Premature birth (≤ 32 weeks gestational age) for infants 28 days to < 12 weeks of age.
2. Anuria or RRT defined as intermittent or continuous hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration or history of kidney transplantation.
3. Evidence of syndromic conditions associated with renal cysts (other than ARPKD).
4. Abnormal liver function tests including ALT and AST, > 1.2 × ULN (upper limit of normal).
5. Has splenomegaly or portal hypertension (HTN).
6. Parents with renal cystic disease.
7. Receiving chronic diuretic that could not be adjusted after tolvaptan initiation.
8. Cannot be monitored for fluid balance.
9. Has or at risk of having sodium and potassium electrolyte imbalances, as determined by the investigator.
10. Has or at risk of having significant hypovolemia as determined by investigator.
11. Clinically significant anemia, as determined by investigator.
12. Platelets < 50000 µL.
13. Severe systolic dysfunction defined as ejection fraction < 14%.
14. Serum sodium levels < 130 mmol/L or >145 mmol/L.
15. Taking any other experimental medications.
16. Require ventilator support.
17. Taking medications known to induce CYP3A4 (CYP = Cytochrome P).
18. Having an infection including viral that would require therapy disruptive to IMP dosing.
19. Females who are breast-feeding or who have a positive pregnancy test result prior to receiving IMP.
20. Subjects with a history of substance abuse (within the last 6 months).
21. Subjects who have bladder dysfunction and/or difficulty voiding.
22. Subjects taking a vasopressin agonist (eg, desmopressin).
23. Subjects with a history of persistent noncompliance with antihypertensive or other important medical therapy.
24. Subjects taking medications or having concomitant illnesses likely to confound endpoint assessments, including taking approved (ie, marketed) therapies for the purpose of affecting PKD cysts such as tolvaptan, vasopressin antagonists, anti-sense ribonucleic acid (RNA) therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs (ie, octreotide, sandostatin).
25. Received or are scheduled to receive a liver transplant.
26. History of cholangitis within the last 6 months.
27. Has findings consistent with clinically significant portal hypertension (eg, varices, variceal bleeding, hypersplenism indicated by thrombocytopenia).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tolvaptan Suspension; Tolvaptan suspension will be administered orally or via feeding/nasogastric tube at doses of 0.15 mg/kg once daily in the AM, 0.30 mg/kg once daily in the AM, 0.5 mg/kg once daily in the AM, 0.75 mg/kg split dose (0.5 mg/kg AM and 0.25 mg/kg 8 hours later), and 1 mg/kg split dose (0.67 mg/kg AM and 0.33 mg/kg 8 hours later) based on age. Treatment duration is 18 months.	Drug: Tolvaptan Suspension; Tolvaptan suspension will be administered orally or via feeding/nasogastric tube at doses of 0.15 mg/kg once daily in the AM, 0.30 mg/kg once daily in the AM, 0.5 mg/kg once daily in the AM, 0.75 mg/kg split dose (0.5 mg/kg AM and 0.25 mg/kg 8 hours later), and 1 mg/kg split dose (0.67 mg/kg AM and 0.33 mg/kg 8 hours later) based on age.
Experimental: Tolvaptan Tablets; Tolvaptan tablets will be administered orally as split-dose regimens (15/7.5 mg, 30/15 mg, and 45/15 mg) upon awakening and 8 hours later (twice daily) based on weight if able to swallow tablets. Treatment duration is 18 months.	Drug: Tolvaptan Tablets; Tolvaptan (OPC-41061) Tolvaptan tablets will be administered orally as split-dose regimens (15/7.5 mg, 30/15 mg, and 45/15 mg) upon awakening and 8 hours later (twice daily) based on weight if able to swallow tablets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs)	Enrollment up to 7 days post last dose

Secondary Outcome Measures

Outcome Measure	Time Frame
Annual rate of change of eGFR (by Schwartz formula) from baseline to post-treatment after 18 months of treatment	From Enrollment to 18 months
Change from baseline of eGFR (by Schwartz formula) while on treatment at Months 1, 6, 12, and 18	1 month, 6 months, 12 months, and 18 months
The percentage of subjects that will receive renal replacement therapy (RRT) by 18 months.	From Enrollment to 18 months
The amount of time between enrollment and 18 months that a subject requires renal replacement therapy (RRT).	From enrollment to 18 months

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Investigators: Study Director: Olga Sergeyeva, MD, Olga.Sergeyeva@otsuka-us.com

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2022
• Primary Completion (Estimated): April 27, 2026
• Study Completion (Estimated): April 27, 2026

Study Registration Dates

• First Submitted: February 19, 2021
• First Submitted That Met QC Criteria: March 3, 2021
• First Posted (Actual): March 4, 2021

Study Record Updates

• Last Update Posted (Actual): November 1, 2023
• Last Update Submitted That Met QC Criteria: October 30, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Adolescent; Anhydramnios; Polycystic Kidney Disease; Autosomal Recessive Polycystic Kidney Disease; ARPKD; Oligohydramnios; Renal Cysts; TOLVAPTAN
• Additional Relevant MeSH Terms: Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Recessive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Tolvaptan
• Other Study ID Numbers: 156-201-00307; 2020-005992-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No