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

• ClinicalTrials.gov Identifier: NCT01451411
• Recruitment Status: Terminated
• First Posted: October 13, 2011
• Results First Posted: March 1, 2016
• Last Update Posted: March 1, 2016
• Sponsor: Cumberland Pharmaceuticals
• Information provided by (Responsible Party): Cumberland Pharmaceuticals

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hyponatremia	Drug: Conivaptan hydrochloride; Drug: Placebo	Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 4 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: February 2012
• Actual Primary Completion Date: January 2014
• Actual Study Completion Date: January 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Conivaptan hydrochloride	Drug: Conivaptan hydrochloride; Intravenous; Other Names: Vaprisol®; YM087
Placebo Comparator: Placebo	Drug: Placebo; Intravenous

Outcome Measures

Primary Outcome Measures :

1. Mean Change From Baseline to the End of the 48-hour Treatment Period in Serum Sodium [ Time Frame: baseline and 48 hours ]

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, New York

Children's Hospital of New York - Presbyterian

New York, New York, United States, 10032

Colombia

Fundación Cardioinfantil - Instituto Cardiológico

Bogota, Colombia

Fundación Valle del Lili

Cali, Valle, Colombia

Sponsors and Collaborators

Cumberland Pharmaceuticals

Investigators

• Study Director: Art Wheeler, MD; Cumberland Pharmaceuticals, Inc.

More Information

• Responsible Party: Cumberland Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01451411
• Other Study ID Numbers: 087-CL-096
• First Posted: October 13, 2011
• Results First Posted: March 1, 2016
• Last Update Posted: March 1, 2016
• Last Verified: February 2016

Keywords provided by Cumberland Pharmaceuticals:

Serum Sodium; Euvolemia; Hypervolemia; Vaprisol®; Conivaptan; YM087

Additional relevant MeSH terms:

Hyponatremia; Water-Electrolyte Imbalance; Metabolic Diseases; Conivaptan; Antidiuretic Hormone Receptor Antagonists; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Physiological Effects of Drugs