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)

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 24 months over the course of the study.

The overall trial duration is expected to be approximately 5 years.

• Tolvaptan Suspension (Drug): Syrup
• Tolvaptan Tablets (Drug): 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.

Primary outcomes

• Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) [From baseline to post-treatment after 24 months or EoTx]: Number of participants with TEAEs will be assessed from Baseline to post-treatment after 24 months or End of Treatment (EOTx). The EOTx visit applies to participants who discontinue IMP before Month 24. TEAEs are defined as Adverse Events (AEs) with an onset date on or after the start of Investigational Medicinal Product (IMP) treatment. TEAEs are also events continuous from baseline which worsened, became serious, were IMP related, or resulted in death, discontinuation, interruption, or reduction of IMP. An AE is defined as any untoward medical occurrence in a clinical trial subject administered an IMP and which does not necessarily have a causal relationship with this treatment.

Secondary outcomes

• Annual rate of change of eGFR (by Schwartz formula) from baseline to post-treatment after 24 months [From Baseline to post-treatment after Month 24 or EOTx]: Annual rate of change of eGFR from Baseline to post-treatment after Month 24 or EOTx is calculated using eGFR Schwartz formula = 0.413 × height \[or length, centimeter (cm)\] /serum creatinine milligram per deciliter (mg/dL). The EOTx visit applies to participants who discontinue IMP before Month 24.
• Change from baseline of eGFR (by Schwartz formula) while on treatment at Months 1, 6, 12, 18 and 24 or EOTx [At Months 1, 6, 12, 18, and 24 or EOTx]: Change from baseline of eGFR is calculated using eGFR Schwartz formula = 0.413 × height \[or length, cm\] /serum creatinine mg/dL) while on treatment at Months 1, 6, 12, 18, and 24 or EoTx. The EOTx visit applies to participants who discontinue IMP before Month 24.
• The amount of time between enrollment and 24 months that a subject requires renal replacement therapy (RRT). [From enrollment to 24 months]: To evaluate the effect of tolvaptan on the need for RRT in pediatric participants with ARPKD.
• The percentage of subjects that will receive renal replacement therapy (RRT) by 24 months [From Baseline to Month 24]: Percentage of subjects who receive RRT from baseline through Month 24. RRT is defined as intermittent or continuous hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration or kidney transplantation.

Sex: All, ages: 28 Days to 18 Years

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 (Investigational Medicinal Product) 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).
28. Subjects who do not agree to remain abstinent or assent to use a combination of 2 of the following highly effective birth control methods for at least 28 days before the first dose of IMP, during the trial (including during IMP dose interruptions), and for at least 30 days after the last dose of IMP:

    * Barrier method of contraception: condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide
    * Intrauterine device
    * Hormone-based contraceptives which are associated with inhibition of ovulation.