A Phase 3b, Multicenter, Extension Follow-up Trial to Evaluate the Safety of Children and Adolescent Subjects With Euvolemic or Hypervolemic Hyponatremia Who Have Previously Participated in a Trial of Tolvapta
- Conditions
- Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]MedDRA version: 19.1Level: LLTClassification code 10021038Term: HyponatremiaSystem Organ Class: 100000004861Euvolemic or Hypervolemic Hyponatremia
- Registration Number
- EUCTR2013-002810-11-CZ
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 38
Inclusion criteria for the core safety follow up component:
1. Enrollment in a previous tolvaptan pediatric trial for hyponatremia
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.
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 years of age (or per local Health Authority age restrictions) and = 10 kg
2. The subject must have been off treatment with the investigational medicinal product (IMP) for at least 7 days following the end of treatment in the previous tolvaptan trial for hyponatremia (euvolemic or hypervolemic)
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 swallow tablets.
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 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 tolvaptan for sexually active females of childbearing potential.
Are the trial subjects under 18? yes
Number of subjects for this age range: 100
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range 0
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0
Safety follow-up component of this trial: There are no exclusion criteria for entry into the core safety follow-up component of this trial.
Ineligibility criteria 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 acute kidney injury 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
18. Patient who has cirrhosis and meets 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 wi
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method