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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Otsuka Pharmaceutical Development & Commercialization Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

17 Aug 2023 → ongoing

Decision date (initial)

2024-05-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-508218-41-00

EudraCT number

2020-005992-10

ClinicalTrials.gov

NCT04782258

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the safety of tolvaptan in pediatric subjects with ARPKD

Secondary objectives 2

1. To evaluate the effect of tolvaptan on the need for RRT in pediatric subjects with ARPKD.
2. To evaluate the pharmacodynamics, safety, tolerability, and efficacy of tolvaptan in pediatric subjects with ARPKD.

Conditions and MedDRA coding

Autosomal Recessive Polycystic Kidney Disease

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001231-PIP02-13

Plan to share IPD

Yes

IPD 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. 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. Otsuka will share data supported by the protocol, statistical analysis plan (SAP) and clinical study report (CSR) on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

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 27

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.
5. Has splenomegaly or portal hypertension.
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 (eg, subjects that lack free access to water [inability to respond to thirst, depending on age], without adequate fluid monitoring and management) 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. Taking any other experimental medications.
15. Require ventilator support.
16. Taking medications known to induce CYP3A4.
17. Having an active infection including viral that would require therapy disruptive to IMP dosing.
18. Females who are breast-feeding or who have a positive pregnancy test result prior to receiving IMP.
19. Subjects with a history of substance abuse within the last 6 months (depending on age).
20. Subjects who have bladder dysfunction and/or difficulty voiding.
21. Subjects taking a vasopressin agonist (eg, desmopressin).
22. Subjects with a history of persistent noncompliance with antihypertensive or other important medical therapy.
23. Subjects having concomitant illnesses or taking medications 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).
24. 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.
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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety assessments which will be summarized by descriptive statistics, and the endpoints will be • Adverse events • Vital signs • Clinical laboratory assessments
2. Serum transaminase elevations for frequency (2 ×, 3 ×, 5 × and 10 × ULN), time to onset, time to peak levels, time of offset (< 3 ×, 2 ×, or 1 × ULN), response to de challenge and re-challenge and frequency of progression to Hy’s laboratory criteria (ALT or AST > 3 × ULN and BT, > 2 × ULN without alkaline phosphatase ≥2 × ULN) • Change from baseline in sNa+

Secondary endpoints 8

1. Annual rate of change of eGFR (eGFR Schwartz formula = 0.413 × height [or length, cm] /serum creatinine mg/dL) from baseline to post‑treatment after 18 months of treatment.
2. Change from baseline of eGFR (eGFR Schwartz formula = 0.413 × height [or length, cm] /serum creatinine mg/dL) while on treatment at Months 1, 6, 12, and 18.
3. Time to RRT
4. Percentage of subjects who receive RRT
5. Percentage of change in kidney size of height adjusted TKV at every time point from baseline to 18 months on treatment via ultrasound using ellipsoid methodology.
6. Change from baseline (last assessment prior to dosing) in growth percentile trajectories for height (stature), weight, and head circumference (for subjects ≤ 2 years or age) at 3 months, 6 months, 12 months, and 18 months.
7. Age-appropriate assessment of palatability and acceptability of suspension formulation for applicable subjects.
8. Proportions of each Tanner Staging by gender and age at baseline and every 6 months until Month 18/EoTx.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Otsuka Pharmaceutical Development & Commercialization Inc.

Sponsor organisation

Otsuka Pharmaceutical Development & Commercialization Inc.

Address

2440 Research Boulevard

City

Rockville

Postcode

20850-3238

Country

United States

Scientific contact point

Organisation

Otsuka Pharmaceutical Development & Commercialization Inc.

Contact name

EU Clinical Trials Helpdesk

Public contact point

Organisation

Otsuka Pharmaceutical Development & Commercialization Inc.

Contact name

EU Clinical Trials Helpdesk

Third parties 18

Locations

4 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 195 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications