Study of the Safety and Effectiveness of SAMSCA® (Tolvaptan) in Children and Adolescents With Euvolemic or Hypervolemic Hyponatremia

Study Overview
=================
Brief Summary
-----------------
The purpose of this trial was to demonstrate that tolvaptan effectively and safely increases and maintains serum sodium concentrations in children and adolescent participants with euvolemic or hypervolemic hyponatremia.

Official Title
-----------------
A Phase 3b, Multicenter, Open-label, Randomized Withdrawal Trial of the Effects of Titrated Oral SAMSCA ® (Tolvaptan) on Serum Sodium, Pharmacokinetics, and Safety in Children and Adolescent Subjects Hospitalized With Euvolemic or Hypervolemic Hyponatremia

Conditions
-----------------
Hyponatremia

Intervention / Treatment
-----------------
* Drug: Tolvaptan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion: Male and female participants ≥4 weeks (or ≥44 weeks adjusted gestational age) to <18 years old Participants hospitalized with euvolemic or hypervolemic hyponatremia resistant to initial standard background therapy Persistent euvolemic or hypervolemic hyponatremia defined as being documented as <130 milliequivalent (mEq)/L and present for at least 48 hours, evidenced by at least 2 serum sodium assessments (12 hours apart) Ability to maintain adequate fluid intake (orally or intravenously) Ability to take oral medications Ability to comply with all requirements of the trial Completion of the trial-specific informed consent/assent as age appropriate Ability to commit to remain fully abstinent or practice double-barrier birth control as required by the trial Exclusion: Evidence of hypovolemia or intravascular volume depletion Serum sodium <120 mEq/L Use of potent cytochrome P450 3A4 (CYP3A4) inhibitors in participants <12 kilogram (kg) or moderate CYP3A4 inhibitors in participants <6 kg Lacks free access to water (inability to respond to thirst) or without intensive care unit level fluid monitoring and management History or current diagnosis of nephrotic syndrome Transient hyponatremia likely to resolve Hyperkalemia Estimated glomerular filtration rate <30 milliliters/minute/1.73 meters squared Acute kidney injury Severe or acute neurological symptoms requiring other intervention Prior treatment for hyponatremia with hypertonic saline within 8 hours of qualifying serum sodium assessments; urea, lithium, demeclocycline, conivaptan, or tolvaptan within 4 days of qualifying serum sodium assessments; any other treatments for the purpose of increasing serum sodium concurrent with dosing of trial medication Anuria or urinary outflow obstruction, unless participant is/can be catheterized History of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives Psychogenic polydipsia Uncontrolled diabetes mellitus (defined as fasting glucose >300 milligrams/deciliter) Screening liver function values >3 times the upper limit of normal Participants who have cirrhosis and meet any of the following conditions: a major GI bleed within the past 6 months, evidence of active bleeding, platelet count <50,000/microliter, or use of concomitant medications known to increase bleeding risk Hyponatremia due to the result of any medication that can safely be withdrawn or that is most appropriately corrected by alternative therapies History of drug or medication abuse within 3 months prior to screening or current alcohol abuse Participants who require suspension formulation and have a Hereditary Fructose Intolerance Has hyponatremia that is more appropriately corrected by alternative therapies Is pregnant or currently breastfeeding Has any medical condition that could interfere with evaluation of trial objectives or participant safety Has participated in another investigational drug trial in the last 30 days Weighs <3 kg Unable to swallow tablets, if suspension unavailable Is deemed unsuitable for trial participation in the opinion of the investigator

Ages Eligible for Study
-----------------
Minimum Age: 4 Weeks
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tolvaptan Early Withdrawal<br>All participants initially received tolvaptan once daily for the first 2 days. A third day of treatment was permitted if a participant had not reached the desired sodium target improvement per the investigator's judgment. At the end of Day 2 (or Day 3), responders (participants who achieved an increase in serum sodium by ≥4 millimoles/liter [mmol/L]) were randomized to either the Early or Late Withdrawal Group. Non-responders could continue treatment with tolvaptan for an additional 2 days. Discontinued tolvaptan treatment immediately after randomization. All participants were observed up to 14 days post randomization. | Drug: Tolvaptan<br> <br> * Other names: SAMSCA®;|
| Experimental: Tolvaptan Late Withdrawal<br>All participants initially received tolvaptan once daily for the first 2 days. A third day of treatment was permitted if a participant had not reached the desired sodium target improvement per the investigator's judgment. At the end of Day 2 (or Day 3), responders (participants who achieved an increase in serum sodium by ≥4 mmol/L) were randomized to either the Early or Late Withdrawal Group in Treatment Phase B. Non-responders could continue treatment with tolvaptan for an additional 2 days. Continued treatment for 2 additional days. All participants were observed up to 14 days post randomization. | Drug: Tolvaptan<br> <br> * Other names: SAMSCA®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change In Serum Sodium Concentration For Responders | Change in serum sodium concentration (mEq/L) for responders from Day 2 (or Day 2a) at the end of Treatment Phase A (where all participants received tolvaptan) to the end of Treatment Phase B for the Early compared to Late Withdrawal groups is reported. Once a participant was randomized to Treatment Phase B, any additional therapies for the purpose of raising serum sodium, including fluid restriction, were considered rescue therapy. Upon receipt of rescue therapy, a participant's endpoint data was collected and then censored from the efficacy analysis thereafter, unless specified. | Day 2/2a, Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change In Serum Sodium Concentration During Treatment Phase A | Change in serum sodium concentration (mEq/L) from baseline to the end of Day 2 (or 2a) during Treatment Phase A for all participants (responders and non-responders) is reported. | Baseline, Day 2/2a | 
| Fluid Balance (Intake Minus Output) During Treatment Phase A | Every 6 hours and for the 24-hour daily interval on Days 1 and 2 during Treatment Phase A, fluid balance (milliliters [mL]) was determined by fluid intake (oral and intravenous) minus urine output. Improved fluid balance would be indicated through the induction of increased urine volume. Fluid balance was monitored per institutional guidelines. | Every 6 hours on Days 1 and 2 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hyponatremia, Euvolemic, Hypervolemic, Serum sodium, Dilutional hyponatremia, Electrolyte abnormality, Electrolyte imbalance, Metabolic disease