<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/NCT02188576</url>
  </required_header>
  <id_info>
    <org_study_id>P00008434</org_study_id>
    <nct_id>NCT02188576</nct_id>
  </id_info>
  <brief_title>The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery</brief_title>
  <official_title>The Efficacy and Population Pharmacokinetics/ Pharmacogenomics of a Reduced Dose of Tranexamic Acid for Craniosynostosis Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boston Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boston Children's Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is being performed to evaluate two different doses of Tranexamic acid&#xD;
      (TXA) in children who have craniosynostosis and have been referred to Boston Children's&#xD;
      Hospital for corrective surgery. This surgery is associated with significant blood loss and&#xD;
      frequently requires the transfusion of blood. TXA is a medication that reduces the amount of&#xD;
      bleeding during surgery by improving clotting of the blood at the surgical site. TXA is an&#xD;
      FDA-approved drug that is routinely used in infants and children undergoing major surgery&#xD;
      including heart surgery, craniofacial surgery and scoliosis surgery. It has been shown to&#xD;
      decrease both the amount of bleeding and the amount of blood transfusion needed. We would&#xD;
      like to compare the different doses of TXA to see if a lower dose has the same effect on&#xD;
      blood loss as a higher dose. We are also interested to learn why TXA seems to work better in&#xD;
      some patients than in others. In order to study the effect of this drug we would like to give&#xD;
      this drug to your child and measure the blood loss and the volume of blood given to your&#xD;
      child during his/her surgery.&#xD;
&#xD;
      The research is being done at two sites; Boston Children's Hospital and Gaslini Children's&#xD;
      Hospital in Genoa, Italy. The main study doctor from Boston Children's Hospital is Dr. Susan&#xD;
      Goobie. The Department of Anesthesiology at Boston Children's Hospital is sponsoring this&#xD;
      study.&#xD;
&#xD;
      We are planning to study a total of 68 infants and children from age 3 months to 6 years old&#xD;
      scheduled for open craniosynostosis surgery at Boston Children's Hospital or Gaslini&#xD;
      Children's Hospital.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction: Over 90% of open craniosynostosis surgical procedures are associated with a&#xD;
      transfusion of blood or blood products. Goobie et. al. recently showed that tranexamic acid&#xD;
      in a dose of 50 mg/kg/15min and 5 mg/kg/h significantly reduced blood loss and transfusion&#xD;
      requirements as well as the overall exposure of children to donor PRBC by two thirds.&#xD;
      However, using a moderately high dosing regimen, TXA plasma concentrations were shown to far&#xD;
      exceed the accepted therapeutic level (by over 10 fold). No side effects of TXA were found in&#xD;
      this study but a recent study suggests that currently recommended high to moderate TXA dosing&#xD;
      regimens are potentially associated with neurological complications in children. Goobie et.&#xD;
      al. developed a population pharmacokinetic model of TXA and simulated a dose response curve&#xD;
      for this population. From this model and simulation, it appears that reducing the loading&#xD;
      dose to 10 mg/kg/15 min followed by a 5 mg/kg/h infusion is adequate to maintain plasma&#xD;
      concentrations above the accepted therapeutic level of 20ug/mL.&#xD;
&#xD;
      It is important to test and validate this reduced dosage scheme in a multicenter study. The&#xD;
      hypothesis is that this reduced dosage scheme (10 mg/kg loading dose and 5 ug/kg/h) is as&#xD;
      effective as the higher dosage scheme (50 mg/kg loading dose and 5 mg/kg/h) in decreasing&#xD;
      blood loss and transfusion requirements in children undergoing open craniosynostosis surgery.&#xD;
      Thus the PK/PD profile of TXA in craniosynostosis patients will be determined with genomics&#xD;
      explored as a cause of interpatient variability in the response to tranexamic acid.&#xD;
&#xD;
      Experimental Design: With IRB approval and informed consent 68 pediatric patients aged 3 m to&#xD;
      6 years coming for open craniofacial surgery will be randomized in a prospective double blind&#xD;
      fashion to either the current standard intravenous TXA dose (50mg/kg/15min and 5 mg/kg/h) or&#xD;
      this lower TXA dose (10 mg/kg/15min and 5 mg/kg/h) until the end of surgery. A standardized&#xD;
      anesthetic and well defined fluid, blood and blood product management protocols will be&#xD;
      followed with improved modifications from the previously described protocol.&#xD;
&#xD;
      Data Analysis Plan: A preliminary power analysis indicated that a total sample size of 56&#xD;
      children (28 in randomized each group) would provide 80% statistical power to test whether&#xD;
      the difference in average blood loss is equivalent to within 25% (ie 15 cc/kg) assuming a&#xD;
      standard deviation of 30% ie +/- 22 ml/kg (moderate effect size = 0.68) . We plan to&#xD;
      randomize 68 patients; 34 per group to ensure that we meet our sample size requirements while&#xD;
      accounting for a potential 20% patient drop out.&#xD;
&#xD;
      Specific Aims:&#xD;
&#xD;
        1. Determine the efficacy of TXA (PD) in infants and children undergoing open craniofacial&#xD;
           surgery with this lower dosage scheme.&#xD;
&#xD;
        2. Determine the population pharmacokinetics (PK) of TXA in infants and children undergoing&#xD;
           open craniofacial surgery with this dosage scheme.&#xD;
&#xD;
        3. Determine the influence of genetics on response to TXA.&#xD;
&#xD;
        4. Attempt to better define efficacy of TXA in a direct manner using a novel and innovative&#xD;
           approach by obtaining pre and post biological markers of fibrinolysis (as bleeding and&#xD;
           blood loss are difficult to measure accurately and are an indirect measure of TXA&#xD;
           efficacy of inhibition of fibrinolysis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">January 2018</completion_date>
  <primary_completion_date type="Actual">December 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy of TXA in Childrens Having Craniosynostosis Surgery</measure>
    <time_frame>perioperatively from the intraoperative period to 24 hours postoperatively</time_frame>
    <description>Determine the efficacy ( as measured by blood loss and blood transfusion) of TXA in infants and children undergoing open craniofacial surgery with this lower dosage scheme.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma Levels of TXA in Children Having Craniosynostosis Surgery</measure>
    <time_frame>up to 24h postoperatively</time_frame>
    <description>Determine the plasma levels (in micrograms/mL) of TXA in infants and children undergoing open craniofacial surgery with this dosage scheme</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">66</enrollment>
  <condition>Craniosynostosis</condition>
  <arm_group>
    <arm_group_label>high dose TXA</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>High dose TXA is the intervention.&#xD;
A higher dose of tranexamic acid will be given to this arm as follows:&#xD;
50 mg/kg loading dose and 5 mg/kg/h infusion</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Low Dose TXA</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Low dose TXA is the intervention.&#xD;
A lower dose of TXa will be given as follows:&#xD;
10 mg/kg loading dose and 5 mg/kg/h infusion</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>high dose TXA</intervention_name>
    <arm_group_label>high dose TXA</arm_group_label>
    <other_name>Tranexamic acid, Cyclokapron</other_name>
    <other_name>Craniofacial surgery</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Low dose TXA</intervention_name>
    <arm_group_label>Low Dose TXA</arm_group_label>
    <other_name>Tranexamic Acid, cyclokapron,</other_name>
    <other_name>Craniofacial surgery</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients (age range 3 months to 6 years) undergoing craniosynostosis repair,&#xD;
             fronto-orbital advancement surgery and cranial remodeling surgery (i.e. total cavernal&#xD;
             remodeling surgery).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Preexisting hematological abnormality (defined as a positive history of bleeding&#xD;
             disorder or a known diagnosis of a genetic or acquired bleeding disorder)&#xD;
&#xD;
          -  Preexisting coagulation defect (defined as PT, PTT or INR &gt;1.5 times normal or a n&#xD;
             pre-existing genetic or acquired coagulation defect))&#xD;
&#xD;
          -  Preexisting hepatic, renal, vascular, ocular and/or metabolic disorder&#xD;
&#xD;
          -  History of acetylsalicylate ingestion within the last 14 days.&#xD;
&#xD;
          -  History of NSAIDs ingestion with 2 days of the scheduled surgery date&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Months</minimum_age>
    <maximum_age>6 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Susan Goobie, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Boston Children's Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Nicola Disma, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Gaslini Children's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Boston Children's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>July 10, 2014</study_first_submitted>
  <study_first_submitted_qc>July 10, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 11, 2014</study_first_posted>
  <results_first_submitted>November 20, 2019</results_first_submitted>
  <results_first_submitted_qc>January 22, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">January 31, 2020</results_first_posted>
  <last_update_submitted>January 22, 2020</last_update_submitted>
  <last_update_submitted_qc>January 22, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 31, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Boston Children's Hospital</investigator_affiliation>
    <investigator_full_name>Susan Goobie</investigator_full_name>
    <investigator_title>Senior Assistant in Perioperative Anesthesia</investigator_title>
  </responsible_party>
  <keyword>Craniofacial Surgery</keyword>
  <keyword>tranexamic acid</keyword>
  <keyword>Antifibrinolytic</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Craniosynostoses</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tranexamic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 3, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/76/NCT02188576/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The recruitment locations were the preoperative clinics at Boston Children's Hospital (Boston, MA) and Gaslini Children's Hospital (Genoa, Italy) from 2014 to 2017.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>High Dose TXA</title>
          <description>High dose TXA is the intervention.&#xD;
A higher dose of tranexamic acid will be given to this arm as follows:&#xD;
50 mg/kg loading dose and 5 mg/kg/h infusion&#xD;
high dose TXA</description>
        </group>
        <group group_id="P2">
          <title>Low Dose TXA</title>
          <description>Low dose TXA is the intervention.&#xD;
A lower dose of TXa will be given as follows:&#xD;
10 mg/kg loading dose and 5 mg/kg/h infusion&#xD;
Low dose TXA</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="32"/>
                <participants group_id="P2" count="34"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="32"/>
                <participants group_id="P2" count="34"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>High Dose TXA</title>
          <description>High dose TXA is the intervention.&#xD;
A higher dose of tranexamic acid will be given to this arm as follows:&#xD;
50 mg/kg loading dose and 5 mg/kg/h infusion&#xD;
high dose TXA</description>
        </group>
        <group group_id="B2">
          <title>Low Dose TXA</title>
          <description>Low dose TXA is the intervention.&#xD;
A lower dose of TXa will be given as follows:&#xD;
10 mg/kg loading dose and 5 mg/kg/h infusion&#xD;
Low dose TXA</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="32"/>
            <count group_id="B2" value="34"/>
            <count group_id="B3" value="66"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <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="32"/>
                    <measurement group_id="B2" value="34"/>
                    <measurement group_id="B3" value="66"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>months</units>
          <param>Mean</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8" lower_limit="4" upper_limit="13.5"/>
                    <measurement group_id="B2" value="8.5" lower_limit="5" upper_limit="16"/>
                    <measurement group_id="B3" value="8.25" lower_limit="4" upper_limit="16"/>
                  </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="13"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="40"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="32"/>
                    <measurement group_id="B2" value="34"/>
                    <measurement group_id="B3" value="66"/>
                  </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>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Italy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Efficacy of TXA in Childrens Having Craniosynostosis Surgery</title>
        <description>Determine the efficacy ( as measured by blood loss and blood transfusion) of TXA in infants and children undergoing open craniofacial surgery with this lower dosage scheme.</description>
        <time_frame>perioperatively from the intraoperative period to 24 hours postoperatively</time_frame>
        <population>To determine if a tranexamic acid dose regimen of 10 mg/kg loading dose and 5 mg/kg/h maintenance dose is as effective as a higher dose regime of 50 mg/kg loading dose and 5 mg/kg/h maintenance infusion rate in reducing blood transfusion volume in pediatric craniosynostosis reconstruction surgery.</population>
        <group_list>
          <group group_id="O1">
            <title>High Dose TXA</title>
            <description>High dose TXA is the intervention.&#xD;
A higher dose of tranexamic acid will be given to this arm as follows:&#xD;
50 mg/kg loading dose and 5 mg/kg/h infusion&#xD;
high dose TXA&#xD;
Outcome: A tranexamic acid dose regimen of 10 mg/kg loading dose and 5 mg/kg/h maintenance dose is as effective as a higher dose regime of 50 mg/kg loading dose and 5 mg/kg/h maintenance infusion rate in reducing blood loss and transfusion requirements in pediatric craniosynostosis reconstruction surgery.</description>
          </group>
          <group group_id="O2">
            <title>Low Dose TXA</title>
            <description>Low dose TXA is the intervention.&#xD;
A lower dose of TXa will be given as follows:&#xD;
10 mg/kg loading dose and 5 mg/kg/h infusion&#xD;
Low dose TXA&#xD;
Outcome: A tranexamic acid dose regimen of 10 mg/kg loading dose and 5 mg/kg/h maintenance dose is as effective as a higher dose regime of 50 mg/kg loading dose and 5 mg/kg/h maintenance infusion rate in reducing blood loss and transfusion requirements in pediatric craniosynostosis reconstruction surgery.</description>
          </group>
        </group_list>
        <measure>
          <title>Efficacy of TXA in Childrens Having Craniosynostosis Surgery</title>
          <description>Determine the efficacy ( as measured by blood loss and blood transfusion) of TXA in infants and children undergoing open craniofacial surgery with this lower dosage scheme.</description>
          <population>To determine if a tranexamic acid dose regimen of 10 mg/kg loading dose and 5 mg/kg/h maintenance dose is as effective as a higher dose regime of 50 mg/kg loading dose and 5 mg/kg/h maintenance infusion rate in reducing blood transfusion volume in pediatric craniosynostosis reconstruction surgery.</population>
          <units>mL/kg</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="34"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23.6" spread="1.5"/>
                    <measurement group_id="O2" value="21.3" spread="1.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Levels of TXA in Children Having Craniosynostosis Surgery</title>
        <description>Determine the plasma levels (in micrograms/mL) of TXA in infants and children undergoing open craniofacial surgery with this dosage scheme</description>
        <time_frame>up to 24h postoperatively</time_frame>
        <group_list>
          <group group_id="O1">
            <title>High Dose TXA</title>
            <description>High dose TXA is the intervention.&#xD;
A higher dose of tranexamic acid will be given to this arm as follows:&#xD;
50 mg/kg loading dose and 5 mg/kg/h infusion&#xD;
high dose TXA&#xD;
Outcome: A tranexamic acid dose regimen of 10 mg/kg loading dose and 5 mg/kg/h maintenance dose is as effective as a higher dose regime of 50 mg/kg loading dose and 5 mg/kg/h maintenance infusion rate in reducing blood loss and transfusion requirements in pediatric craniosynostosis reconstruction surgery.</description>
          </group>
          <group group_id="O2">
            <title>Low Dose TXA</title>
            <description>Low dose TXA is the intervention.&#xD;
A lower dose of TXa will be given as follows:&#xD;
10 mg/kg loading dose and 5 mg/kg/h infusion&#xD;
Low dose TXA&#xD;
Outcome: A tranexamic acid dose regimen of 10 mg/kg loading dose and 5 mg/kg/h maintenance dose is as effective as a higher dose regime of 50 mg/kg loading dose and 5 mg/kg/h maintenance infusion rate in reducing blood loss and transfusion requirements in pediatric craniosynostosis reconstruction surgery.</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Levels of TXA in Children Having Craniosynostosis Surgery</title>
          <description>Determine the plasma levels (in micrograms/mL) of TXA in infants and children undergoing open craniofacial surgery with this dosage scheme</description>
          <units>ug/mL</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="34"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50.2" spread="8.0"/>
                    <measurement group_id="O2" value="29.6" spread="7.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>while the patient was in hospital which was up to a maximum of 15 days</time_frame>
      <desc>side effects including VTE, seizures</desc>
      <group_list>
        <group group_id="E1">
          <title>High Dose TXA</title>
          <description>High dose TXA is the intervention.&#xD;
A higher dose of tranexamic acid will be given to this arm as follows:&#xD;
50 mg/kg loading dose and 5 mg/kg/h infusion&#xD;
high dose TXA</description>
        </group>
        <group group_id="E2">
          <title>Low Dose TXA</title>
          <description>Low dose TXA is the intervention.&#xD;
A lower dose of TXa will be given as follows:&#xD;
10 mg/kg loading dose and 5 mg/kg/h infusion&#xD;
Low dose TXA</description>
        </group>
      </group_list>
      <serious_events>
        <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="32"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="32"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</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="32"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="34"/>
              </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. Susan Goobie, PI</name_or_title>
      <organization>Boston Childrens Hospital</organization>
      <phone>6173557737</phone>
      <email>susan.goobie@childrens.harvard.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/NCT02188576
org study id: P00008434
nct id: NCT02188576
lead sponsor: 
has dmc: Yes
This research study is being performed to evaluate two different doses of Tranexamic acid
      (TXA) in children who have craniosynostosis and have been referred to Boston Children's
      Hospital for corrective surgery. This surgery is associated with significant blood loss and
      frequently requires the transfusion of blood. TXA is a medication that reduces the amount of
      bleeding during surgery by improving clotting of the blood at the surgical site. TXA is an
      FDA-approved drug that is routinely used in infants and children undergoing major surgery
      including heart surgery, craniofacial surgery and scoliosis surgery. It has been shown to
      decrease both the amount of bleeding and the amount of blood transfusion needed. We would
      like to compare the different doses of TXA to see if a lower dose has the same effect on
      blood loss as a higher dose. We are also interested to learn why TXA seems to work better in
      some patients than in others. In order to study the effect of this drug we would like to give
      this drug to your child and measure the blood loss and the volume of blood given to your
      child during his/her surgery.

      The research is being done at two sites; Boston Children's Hospital and Gaslini Children's
      Hospital in Genoa, Italy. The main study doctor from Boston Children's Hospital is Dr. Susan
      Goobie. The Department of Anesthesiology at Boston Children's Hospital is sponsoring this
      study.

      We are planning to study a total of 68 infants and children from age 3 months to 6 years old
      scheduled for open craniosynostosis surgery at Boston Children's Hospital or Gaslini
      Children's Hospital.
Introduction: Over 90% of open craniosynostosis surgical procedures are associated with a
      transfusion of blood or blood products. Goobie et. al. recently showed that tranexamic acid
      in a dose of 50 mg/kg/15min and 5 mg/kg/h significantly reduced blood loss and transfusion
      requirements as well as the overall exposure of children to donor PRBC by two thirds.
      However, using a moderately high dosing regimen, TXA plasma concentrations were shown to far
      exceed the accepted therapeutic level (by over 10 fold). No side effects of TXA were found in
      this study but a recent study suggests that currently recommended high to moderate TXA dosing
      regimens are potentially associated with neurological complications in children. Goobie et.
      al. developed a population pharmacokinetic model of TXA and simulated a dose response curve
      for this population. From this model and simulation, it appears that reducing the loading
      dose to 10 mg/kg/15 min followed by a 5 mg/kg/h infusion is adequate to maintain plasma
      concentrations above the accepted therapeutic level of 20ug/mL.

      It is important to test and validate this reduced dosage scheme in a multicenter study. The
      hypothesis is that this reduced dosage scheme (10 mg/kg loading dose and 5 ug/kg/h) is as
      effective as the higher dosage scheme (50 mg/kg loading dose and 5 mg/kg/h) in decreasing
      blood loss and transfusion requirements in children undergoing open craniosynostosis surgery.
      Thus the PK/PD profile of TXA in craniosynostosis patients will be determined with genomics
      explored as a cause of interpatient variability in the response to tranexamic acid.

      Experimental Design: With IRB approval and informed consent 68 pediatric patients aged 3 m to
      6 years coming for open craniofacial surgery will be randomized in a prospective double blind
      fashion to either the current standard intravenous TXA dose (50mg/kg/15min and 5 mg/kg/h) or
      this lower TXA dose (10 mg/kg/15min and 5 mg/kg/h) until the end of surgery. A standardized
      anesthetic and well defined fluid, blood and blood product management protocols will be
      followed with improved modifications from the previously described protocol.

      Data Analysis Plan: A preliminary power analysis indicated that a total sample size of 56
      children (28 in randomized each group) would provide 80% statistical power to test whether
      the difference in average blood loss is equivalent to within 25% (ie 15 cc/kg) assuming a
      standard deviation of 30% ie +/- 22 ml/kg (moderate effect size = 0.68) . We plan to
      randomize 68 patients; 34 per group to ensure that we meet our sample size requirements while
      accounting for a potential 20% patient drop out.

      Specific Aims:

        1. Determine the efficacy of TXA (PD) in infants and children undergoing open craniofacial
           surgery with this lower dosage scheme.

        2. Determine the population pharmacokinetics (PK) of TXA in infants and children undergoing
           open craniofacial surgery with this dosage scheme.

        3. Determine the influence of genetics on response to TXA.

        4. Attempt to better define efficacy of TXA in a direct manner using a novel and innovative
           approach by obtaining pre and post biological markers of fibrinolysis (as bleeding and
           blood loss are difficult to measure accurately and are an indirect measure of TXA
           efficacy of inhibition of fibrinolysis.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Efficacy of TXA in Childrens Having Craniosynostosis Surgery
time frame: perioperatively from the intraoperative period to 24 hours postoperatively
description: Determine the efficacy ( as measured by blood loss and blood transfusion) of TXA in infants and children undergoing open craniofacial surgery with this lower dosage scheme.
measure: Plasma Levels of TXA in Children Having Craniosynostosis Surgery
time frame: up to 24h postoperatively
description: Determine the plasma levels (in micrograms/mL) of TXA in infants and children undergoing open craniofacial surgery with this dosage scheme
arm group label: high dose TXA
arm group type: Experimental
description: High dose TXA is the intervention.
A higher dose of tranexamic acid will be given to this arm as follows:
50 mg/kg loading dose and 5 mg/kg/h infusion
arm group label: Low Dose TXA
arm group type: Experimental
description: Low dose TXA is the intervention.
A lower dose of TXa will be given as follows:
10 mg/kg loading dose and 5 mg/kg/h infusion
intervention type: Drug
intervention name: high dose TXA
arm group label: high dose TXA
other name: Tranexamic acid, Cyclokapron
other name: Craniofacial surgery
intervention type: Drug
intervention name: Low dose TXA
arm group label: Low Dose TXA
other name: Tranexamic Acid, cyclokapron,
other name: Craniofacial surgery
criteria: 
gender: All
minimum age: 3 Months
maximum age: 6 Years
healthy volunteers: No
last name: Susan Goobie, MD
role: Principal Investigator
affiliation: Boston Children's Hospital
last name: Nicola Disma, MD
role: Principal Investigator
affiliation: Gaslini Children's Hospital
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Boston Children's Hospital
investigator full name: Susan Goobie
investigator title: Senior Assistant in Perioperative Anesthesia
mesh term: Craniosynostoses
mesh term: Tranexamic Acid
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 