Hyponatremia | An Extension Follow-up Trial to Evaluate the Long-term Safety of Children and Adolescent Subjects With Euvolemic or Hypervolemic Hyponatremia
Hyponatremia research study
What is the primary objective of this study?
The objective of this trial is to provide 6 months of safety follow-up for children and adolescents with dilutional (euvolemic or hypervolemic) hyponatremia who have previously participated in a tolvaptan hyponatremia trial, and to assess the efficacy of tolvaptan in increasing serum sodium for those subjects who receive optional continuing tolvaptan treatment of variable duration (up to 6 months).
Who is eligible to participate?
Core Safety Follow-up Component: Inclusion Criteria: Participation in a prior pediatric trial with Tolvaptan for euvolemic or hypervolemic hyponatremia.Exclusion Criteria: None Optional Tolvaptan Treatment Component (per treatment cycle): Eligibility Criteria: 1. Male and female subjects ≥ 4 years of age (or per local Health Authority age restrictions) and ≥ 10kg 2. Subject must have been off treatment with the investigational medicinal product for at least 7 days following the end of treatment in the previous tolvaptan trial for hyponatremia . 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/L (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/legal 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 IMP for sexually active females of childbearing potential Ineligibility 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. 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 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. 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 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 < 4 years of age (or per local Health Authority age restrictions), weight < 10 kg, or who are unable to swallow tablets
Which medical condition, disease, disorder, syndrome, illness, or injury is researched?
Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.
Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.
Follow-upSubjects enrolled in this trial may be eligible to receive open-label tolvaptan if they have a clinical need as determined by the investigator and meet the eligibility criteria for optional tolvaptan treatment. Tolvaptan will initially be supplied as 3.75-, 7.5-, 15-, and 30-mg spray-dried tablets. Initial dose administration is dependent on age and weight with subsequent changes dependent on serum sodium levels. Daily dose levels include 3.75 mg, 7.5 mg, 15 mg, 30 mg, and 60 mg.
Start Date: April 2016
Completed Date: October 23, 2017
Phase: Phase 3
Primary Outcome: Change from baseline in serum sodium while tolvaptan is being administered
Secondary Outcome: Percentage of subjects who require rescue therapy while on tolvaptan treatment
Study sponsors, principal investigator, and references
Principal Investigator: Ann Dandurand, MD
Collaborator: INC Research