| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Euvolemic or Hypervolemic Hyponatremia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Low amount of sodium or salt in the blood |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021038 |
| E.1.2 | Term | Hyponatremia |
| E.1.2 | System Organ Class | 100000004861 |
|
| 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 |
| The primary objective is to demonstrate that tolvaptan effectively and safely increases and maintains serum sodium concentrations in children and adolescent subjects with euvolemic or hypervolemic hyponatremia. |
|
| E.2.2 | Secondary objectives of the trial |
| The key secondary objective is to assess the PK of tolvaptan and the effect on fluid balance in children and adolescent subjects with euvolemic or hypervolemic hyponatremia. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects ≥ 4 weeks (or ≥ 44 weeks adjusted gestational age) to < 18 years old.
2. Subjects hospitalized with euvolemic or hypervolemic hyponatremia resistant to initial standard background therapy (including fluid restriction and excluding a vasopressin antagonist) and who are deemed by the investigator as likely to benefit from a therapy that raises serum sodium levels.
3. Persistent euvolemic or hypervolemic hyponatremia defined as being documented as present for at least 48 hours, evidenced by at least 2 serum sodium assessments < 130 mEq/L (mmol/L) drawn at
least 12 hours apart (these values can be documented using historical values previously obtained per standard of care); a third (STAT) serum sodium assessment < 130 mEq/L (mmol/L), which will
serve as the baseline value for final trial qualification and clinical management strategy, is to be obtained within 2-4 hours prior to the first dose of tolvaptan.
4. Ability to take oral medication.
5. Ability to maintain adequate fluid intake whether orally or via IV support with adequate monitoring.
6. Ability to comply with all requirements of the trial.
7. Trial-specific written informed consent/assent obtained from a parent/legal guardian or legally acceptable representative, as applicable per age of subject or local laws, prior to the initiation of any protocolrequired procedures. In addition, the subject as required by local laws must provide informed assent at Screening and must be able to understand that he or she can withdraw from the trial at any time. All informed consent/assent procedures must be in accordance with the trial center’s IRB/IEC and local regulatory requirements.
8. 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 practice double-barrier 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. Has evidence of hypovolemia or intravascular volume depletion (eg, hypotension, clinical evidence of volume depletion, response to saline challenge); if the subject has systolic blood pressure or heart
rate outside of the normal range for that age volume status should be specifically clinically assessed to rule out volume depletion.
2. Has serum sodium < 120 mEq/L (mmol/L), with or without associated neurologic impairment (ie, symptoms such as apathy, confusion, or seizures).
3. Current use or expected use during the trial of a potent CYP3A4 inhibitor in subjects weighing < 12 kg or a moderate CYP3A4 inhibitor in subjects weighing < 6 kg.
4. Lacks free access to water (inability to respond to thirst) or without ICU-level fluid monitoring and management.
5. Has a history or current diagnosis of nephrotic syndrome.
6. Has transient hyponatremia likely to resolve (eg, head trauma or post-operative state).
7. Has hyperkalemia defined as serum potassium above the ULN for the appropriate pediatric age range.
8. Has eGFR < 30 mL/min/1.73 m2 calculated by the following equation:
eGFR (mL/min/1.73 m2) = 0.413 x height (cm)/serum creatinine (mg/dL).
9. Has AKI defined as:
• Increase in serum creatinine by ≥ 0.3 mg/dL (≥ 26.5 µmol/L) within 48 hours; or
• Increase in serum creatinine to ≥ 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or
• Urine volume < 0.5 mL/kg/h for 6 hours.
10. Has severe or acute neurological symptoms requiring other intervention (eg, hyperemesis, obtundation, seizures).
11. Has had treatment for hyponatremia with:
• Hypertonic saline (including normal saline challenge) within 8 hours of qualifying serum sodium assessments;
• Urea, lithium, demeclocycline, conivaptan, or tolvaptan within 4 days of qualifying serum sodium assessments;
• Other treatment for the purpose of increasing serum sodium concurrent with dosing of trial medication.
12. Has anuria or urinary outflow obstruction, unless the subject is, or can be, catheterized during the trial.
13. Has a history of drug or medication abuse within 3 months prior to Screening or current alcohol abuse.
14. Has a history of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives (such as benazepril).
15. Has psychogenic polydipsia (subjects with other psychiatric illness may be included per medical monitor approval).
16. Has uncontrolled diabetes mellitus, defined as fasting glucose > 300 mg/dL (16.7 mEq/L [mmol/L]).
17. Has screening liver function values > 3 x ULN.
18. Subjects who have cirrhosis and meet any of the following conditions: a major GI bleed within the past 6 months, evidence of active bleeding (eg,
epistaxis, petechiae/purpura, hematuria, or hematochezia), platelet count < 50,000/µL, or use of concomitant medications known to increase bleeding risk.
19. Has hyponatremia due to the result of any medication that can safely be withdrawn (eg, thiazide diuretics).
20. Has hyponatremia (eg, hyponatremia in the setting of adrenal insufficiency, untreated hypothyroidism, or hypotonic fluid administration) that is most appropriately corrected by alternative therapies.
21. Is currently pregnant or breastfeeding.
22. Has any medical condition that, in the opinion of the investigator, could interfere with evaluation of the trial objectives or safety of the subjects.
23. Is deemed unsuitable for trial participation in the opinion of the investigator.
24. Participation in another investigational drug trial within the past 30 days, without prior approval from the sponsor medical monitor.
25. Subjects who weigh < 3kg.
26. Unable to swallow tablets if the suspension formulation is unavailable.
27. Subjects who require the suspension formulation and have Hereditary Fructose Intolerance. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
For subjects with serum sodium level increases of ≥ 4 mEq/L (mmol/L) (ie, responders), change in serum sodium concentration from Day 2 (or 2a) at the end of Treatment Phase A to the end of Treatment Phase B for Early compared to Late Withdrawal groups. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From Day 2 (or 2a) at the end of Treatment Phase A to the end of Treatment Phase B for Early compared to Late Withdrawal groups. |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoint:
For all subjects, the key secondary endpoint is the change in serum sodium concentration at the end of Day 2 (or 2a) in Treatment Phase A from baseline. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At the end of Day 2 (or 2a) in Treatment Phase A |
|
| 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 | No |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Randomized Withdrawal Trial |
|
| 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 | 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 |
| Belgium |
| Canada |
| Czech Republic |
| Germany |
| Italy |
| Poland |
| Romania |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| 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 Post-treatment 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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 |
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