Pharmacokinetics and Clinical Response of Tolvaptan in Neurocritical Care Patients

Brain Injury Clinical Trial

Official title:

Pharmacokinetics and Clinical Response of Tolvaptan in Neurocritical Care Patients

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02215148
• Other study ID #: 13-3991
• Secondary ID: 20141663
• Status: Terminated
• Phase: N/A
• First received: August 11, 2014
• Last updated: September 6, 2016
• Start date: November 2014
• Est. completion date: August 2016

Study information

• Verified date: September 2016
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial Summary

To assess the pharmacokinetic profile of tolvaptan in critically ill acute brain injury patients and to secondarily evaluate the clinical response and safety of tolvaptan in acute brain injured patients

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1
• Est. completion date: August 2016
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Acute brain injury patients in the ICU with hyponatremia (Na < 135 mmol/L) necessitating treatment in addition to fluid restriction per clinical judgement or patients at risk for worsening cerebral edema

2. Informed consent obtained from patient or authorized legal representative

3. Age = 18 years

Exclusion Criteria:

1. Use of CYP3A4 inhibitors or inducers as medications, juices, or herbal supplements within 96 hours prior to the study period.

2. A positive urine or serum pregnancy test, or are currently breast-feeding

3. Patients with subarachnoid hemorrhage or in patients suspected to have cerebral salt wasting or any signs of volume depletion

4. Imminent death or brain death

5. Concomitant fungal infection

6. History of HIV

7. Concomitant administration of continuous infusion hypertonic saline, conivaptan or hypertonic saline bolus within 24 hours of study drug administration

8. Diuretic or mannitol administration within 6 hours

9. Serum creatinine = 3.5 mg/dL

10. Diagnosis of cirrhosis or liver function tests > 2x the upper limit of normal

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injury
• Hyponatremia

Intervention

Drug:
• Tolvaptan

Locations

Country	Name	City	State
United States	University of North Carolina Hospitals	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Barnes-Jewish Hospital	St. Louis	Missouri

Sponsors (4)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	Barnes-Jewish Hospital, Medical University of South Carolina, Otsuka America Pharmaceutical

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum observed plasma concentration (Cmax) and time to maximum observed plasma concentration (Tmax) of tolvaptan over 36 hours post-dose	Cmax will be derived from plasma concentrations versus time using a validated LS/MS/MS assay is sodium heparinized plasma. The tolvaptan assay has a range of 1.00 - 200 mg/mL. Blood samples will be collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 30 and 36 hours after the dose of tolvaptan is administered. The first 15 patients will receive single dose 15mg of tolvaptan via a gastric tube and if determined not bioequivalent and no clinical response to oral administration and safe to administer, then last 15 patients will receive 30mg single dose via a gastric tube.	Over 36 hours from drug administration	No
Primary	The elimination rate constant (ke) of tolvaptan over 36 hours post-dose	Ke derived from plasma concentrations versus time using a validated LS/MS/MS assay is sodium heparinized plasma. The tolvaptan assay has a range of 1.00 - 200 mg/mL. Blood samples will be collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 30 and 36 hours after the dose of tolvaptan is administered. The first 15 patients will receive single dose 15mg of tolvaptan via a gastric tube and if determined not bioequivalent and no clinical response to oral administration and safe to administer, then last 15 patients will receive 30mg single dose via a gastric tube.	Over 36 hours from drug administration	No
Primary	Area under the plasma concentration time curve (AUC) of tolvaptan from time zero to 36 hours post-dose	AUC will be computed from 0 to 36 hours using the linear-log trapezoidal method and extrapolated to infinity. Tolvaptan concentrations will be determined using a validated LS/MS/MS assay is sodium heparinized plasma. The tolvaptan assay has a range of 1.00 - 200 mg/mL. Blood samples will be collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 30 and 36 hours after the dose of tolvaptan is administered. The first 15 patients will receive single dose 15mg of tolvaptan via a gastric tube and if determined not bioequivalent and no clinical response to oral administration and safe to administer, then last 15 patients will receive 30mg single dose via a gastric tube.	Over 36 hours from drug administration	No
Secondary	The clinical response of tolvaptan administered through the nasogastric tube in acute brain injured patients	Clinical response is defined as a change in serum sodium of 4 - 6 mEq/L	Over 36 hours from drug administration	No
Secondary	The safety of tolvaptan administered via a nasogastric tube in acute brain injured patients	Safety assessments will include: vital signs, clinical laboratory tests, concomitant medications, and reported or observed adverse events. The rate of sodium correction will also be assessed. Excessive correction in sodium is defined as = 12 mE/L increased in serum sodium within 24 hours of the dose. Excessive drop in blood pressure will be defined as >20% reduction in MAP from baseline.	Over 36 hours from drug administration	Yes