<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02215148</url>
  </required_header>
  <id_info>
    <org_study_id>13-3991</org_study_id>
    <secondary_id>20141663</secondary_id>
    <nct_id>NCT02215148</nct_id>
  </id_info>
  <brief_title>Pharmacokinetics and Clinical Response of Tolvaptan in Neurocritical Care Patients</brief_title>
  <official_title>Pharmacokinetics and Clinical Response of Tolvaptan in Neurocritical Care Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of North Carolina, Chapel Hill</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Otsuka America Pharmaceutical</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medical University of South Carolina</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Barnes-Jewish Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of North Carolina, Chapel Hill</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To assess the pharmacokinetic profile of tolvaptan in critically ill acute brain injury&#xD;
      patients and to secondarily evaluate the clinical response and safety of tolvaptan in acute&#xD;
      brain injured patients&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Slow subject enrollment and contracting issues; sponsor decided to abort study&#xD;
  </why_stopped>
  <start_date>November 2014</start_date>
  <completion_date type="Actual">August 2016</completion_date>
  <primary_completion_date type="Actual">August 2016</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum observed plasma concentration (Cmax) and time to maximum observed plasma concentration (Tmax) of tolvaptan over 36 hours post-dose</measure>
    <time_frame>Over 36 hours from drug administration</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The elimination rate constant (ke) of tolvaptan over 36 hours post-dose</measure>
    <time_frame>Over 36 hours from drug administration</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the plasma concentration time curve (AUC) of tolvaptan from time zero to 36 hours post-dose</measure>
    <time_frame>Over 36 hours from drug administration</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The clinical response of tolvaptan administered through the nasogastric tube in acute brain injured patients</measure>
    <time_frame>Over 36 hours from drug administration</time_frame>
    <description>Clinical response is defined as a change in serum sodium of 4 - 6 mEq/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The safety of tolvaptan administered via a nasogastric tube in acute brain injured patients</measure>
    <time_frame>Over 36 hours from drug administration</time_frame>
    <description>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 &gt;20% reduction in MAP from baseline.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">1</enrollment>
  <condition>Brain Injury</condition>
  <condition>Hyponatremia</condition>
  <arm_group>
    <arm_group_label>Brain injured patients with hyponatremia</arm_group_label>
    <description>Patients with acute brain injury who develop hyponatremia and are administered tolvaptan via the nasogastric tube, deemed necessary by the primary medical team.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tolvaptan</intervention_name>
    <arm_group_label>Brain injured patients with hyponatremia</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood samples for pharmacokinetic sampling will be collected in serum separator tubes at 0,&#xD;
      0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 30 and 36 hours after the dose of study drug is&#xD;
      administered. Serum sodium will be collected at baseline and 2, 4, 6, 8, 12, 24, and 36 hours&#xD;
      after study drug administration. Approximately 180 mL of blood will be collected over 36&#xD;
      hours. Urinary output and urine specific gravity will be collected 0-2, 2-4, 3-6, 6-8, 8-12,&#xD;
      and 12-24 hours after tolvaptan administration.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The population will be comprised of 30 acute brain injury patients in the ICU.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Acute brain injury patients in the ICU with hyponatremia (Na &lt; 135 mmol/L)&#xD;
             necessitating treatment in addition to fluid restriction per clinical judgement or&#xD;
             patients at risk for worsening cerebral edema&#xD;
&#xD;
          2. Informed consent obtained from patient or authorized legal representative&#xD;
&#xD;
          3. Age ≥ 18 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Use of CYP3A4 inhibitors or inducers as medications, juices, or herbal supplements&#xD;
             within 96 hours prior to the study period.&#xD;
&#xD;
          2. A positive urine or serum pregnancy test, or are currently breast-feeding&#xD;
&#xD;
          3. Patients with subarachnoid hemorrhage or in patients suspected to have cerebral salt&#xD;
             wasting or any signs of volume depletion&#xD;
&#xD;
          4. Imminent death or brain death&#xD;
&#xD;
          5. Concomitant fungal infection&#xD;
&#xD;
          6. History of HIV&#xD;
&#xD;
          7. Concomitant administration of continuous infusion hypertonic saline, conivaptan or&#xD;
             hypertonic saline bolus within 24 hours of study drug administration&#xD;
&#xD;
          8. Diuretic or mannitol administration within 6 hours&#xD;
&#xD;
          9. Serum creatinine ≥ 3.5 mg/dL&#xD;
&#xD;
         10. Diagnosis of cirrhosis or liver function tests &gt; 2x the upper limit of normal&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kathryn A Morbitzer, PharmD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of North Carolina, Chapel Hill</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Denise H. Rhoney, PharmD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of North Carolina, Chapel Hill</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Barnes-Jewish Hospital</name>
      <address>
        <city>St. Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of North Carolina Hospitals</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical University of South Carolina</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29425</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2016</verification_date>
  <study_first_submitted>August 11, 2014</study_first_submitted>
  <study_first_submitted_qc>August 11, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 13, 2014</study_first_posted>
  <last_update_submitted>September 6, 2016</last_update_submitted>
  <last_update_submitted_qc>September 6, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 8, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Hyponatremia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tolvaptan</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02215148
org study id: 13-3991
secondary id: 20141663
nct id: NCT02215148
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
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
observational model: Cohort
time perspective: Prospective
measure: Maximum observed plasma concentration (Cmax) and time to maximum observed plasma concentration (Tmax) of tolvaptan over 36 hours post-dose
time frame: Over 36 hours from drug administration
description: 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.
measure: The elimination rate constant (ke) of tolvaptan over 36 hours post-dose
time frame: Over 36 hours from drug administration
description: 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.
measure: Area under the plasma concentration time curve (AUC) of tolvaptan from time zero to 36 hours post-dose
time frame: Over 36 hours from drug administration
description: 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.
measure: The clinical response of tolvaptan administered through the nasogastric tube in acute brain injured patients
time frame: Over 36 hours from drug administration
description: Clinical response is defined as a change in serum sodium of 4 - 6 mEq/L
measure: The safety of tolvaptan administered via a nasogastric tube in acute brain injured patients
time frame: Over 36 hours from drug administration
description: 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.
arm group label: Brain injured patients with hyponatremia
description: Patients with acute brain injury who develop hyponatremia and are administered tolvaptan via the nasogastric tube, deemed necessary by the primary medical team.
intervention type: Drug
intervention name: Tolvaptan
arm group label: Brain injured patients with hyponatremia
Blood samples for pharmacokinetic sampling will be collected in serum separator tubes at 0,
      0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 30 and 36 hours after the dose of study drug is
      administered. Serum sodium will be collected at baseline and 2, 4, 6, 8, 12, 24, and 36 hours
      after study drug administration. Approximately 180 mL of blood will be collected over 36
      hours. Urinary output and urine specific gravity will be collected 0-2, 2-4, 3-6, 6-8, 8-12,
      and 12-24 hours after tolvaptan administration.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kathryn A Morbitzer, PharmD
role: Principal Investigator
affiliation: University of North Carolina, Chapel Hill
last name: Denise H. Rhoney, PharmD
role: Principal Investigator
affiliation: University of North Carolina, Chapel Hill
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Brain Injuries
mesh term: Hyponatremia
mesh term: Tolvaptan