<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/NCT03787641</url>
  </required_header>
  <id_info>
    <org_study_id>107681</org_study_id>
    <nct_id>NCT03787641</nct_id>
  </id_info>
  <brief_title>Systematic Evaluation of Protamine Doze in Cardiac Surgery</brief_title>
  <acronym>HART</acronym>
  <official_title>Sysytematic Evaluation of Heparin and Protamine in Cardiac Surgery</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lawson Health Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Lawson Health Research Institute</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The precise amount of protamine required to neutralize unfractionated heparin (UFH) remains&#xD;
      unknown. This study will systematically identify the doze needed to neutralize UFH following&#xD;
      cardiopulmonary bypass (CPB).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The precise dose of protamine needed to neutralize unfractionated heparin (UFH) is unknown.&#xD;
      Research suggests that low dose protamine is associated with decreased need for transfusions&#xD;
      in cardiac surgery. The ATS guidelines recommend that half of the total UFH dose given for&#xD;
      cardiopulmonary bypass (CPB) should be neutralized with protamine. However, it is unknown if&#xD;
      this is routinely followed by anesthesiologists. Furthermore, the reference standard for UFH&#xD;
      has changed recently and it is unknown how this has affected the dose of protamine in the&#xD;
      perioperative period. Protamine does have a very short life and heparin rebound occurs very&#xD;
      commonly.&#xD;
&#xD;
      It is common practice to divert the suctioned mediastinal blood following CPB while the&#xD;
      patient is still anticoagulated. The traditional practice is that once half dose protamine&#xD;
      has been given, suction to the cardiotomy reservoir is turned off. All surgical field blood&#xD;
      loss is then diverted to wall suction. The inherent risk of letting too much protamine into&#xD;
      the CPB reservoir is that UFH therein may get neutralized and predispose to clot formation in&#xD;
      the venous reservoir. This precludes an emergency 'crash' on to CPB, should that be required&#xD;
      for some reason. Experience of the Investigators indicates that most surgeons will turn off&#xD;
      suction leading to the cardiotomy reservoir once half the total protamine dose has been&#xD;
      administered. The concern with this is that &quot;half dose&quot; protamine may be quite different for&#xD;
      different anesthesiologists.&#xD;
&#xD;
      The research investigators hypothesize low dose protamine is sufficient to neutralize the&#xD;
      effects of UFH as monitored through activated clotting time (ACT). Anesthesiologists&#xD;
      administer varying doses of protamine to neutralize UFH in cardiac surgery and the rationale&#xD;
      behind such decisions is unclear.&#xD;
&#xD;
      Thus, the primary objective of this study is to evaluate the dose of protamine required to&#xD;
      neutralize UFH following CPB. Secondary objectives are 1) to assess the amount of protamine&#xD;
      needed to neutralize UFH in intravenously administered cardiotomy reservoir blood. 2) To&#xD;
      examine the amount of residual heparin postoperatively in the cardiac surgery ICU; 3) to&#xD;
      examine, through semi-structured interviews, the decision-making processes involved in&#xD;
      managing (anti)coagulation in cardiac surgery.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 20, 2018</start_date>
  <completion_date type="Anticipated">February 28, 2020</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2019</primary_completion_date>
  <phase>N/A</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>Change in heparin activity</measure>
    <time_frame>Duriing surgery (at baseline, before and after protamine adminitration following cardiopulmonary bypass). Samples will also be quantified at Intensive Care Unit (ICU) admission and 4 hours following ICU admission.</time_frame>
    <description>The functional activity is ideally measured via its ability to accelerate the inhibition of activated coagulation enzymes IIa (thrombin) and Xa respectively.&#xD;
These tests are available commercially as ELISA kits. Briefly, an excess of coagulation factor IIa or Xa respectively is added to the sample and residual anti-IIa/Xa activity is quantified with a synthetic chromogenic substrate.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Activated Clotting time (ACT)</measure>
    <time_frame>Duriing surgery (at baseline, before and after protamine adminitration following cardiopulmonary bypass).</time_frame>
    <description>ACT is the standard point of care test used in cardiac surgery. Blood is added to a tube containing predefined amount of coagulation accelerator (available commercially) and heparin activity is measured by prolongation or neutralization of ACT</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rationale for choosing a certain doze of protamine</measure>
    <time_frame>During surgery. (Average cardiac surgery lasts for 4-6 hours)</time_frame>
    <description>Anesthesiologists will undergo semi-structured face to face interviews and asked their rationale for choosing a certain doze of protamine</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Cardiac Surgery With Cardiopulmonary Bypass</condition>
  <arm_group>
    <arm_group_label>Protamine doze</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Protamine Sulfate will be administered through an infusion pump in aliquots at a predefined rate (25 mg/min). Blood samples will be withdrawn after each aliquot and quantified for anti-Xa, IIa and ACT.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Protamine Sulfate</intervention_name>
    <description>Protamine Sulfate will be administered via an infusion pump to administer a 50 mg test doze, then 100 mg after 5 min waiting period. Following blood samples, additional alliquots of 50 mg will be measured to a maximum of 300 mg.</description>
    <arm_group_label>Protamine doze</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Elective cardiac surgery patients &gt; 18 years age who can provide written consent for&#xD;
             the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of any known coagulopathies, liver dysfunction, previous cardiac surgery,&#xD;
             preoperative abnormal coagulation profiles, recent exposure to heparin (unfractionated&#xD;
             or low molecular weight), warfarin, clopidogrel or other direct thrombin inhibitors in&#xD;
             the preceding 7 days.&#xD;
&#xD;
          -  History of heparin resistance&#xD;
&#xD;
          -  History of adverse reactions to protamine&#xD;
&#xD;
          -  Patients identified as having heparin resistance&#xD;
&#xD;
          -  Anticipated CPB time &gt; 2-2.5 hrs&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Ravi Taneja, FRCPC</last_name>
    <phone>5196858500</phone>
    <email>Ravi.Taneja@lhsc.on.ca</email>
  </overall_contact>
  <location>
    <facility>
      <name>London Health Sciences Centre</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 5A5</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ravi Taneja, FRCPC</last_name>
      <phone>5196858500</phone>
      <email>Ravi.Taneja@lhsc.on.ca</email>
    </contact>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>May 13, 2016</study_first_submitted>
  <study_first_submitted_qc>December 24, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 26, 2018</study_first_posted>
  <last_update_submitted>December 27, 2018</last_update_submitted>
  <last_update_submitted_qc>December 27, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 31, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Lawson Health Research Institute</investigator_affiliation>
    <investigator_full_name>Ravi Taneja</investigator_full_name>
    <investigator_title>Associate Scientist</investigator_title>
  </responsible_party>
  <keyword>cardiopulmonary bypass</keyword>
  <keyword>heparin</keyword>
  <keyword>protamine</keyword>
  <keyword>anti-IIa assay</keyword>
  <keyword>anti-Xa assay</keyword>
  <keyword>activated clotting time</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Protamines</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/NCT03787641
org study id: 107681
nct id: NCT03787641
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The precise amount of protamine required to neutralize unfractionated heparin (UFH) remains
      unknown. This study will systematically identify the doze needed to neutralize UFH following
      cardiopulmonary bypass (CPB).
The precise dose of protamine needed to neutralize unfractionated heparin (UFH) is unknown.
      Research suggests that low dose protamine is associated with decreased need for transfusions
      in cardiac surgery. The ATS guidelines recommend that half of the total UFH dose given for
      cardiopulmonary bypass (CPB) should be neutralized with protamine. However, it is unknown if
      this is routinely followed by anesthesiologists. Furthermore, the reference standard for UFH
      has changed recently and it is unknown how this has affected the dose of protamine in the
      perioperative period. Protamine does have a very short life and heparin rebound occurs very
      commonly.

      It is common practice to divert the suctioned mediastinal blood following CPB while the
      patient is still anticoagulated. The traditional practice is that once half dose protamine
      has been given, suction to the cardiotomy reservoir is turned off. All surgical field blood
      loss is then diverted to wall suction. The inherent risk of letting too much protamine into
      the CPB reservoir is that UFH therein may get neutralized and predispose to clot formation in
      the venous reservoir. This precludes an emergency 'crash' on to CPB, should that be required
      for some reason. Experience of the Investigators indicates that most surgeons will turn off
      suction leading to the cardiotomy reservoir once half the total protamine dose has been
      administered. The concern with this is that "half dose" protamine may be quite different for
      different anesthesiologists.

      The research investigators hypothesize low dose protamine is sufficient to neutralize the
      effects of UFH as monitored through activated clotting time (ACT). Anesthesiologists
      administer varying doses of protamine to neutralize UFH in cardiac surgery and the rationale
      behind such decisions is unclear.

      Thus, the primary objective of this study is to evaluate the dose of protamine required to
      neutralize UFH following CPB. Secondary objectives are 1) to assess the amount of protamine
      needed to neutralize UFH in intravenously administered cardiotomy reservoir blood. 2) To
      examine the amount of residual heparin postoperatively in the cardiac surgery ICU; 3) to
      examine, through semi-structured interviews, the decision-making processes involved in
      managing (anti)coagulation in cardiac surgery.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in heparin activity
time frame: Duriing surgery (at baseline, before and after protamine adminitration following cardiopulmonary bypass). Samples will also be quantified at Intensive Care Unit (ICU) admission and 4 hours following ICU admission.
description: The functional activity is ideally measured via its ability to accelerate the inhibition of activated coagulation enzymes IIa (thrombin) and Xa respectively.
These tests are available commercially as ELISA kits. Briefly, an excess of coagulation factor IIa or Xa respectively is added to the sample and residual anti-IIa/Xa activity is quantified with a synthetic chromogenic substrate.
measure: Change in Activated Clotting time (ACT)
time frame: Duriing surgery (at baseline, before and after protamine adminitration following cardiopulmonary bypass).
description: ACT is the standard point of care test used in cardiac surgery. Blood is added to a tube containing predefined amount of coagulation accelerator (available commercially) and heparin activity is measured by prolongation or neutralization of ACT
measure: Rationale for choosing a certain doze of protamine
time frame: During surgery. (Average cardiac surgery lasts for 4-6 hours)
description: Anesthesiologists will undergo semi-structured face to face interviews and asked their rationale for choosing a certain doze of protamine
arm group label: Protamine doze
arm group type: Other
description: Protamine Sulfate will be administered through an infusion pump in aliquots at a predefined rate (25 mg/min). Blood samples will be withdrawn after each aliquot and quantified for anti-Xa, IIa and ACT.
intervention type: Drug
intervention name: Protamine Sulfate
description: Protamine Sulfate will be administered via an infusion pump to administer a 50 mg test doze, then 100 mg after 5 min waiting period. Following blood samples, additional alliquots of 50 mg will be measured to a maximum of 300 mg.
arm group label: Protamine doze
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ravi Taneja, FRCPC
phone: 5196858500
email: Ravi.Taneja@lhsc.on.ca
facility: 
status: Recruiting
contact: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: Lawson Health Research Institute
investigator full name: Ravi Taneja
investigator title: Associate Scientist
mesh term: Protamines