<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/NCT01660672</url>
  </required_header>
  <id_info>
    <org_study_id>LVT1R01NS074409</org_study_id>
    <secondary_id>1R01NS074409-01A1</secondary_id>
    <nct_id>NCT01660672</nct_id>
  </id_info>
  <brief_title>Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria</brief_title>
  <acronym>LVT1</acronym>
  <official_title>A Dose-Escalation, Safety And Feasibility Study Of Enteral Levetiracetam For Seizure Control In Pediatric Cerebral Malaria</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Rochester</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Neurological Disorders and Stroke (NINDS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Rochester</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Pediatric cerebral malaria (CM) affects more than 3 million children each year killing ~20%&#xD;
      and leaving one third of survivors with long term neurologic and psychiatric sequelae.&#xD;
      Seizures occur commonly with CM and are associated with an increased risk of death and&#xD;
      neuropsychiatric disabilities. In this Malawi-based, dose- escalation, safety and feasibility&#xD;
      study of enteral levetiracetam in pediatric CM, the investigators will lay the groundwork for&#xD;
      future efficacy studies aimed at improving seizure control and ultimately decreasing the&#xD;
      neurologic morbidity of pediatric CM.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cerebral malaria (CM) affects ~3 million children each year, primarily in sub-Saharan Africa.&#xD;
      Antimalarial medications can rapidly clear P. falciparum parasites, but mortality rates&#xD;
      remain high (12-25%). Survivors do not escape unscathed--~30% experience neurologic sequelae&#xD;
      including epilepsy, behavioral disorders and gross neurologic deficits. Acute seizures occur&#xD;
      commonly in CM and are associated with higher neurologic morbidity and mortality. Seizure&#xD;
      management in malaria endemic regions is challenging because the available antiepileptic&#xD;
      drugs (AED) induce respiratory suppression and assisted ventilation is unavailable. More&#xD;
      optimal seizure control may improve neurologic outcomes in pediatric CM survivors, especially&#xD;
      if the medication used is affordable and can be delivered safely and easily in resource&#xD;
      limited settings. The investigators propose to conduct a dose- escalation, safety and&#xD;
      feasibility study of enteral levetiracetam (LVT) for seizure control in children with CM and&#xD;
      seizures admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Enteral LVT given&#xD;
      via nasogastric tube (NGT) rather than an intravenous (IV) formulation will be used since LVT&#xD;
      has excellent enteral bioavailability and IV formations are not affordable in most&#xD;
      malaria-endemic regions. LVT will be escalated based upon efficacy and toxicity endpoints&#xD;
      with efficacy defined as seizure freedom in 75% of children during the 24 hours post LVT&#xD;
      administration. Generally, only ~20% of children admitted with CM and seizures who receive&#xD;
      standard AED treatment remain seizure free during the first 24 hours after admission. Safety&#xD;
      assessments will include monitoring for problems related to NGT placement and medication&#xD;
      delivery, laboratory parameters at 24 hours and 7 days post LVT, and overall case fatality&#xD;
      rates. If efficacy endpoints are not met but enteral LVT is otherwise tolerated, LVT doses of&#xD;
      ~3 times the standard dose used for other seizure-related conditions will be assessed.&#xD;
      Pharmacokinetic (Pk) data on the absorption and elimination of LVT in CM will be obtained&#xD;
      since enteral formulations are not typically used in critically ill children and malaria has&#xD;
      been shown to impact drug absorption and elimination for some other medications. The safety,&#xD;
      feasibility, Pk, optimal dosing and preliminary efficacy data from this proposed work will&#xD;
      provide the information needed to determine whether to proceed with a randomized clinical&#xD;
      trial of LVT in pediatric CM patients which would include acute seizure control as well as&#xD;
      long term neurologic outcomes as critical endpoints. Since enteral LVT is relatively&#xD;
      affordable for short-term use and could be feasibly delivered in resource limited settings,&#xD;
      this therapy could potentially be scaled up for broad use throughout malaria endemic African&#xD;
      countries&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2013</start_date>
  <completion_date type="Actual">July 2013</completion_date>
  <primary_completion_date type="Actual">July 2013</primary_completion_date>
  <phase>Phase 1/Phase 2</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>Freedom From Seizure</measure>
    <time_frame>24 hours</time_frame>
    <description>Number of subjects free of seizure at 24 hours after initiation of treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Toxicity Related to LVT</measure>
    <time_frame>1 week</time_frame>
    <description>Toxicity including vomiting, aspiration, complications related to the NGT, laboratory parameters at 24 hours and 1 week post LVT administration, and an overall acute case fatality rate significantly above the consistent historical ward average for CM. Pk studies to evaluate LVT absorption and elimination in pediatric CM.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Range of Plasma Concentration of LVT Across All Individuals</measure>
    <time_frame>72 hours</time_frame>
    <description>Range of plasma LVT concentrations will be determined through HPLC method at eight timepoints post administration to evaluate LVT absorption and elimination in pediatric CM.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of Participants With Neurologic Sequelae at Discharge</measure>
    <time_frame>day 7</time_frame>
    <description>Number of participants with neurologic sequelae at discharge</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Subjects With Retinopathy at Enrollment</measure>
    <time_frame>Upon admission</time_frame>
    <description>Retinopathy status may impact LVT efficacy and subject status will be analyzed based on this characteristic.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Subjects Exposed to Phenobarbitone Prior to Enrollment</measure>
    <time_frame>0 hour</time_frame>
    <description>Pre-enrollment exposure to phenobarbitone may impact LVT efficacy, and analysis base on this characteristic will be evaluated.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Participants Requiring AED During Admission</measure>
    <time_frame>7 days</time_frame>
    <description>Number of participants who required AEDS during admission(including for breakthrough seizures in the LVT group) during admission.</description>
  </other_outcome>
  <other_outcome>
    <measure>Mean Time to Return to a BCS Score Greater Than or Equal to 4</measure>
    <time_frame>7 days</time_frame>
    <description>Mean time from admission to a BCS score greater than or equal to 4. The BCS (Blantyre Coma Scale) is a 0-5 scale measuring motor response, verbal response and eye movement assessing the severity of coma in children with cerebral malaria. Lower scores correspond to more profound coma.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">7</enrollment>
  <condition>Seizure</condition>
  <condition>Epilepsy</condition>
  <condition>Cerebral Malaria</condition>
  <arm_group>
    <arm_group_label>LEVETIRACETAM</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Open label, dose escalation to optimal dose.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>LEVETIRACETAM</intervention_name>
    <description>liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose. If primary outcome is not reached, dose escalation to 150, 225, and 300% standard, as needed, will be conducted.</description>
    <arm_group_label>LEVETIRACETAM</arm_group_label>
    <other_name>Keppra</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Comatose with Blantyre Comas Score ≤ 3&#xD;
&#xD;
          -  P. falciparum parasitemia&#xD;
&#xD;
          -  Active seizure&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Serum creatinine &gt; 2mg/dL&#xD;
&#xD;
          -  Pre-admission/concomitant treatment with antiretroviral medications for HIV (ARVs),&#xD;
             antituberculous treatments(ATTs), or chronic use of any other enzyme-inducing&#xD;
             medications&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>6 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gretchen L Birbeck, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Rochester</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Queen Elizabeth Central Hospital</name>
      <address>
        <city>Blantyre</city>
        <zip>3</zip>
        <country>Malawi</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Malawi</country>
  </location_countries>
  <verification_date>August 2016</verification_date>
  <study_first_submitted>July 19, 2012</study_first_submitted>
  <study_first_submitted_qc>August 6, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 9, 2012</study_first_posted>
  <results_first_submitted>August 11, 2014</results_first_submitted>
  <results_first_submitted_qc>October 16, 2014</results_first_submitted_qc>
  <results_first_posted type="Estimate">October 17, 2014</results_first_posted>
  <last_update_submitted>August 3, 2016</last_update_submitted>
  <last_update_submitted_qc>August 3, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 15, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Rochester</investigator_affiliation>
    <investigator_full_name>Gretchen Birbeck</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Malaria</mesh_term>
    <mesh_term>Malaria, Cerebral</mesh_term>
    <mesh_term>Seizures</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Levetiracetam</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>LEVETIRACETAM</title>
          <description>Open label, dose escalation to optimal dose.&#xD;
LEVETIRACETAM: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose. If primary outcome is not reached, dose escalation to 150, 225, and 300% standard, as needed, will be conducted.</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>LEVETIRACETAM</title>
          <description>Open label, dose escalation to optimal dose.&#xD;
LEVETIRACETAM: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose. If primary outcome is not reached, dose escalation to 150, 225, and 300% standard, as needed, will be conducted.</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>months</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="40.8" lower_limit="27" upper_limit="71"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </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="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Malawi</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>Freedom From Seizure</title>
        <description>Number of subjects free of seizure at 24 hours after initiation of treatment</description>
        <time_frame>24 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>LEVETIRACETAM</title>
            <description>Open label, dose escalation to optimal dose.&#xD;
LEVETIRACETAM: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose.</description>
          </group>
        </group_list>
        <measure>
          <title>Freedom From Seizure</title>
          <description>Number of subjects free of seizure at 24 hours after initiation of treatment</description>
          <units>individuals</units>
          <param>Number</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="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Toxicity Related to LVT</title>
        <description>Toxicity including vomiting, aspiration, complications related to the NGT, laboratory parameters at 24 hours and 1 week post LVT administration, and an overall acute case fatality rate significantly above the consistent historical ward average for CM. Pk studies to evaluate LVT absorption and elimination in pediatric CM.</description>
        <time_frame>1 week</time_frame>
        <group_list>
          <group group_id="O1">
            <title>LEVETIRACETAM</title>
            <description>Open label, dose escalation to optimal dose.&#xD;
LEVETIRACETAM: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose.</description>
          </group>
        </group_list>
        <measure>
          <title>Toxicity Related to LVT</title>
          <description>Toxicity including vomiting, aspiration, complications related to the NGT, laboratory parameters at 24 hours and 1 week post LVT administration, and an overall acute case fatality rate significantly above the consistent historical ward average for CM. Pk studies to evaluate LVT absorption and elimination in pediatric CM.</description>
          <units>participants</units>
          <param>Number</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>Range of Plasma Concentration of LVT Across All Individuals</title>
        <description>Range of plasma LVT concentrations will be determined through HPLC method at eight timepoints post administration to evaluate LVT absorption and elimination in pediatric CM.</description>
        <time_frame>72 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>LEVETIRACETAM</title>
            <description>Open label, dose escalation to optimal dose.&#xD;
LEVETIRACETAM: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose.</description>
          </group>
        </group_list>
        <measure>
          <title>Range of Plasma Concentration of LVT Across All Individuals</title>
          <description>Range of plasma LVT concentrations will be determined through HPLC method at eight timepoints post administration to evaluate LVT absorption and elimination in pediatric CM.</description>
          <units>mcg/ml</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="35" lower_limit="20" upper_limit="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants With Neurologic Sequelae at Discharge</title>
        <description>Number of participants with neurologic sequelae at discharge</description>
        <time_frame>day 7</time_frame>
        <group_list>
          <group group_id="O1">
            <title>LEVETIRACETAM</title>
            <description>Open label, dose escalation to optimal dose.&#xD;
LEVETIRACETAM: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Neurologic Sequelae at Discharge</title>
          <description>Number of participants with neurologic sequelae at discharge</description>
          <units>participants</units>
          <param>Number</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="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Subjects With Retinopathy at Enrollment</title>
        <description>Retinopathy status may impact LVT efficacy and subject status will be analyzed based on this characteristic.</description>
        <time_frame>Upon admission</time_frame>
        <group_list>
          <group group_id="O1">
            <title>LEVETIRACETAM</title>
            <description>Open label, dose escalation to optimal dose.&#xD;
LEVETIRACETAM: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose. If primary outcome is not reached, dose escalation to 150, 225, and 300% standard, as needed, will be conducted.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects With Retinopathy at Enrollment</title>
          <description>Retinopathy status may impact LVT efficacy and subject status will be analyzed based on this characteristic.</description>
          <units>participants</units>
          <param>Number</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="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Subjects Exposed to Phenobarbitone Prior to Enrollment</title>
        <description>Pre-enrollment exposure to phenobarbitone may impact LVT efficacy, and analysis base on this characteristic will be evaluated.</description>
        <time_frame>0 hour</time_frame>
        <group_list>
          <group group_id="O1">
            <title>LEVETIRACETAM</title>
            <description>Open label, dose escalation to optimal dose.&#xD;
LEVETIRACETAM: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects Exposed to Phenobarbitone Prior to Enrollment</title>
          <description>Pre-enrollment exposure to phenobarbitone may impact LVT efficacy, and analysis base on this characteristic will be evaluated.</description>
          <units>participants</units>
          <param>Number</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="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants Requiring AED During Admission</title>
        <description>Number of participants who required AEDS during admission(including for breakthrough seizures in the LVT group) during admission.</description>
        <time_frame>7 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>LEVETIRACETAM</title>
            <description>Open label, dose escalation to optimal dose.&#xD;
LEVETIRACETAM: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose. If primary outcome is not reached, dose escalation to 150, 225, and 300% standard, as needed, will be conducted.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Requiring AED During Admission</title>
          <description>Number of participants who required AEDS during admission(including for breakthrough seizures in the LVT group) during admission.</description>
          <units>participants</units>
          <param>Number</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="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Mean Time to Return to a BCS Score Greater Than or Equal to 4</title>
        <description>Mean time from admission to a BCS score greater than or equal to 4. The BCS (Blantyre Coma Scale) is a 0-5 scale measuring motor response, verbal response and eye movement assessing the severity of coma in children with cerebral malaria. Lower scores correspond to more profound coma.</description>
        <time_frame>7 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>LEVETIRACETAM</title>
            <description>Open label, dose escalation to optimal dose.&#xD;
LEVETIRACETAM: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose. If primary outcome is not reached, dose escalation to 150, 225, and 300% standard, as needed, will be conducted.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Time to Return to a BCS Score Greater Than or Equal to 4</title>
          <description>Mean time from admission to a BCS score greater than or equal to 4. The BCS (Blantyre Coma Scale) is a 0-5 scale measuring motor response, verbal response and eye movement assessing the severity of coma in children with cerebral malaria. Lower scores correspond to more profound coma.</description>
          <units>hours</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="35.3" lower_limit="7" upper_limit="78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>LEVETIRACETAM</title>
          <description>Open label, dose escalation to optimal dose.&#xD;
LEVETIRACETAM: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose. This dose was effective in 7/7 children.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Electrolyte</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Hematologic abnormality</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>GI Symptoms</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>Gretchen Birbeck</name_or_title>
      <organization>University of Rochester Medical Center</organization>
      <phone>585-273-4265</phone>
      <email>Gretchen_Birbeck@URMC.Rochester.edu</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/NCT01660672
org study id: LVT1R01NS074409
secondary id: 1R01NS074409-01A1
nct id: NCT01660672
lead sponsor: 
collaborator: 
has dmc: Yes
Pediatric cerebral malaria (CM) affects more than 3 million children each year killing ~20%
      and leaving one third of survivors with long term neurologic and psychiatric sequelae.
      Seizures occur commonly with CM and are associated with an increased risk of death and
      neuropsychiatric disabilities. In this Malawi-based, dose- escalation, safety and feasibility
      study of enteral levetiracetam in pediatric CM, the investigators will lay the groundwork for
      future efficacy studies aimed at improving seizure control and ultimately decreasing the
      neurologic morbidity of pediatric CM.
Cerebral malaria (CM) affects ~3 million children each year, primarily in sub-Saharan Africa.
      Antimalarial medications can rapidly clear P. falciparum parasites, but mortality rates
      remain high (12-25%). Survivors do not escape unscathed--~30% experience neurologic sequelae
      including epilepsy, behavioral disorders and gross neurologic deficits. Acute seizures occur
      commonly in CM and are associated with higher neurologic morbidity and mortality. Seizure
      management in malaria endemic regions is challenging because the available antiepileptic
      drugs (AED) induce respiratory suppression and assisted ventilation is unavailable. More
      optimal seizure control may improve neurologic outcomes in pediatric CM survivors, especially
      if the medication used is affordable and can be delivered safely and easily in resource
      limited settings. The investigators propose to conduct a dose- escalation, safety and
      feasibility study of enteral levetiracetam (LVT) for seizure control in children with CM and
      seizures admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Enteral LVT given
      via nasogastric tube (NGT) rather than an intravenous (IV) formulation will be used since LVT
      has excellent enteral bioavailability and IV formations are not affordable in most
      malaria-endemic regions. LVT will be escalated based upon efficacy and toxicity endpoints
      with efficacy defined as seizure freedom in 75% of children during the 24 hours post LVT
      administration. Generally, only ~20% of children admitted with CM and seizures who receive
      standard AED treatment remain seizure free during the first 24 hours after admission. Safety
      assessments will include monitoring for problems related to NGT placement and medication
      delivery, laboratory parameters at 24 hours and 7 days post LVT, and overall case fatality
      rates. If efficacy endpoints are not met but enteral LVT is otherwise tolerated, LVT doses of
      ~3 times the standard dose used for other seizure-related conditions will be assessed.
      Pharmacokinetic (Pk) data on the absorption and elimination of LVT in CM will be obtained
      since enteral formulations are not typically used in critically ill children and malaria has
      been shown to impact drug absorption and elimination for some other medications. The safety,
      feasibility, Pk, optimal dosing and preliminary efficacy data from this proposed work will
      provide the information needed to determine whether to proceed with a randomized clinical
      trial of LVT in pediatric CM patients which would include acute seizure control as well as
      long term neurologic outcomes as critical endpoints. Since enteral LVT is relatively
      affordable for short-term use and could be feasibly delivered in resource limited settings,
      this therapy could potentially be scaled up for broad use throughout malaria endemic African
      countries
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Freedom From Seizure
time frame: 24 hours
description: Number of subjects free of seizure at 24 hours after initiation of treatment
measure: Toxicity Related to LVT
time frame: 1 week
description: Toxicity including vomiting, aspiration, complications related to the NGT, laboratory parameters at 24 hours and 1 week post LVT administration, and an overall acute case fatality rate significantly above the consistent historical ward average for CM. Pk studies to evaluate LVT absorption and elimination in pediatric CM.
measure: Range of Plasma Concentration of LVT Across All Individuals
time frame: 72 hours
description: Range of plasma LVT concentrations will be determined through HPLC method at eight timepoints post administration to evaluate LVT absorption and elimination in pediatric CM.
measure: Number of Participants With Neurologic Sequelae at Discharge
time frame: day 7
description: Number of participants with neurologic sequelae at discharge
measure: Number of Subjects With Retinopathy at Enrollment
time frame: Upon admission
description: Retinopathy status may impact LVT efficacy and subject status will be analyzed based on this characteristic.
measure: Number of Subjects Exposed to Phenobarbitone Prior to Enrollment
time frame: 0 hour
description: Pre-enrollment exposure to phenobarbitone may impact LVT efficacy, and analysis base on this characteristic will be evaluated.
measure: Number of Participants Requiring AED During Admission
time frame: 7 days
description: Number of participants who required AEDS during admission(including for breakthrough seizures in the LVT group) during admission.
measure: Mean Time to Return to a BCS Score Greater Than or Equal to 4
time frame: 7 days
description: Mean time from admission to a BCS score greater than or equal to 4. The BCS (Blantyre Coma Scale) is a 0-5 scale measuring motor response, verbal response and eye movement assessing the severity of coma in children with cerebral malaria. Lower scores correspond to more profound coma.
arm group label: LEVETIRACETAM
arm group type: Other
description: Open label, dose escalation to optimal dose.
intervention type: Drug
intervention name: LEVETIRACETAM
description: liquid, 40 mg/kg loading dose and 30mg/kg every 12 hours via nasogastric tube for 3 days--this is standard dose. If primary outcome is not reached, dose escalation to 150, 225, and 300% standard, as needed, will be conducted.
arm group label: LEVETIRACETAM
other name: Keppra
criteria: 
gender: All
minimum age: 2 Years
maximum age: 6 Years
healthy volunteers: No
last name: Gretchen L Birbeck, M.D.
role: Principal Investigator
affiliation: University of Rochester
facility: 
country: Malawi
responsible party type: Principal Investigator
investigator affiliation: University of Rochester
investigator full name: Gretchen Birbeck
investigator title: Professor
mesh term: Malaria
mesh term: Malaria, Cerebral
mesh term: Seizures
mesh term: Levetiracetam
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 