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)

• ClinicalTrials.gov Identifier: NCT04782258
• Recruitment Status: Not yet recruiting
• First Posted: March 4, 2021
• Last Update Posted: March 4, 2021
• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Information provided by (Responsible Party): Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Autosomal Recessive Polycystic Kidney (ARPKD)	Drug: Tolvaptan Suspension; Drug: Tolvaptan Tablets	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), a closely related indication to ARPKD, as measured by estimated glomerular filtration rate (eGFR) and Total Kidney Volume (TKV).

The trial will be the first trial of tolvaptan in a pediatric ARPKD population.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Estimated Study Start Date: April 1, 2021
• Estimated Primary Completion Date: March 31, 2025
• Estimated Study Completion Date: June 1, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tolvaptan Suspension; Tolvaptan suspension will be administered orally or via 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 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.
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 based on weight if able to swallow tablets.	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 based on weight if able to swallow tablets. Treatment duration is 18 months.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Enrollment up to 7 days post last dose ]

Secondary Outcome Measures :

1. Rate of change of eGFR (by Schwartz formula) from baseline to post-treatment after 18 months of treatment [ Time Frame: From Enrollment to 18 months ]
2. The percentage of subjects that will receive renal replacement therapy (RRT) by 18 months. [ Time Frame: From Enrollment to 18 months ]
3. The amount of time between enrollment and 18 months that a subject requires renal replacement therapy (RRT). [ Time Frame: From enrollment to 18 months ]

Eligibility Criteria

• Ages Eligible for Study: up to 18 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male or female subjects from Trial 156-12-204 who have completed treatment or male or female subjects between 28 days and less than 18 years of age, who have been diagnosed with a clinical diagnosis of ARPKD.
2. Ability for parent or 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.
3. Ability to commit to remain fully abstinent or use two approved methods of birth control.

(periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] or withdrawal are not acceptable methods of contraception) during the trial and for 30 days following the last dose of IMP for sexually active females of childbearing potential.

Exclusion Criteria:

1. Premature birth (≤ 32 weeks gestational age).
2. Anuria or RRT.
3. Evidence of syndromic conditions associated with renal cysts (other than ARPKD).
4. Abnormal liver function tests including ALT and AST, > 1.2 × ULN.
5. Has splenomegaly or portal HTN.
6. Parents with renal cystic disease.
7. Need for chronic diuretic use.
8. Cannot be monitored for fluid balance.
9. Critical 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.
15. Cannot be taking any other experimental medications.
16. Require ventilator support.
17. Taking medications known to induce CYP3A4.
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 12 years of age and older having contraindications to, or interference with MRI assessments (eg, ferro-magnetic prostheses, aneurysm clips, severe claustrophobia).
23. Subjects taking a vasopressin agonist (eg, desmopressin).
24. Subjects with a history of persistent noncompliance with antihypertensive or other important medical therapy.
25. 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 RNA therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs (ie, octreotide, sandostatin).

CYP = Cytochrome P; HTN = hypertension; RNA = ribonucleic acid; ULN = upper limit of normal

Contacts and Locations

Contacts

Contact: Lindsay Getz; (919) 797-9591; Lindsay.Getz@paidion.com

Sponsors and Collaborators

Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

• Study Director: Rosa Real, MD; Rosa.Real@otsuka-us.com

More Information

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT04782258
• Other Study ID Numbers: 156-201-00307
• First Posted: March 4, 2021
• Last Update Posted: March 4, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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.:

ARPKD; TOLVAPTAN; Polycystic Kidney Disease; Autosomal Recessive Polycystic Kidney Disease; Adolescent; Renal Cysts; Oligohydramnios; Anhydramnios

Additional relevant MeSH terms:

Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Recessive; Urologic Diseases; Kidney Diseases, Cystic; Abnormalities, Multiple; Congenital Abnormalities; Ciliopathies; Genetic Diseases, Inborn; Tolvaptan; Antidiuretic Hormone Receptor Antagonists; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Physiological Effects of Drugs