E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Autosomal Recessive Polycystic Kidney Disease (ARPKD) |
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E.1.1.1 | Medical condition in easily understood language |
Genetic disorder that causes numerous cysts to grow in the kidneys. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036047 |
E.1.2 | Term | Polycystic kidney, autosomal recessive |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety of tolvaptan in pediatric subjects with ARPKD |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of tolvaptan on the need for RRT in pediatric subjects with ARPKD
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
This is optional further research performed on the remainder of the samples collected during the study to understand the genetics of ARPKD |
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E.3 | Principal inclusion criteria |
1. Male or female subjects between 28 days and less than 18 years of age, with clinical and imaging features that are consistent with a diagnosis of ARPKD with all the following characteristics: nephromegaly (> 2 standard deviations from age-appropriate standard via ultrasound); multiple renal cysts; and a history of oligohydramnios or anhydramnios in utero. 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.
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E.4 | Principal 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 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 (e.g. 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. Serum sodium levels < 130 mmol/L or >145 mmol/L (or the ULN of the local laboratory, whichever is lower) 15. Taking any other experimental medications 16. Require ventilator support 17. Taking medications known to induce CYP3A4 18. Having an active 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 (depending on age). 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 non-compliance with antihypertensive or other important medical therapy 24. 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). 25. Subjects who do not agree to remain abstinent or assent to use a combination of two 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. 26. Received or are scheduled to receive a liver transplant. 27. History of cholangitis within the last 6 months 28. Has findings consistent with clinically significant portal hypertension (eg, varices, variceal bleeding, hypersplenism indicated by thrombocytopenia). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety assessments which will be summarized by descriptive statistics, and the endpoints will be - Adverse events - Vital signs - Clinical laboratory assessments - 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 greater than or equal to 2 × ULN) - Change from baseline in sNa+ |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
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 -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 -Time to RRT -Percentage of subjects who receive RRT
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
United Kingdom |
United States |
Belgium |
Czechia |
France |
Germany |
Italy |
Poland |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The overall trial duration is considered from the time the first ICF is signed to the final subject assessment and is expected to be approximately 3.5 years. All subjects may be followed for 18 months after the first dose of IMP, regardless of continued compliance with taking IMP.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |