Hyponatremia
Conditions
Brief summary
Conivaptan (Vaprisol) is FDA-Approved for the treatment of low serum sodium (hyponatremia), but there are few data in patients with neurologic disease. Very low serum sodium in patients with brain injury can be life-threatening and is associated with cerebral edema (swelling of brain tissue). This can be important in patients with brain hemorrhage, brain tumors, or stroke (cerebral infarction). This is a pilot study to test the hypothesis that conivaptan (Vaprisol) leads to a greater increase in sodium than usual care. Patients will be randomly assigned to usual care or the lower FDA-approved dose of conivaptan (Vaprisol). We will track the use of other interventions, such as the use of hypertonic saline (concentrated salt solution), diuretics and salt tablets. A blinded co-investigator will record neurologic examination results (NIH Stroke Scale and Glasgow Coma Scale).
Interventions
DRUGConivaptan
Conivaptan 20 mg once, followed by conivaptan 20 mg over 24 hours
Sponsors
Astellas Pharma US, Inc.
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* severe hyponatremia (Na \< 130 mmol/L) or * symptomatic hyponatremia - Na \< 135 mmol/L for at least six hours with Glasgow Coma Scale \< 15
Exclusion criteria
* Enrollment in the NMH high-risk spine protocol. These patients receive large amounts of fluids, have rapid changes in electrolytes, and are typically corrected in 48 hours * Expected death from any cause * Known sensitivity or allergy to conivaptan * Renal failure (baseline creatinine \> 1.5 mg/dL) * Clinical diagnosis of hypovolemia, or by central venous pressure (CVP) \< 5 mm Hg if a central venous catheter is in place * Concomitant use of potent inhibitors of cytochrome P-450 isoenzyme 3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir). These agents are not commonly used in the Neuro-ICU * Clinical diagnosis of liver failure or insufficiency * Pregnancy (must be excluded before entry) * Lack of informed consent from the patient or a legally authorized representative (LAR) * Use of intra-arterial vasodilators (e.g. verapamil, nicardipine) within 24 hours (e.g. for vasospasm after SAH) * Concern by the Neuro-ICU pharmacist of a drug-drug interaction that would meaningfully impact care (the Neuro-ICU pharmacist will review the medication regimen before recruitment) * Patients with a diagnosis of diabetes insipidus or treated with vasopressin, since these patients are already treated for abnormal free water balance * Patients with congestive heart failure, since this is an approved use of the drug (these patients are typically not cared for in the Neuro-ICU) * Age\<18 years (these patients are not cared for at NMH) * Inclusion declined by the attending physician or consulting study nephrologist
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Serum Sodium From Baseline to 6 Hours | 48 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| NIH Stroke Scale | 48 hours | Standardized neurologic examination, ranging from 0 (best) to 42 (worst possible). |
| Glasgow Coma Scale | 48 hours | Standardized examination of mental status ranging from 3 (worst) to 15 (best possible) |
Other
| Measure | Time frame |
|---|---|
| Change in Serum Sodium From Baseline to 36 Hours | 36 hours |
| Change in Serum Sodium From Baseline to 12 Hours | 12 hours |
| Change in Serum Sodium From Baseline to 48 Hours | 48 hours |
| Change in Serum Sodium From Baseline to 18 Hours | 18 hours |
| Change in Serum Sodium From Baseline to 24 Hours | 24 hours |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment: Conivaptan Conivaptan per package labeling, 20 mg IV bolus followed by 20 mg IV infusion over 24 hours | 3 |
| Usual Medical Care Usual care by the attending physician staff | 3 |
| Total | 6 |
Baseline characteristics
| Characteristic | Treatment: Conivaptan | Usual Medical Care | Total |
|---|---|---|---|
| Age, Continuous | 43 years STANDARD_DEVIATION 22 | 67 years STANDARD_DEVIATION 2 | 55 years STANDARD_DEVIATION 19.2 |
| Age, Customized <=18 years | 0 participants | 0 participants | 0 participants |
| Age, Customized >70 years | 0 participants | 0 participants | 0 participants |
| Age, Customized Between 18 and 70 years | 3 participants | 3 participants | 6 participants |
| Region of Enrollment United States | 3 participants | 3 participants | 6 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 3 | 0 / 3 |
| serious Total, serious adverse events | 2 / 3 | 2 / 3 |
Outcome results
Primary
Change in Serum Sodium From Baseline to 6 Hours
Time frame: 48 hours
Population: Intention to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment: Conivaptan | Change in Serum Sodium From Baseline to 6 Hours | 7 mMol/L | Standard Deviation 1.7 |
| Usual Medical Care | Change in Serum Sodium From Baseline to 6 Hours | -0.6 mMol/L | Standard Deviation 2.1 |
Comparison: Null Hypothesis: Change in serum sodium from baseline is not different between groupsp-value: <0.05t-test, 2 sided
Secondary
Glasgow Coma Scale
Standardized examination of mental status ranging from 3 (worst) to 15 (best possible)
Time frame: 48 hours
Population: all enrolled patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment: Conivaptan | Glasgow Coma Scale | 9 score on a scale |
| Usual Medical Care | Glasgow Coma Scale | 12 score on a scale |
Secondary
NIH Stroke Scale
Standardized neurologic examination, ranging from 0 (best) to 42 (worst possible).
Time frame: 48 hours
Population: Comparison of distribution; n enrolled was insufficient and trial was halted for poor recruitment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment: Conivaptan | NIH Stroke Scale | 19 score on a scale |
| Usual Medical Care | NIH Stroke Scale | 12 score on a scale |
Other Pre-specified
Change in Serum Sodium From Baseline to 12 Hours
Time frame: 12 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment: Conivaptan | Change in Serum Sodium From Baseline to 12 Hours | 7.7 mMol/L | Standard Deviation 4 |
| Usual Medical Care | Change in Serum Sodium From Baseline to 12 Hours | 1.7 mMol/L | Standard Deviation 0.6 |
Other Pre-specified
Change in Serum Sodium From Baseline to 18 Hours
Time frame: 18 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment: Conivaptan | Change in Serum Sodium From Baseline to 18 Hours | 7.3 mMol/L | Standard Deviation 4 |
| Usual Medical Care | Change in Serum Sodium From Baseline to 18 Hours | 1.3 mMol/L | Standard Deviation 2.1 |
Other Pre-specified
Change in Serum Sodium From Baseline to 24 Hours
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment: Conivaptan | Change in Serum Sodium From Baseline to 24 Hours | 9.7 mMol/L | Standard Deviation 3.2 |
| Usual Medical Care | Change in Serum Sodium From Baseline to 24 Hours | 0 mMol/L | Standard Deviation 1 |
Other Pre-specified
Change in Serum Sodium From Baseline to 36 Hours
Time frame: 36 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment: Conivaptan | Change in Serum Sodium From Baseline to 36 Hours | 8 mMol/L | Standard Deviation 5.6 |
| Usual Medical Care | Change in Serum Sodium From Baseline to 36 Hours | -1.7 mMol/L | Standard Deviation 2.1 |
Other Pre-specified
Change in Serum Sodium From Baseline to 48 Hours
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment: Conivaptan | Change in Serum Sodium From Baseline to 48 Hours | 6 mMol/L | Standard Deviation 5 |
| Usual Medical Care | Change in Serum Sodium From Baseline to 48 Hours | -0.7 mMol/L | Standard Deviation 3.2 |