A Study to Assess the Efficacy, Safety and Pharmacokinetics of Intravenous Conivaptan (Vaprisol®) in Pediatric Subjects With Euvolemic or Hypervolemic Hyponatremia

Study Overview
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Brief Summary
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The objective of this study is to evaluate the efficacy, safety and pharmacokinetics of intravenous conivaptan in pediatric subjects with abnormally low concentration of sodium in blood.

Detailed Description
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A 3:1 randomization between conivaptan and placebo will be implemented and randomization will be further stratified in a 1:1:2 ratio for age groups: 2-5 years, 6-10 years, and 11-17 years. Subjects will need to remain hospitalized for the 48-hour Treatment Period through Hour 96 (Day 4). There will be a follow-up safety visit on Day 9 or day of hospital discharge, whichever occurs first. There is a final follow-up phone call at Day 32 to assess if any serious adverse events have occurred since hospital discharge.

Official Title
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A Phase III, Double-Blind, Randomized, Placebo-Controlled, Multi-Center, Dose-Titration Study to Assess the Efficacy, Safety and Pharmacokinetics of Intravenous Conivaptan (Vaprisol®) in Pediatric Subjects With Euvolemic or Hypervolemic Hyponatremia

Conditions
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Hyponatremia

Intervention / Treatment
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* Drug: Conivaptan hydrochloride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is euvolemic or hypervolemic hyponatremia upon clinical presentation Subject has serum sodium value ≥ 115 mEq/L (115 mmol/L) and < 130 mEq/L (130 mmol/L) during the 24 hours preceding inclusion into the study Female subject of childbearing potential must have a negative serum pregnancy test and must be premenarchal, surgically sterile or must practice a method of birth control Exclusion Criteria: Female subject is pregnant or lactating Subject has a body mass index (BMI) < the 3rd percentile or > the 97th percentile for their age and stature according to the World Health Organization; Body mass index-for-age percentiles charts for boys and girls ages 2 to 20 Subject has clinical evidence of volume depletion, dehydration or hypovolemia Subject with hypovolemic hyponatremia or transient causes of hyponatremia that are likely to resolve during the time of study participation Subjects with a cause of hyponatremia that is most appropriately corrected by alternative therapies Subject is expected to receive emergent treatment for hyponatremia during the treatment period of the study Subject has clinical evidence of hypotension Subject has uncontrolled hypertension > the 99th percentile for their age Subject has uncontrolled bradyarrhythmias or tachyarrhythmias requiring emergent pacemaker placement or treatment Subject has untreated severe hypothyroidism, hyperthyroidism or adrenal insufficiency Subject has known urinary outflow obstruction, unless subject is, or can be catheterized during the study Subject has estimated creatinine clearance < 30 mL/min during the seven days prior to study drug administration Subject has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations > 3 times the upper limit of normal reference range during the seven days prior to study drug administration Subject has serum albumin ≤ 1.5 g/dL during the seven days prior to study drug administration Subject has white blood cell count (WBC) < 3000/micro-liter documented any time during seven days prior to study drug administration or anticipated drop in WBC to < 3000/micro-liter during the period of the study due to chemotherapy Subject currently has unstable hepatic function or a history of hepatic encephalopathy, or bleeding esophageal varices within the last 3 months Subject has acute heart failure. Prior history of heart failure is allowed if there are no current signs/symptoms Subject has a non-fasting blood glucose value ≥ 275 mg/dL Subject requires or is suspected to require treatment with potent inhibitors or potent inducers of CYP3A4 Subject was administered hypertonic saline or oral salt supplement within 24 hours prior to study drug administration Subject requires the use of medications used in the treatment of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): including lithium salts, urea or demeclocycline during the week prior to screening and throughout the study drug treatment period Subject has any condition that may interfere with treatment or evaluation of safety Subject has received investigational therapy (including placebo) within 28 days or 5 half lives, whichever is longer

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conivaptan hydrochloride<br> | Drug: Conivaptan hydrochloride<br>* Intravenous<br>* Other names: YM087;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to the End of the 48-hour Treatment Period in Serum Sodium |  | baseline and 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From the First Dose of Study Medication to a Confirmed ≥ 4 mEq/L Increase From Baseline in Serum Sodium |  | 48 hours | 
| Number of Patients With Confirmed ≥ 4 mEq/L Increase From Baseline in Serum Sodium |  | baseline and 48 hours | 
| Number of Subjects With Confirmed > 6 mEq/L Increase From Baseline in Serum Sodium or a Confirmed Normal Serum Sodium Level (Greater Than or Equal to 135 mEq/L) |  | baseline and 48 hours | 
| Change From Baseline in Effective Water Clearance (EWC) Every 12 Hours |  | Baseline, Hours 12, 24, 36 and 48 | 
| Change From Baseline in Free Water Clearance (FWC) |  | Baseline and 48 hours | 
| Number of Participants With an Overly Rapid Rise in Serum Sodium From Baseline | an absolute serum sodium of 145 mEq/L at Hour 24 or an increase in serum sodium of greater than 12 mEq/L | baseline and Hours 3, 8, 12 and 24. | 
| Population Pharmacokinetics: Clearance (CL) | Based on conivaptan concentrations, the pharmacokinetics of the study population will be analyzed to determine median CL | Up to Hour 60 | 
| Population Pharmacokinetics: Volume of Distribution (Vd) | Based on conivaptan concentrations, the pharmacokinetics of the study population will be analyzed to determine median Vd | Up to Hour 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Euvolemia, Serum Sodium, Hypervolemia, Vaprisol®, Conivaptan, YM087