| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Autosomal Dominant Polycystic Kidney Disease (ADPKD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Genetic disorder that causes numerous cysts to grow in the kidneys. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| 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 | 10036046 |
| E.1.2 | Term | Polycystic kidney, autosomal dominant |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the long term safety of treatment with tolvaptan in a pediatric and adolescent ADPKD population. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the pharmacodynamics (PD), pharmacokinetics (PK), and efficacy of tolvaptan in children and adolescent subjects with ADPKD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects aged 4 to 17 years (inclusive) with a diagnosis of ADPKD as defined by the presence of family history and/or genetic criteria AND who have at least 10 renal cysts, each of which measure at least 0.5 cm, confirmed upon MRI inspection; subjects under the age of 12 years must have at least 4 cysts that are at least 1 cm in size, confirmed by ultrasound.
2. Weight ≥ 20 kg.
3. Subjects with eGFR ≥ 60 mL/min/1.73m2 within 31 days prior to randomization (using the Schwartz formula, eGFR = 0.413 × height [cm] /serum creatinine mg/dL).
4. Independent in toileting.
5. Trial-specific written informed consent obtained from a parent/guardian or legally acceptable representative, as applicable for local laws, at screening, prior to the initiation of any protocol required procedures. In addition, the subject must provide age-appropriate informed assent at screening and must be able to understand that he or she can withdraw from the trial at any time.
6. Ability to swallow a tablet [Must also meet Health Authority/Ethics Committee age restrictions on tablet use (if applicable)].
7. Ability to commit to remain fully abstinent (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] or withdrawal are not acceptable methods of contraception) or use two approved methods of birth control during the trial and for 30 days following the last dose of IMP for sexually active females of childbearing potential. |
|
| E.4 | Principal exclusion criteria |
1. Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving IMP.
2. Liver function tests including AST, ALT ≥ 1.5 × ULN.
3. Nocturnal enuresis.
4. Need for chronic diuretic use.
5. Subjects with advanced diabetes (eg, glycosylated hemoglobin [HgbA1c] > 7.5, and/or glycosuria by dipstick, significant proteinuria, retinopathy), evidence of additional significant renal disease(s) (ie, currently active glomerular nephritides), renal cancer, single kidney, or recent (within 6 months of screening) renal surgery or acute kidney injury.
6. Subjects who have known clinically significant allergic reactions to chemicals with structure similar to tolvaptan (ie benzazepines): benzazepril, conivaptan, fenoldopam mesylate or mirtazapine.
7. Subjects having disorders in thirst recognition or inability to access fluids.
8. Subjects who have bladder dysfunction and/or difficulty voiding.
9. Subjects with critical electrolyte imbalances, as determined by the investigator.
10. Subjects with or at risk of significant hypovolemia, as determined by investigator.
11. Subjects with a history of substance abuse (within the last 6 months).
12. Subjects 12 years of age and older having contraindications to, or interference with MRI assessments (eg, ferro-magnetic prostheses, aneurysm clips, severe claustrophobia).
13. Subjects taking a vasopressin agonist (eg, desmopressin).
14. Subjects with a history of persistent noncompliance with antihypertensive or other important medical therapy.
15. 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).
16. Has any medical condition that, in the opinion of the investigator, could interfere with evaluation of the trial objectives or safety of the subjects.
17. Is deemed unsuitable for trial participation in the opinion of the investigator.
18. Subjects who received any investigational agent in a clinical trial within 30 days prior to screening.
19. Subjects who have a known lactose intolerance
20. Subjects who have had cyst reduction surgery within 6 weeks of the screening visit |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The co-primary endpoints are the change from baseline in spot urine osmolality (premorning dose) and specific gravity (premorning dose) after 1 week of daily dosing in Phase A. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After 1 week of daily dosing in Phase A. |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoint is the percent change from Phase A baseline in height-adjusted (htTKV) as measured by MRI at 12 months.
Other secondary endpoints:
- 24-hour fluid balance prior to Week 1.
- Change from baseline in renal function (eGFR by Schwartz formula) at each clinic visit (Week 1, Month 1, Month 6, and Month 12 in Phase A).
- Change from baseline in renal function (eGFR by Schwartz formula) at each clinic visit (Week 1, Month 1, Month 6, Month 12, Month18, and Month 24 in Phase B).
- Percent change in htTKV as measured by MRI from Phase B baseline to Phase B Month 12.
- Percent change in htTKV as measured by MRI from Phase B baseline to Phase B Month 24.
- Pharmacodynamic (PD) endpoints of urine volume (including 24-hour fluid volume), fluid intake and fluid balance, sodium, creatinine, and free water clearance during dense PK sampling (after at least 1 Month on IMP).
- Proportions of each Tanner Stage by gender and age compared to normative populations at baseline, 6 months, and 12 months during the placebo-controlled phase (Phase A), and every 6 months during the open-label extension phase (Phase B).
- Description of changes from baseline percentiles for height and weight by gender and age at baseline, 6 months, and 12 months during the placebo-controlled phase (Phase A), and every 6 months during the open-label extension phase (Phase B).
- Safety variables (changes from baseline in creatinine, vital signs, laboratory values including liver function tests [LFTs], rate of aquaretic AEs) in placebo and tolvaptan. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At the end of Phase A (at 12 months) and at various timepoints during phase B. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase A - double-blind (12 months), Phase B - open label (following 24 months) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.3.1 | Comparator description |
| Placebo will be used only in Phase A (first 12 months) |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| The end of trial date is defined as the last date of contact or the date of final contact attempt from the posttreatment follow-up eCRF page for the last subject completing or withdrawing from the trial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 45 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 45 |
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