<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/NCT03000283</url>
  </required_header>
  <id_info>
    <org_study_id>NSJC-1601</org_study_id>
    <nct_id>NCT03000283</nct_id>
  </id_info>
  <brief_title>Conivaptan for the Reduction of Cerebral Edema in Intracerebral Hemorrhage- A Safety and Tolerability Study</brief_title>
  <official_title>Conivaptan for the Reduction of Cerebral Edema in Intracerebral Hemorrhage- A Safety and Tolerability Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jesse Corry</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Allina Health System</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The goal of this study is to preliminarily determine/estimate feasibility and whether&#xD;
      frequent and early conivaptan use, at a dose currently determined to be safe (i.e.,&#xD;
      40mg/day), is safe and well-tolerated in patients with cerebral edema from intracerebral&#xD;
      hemorrhage (ICH) and pressure (ICP). A further goal is to preliminarily estimate whether&#xD;
      conivaptan at this same dose can reduce cerebral edema (CE) in these same patients. This&#xD;
      study is also an essential first step in understanding the role of conivaptan in CE&#xD;
      management.&#xD;
&#xD;
      Hypothesis: The frequent and early use of conivaptan at 40mg/day will be safe and&#xD;
      well-tolerated, and also reduce cerebral edema, in patients with intracerebral hemorrhage and&#xD;
      pressure.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a single-center, open-label, safety and tolerability study. Based on findings in the&#xD;
      literature from both animal research and clinical observations with ICH (intracerebral&#xD;
      hemorrhage) associated with TBI (traumatic brain injury), this study will begin to look at&#xD;
      the safety, tolerability, as well as potential effectiveness, of conivaptan to reduce CE&#xD;
      (cerebral edema) in patients with non-traumatic ICH.&#xD;
&#xD;
      The seven patients in this study will receive 40mg/day of the study medication conivaptan. In&#xD;
      this early phase study, our focus will be to assess the safety and tolerability of this&#xD;
      medication. The available clinical data on conivaptan in the neurocritical care population&#xD;
      suggest the potential harm is negligible. Data in TBI patients demonstrate conivaptan is safe&#xD;
      and well tolerated using a single dose (20mg) to increase Na+ in a controlled fashion to&#xD;
      reduce ICP. Previous work has demonstrated the safety and tolerability of conivaptan, in&#xD;
      doses ranging from 20-80mg/day, in the neurocritical care population. Conivaptan has been&#xD;
      demonstrated to be safe and effective in lowering ICP, and increasing serum sodium, in the&#xD;
      neurocritical care population. Also noted have been improvements in cerebral perfusion&#xD;
      pressure (CPP) and stable blood pressure, and a prolonged reduction in ICP. Finally, the&#xD;
      method of intermittent bolus dosing of conivaptan is equally effective in raising and&#xD;
      maintaining serum sodium in the neurocritical care population as continuous infusion, with&#xD;
      potentially less risk of adverse reactions including phlebitis.&#xD;
&#xD;
      Conivaptan, a non-selective Arginine-Vasopressin (AVP) V1A/V2 antagonist that reduces&#xD;
      aquaporin 4 production and promotes aquaresis, is approved for the treatment of euvolemic and&#xD;
      hypervolemic hyponatremia. The exact cause of the observed reduction in ICP with conivaptan&#xD;
      is uncertain. However, the mechanism most likely represents a combination of an acute pure&#xD;
      aquaresis, removing free water from brain tissue, and a sustained down regulation of&#xD;
      aquaporin 4 to abate/slow development of CE. The V2 antagonism of conivaptan promotes free&#xD;
      water loss, and the V1 antagonism may improve cerebral blood flow (CBF) and reduce blood&#xD;
      brain barrier permeability. Notably, serum sodium tends to correlate inversely with both ICP&#xD;
      and CE. The early use of conivaptan could potentially be used clinically to reduce CE by&#xD;
      these means.&#xD;
&#xD;
      It is with this in mind, the research team feels justified in pursuing this study with the&#xD;
      hopes that the data obtained will lead to potential good and removal of harm in future&#xD;
      patients with this devastating disease. Given the enormous costs of ICH, problems with&#xD;
      current therapies, and variability in treatment, there is an urgent need to identify a&#xD;
      therapy that has a better safety and effectiveness profile compared to the currently used&#xD;
      agents. This study will use a dose (40mg/day) currently approved. Further, given that the&#xD;
      primary purpose of the use of this medication in this study is not to correct hyponatremia,&#xD;
      an investigational new drug (IND) application to the FDA was submitted, and the study was&#xD;
      determined exempt.&#xD;
&#xD;
      Our central hypothesis is that through reductions in aquaporin-4 (AQP4) expression, the early&#xD;
      use of conivaptan will reduce CE while also being safe to the patient. Our long term goal is&#xD;
      to show that early use of conivaptan in ICH will reduce CE. If this reduction is possible, we&#xD;
      hypothesize improved outcome and reducing the need for rescue therapies, ICU length of stay,&#xD;
      and overall treatment cost will follow. However, more data is needed to evaluate the dosing&#xD;
      and amount of drug. With respect to conivaptan's efficacy in correction of hyponatremia, a&#xD;
      direct dose-response relationship exists. Further, this effect was more noted at milder&#xD;
      degrees of hyponatremia.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 22, 2017</start_date>
  <completion_date type="Actual">April 15, 2019</completion_date>
  <primary_completion_date type="Actual">February 12, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Patient Tolerance of Conivaptan</measure>
    <time_frame>Baseline to 168 hours post-enrollment</time_frame>
    <description>The number of participants with abnormal seizure activity and/or abnormal lab values and/or increase in infection rate and/or any drug-related adverse events.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>In-hospital Mortality</measure>
    <time_frame>Enrollment through hospital discharge, up to 3 weeks</time_frame>
    <description>All-cause deaths during hospitalization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Cerebral Edema</measure>
    <time_frame>Baseline to 168 hours post-enrollment</time_frame>
    <description>Changes in cerebral edema (CE) as measured on CT. Goal is a -5 to -10% change in CE over time. Change will be measured both as absolute change in volume, calculated as the final volume minus the baseline volume measure and converted to a percentage of the baseline volume measure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost</measure>
    <time_frame>Enrollment through hospital discharge, up to 3 weeks</time_frame>
    <description>Cost as measured by length of stay in the neuro ICU.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost</measure>
    <time_frame>Baseline to 168 hours post-enrollment</time_frame>
    <description>Cost as measured by:&#xD;
Need for external ventricular drain (EVD)/bolt or surgical procedures (craniectomy, clot evacuation,VPS) for reduction/management of CE.&#xD;
Need for central venous lines, arterial lines, peripherally inserted central venous catheter (PICC) lines, tracheostomy/percutaneous endoscopic gastrostomies (PEGs).&#xD;
Number of patients requiring a ventilator.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Modified Rankin Scale (mRS) Score</measure>
    <time_frame>At discharge from ICU and from hospital, up to 3 weeks</time_frame>
    <description>Modified Rankin Scale (0 to 6) at discharge from the hospital. A score of 0 indicates no disability and a score of 6 indicates the patient died. Functional independence is defined as a score of 2 or less.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">7</enrollment>
  <condition>Cerebral Hemorrhage</condition>
  <condition>Cerebral Edema</condition>
  <condition>Intracerebral Hemorrhage</condition>
  <condition>Stroke</condition>
  <arm_group>
    <arm_group_label>Conivaptan Treatment Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All seven patients in this arm will receive conivaptan as described in Interventions.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Conivaptan</intervention_name>
    <description>Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 doses total), in addition to the standardized ICH management targets using the PI's version of standardized ICH management targets.Usual standard of care can include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as needed to reduce ICP, and temperature control with antipyretics such as acetaminophen.&#xD;
The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused (peripherally) over 30 minutes, most commonly through an already placed central line.</description>
    <arm_group_label>Conivaptan Treatment Group</arm_group_label>
    <other_name>Vaprisol</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age &gt;18 years old and &lt; 80 years.&#xD;
&#xD;
          2. Diagnosis of primary ICH &gt; 20 cc in volume.&#xD;
&#xD;
          3. Enrollment within 48 hours from initial symptoms.&#xD;
&#xD;
          4. Signed informed consent from the patient or obtained via their legally authorized&#xD;
             representative (if the patient is not able to sign the informed consent themselves).&#xD;
             The patient's decisional capacity to either provide or refuse consent will be&#xD;
             determined using the Glasgow Coma Scale (GCS), which is being assessed at baseline and&#xD;
             at 24 hours (+/-6hrs) after enrollment. A potential study participant with a GCS &gt; 14&#xD;
             will be asked to provide their own initial study consent. A GCS ≤ 14 would indicate&#xD;
             the need to pursue consent via legally authorized representative.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Current need for renal replacement therapy (RRT).&#xD;
&#xD;
          2. Glomerular filtration rate (GFR) of &lt;30 mL/minute at time of admission.&#xD;
&#xD;
          3. Participation in another study for ICH or intraventricular hemorrhage.&#xD;
&#xD;
          4. ICH related to infection, thrombolysis, subarachnoid hemorrhage, trauma or tumor.&#xD;
&#xD;
          5. Presence of HIV or active fungal infection that is known based on information in the&#xD;
             electronic medical record (EMR).&#xD;
&#xD;
          6. Continued use of digoxin or amlodipine (as recommended by the manufacturer due to&#xD;
             cytochrome P450 3A4 &quot;CYP3A&quot; inhibition).&#xD;
&#xD;
          7. Active hepatic failure as defined by aspartate aminotransferase (AST) &gt;160 units/L&#xD;
             and/or alanine transaminase (ALT) &gt;180 units/L, or total bilirubin levels greater than&#xD;
             four times normal levels (&gt;4.8mg/dL).&#xD;
&#xD;
          8. Serum Na+&gt; 145 mmol/L (admission labs or any time prior to recruitment/enrollment).&#xD;
&#xD;
          9. Unable to receive conivaptan based on contraindications indicated by the manufacturer.&#xD;
&#xD;
         10. Pregnant or lactating females.&#xD;
&#xD;
         11. Not expected to survive within 48 hours of admission, or a presumed diagnosis of brain&#xD;
             death.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>79 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jesse J Corry, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Allina Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>United Hospital</name>
      <address>
        <city>Saint Paul</city>
        <state>Minnesota</state>
        <zip>55102</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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  <verification_date>April 2020</verification_date>
  <study_first_submitted>December 14, 2016</study_first_submitted>
  <study_first_submitted_qc>December 21, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 22, 2016</study_first_posted>
  <results_first_submitted>April 3, 2020</results_first_submitted>
  <results_first_submitted_qc>April 15, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">April 17, 2020</results_first_posted>
  <last_update_submitted>April 15, 2020</last_update_submitted>
  <last_update_submitted_qc>April 15, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">April 17, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Allina Health System</investigator_affiliation>
    <investigator_full_name>Jesse Corry</investigator_full_name>
    <investigator_title>Neurologist</investigator_title>
  </responsible_party>
  <keyword>Conivaptan</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cerebral Hemorrhage</mesh_term>
    <mesh_term>Brain Edema</mesh_term>
    <mesh_term>Hemorrhage</mesh_term>
    <mesh_term>Edema</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Conivaptan</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 4, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/83/NCT03000283/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 3, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/83/NCT03000283/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were recruited based on physician referral at a single medical institution between March 1, 2017 and November 7, 2018. The first participant was enrolled on March 22, 2017 and the last participant was enrolled on November 7, 2018.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Conivaptan Treatment Group</title>
          <description>All seven patients in this arm will receive conivaptan as described in Interventions.&#xD;
Conivaptan: Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 doses total), in addition to the standardized ICH management targets using the PI's version of standardized ICH management targets.Usual standard of care can include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as needed to reduce ICP, and temperature control with antipyretics such as acetaminophen.&#xD;
The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused (peripherally) over 30 minutes, most commonly through an already placed central line.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Conivaptan Treatment Group</title>
          <description>All seven patients in this arm will receive conivaptan as described in Interventions.&#xD;
Conivaptan: Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 doses total), in addition to the standardized ICH management targets using the PI's version of standardized ICH management targets.Usual standard of care can include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as needed to reduce ICP, and temperature control with antipyretics such as acetaminophen.&#xD;
The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused (peripherally) over 30 minutes, most commonly through an already placed central line.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="7"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="58.5" lower_limit="36" upper_limit="69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Patient Tolerance of Conivaptan</title>
        <description>The number of participants with abnormal seizure activity and/or abnormal lab values and/or increase in infection rate and/or any drug-related adverse events.</description>
        <time_frame>Baseline to 168 hours post-enrollment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Conivaptan Treatment Group</title>
            <description>All seven patients in this arm will receive conivaptan as described in Interventions.&#xD;
Conivaptan: Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 doses total), in addition to the standardized ICH management targets using the PI's version of standardized ICH management targets.Usual standard of care can include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as needed to reduce ICP, and temperature control with antipyretics such as acetaminophen.&#xD;
The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused (peripherally) over 30 minutes, most commonly through an already placed central line.</description>
          </group>
        </group_list>
        <measure>
          <title>Patient Tolerance of Conivaptan</title>
          <description>The number of participants with abnormal seizure activity and/or abnormal lab values and/or increase in infection rate and/or any drug-related adverse events.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Abnormal Seizure Activity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abnormal Lab Values</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Infections</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Drug-related Adverse Events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>In-hospital Mortality</title>
        <description>All-cause deaths during hospitalization</description>
        <time_frame>Enrollment through hospital discharge, up to 3 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Conivaptan Treatment Group</title>
            <description>All seven patients in this arm will receive conivaptan as described in Interventions.&#xD;
Conivaptan: Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 doses total), in addition to the standardized ICH management targets using the PI's version of standardized ICH management targets.Usual standard of care can include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as needed to reduce ICP, and temperature control with antipyretics such as acetaminophen.&#xD;
The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused (peripherally) over 30 minutes, most commonly through an already placed central line.</description>
          </group>
        </group_list>
        <measure>
          <title>In-hospital Mortality</title>
          <description>All-cause deaths during hospitalization</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Cerebral Edema</title>
        <description>Changes in cerebral edema (CE) as measured on CT. Goal is a -5 to -10% change in CE over time. Change will be measured both as absolute change in volume, calculated as the final volume minus the baseline volume measure and converted to a percentage of the baseline volume measure.</description>
        <time_frame>Baseline to 168 hours post-enrollment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Conivaptan Treatment Group</title>
            <description>All seven patients in this arm will receive conivaptan as described in Interventions.&#xD;
Conivaptan: Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 doses total), in addition to the standardized ICH management targets using the PI's version of standardized ICH management targets.Usual standard of care can include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as needed to reduce ICP, and temperature control with antipyretics such as acetaminophen.&#xD;
The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused (peripherally) over 30 minutes, most commonly through an already placed central line.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Cerebral Edema</title>
          <description>Changes in cerebral edema (CE) as measured on CT. Goal is a -5 to -10% change in CE over time. Change will be measured both as absolute change in volume, calculated as the final volume minus the baseline volume measure and converted to a percentage of the baseline volume measure.</description>
          <units>percentage of change from baseline</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-37.1" lower_limit="-96.2" upper_limit="70.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cost</title>
        <description>Cost as measured by length of stay in the neuro ICU.</description>
        <time_frame>Enrollment through hospital discharge, up to 3 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Conivaptan Treatment Group</title>
            <description>All seven patients in this arm will receive conivaptan as described in Interventions.&#xD;
Conivaptan: Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 doses total), in addition to the standardized ICH management targets using the PI's version of standardized ICH management targets.Usual standard of care can include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as needed to reduce ICP, and temperature control with antipyretics such as acetaminophen.&#xD;
The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused (peripherally) over 30 minutes, most commonly through an already placed central line.</description>
          </group>
        </group_list>
        <measure>
          <title>Cost</title>
          <description>Cost as measured by length of stay in the neuro ICU.</description>
          <units>days</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.4" lower_limit="9.7" upper_limit="28.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cost</title>
        <description>Cost as measured by:&#xD;
Need for external ventricular drain (EVD)/bolt or surgical procedures (craniectomy, clot evacuation,VPS) for reduction/management of CE.&#xD;
Need for central venous lines, arterial lines, peripherally inserted central venous catheter (PICC) lines, tracheostomy/percutaneous endoscopic gastrostomies (PEGs).&#xD;
Number of patients requiring a ventilator.</description>
        <time_frame>Baseline to 168 hours post-enrollment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Conivaptan Treatment Group</title>
            <description>All seven patients in this arm will receive conivaptan as described in Interventions.&#xD;
Conivaptan: Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 doses total), in addition to the standardized ICH management targets using the PI's version of standardized ICH management targets.Usual standard of care can include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as needed to reduce ICP, and temperature control with antipyretics such as acetaminophen.&#xD;
The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused (peripherally) over 30 minutes, most commonly through an already placed central line.</description>
          </group>
        </group_list>
        <measure>
          <title>Cost</title>
          <description>Cost as measured by:&#xD;
Need for external ventricular drain (EVD)/bolt or surgical procedures (craniectomy, clot evacuation,VPS) for reduction/management of CE.&#xD;
Need for central venous lines, arterial lines, peripherally inserted central venous catheter (PICC) lines, tracheostomy/percutaneous endoscopic gastrostomies (PEGs).&#xD;
Number of patients requiring a ventilator.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>EVD/bolt or surgical procedures</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Lines or tracheostomy/PEG</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ventilator</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Modified Rankin Scale (mRS) Score</title>
        <description>Modified Rankin Scale (0 to 6) at discharge from the hospital. A score of 0 indicates no disability and a score of 6 indicates the patient died. Functional independence is defined as a score of 2 or less.</description>
        <time_frame>At discharge from ICU and from hospital, up to 3 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Conivaptan Treatment Group</title>
            <description>All seven patients in this arm will receive conivaptan as described in Interventions.&#xD;
Conivaptan: Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 doses total), in addition to the standardized ICH management targets using the PI's version of standardized ICH management targets.Usual standard of care can include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as needed to reduce ICP, and temperature control with antipyretics such as acetaminophen.&#xD;
The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused (peripherally) over 30 minutes, most commonly through an already placed central line.</description>
          </group>
        </group_list>
        <measure>
          <title>Modified Rankin Scale (mRS) Score</title>
          <description>Modified Rankin Scale (0 to 6) at discharge from the hospital. A score of 0 indicates no disability and a score of 6 indicates the patient died. Functional independence is defined as a score of 2 or less.</description>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5" lower_limit="3" upper_limit="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Throughout study participation. For each patient this extended from enrollment to 3 months after enrollment.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Conivaptan Treatment Group</title>
          <description>All seven patients in this arm will receive conivaptan as described in Interventions.&#xD;
Conivaptan: Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 doses total), in addition to the standardized ICH management targets using the PI's version of standardized ICH management targets.Usual standard of care can include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as needed to reduce ICP, and temperature control with antipyretics such as acetaminophen.&#xD;
The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused (peripherally) over 30 minutes, most commonly through an already placed central line.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MeSH</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary Tract Infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Intracranial Hemorrhage Expansion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Increase in Cerebral Edema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pulmonary Edema</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Catheterization, Central Venous (PICC)</sub_title>
                <description>Need for a peripherally inserted central catheter line</description>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Tracheostomy</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Gastostomy (PEG)</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Deep Vein Thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Jesse Corry</name_or_title>
      <organization>Allina Health</organization>
      <phone>651-241-6550</phone>
      <email>Jesse.Corry@allina.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03000283
org study id: NSJC-1601
nct id: NCT03000283
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The goal of this study is to preliminarily determine/estimate feasibility and whether
      frequent and early conivaptan use, at a dose currently determined to be safe (i.e.,
      40mg/day), is safe and well-tolerated in patients with cerebral edema from intracerebral
      hemorrhage (ICH) and pressure (ICP). A further goal is to preliminarily estimate whether
      conivaptan at this same dose can reduce cerebral edema (CE) in these same patients. This
      study is also an essential first step in understanding the role of conivaptan in CE
      management.

      Hypothesis: The frequent and early use of conivaptan at 40mg/day will be safe and
      well-tolerated, and also reduce cerebral edema, in patients with intracerebral hemorrhage and
      pressure.
This is a single-center, open-label, safety and tolerability study. Based on findings in the
      literature from both animal research and clinical observations with ICH (intracerebral
      hemorrhage) associated with TBI (traumatic brain injury), this study will begin to look at
      the safety, tolerability, as well as potential effectiveness, of conivaptan to reduce CE
      (cerebral edema) in patients with non-traumatic ICH.

      The seven patients in this study will receive 40mg/day of the study medication conivaptan. In
      this early phase study, our focus will be to assess the safety and tolerability of this
      medication. The available clinical data on conivaptan in the neurocritical care population
      suggest the potential harm is negligible. Data in TBI patients demonstrate conivaptan is safe
      and well tolerated using a single dose (20mg) to increase Na+ in a controlled fashion to
      reduce ICP. Previous work has demonstrated the safety and tolerability of conivaptan, in
      doses ranging from 20-80mg/day, in the neurocritical care population. Conivaptan has been
      demonstrated to be safe and effective in lowering ICP, and increasing serum sodium, in the
      neurocritical care population. Also noted have been improvements in cerebral perfusion
      pressure (CPP) and stable blood pressure, and a prolonged reduction in ICP. Finally, the
      method of intermittent bolus dosing of conivaptan is equally effective in raising and
      maintaining serum sodium in the neurocritical care population as continuous infusion, with
      potentially less risk of adverse reactions including phlebitis.

      Conivaptan, a non-selective Arginine-Vasopressin (AVP) V1A/V2 antagonist that reduces
      aquaporin 4 production and promotes aquaresis, is approved for the treatment of euvolemic and
      hypervolemic hyponatremia. The exact cause of the observed reduction in ICP with conivaptan
      is uncertain. However, the mechanism most likely represents a combination of an acute pure
      aquaresis, removing free water from brain tissue, and a sustained down regulation of
      aquaporin 4 to abate/slow development of CE. The V2 antagonism of conivaptan promotes free
      water loss, and the V1 antagonism may improve cerebral blood flow (CBF) and reduce blood
      brain barrier permeability. Notably, serum sodium tends to correlate inversely with both ICP
      and CE. The early use of conivaptan could potentially be used clinically to reduce CE by
      these means.

      It is with this in mind, the research team feels justified in pursuing this study with the
      hopes that the data obtained will lead to potential good and removal of harm in future
      patients with this devastating disease. Given the enormous costs of ICH, problems with
      current therapies, and variability in treatment, there is an urgent need to identify a
      therapy that has a better safety and effectiveness profile compared to the currently used
      agents. This study will use a dose (40mg/day) currently approved. Further, given that the
      primary purpose of the use of this medication in this study is not to correct hyponatremia,
      an investigational new drug (IND) application to the FDA was submitted, and the study was
      determined exempt.

      Our central hypothesis is that through reductions in aquaporin-4 (AQP4) expression, the early
      use of conivaptan will reduce CE while also being safe to the patient. Our long term goal is
      to show that early use of conivaptan in ICH will reduce CE. If this reduction is possible, we
      hypothesize improved outcome and reducing the need for rescue therapies, ICU length of stay,
      and overall treatment cost will follow. However, more data is needed to evaluate the dosing
      and amount of drug. With respect to conivaptan's efficacy in correction of hyponatremia, a
      direct dose-response relationship exists. Further, this effect was more noted at milder
      degrees of hyponatremia.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Patient Tolerance of Conivaptan
time frame: Baseline to 168 hours post-enrollment
description: The number of participants with abnormal seizure activity and/or abnormal lab values and/or increase in infection rate and/or any drug-related adverse events.
measure: In-hospital Mortality
time frame: Enrollment through hospital discharge, up to 3 weeks
description: All-cause deaths during hospitalization
measure: Change in Cerebral Edema
time frame: Baseline to 168 hours post-enrollment
description: Changes in cerebral edema (CE) as measured on CT. Goal is a -5 to -10% change in CE over time. Change will be measured both as absolute change in volume, calculated as the final volume minus the baseline volume measure and converted to a percentage of the baseline volume measure.
measure: Cost
time frame: Enrollment through hospital discharge, up to 3 weeks
description: Cost as measured by length of stay in the neuro ICU.
measure: Cost
time frame: Baseline to 168 hours post-enrollment
description: Cost as measured by:
Need for external ventricular drain (EVD)/bolt or surgical procedures (craniectomy, clot evacuation,VPS) for reduction/management of CE.
Need for central venous lines, arterial lines, peripherally inserted central venous catheter (PICC) lines, tracheostomy/percutaneous endoscopic gastrostomies (PEGs).
Number of patients requiring a ventilator.
measure: Modified Rankin Scale (mRS) Score
time frame: At discharge from ICU and from hospital, up to 3 weeks
description: Modified Rankin Scale (0 to 6) at discharge from the hospital. A score of 0 indicates no disability and a score of 6 indicates the patient died. Functional independence is defined as a score of 2 or less.
arm group label: Conivaptan Treatment Group
arm group type: Experimental
description: All seven patients in this arm will receive conivaptan as described in Interventions.
intervention type: Drug
intervention name: Conivaptan
description: Patients will receive 20mg IV of the study drug every 12 hours equaling 40mg/day over 2 days (4 doses total), in addition to the standardized ICH management targets using the PI's version of standardized ICH management targets.Usual standard of care can include sedation and analgesia as needed, elevation of the head of the bed, mannitol and/or saline as needed to reduce ICP, and temperature control with antipyretics such as acetaminophen.
The conivaptan bolus (20mg), which is premixed with 100ml of 5% dextrose in water, is infused (peripherally) over 30 minutes, most commonly through an already placed central line.
arm group label: Conivaptan Treatment Group
other name: Vaprisol
criteria: 
gender: All
minimum age: 19 Years
maximum age: 79 Years
healthy volunteers: No
last name: Jesse J Corry, MD
role: Principal Investigator
affiliation: Allina Health
facility: 
country: United States
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responsible party type: Sponsor-Investigator
investigator affiliation: Allina Health System
investigator full name: Jesse Corry
investigator title: Neurologist
mesh term: Cerebral Hemorrhage
mesh term: Brain Edema
mesh term: Hemorrhage
mesh term: Edema
mesh term: Conivaptan
sharing ipd: No
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