<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/NCT02229968</url>
  </required_header>
  <id_info>
    <org_study_id>PRO00004263</org_study_id>
    <nct_id>NCT02229968</nct_id>
  </id_info>
  <brief_title>Efficacy of Amicar for Children Having Craniofacial Surgery</brief_title>
  <official_title>Efficacy of ε-Aminocaproic Acid (EACA) in Children Undergoing Craniofacial Reconstruction Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's National Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Children's National Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine whether Amicar (ε-aminocaproic acid) is effective&#xD;
      in reducing blood loss in children undergoing craniofacial reconstruction surgery.&#xD;
&#xD;
      The investigators hypothesize that Amicar will decrease intraoperative blood loss and&#xD;
      decrease the need for perioperative blood product administration in children undergoing&#xD;
      craniofacial surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Craniosynostosis is a condition in which there is premature fusion of one or more of the&#xD;
      sutures between the bones of the skull. Premature fusion of sutures in the skull limits the&#xD;
      ability of the cranial vault to expand to accommodate the rapidly growing brain in infancy&#xD;
      and early childhood and leads to bony deformation. Left uncorrected, craniosynostosis may&#xD;
      adversely impact both neurologic and psychosocial development and in some cases, can result&#xD;
      in high intracranial pressure and blindness.&#xD;
&#xD;
      Craniofacial (CF) reconstructive surgery is performed in young children with craniosynostosis&#xD;
      to improve physical appearance, prevent functional neurologic disturbances, and enhance&#xD;
      psychosocial development. Due to the complexities of the surgery as well as the young age and&#xD;
      size of the patients, CF reconstruction carries potential life threatening risks and can&#xD;
      result in significant morbidity. Reported complications include massive intraoperative&#xD;
      hemorrhage, intraoperative cardiac arrest, transfusion-related reactions, venous air&#xD;
      embolism, hypotension, coagulopathy, bradycardia, postoperative seizures, surgical site&#xD;
      infections, facial swelling with airway compromise, and unplanned postoperative mechanical&#xD;
      ventilation. The most severe and most common perioperative issues relate to the rate and&#xD;
      extent of blood loss.&#xD;
&#xD;
      Fibrinolysis, which impairs adequate hemostasis, has been shown to occur in children during&#xD;
      CF reconstruction. This most certainly contributes to the magnitude of blood loss in these&#xD;
      types of operations. Thus, targeting this defect in clot hemostasis with the use of&#xD;
      antifibrinolytics is a reasonable therapeutic approach.&#xD;
&#xD;
      Amicar (ε-aminocaproic acid) is a synthetic lysine analog that blocks the lysine binding&#xD;
      sites on plasminogen, resulting in antifibrinolytic activity through inhibition of plasmin&#xD;
      formation. We have chosen to study Amicar in this clinical context for a number of reasons.&#xD;
      First, major hemorrhage continues to be a significant perioperative issue in this cohort.&#xD;
      Secondly, Amicar is commonly and safely administered to children undergoing other types of&#xD;
      high-risk surgery (i.e., spinal fusion surgery and open heart surgery). In addition, Amicar&#xD;
      is inexpensive and easily administered, making it a viable and novel therapeutic option if&#xD;
      shown to be effective for this type of surgery.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>October 2014</start_date>
  <completion_date type="Anticipated">March 2025</completion_date>
  <primary_completion_date type="Anticipated">January 2025</primary_completion_date>
  <phase>Phase 2</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>Intraoperative blood loss</measure>
    <time_frame>within the first 72 hours after surgery</time_frame>
    <description>As estimated blood loss is known to be inaccurate in this setting, mean intraoperative blood loss (in mL/kg) will be calculated using a formula previously described in this population.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Blood donor exposure</measure>
    <time_frame>within the first 30 days after surgery</time_frame>
    <description>To establish that intraoperative administration of Amicar decreases perioperative blood donor exposure and need for transfusion following craniofacial reconstructive surgery</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Craniosynostosis</condition>
  <arm_group>
    <arm_group_label>Amicar (ε-aminocaproic acid)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Treatment group 1: Amicar 100 mg/kg (0.4 mL/kg) IV loading dose, followed by an intraoperative continuous infusion at 40 mg/kg/hr (0.16 mL/kg/hr) to be continued until skin closure.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>normal saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Treatment group 2: Equal volume of normal saline (placebo control) at the same rate as treatment group 1.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Amicar (ε-aminocaproic acid)</intervention_name>
    <arm_group_label>Amicar (ε-aminocaproic acid)</arm_group_label>
    <other_name>Amicar</other_name>
    <other_name>6-aminohexanoic acid</other_name>
    <other_name>epsilon aminocaproic acid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>normal saline</intervention_name>
    <arm_group_label>normal saline</arm_group_label>
    <other_name>normal saline 0.9%</other_name>
    <other_name>placebo</other_name>
    <other_name>placebo control</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Any child diagnosed with craniosynostosis in need of surgical repair&#xD;
&#xD;
          -  Males and females between the ages of 2 - 36 months (minorities will be included)&#xD;
&#xD;
          -  Surgical procedure involving complex craniofacial reconstruction and craniotomy&#xD;
&#xD;
          -  Written informed consent from parent/guardian&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects with known or suspected hypersensitivity reaction to Amicar or history of&#xD;
             prior Amicar exposure&#xD;
&#xD;
          -  Presence or prior history of a known coagulation disorder or hypercoagulable state&#xD;
&#xD;
          -  Preoperative laboratory values that indicate clinically significant hematologic&#xD;
             disease (hemoglobin, platelet count, prothrombin time, or partial thromboplastin time&#xD;
             outside of normal range)&#xD;
&#xD;
          -  Subjects who are on anticoagulant therapy (Coumadin, heparin, aspirin, etc.)&#xD;
&#xD;
          -  Subjects with a prior history of a thrombotic event&#xD;
&#xD;
          -  History of renal malformation&#xD;
&#xD;
          -  Presence of hematuria&#xD;
&#xD;
          -  History of abnormal renal function - serum creatinine or blood urea nitrogen (BUN)&#xD;
             value greater than 1.5 times the upper limit of the normal range&#xD;
&#xD;
          -  Craniofacial reconstruction surgery performed in conjunction with an additional&#xD;
             surgical procedure associated with blood loss&#xD;
&#xD;
          -  Subjects who have been previously enrolled in this protocol may not be enrolled again&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Months</minimum_age>
    <maximum_age>36 Months</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Srijaya K Reddy, MD, MBA</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Stricker PA, Zuppa AF, Fiadjoe JE, Maxwell LG, Sussman EM, Pruitt EY, Goebel TK, Gastonguay MR, Taylor JA, Bartlett SP, Schreiner MS. Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery. Br J Anaesth. 2013 May;110(5):788-99. doi: 10.1093/bja/aes507. Epub 2013 Jan 25.</citation>
    <PMID>23353035</PMID>
  </reference>
  <reference>
    <citation>Faberowski LW, Black S, Mickle JP. Blood loss and transfusion practice in the perioperative management of craniosynostosis repair. J Neurosurg Anesthesiol. 1999 Jul;11(3):167-72. doi: 10.1097/00008506-199907000-00002.</citation>
    <PMID>10414670</PMID>
  </reference>
  <reference>
    <citation>Stricker PA, Shaw TL, Desouza DG, Hernandez SV, Bartlett SP, Friedman DF, Sesok-Pizzini DA, Jobes DR. Blood loss, replacement, and associated morbidity in infants and children undergoing craniofacial surgery. Paediatr Anaesth. 2010 Feb;20(2):150-9. doi: 10.1111/j.1460-9592.2009.03227.x.</citation>
    <PMID>20078812</PMID>
  </reference>
  <reference>
    <citation>Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, Fergusson DA, Ker K. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011 Mar 16;2011(3):CD001886. doi: 10.1002/14651858.CD001886.pub4.</citation>
    <PMID>21412876</PMID>
  </reference>
  <reference>
    <citation>Oppenheimer AJ, Ranganathan K, Levi B, Strahle JM, Kapurch J, Muraszko KM, Buchman SR. Minimizing transfusions in primary cranial vault remodeling: the role of aminocaproic acid. J Craniofac Surg. 2014 Jan;25(1):82-6. doi: 10.1097/SCS.0b013e3182a2e23f.</citation>
    <PMID>24240766</PMID>
  </reference>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>August 28, 2014</study_first_submitted>
  <study_first_submitted_qc>September 2, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 3, 2014</study_first_posted>
  <last_update_submitted>August 31, 2023</last_update_submitted>
  <last_update_submitted_qc>August 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>craniosynostosis</keyword>
  <keyword>craniofacial</keyword>
  <keyword>amicar</keyword>
  <keyword>epsilon aminocaproic acid</keyword>
  <keyword>ε-aminocaproic acid</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>Aminocaproic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02229968
org study id: PRO00004263
nct id: NCT02229968
lead sponsor: 
has dmc: Yes
The purpose of this study is to determine whether Amicar (ε-aminocaproic acid) is effective
      in reducing blood loss in children undergoing craniofacial reconstruction surgery.

      The investigators hypothesize that Amicar will decrease intraoperative blood loss and
      decrease the need for perioperative blood product administration in children undergoing
      craniofacial surgery.
Craniosynostosis is a condition in which there is premature fusion of one or more of the
      sutures between the bones of the skull. Premature fusion of sutures in the skull limits the
      ability of the cranial vault to expand to accommodate the rapidly growing brain in infancy
      and early childhood and leads to bony deformation. Left uncorrected, craniosynostosis may
      adversely impact both neurologic and psychosocial development and in some cases, can result
      in high intracranial pressure and blindness.

      Craniofacial (CF) reconstructive surgery is performed in young children with craniosynostosis
      to improve physical appearance, prevent functional neurologic disturbances, and enhance
      psychosocial development. Due to the complexities of the surgery as well as the young age and
      size of the patients, CF reconstruction carries potential life threatening risks and can
      result in significant morbidity. Reported complications include massive intraoperative
      hemorrhage, intraoperative cardiac arrest, transfusion-related reactions, venous air
      embolism, hypotension, coagulopathy, bradycardia, postoperative seizures, surgical site
      infections, facial swelling with airway compromise, and unplanned postoperative mechanical
      ventilation. The most severe and most common perioperative issues relate to the rate and
      extent of blood loss.

      Fibrinolysis, which impairs adequate hemostasis, has been shown to occur in children during
      CF reconstruction. This most certainly contributes to the magnitude of blood loss in these
      types of operations. Thus, targeting this defect in clot hemostasis with the use of
      antifibrinolytics is a reasonable therapeutic approach.

      Amicar (ε-aminocaproic acid) is a synthetic lysine analog that blocks the lysine binding
      sites on plasminogen, resulting in antifibrinolytic activity through inhibition of plasmin
      formation. We have chosen to study Amicar in this clinical context for a number of reasons.
      First, major hemorrhage continues to be a significant perioperative issue in this cohort.
      Secondly, Amicar is commonly and safely administered to children undergoing other types of
      high-risk surgery (i.e., spinal fusion surgery and open heart surgery). In addition, Amicar
      is inexpensive and easily administered, making it a viable and novel therapeutic option if
      shown to be effective for this type of surgery.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Intraoperative blood loss
time frame: within the first 72 hours after surgery
description: As estimated blood loss is known to be inaccurate in this setting, mean intraoperative blood loss (in mL/kg) will be calculated using a formula previously described in this population.
measure: Blood donor exposure
time frame: within the first 30 days after surgery
description: To establish that intraoperative administration of Amicar decreases perioperative blood donor exposure and need for transfusion following craniofacial reconstructive surgery
arm group label: Amicar (ε-aminocaproic acid)
arm group type: Experimental
description: Treatment group 1: Amicar 100 mg/kg (0.4 mL/kg) IV loading dose, followed by an intraoperative continuous infusion at 40 mg/kg/hr (0.16 mL/kg/hr) to be continued until skin closure.
arm group label: normal saline
arm group type: Placebo Comparator
description: Treatment group 2: Equal volume of normal saline (placebo control) at the same rate as treatment group 1.
intervention type: Drug
intervention name: Amicar (ε-aminocaproic acid)
arm group label: Amicar (ε-aminocaproic acid)
other name: Amicar
other name: 6-aminohexanoic acid
other name: epsilon aminocaproic acid
intervention type: Drug
intervention name: normal saline
arm group label: normal saline
other name: normal saline 0.9%
other name: placebo
other name: placebo control
criteria: 
gender: All
minimum age: 2 Months
maximum age: 36 Months
healthy volunteers: No
last name: Srijaya K Reddy, MD, MBA
role: Principal Investigator
affiliation: Vanderbilt University Medical Center
facility: 
country: United States
citation: Stricker PA, Zuppa AF, Fiadjoe JE, Maxwell LG, Sussman EM, Pruitt EY, Goebel TK, Gastonguay MR, Taylor JA, Bartlett SP, Schreiner MS. Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery. Br J Anaesth. 2013 May;110(5):788-99. doi: 10.1093/bja/aes507. Epub 2013 Jan 25.
PMID: 23353035
citation: Faberowski LW, Black S, Mickle JP. Blood loss and transfusion practice in the perioperative management of craniosynostosis repair. J Neurosurg Anesthesiol. 1999 Jul;11(3):167-72. doi: 10.1097/00008506-199907000-00002.
PMID: 10414670
citation: Stricker PA, Shaw TL, Desouza DG, Hernandez SV, Bartlett SP, Friedman DF, Sesok-Pizzini DA, Jobes DR. Blood loss, replacement, and associated morbidity in infants and children undergoing craniofacial surgery. Paediatr Anaesth. 2010 Feb;20(2):150-9. doi: 10.1111/j.1460-9592.2009.03227.x.
PMID: 20078812
citation: Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, Fergusson DA, Ker K. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011 Mar 16;2011(3):CD001886. doi: 10.1002/14651858.CD001886.pub4.
PMID: 21412876
citation: Oppenheimer AJ, Ranganathan K, Levi B, Strahle JM, Kapurch J, Muraszko KM, Buchman SR. Minimizing transfusions in primary cranial vault remodeling: the role of aminocaproic acid. J Craniofac Surg. 2014 Jan;25(1):82-6. doi: 10.1097/SCS.0b013e3182a2e23f.
PMID: 24240766
responsible party type: Sponsor
mesh term: Craniosynostoses
mesh term: Aminocaproic Acid
sharing ipd: No