Hyponatremia
Conditions
Keywords
Serum Sodium, Euvolemia, Hypervolemia, Vaprisol®, Conivaptan, YM087
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.
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.
Interventions
Intravenous
DRUGPlacebo
Intravenous
Sponsors
Cumberland Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Mean Change From Baseline to the End of the 48-hour Treatment Period in Serum Sodium | baseline and 48 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Time From the First Dose of Study Medication to a Confirmed ≥ 4 mEq/L Increase From Baseline in Serum Sodium | 48 hours | — |
| Number of Participants With an Overly Rapid Rise in Serum Sodium From Baseline | 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 |
| Population Pharmacokinetics: Clearance (CL) | Up to Hour 60 | Based on conivaptan concentrations, the pharmacokinetics of the study population will be analyzed to determine median CL |
| Population Pharmacokinetics: Volume of Distribution (Vd) | Up to Hour 60 | Based on conivaptan concentrations, the pharmacokinetics of the study population will be analyzed to determine median Vd |
| Change From Baseline in Free Water Clearance (FWC) | Baseline and 48 hours | — |
Countries
Colombia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Conivaptan Hydrochloride Conivaptan hydrochloride: Intravenous | 3 |
| Placebo Placebo: Intravenous | 1 |
| Total | 4 |
Baseline characteristics
| Characteristic | Total | Placebo | Conivaptan Hydrochloride |
|---|---|---|---|
| Age, Customized 11 - 17 years | 2 participants | 1 participants | 1 participants |
| Age, Customized 2 - 5 years | 0 participants | 0 participants | 0 participants |
| Age, Customized 6 - 10 years | 2 participants | 0 participants | 2 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Colombia | 2 participants | 0 participants | 2 participants |
| Region of Enrollment United States | 2 participants | 1 participants | 1 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 0 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 3 | 1 / 1 |
| serious Total, serious adverse events | 1 / 3 | 0 / 1 |
Outcome results
Primary
Mean Change From Baseline to the End of the 48-hour Treatment Period in Serum Sodium
Time frame: baseline and 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conivaptan Hydrochloride | Mean Change From Baseline to the End of the 48-hour Treatment Period in Serum Sodium | 6.0 mEq/L | Standard Deviation 5.3 |
| Placebo | Mean Change From Baseline to the End of the 48-hour Treatment Period in Serum Sodium | -4.0 mEq/L | — |
Secondary
Change From Baseline in Effective Water Clearance (EWC) Every 12 Hours
Time frame: Baseline, Hours 12, 24, 36 and 48
Population: The protocol specifies that calculations for this endpoint were to be derived by the statistical team. Due to the terminated status of the study, a statistical team was not employed and calculations to determine this variable were not performed.
Secondary
Change From Baseline in Free Water Clearance (FWC)
Time frame: Baseline and 48 hours
Population: The protocol specifies that calculations for this endpoint were to be derived by the statistical team. Due to the terminated status of the study, a statistical team was not employed and calculations to determine this variable were not performed.
Secondary
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
Time frame: baseline and Hours 3, 8, 12 and 24.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conivaptan Hydrochloride | Number of Participants With an Overly Rapid Rise in Serum Sodium From Baseline | 0 participants |
| Placebo | Number of Participants With an Overly Rapid Rise in Serum Sodium From Baseline | 0 participants |
Secondary
Number of Patients With Confirmed ≥ 4 mEq/L Increase From Baseline in Serum Sodium
Time frame: baseline and 48 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conivaptan Hydrochloride | Number of Patients With Confirmed ≥ 4 mEq/L Increase From Baseline in Serum Sodium | 2 participants |
| Placebo | Number of Patients With Confirmed ≥ 4 mEq/L Increase From Baseline in Serum Sodium | 0 participants |
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Conivaptan Hydrochloride | 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) | 1 participants |
| Placebo | 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) | 0 participants |
Secondary
Population Pharmacokinetics: Clearance (CL)
Based on conivaptan concentrations, the pharmacokinetics of the study population will be analyzed to determine median CL
Time frame: Up to Hour 60
Population: Due to the terminated status of the study, pharmacokinetic samples were not analyzed.
Secondary
Population Pharmacokinetics: Volume of Distribution (Vd)
Based on conivaptan concentrations, the pharmacokinetics of the study population will be analyzed to determine median Vd
Time frame: Up to Hour 60
Population: Due to the terminated status of the study, pharmacokinetic samples were not analyzed.
Secondary
Time From the First Dose of Study Medication to a Confirmed ≥ 4 mEq/L Increase From Baseline in Serum Sodium
Time frame: 48 hours
Population: Data from two subjects (one conivaptan, and one placebo) were censored as the serum sodium never achieved a value greater or equal to 4 mEq/L above the baseline value.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Conivaptan Hydrochloride | Time From the First Dose of Study Medication to a Confirmed ≥ 4 mEq/L Increase From Baseline in Serum Sodium | 21.5 hours |