<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/NCT01698567</url>
  </required_header>
  <id_info>
    <org_study_id>38402</org_study_id>
    <nct_id>NCT01698567</nct_id>
  </id_info>
  <brief_title>Antithrombin III in Infants With Cardiopulmonary Bypass (CPB)</brief_title>
  <official_title>Antithrombin III Supplementation for Infants Undergoing Cardiac Surgery With Cardiopulmonary Bypass.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Rochester</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Rochester</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to discern whether supplementation of Antithrombin III will&#xD;
      decrease coagulation and inflammation associated with cardiopulmonary bypass in infants&#xD;
      undergoing cardiac surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cardiopulmonary bypass (CPB) and cardiovascular surgery initiate diffuse activation of&#xD;
      coagulation, inflammation and fibrinolysis that often has deleterious effects on patient&#xD;
      outcomes, including bleeding, transfusion, myocardial dysfunction, renal failure, pulmonary&#xD;
      dysfunction, prolonged intubation, ICU and hospital length of stay, stroke and neurocognitive&#xD;
      dysfunction, and mortality.Pediatric patients are especially at risk for hematologic&#xD;
      derangement related to CPB. Not only are infants and children subject to the same diffuse&#xD;
      activations of coagulation, inflammation, and fibrinolysis as adults, but their size,&#xD;
      immaturity, and circulatory abnormalities secondary to congenital heart disease increase the&#xD;
      risk of loss of hematologic homeostasis. Since an infant's blood volume is much smaller than&#xD;
      that of the prime in the CPB pump, hemodilution alone produces impaired hemostasis related to&#xD;
      thrombocytopenia and coagulation factor dilution The incidence of each of these complications&#xD;
      is variable and depends on the diagnosis, operation, time on CPB and other factors.&#xD;
&#xD;
      Adequate anticoagulation during cardiopulmonary bypass (CPB) is essential to preserve the&#xD;
      hemostatic system and ensure hemostasis after surgery. Heparin has long been the mainstay of&#xD;
      anticoagulation for CPB, due to its ease of use, familiarity, and reversibility. For heparin&#xD;
      to exert its anticoagulant effect, it must bind with an intrinsic cofactor, antithrombin III&#xD;
      (ATIII) to inhibit enzymes of the intrinsic and final common coagulation pathways. It has&#xD;
      been established that neonates have significantly decreased levels of ATIII relative to&#xD;
      adults, and that this relative deficiency continues at least until 6 months of age. Children&#xD;
      with congenital heart disease have further decreases in ATIII and other abnormalities of&#xD;
      coagulation which may contribute to adverse outcomes. Given this ATIII deficiency, it is not&#xD;
      surprising that heparin anticoagulation does not fully suppress coagulation during CPB.&#xD;
      Neonates anticoagulated for CPB with heparin have ongoing activation of humoral and cellular&#xD;
      coagulation with associated activation of inflammation and fibrinolysis. Improved&#xD;
      anticoagulation may reduce activation of these cascades and improve outcomes. In addition,&#xD;
      infants are at high risk for post cardiac surgery intervascular thrombosis. Baseline ATIII&#xD;
      deficiency, and consumption of ATIII during bypass may contribute to a postoperative&#xD;
      prothrombotic state esulting in this often fatal complication. ATIII supplementation may&#xD;
      decrease this risk.&#xD;
&#xD;
      ATIII is available as a lyophilized product derived from pooled human plasma. Treatment with&#xD;
      ATIII has been shown to improve the anticoagulant effects of heparin and attenuate activation&#xD;
      of hemostasis and inflammation during adult CPB, and to decrease the incidence of thrombosis&#xD;
      associated with central venous cannulation in children. The incidence of central venous&#xD;
      thrombosis in infants undergoing cardiac surgery has been reported as 5.8 - 22% in neonates,&#xD;
      with a resultant mortality of 20%.&#xD;
&#xD;
      The biologic half-life of antithrombin in healthy adult volunteers is 2.5 - 3.8 days.&#xD;
      Pharmacokinetic data in neonates is not available, but biologic activity should certainly&#xD;
      persist through the 2 highest risk periods:&#xD;
&#xD;
      CPB, where activation of coagulation produces activation of inflammation, both cellular and&#xD;
      humoral, and fibrinolysis.&#xD;
&#xD;
      The early post-op period when patients typically become hypercoagulable as part of the stress&#xD;
      response to surgery. Hypercoagulability places the patients at high risk for central&#xD;
      line-associated thrombosis despite by heparin-containing flush solutions which are standard&#xD;
      of care. Ensuring a near normal level of antithrombin appears to enhance the ability of the&#xD;
      flush solutions to inhibit thrombin generation on the catheter.&#xD;
&#xD;
      ATIII has been used in infants after cardiac surgery to prophylax against central venous&#xD;
      thrombosis, for infants with necrotizing enterocolitis (NEC), and as treatment for neonates&#xD;
      with congenital ATIII deficiency. Neonates appear to respond as expected to ATIII&#xD;
      supplementation, with clinical efficacy for central venous thrombosis but not NEC. No&#xD;
      complications unique to infants were reported in any of these publications.&#xD;
&#xD;
      It is reasonable to expect that ATIII would be even more beneficial in infants less than 6&#xD;
      months old.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Challenges enrolling subjects in study&#xD;
  </why_stopped>
  <start_date>July 2012</start_date>
  <completion_date type="Actual">March 2016</completion_date>
  <primary_completion_date type="Actual">March 2016</primary_completion_date>
  <phase>Phase 1</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>The primary hypothesis is that treatment with ATIII before bypass will decrease the activation of inflammation during CPB as measured by plasma neutrophil elastase.</measure>
    <time_frame>Expected average of 24 months</time_frame>
    <description>Patients treated with ATIII as standard of care (good clinical practice) will remain in the study and be analyzed by their intention to treat group. Review of our clinical experience shows that treatment with ATIII for heparin resistance occurs in 2-3% of cases. If there are more than two patients so treated, we will also perform an &quot;as-treated&quot; analysis.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>p-selectin</measure>
    <time_frame>expected average of 24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>interleukin-6</measure>
    <time_frame>Expected average of 24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>prothrombin fragment 1.2</measure>
    <time_frame>expected average of 24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>24 hour blood loss</measure>
    <time_frame>24 hours post surgery</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICU length of stay</measure>
    <time_frame>Expected average of 3 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital length of stay</measure>
    <time_frame>Expected average of 3 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Congenital Heart Disease</condition>
  <arm_group>
    <arm_group_label>Antithrombin III</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Product- Antithrombin III is derived from pooled human plasma&#xD;
ATIII will be dosed using the formula recommended by the manufacturer:&#xD;
(goal activity - baseline activity) x weight (kg) x .714 (Assume: start with 35% activity [7], goal 120% activity[18], so dose = 120-35 x wt (kg) x .714, e.g. 5 kg infant: 85 x 5 x .714 = 303 units)&#xD;
a.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>placebo (normal saline)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Antithrombin III</intervention_name>
    <description>ATIII will be dosed using the formula recommended by the manufacturer:&#xD;
(goal activity - baseline activity) x weight (kg) x .714 (Assume: start with 35% activity [7], goal 120% activity[18], so dose = 120-35 x wt (kg) x .714, e.g. 5 kg infant: 85 x 5 x .714 = 303 units)</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Thrombate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>placebo (normal saline) after induction of anesthesia and before commencement of bypass. ATIII will be dosed using the formula recommended by the manufacturer: (goal activity - baseline activity) x weight (kg) x .714 (Assume: start with 35% activity [7], goal 120% activity[18], so dose = 120-35 x wt (kg) x .714, e.g. 5 kg infant: 85 x 5 x .714 = 303 units)</description>
    <arm_group_label>Antithrombin III</arm_group_label>
    <other_name>Normal Saline</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects will be included if they are presenting for elective cardiac surgery using&#xD;
             cardiopulmonary bypass and are 180 days of age or less.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Sensitivity to ATIII product (Thrombate, Grifols, Los Angeles, CA)&#xD;
&#xD;
          -  Known inherited or acquired coagulation defect&#xD;
&#xD;
          -  Current or prior treatment with pro-or anticoagulant medication within past 30 days&#xD;
             (except aspirin or a single dose of heparin, e.g. for catheterization)&#xD;
&#xD;
          -  Known central venous thrombosis&#xD;
&#xD;
          -  Recent (30 days) transfusion with hemostatic blood products (fresh-frozen plasma,&#xD;
             platelets, cryoprecipitate, whole blood)&#xD;
&#xD;
          -  wt less than 3000g&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Day</minimum_age>
    <maximum_age>180 Days</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael Eaton, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Rochester</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Michael Eaton, MD</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2016</verification_date>
  <study_first_submitted>September 4, 2012</study_first_submitted>
  <study_first_submitted_qc>September 28, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 3, 2012</study_first_posted>
  <last_update_submitted>March 21, 2016</last_update_submitted>
  <last_update_submitted_qc>March 21, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">March 22, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Rochester</investigator_affiliation>
    <investigator_full_name>Michael Eaton</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Infants</keyword>
  <keyword>Cardiopulmonary bypass</keyword>
  <keyword>anticoaglution</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Diseases</mesh_term>
    <mesh_term>Heart Defects, Congenital</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Antithrombins</mesh_term>
    <mesh_term>Antithrombin III</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01698567
org study id: 38402
nct id: NCT01698567
lead sponsor: 
has dmc: Yes
The purpose of this study is to discern whether supplementation of Antithrombin III will
      decrease coagulation and inflammation associated with cardiopulmonary bypass in infants
      undergoing cardiac surgery.
Cardiopulmonary bypass (CPB) and cardiovascular surgery initiate diffuse activation of
      coagulation, inflammation and fibrinolysis that often has deleterious effects on patient
      outcomes, including bleeding, transfusion, myocardial dysfunction, renal failure, pulmonary
      dysfunction, prolonged intubation, ICU and hospital length of stay, stroke and neurocognitive
      dysfunction, and mortality.Pediatric patients are especially at risk for hematologic
      derangement related to CPB. Not only are infants and children subject to the same diffuse
      activations of coagulation, inflammation, and fibrinolysis as adults, but their size,
      immaturity, and circulatory abnormalities secondary to congenital heart disease increase the
      risk of loss of hematologic homeostasis. Since an infant's blood volume is much smaller than
      that of the prime in the CPB pump, hemodilution alone produces impaired hemostasis related to
      thrombocytopenia and coagulation factor dilution The incidence of each of these complications
      is variable and depends on the diagnosis, operation, time on CPB and other factors.

      Adequate anticoagulation during cardiopulmonary bypass (CPB) is essential to preserve the
      hemostatic system and ensure hemostasis after surgery. Heparin has long been the mainstay of
      anticoagulation for CPB, due to its ease of use, familiarity, and reversibility. For heparin
      to exert its anticoagulant effect, it must bind with an intrinsic cofactor, antithrombin III
      (ATIII) to inhibit enzymes of the intrinsic and final common coagulation pathways. It has
      been established that neonates have significantly decreased levels of ATIII relative to
      adults, and that this relative deficiency continues at least until 6 months of age. Children
      with congenital heart disease have further decreases in ATIII and other abnormalities of
      coagulation which may contribute to adverse outcomes. Given this ATIII deficiency, it is not
      surprising that heparin anticoagulation does not fully suppress coagulation during CPB.
      Neonates anticoagulated for CPB with heparin have ongoing activation of humoral and cellular
      coagulation with associated activation of inflammation and fibrinolysis. Improved
      anticoagulation may reduce activation of these cascades and improve outcomes. In addition,
      infants are at high risk for post cardiac surgery intervascular thrombosis. Baseline ATIII
      deficiency, and consumption of ATIII during bypass may contribute to a postoperative
      prothrombotic state esulting in this often fatal complication. ATIII supplementation may
      decrease this risk.

      ATIII is available as a lyophilized product derived from pooled human plasma. Treatment with
      ATIII has been shown to improve the anticoagulant effects of heparin and attenuate activation
      of hemostasis and inflammation during adult CPB, and to decrease the incidence of thrombosis
      associated with central venous cannulation in children. The incidence of central venous
      thrombosis in infants undergoing cardiac surgery has been reported as 5.8 - 22% in neonates,
      with a resultant mortality of 20%.

      The biologic half-life of antithrombin in healthy adult volunteers is 2.5 - 3.8 days.
      Pharmacokinetic data in neonates is not available, but biologic activity should certainly
      persist through the 2 highest risk periods:

      CPB, where activation of coagulation produces activation of inflammation, both cellular and
      humoral, and fibrinolysis.

      The early post-op period when patients typically become hypercoagulable as part of the stress
      response to surgery. Hypercoagulability places the patients at high risk for central
      line-associated thrombosis despite by heparin-containing flush solutions which are standard
      of care. Ensuring a near normal level of antithrombin appears to enhance the ability of the
      flush solutions to inhibit thrombin generation on the catheter.

      ATIII has been used in infants after cardiac surgery to prophylax against central venous
      thrombosis, for infants with necrotizing enterocolitis (NEC), and as treatment for neonates
      with congenital ATIII deficiency. Neonates appear to respond as expected to ATIII
      supplementation, with clinical efficacy for central venous thrombosis but not NEC. No
      complications unique to infants were reported in any of these publications.

      It is reasonable to expect that ATIII would be even more beneficial in infants less than 6
      months old.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: The primary hypothesis is that treatment with ATIII before bypass will decrease the activation of inflammation during CPB as measured by plasma neutrophil elastase.
time frame: Expected average of 24 months
description: Patients treated with ATIII as standard of care (good clinical practice) will remain in the study and be analyzed by their intention to treat group. Review of our clinical experience shows that treatment with ATIII for heparin resistance occurs in 2-3% of cases. If there are more than two patients so treated, we will also perform an "as-treated" analysis.
measure: p-selectin
time frame: expected average of 24 months
measure: interleukin-6
time frame: Expected average of 24 months
measure: prothrombin fragment 1.2
time frame: expected average of 24 months
measure: 24 hour blood loss
time frame: 24 hours post surgery
measure: ICU length of stay
time frame: Expected average of 3 days
measure: Hospital length of stay
time frame: Expected average of 3 weeks
arm group label: Antithrombin III
arm group type: Active Comparator
description: Product- Antithrombin III is derived from pooled human plasma
ATIII will be dosed using the formula recommended by the manufacturer:
(goal activity - baseline activity) x weight (kg) x .714 (Assume: start with 35% activity [7], goal 120% activity[18], so dose = 120-35 x wt (kg) x .714, e.g. 5 kg infant: 85 x 5 x .714 = 303 units)
a.
arm group label: Placebo
arm group type: Placebo Comparator
description: placebo (normal saline)
intervention type: Drug
intervention name: Antithrombin III
description: ATIII will be dosed using the formula recommended by the manufacturer:
(goal activity - baseline activity) x weight (kg) x .714 (Assume: start with 35% activity [7], goal 120% activity[18], so dose = 120-35 x wt (kg) x .714, e.g. 5 kg infant: 85 x 5 x .714 = 303 units)
arm group label: Placebo
other name: Thrombate
intervention type: Drug
intervention name: Placebo
description: placebo (normal saline) after induction of anesthesia and before commencement of bypass. ATIII will be dosed using the formula recommended by the manufacturer: (goal activity - baseline activity) x weight (kg) x .714 (Assume: start with 35% activity [7], goal 120% activity[18], so dose = 120-35 x wt (kg) x .714, e.g. 5 kg infant: 85 x 5 x .714 = 303 units)
arm group label: Antithrombin III
other name: Normal Saline
criteria: 
gender: All
minimum age: 1 Day
maximum age: 180 Days
healthy volunteers: No
last name: Michael Eaton, MD
role: Principal Investigator
affiliation: University of Rochester
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Rochester
investigator full name: Michael Eaton
investigator title: Principal Investigator
mesh term: Heart Diseases
mesh term: Heart Defects, Congenital
mesh term: Antithrombins
mesh term: Antithrombin III