| 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 | 18.0 |
| 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 |
For all subjects: To evaluate the post-treatment safety follow-up of children and adolescent subjects with dilutional (euvolemic or hypervolemic) hyponatremia who have previously participated in a trial of titrated oral investigational medicinal product (IMP [tolvaptan in Trial 156-08-276, tolvaptan or placebo in Trials 156-13-207 and 156-12-205]).
For subjects who receive tolvaptan: To demonstrate that tolvaptan safely and effectively achieves and maintains increased serum sodium concentrations in children and adolescent subjects with dilutional (euvolemic or hypervolemic) hyponatremia when used for both multiple short-term treatments and/or longer chronic treatments. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria for the core safety follow up component:
1. Enrollment in one of the previous tolvaptan pediatric trials for hyponatremia (ie, Trial 156-08-276, 156-13-207, or 156-12-205)
2. Trial-specific written informed consent/assent obtained from a parent/guardian or legally acceptable representative, as applicable for local laws, prior to the initiation of any protocol-required procedures. In addition, the subject must provide informed assent at baseline 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.
3. Ability to comply with all requirements of the trial
4. Willingness to be clinically followed for 6 months
Eligibility criteria for optional treatment component:
1. Male or female subjects ≥ 4 weeks (or ≥ 44 weeks adjusted gestational age to < 18 years old.
2. The subject must have been off treatment with the investigational medicinal product (IMP) for 7 days following the end of treatment in the previous trial of titrated oral IMP (tolvaptan in Trial 156-08-276, tolvaptan or placebo in Trials 156-13-207 and 156-12-205) to assess the subject's clinical need for dosing.
3. Persistent dilutional (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/ (mmol/L), which will serve as the baseline value for efficacy endpoints, is to be obtained within 2 to 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/guardian or legally acceptable representative, as applicable per age of subject or local laws, prior to the initiation of any protocol required procedures. In addition, the subject as required by local laws must provide informed assent at the pretreatment baseline for this trial 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 abstinent or practice double-barrier birth control during the trial and for 14 days following the last dose of tolvaptan for sexually active females of childbearing potential.
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|
| E.4 | Principal exclusion criteria |
Safety follow-up component of this trial: There are no exclusion criteria.
Ineligibility criteria for Optional Tolvaptan Treatment Component of this trial:
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. Use of potent CYP3A4 inhibitors in subjects ≤ 50 kg or moderate CYP3A4 inhibitors in subjects < 20 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 the pretreatment visit 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. An IRE form will be completed if the subject is a potential Hy’s Law case (any increase of AST or ALT ≥ 2 X ULN or baseline value with an increase
in BT ≥ 2 X ULN or baseline value)
18. Has deficient coagulation (eg, cirrhotic at risk of GI bleed), including subjects who meet any of the following criteria: 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 an investigational drug trial (other than Trials 156-08-276, or 156-13-207 or 156-12-205) within the past 30 days, without prior approval from the medical monitor
25. Subjects <2 years of age, weight <10 kg, or who cannot swallow an oral tablet are excluded until an alternate formulation becomes available
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in serum sodium while tolvaptan is being administered. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change from baseline in serum sodium while tolvaptan is being administered by Visit so there will be several primary end-points depending on the number of visits that the subject will have. Hence, the change in serum sodium at each visit will be measured and the mean value will be the primary end point.
|
|
| E.5.2 | Secondary end point(s) |
Optional Tolvaptan Treatment Component:
1. Percentage of subjects who require rescue therapy while on tolvaptan treatment
2. Percentage of subjects requiring continuation of tolvaptan following 30 days of treatment
3. Percentage of subjects with overly rapid correction in serum sodium
(≥12 mmol/L in 24 hours after the first dose at introduction or reintroduction of tolvaptan)
4. Changes from baseline in ALT, AST and BT.
Core Safety Follow up Component:
1. Frequency of AE reports
2. Change from baseline in QoL assessments
3. Change from baseline in growth percentiles
-for body weight
- body height
4. Tanner Staging progression score
5. Change from baseline in serum sodium by visit
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Optional Tolvaptan Treatment Component:
1. Percentage of subjects who require rescue therapy while on tolvaptan treatment (Evaluation time point: all trial duration)
2. Percentage of subjects requiring continuation of tolvaptan following 30 days of treatment (Evaluation timepoint after 30 days of treatment minimum)
3. Percentage of subjects with overly rapid correction in serum sodium (≥12 mmol/L in 24 hours after the first dose at introduction or reintroduction of tolvaptan) (Evaluation timepoint: Any visit with this increase)
4. Changes from baseline in ALT, AST and BT (Evaluation timepoint: Each visit).
Core Safety Followup Component:
Evaluation timepoint for most of the secondary endpoints is Any Visit. |
|
| 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 | 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 | 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Extension Follow-Up 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 | 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 54 |
| 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
|
| Completion of at least 6 months follow-up by all subjects and for those participating in the optional treatment cycles will be the last date of contact following the last treatment cycle. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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