<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/NCT03005704</url>
  </required_header>
  <id_info>
    <org_study_id>PopulationHRI</org_study_id>
    <nct_id>NCT03005704</nct_id>
  </id_info>
  <brief_title>Reversal of the Antiplatelet Effects of Ticagrelor in Combination With Aspirin, Using Normal Platelets</brief_title>
  <acronym>REVSTARTS</acronym>
  <official_title>Reversal of the Antiplatelet Effects of Ticagrelor in Combination With Aspirin, Using Normal Platelets</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hamilton Health Sciences Corporation</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hamilton Health Sciences Corporation</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The specific objective of this study is to investigate the potential for normal platelets to&#xD;
      reverse the inhibition of platelet aggregation in patients treated with ticagrelor in&#xD;
      combination with aspirin.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Ticagrelor is one of three commercially available antiplatelet adenosine diphosphate (ADP)&#xD;
      antagonists (the other two are clopidogrel and prasugrel). They exert their antiplatelet&#xD;
      effects by binding to P2Y12 receptors on the platelet surface. Ticagrelor is used in&#xD;
      combination with aspirin to prevent and treat thrombosis in patients with acute coronary&#xD;
      syndrome, particularly after stent implantation. ADP antagonists are combined with aspirin&#xD;
      because aspirin blocks platelet aggregation by preventing thromboxane production, and&#xD;
      blocking two different pathways leads to greater efficacy than either drug used alone. Recent&#xD;
      clinical trials indicate ticagrelor in combination with aspirin is more effective for&#xD;
      prevention of thrombotic events in patients with symptomatic coronary artery disease than&#xD;
      aspirin in combination with clopidogrel, but causes significantly more bleeding. The improved&#xD;
      efficacy and reduced safety occurs because ticagrelor causes greater inhibition of&#xD;
      ADP-mediated platelet activation. The latter can be reliably measured in the laboratory.&#xD;
&#xD;
      Management of patients who bleed while taking an ADP antagonist in combination with aspirin&#xD;
      is challenging because there is no specific antidote, Platelet transfusion has the potential&#xD;
      to reverse the effects of clopidogrel or prasugrel and aspirin, but these findings cannot be&#xD;
      extrapolated to ticagrelor in combination with aspirin because the pharmacokinetic and&#xD;
      pharmacodynamic effects of ticagrelor differ.&#xD;
&#xD;
      Aspirin, clopidogrel active metabolite, and prasugrel active metabolite have half-lives of&#xD;
      15-20 minutes, 30 minutes, and four hours respectively. They are irreversible platelet&#xD;
      inhibitors which bind to and permanently block platelet function. After their drug&#xD;
      elimination, new platelets which enter the circulation from megakaryocytes in the bone marrow&#xD;
      are unaffected. Therefore, after elimination, newly transfused platelets have the potential&#xD;
      to restore haemostasis. In contrast, ticagrelor, a reversible platelet inhibitor, has a&#xD;
      longer half-life (7.7 to 14.1 hours). As a result of its longer half-life, newly added&#xD;
      platelets (both from the bone marrow and transfused platelets) are inhibited by ticagrelor&#xD;
      for at least 24 hours after the last dose. Therefore, reversing platelet inhibition and&#xD;
      controlling excessive bleeding associated with ticagrelor by platelet transfusion poses a&#xD;
      greater challenge than with clopidogrel and prasugrel. Nevertheless, because of its greater&#xD;
      efficacy, ticagrelor is preferred over clopidogrel in high risk patients.&#xD;
&#xD;
      Previous studies of platelet transfusion and ev vivo mixing within 24 hours of drug&#xD;
      administration have shown than the inhibition of ADP-mediated platelet activation by&#xD;
      clopidogrel and prasugrel, but not ticagrelor can be reversed or modulated by the addition of&#xD;
      donor platelets. Although reversing the platelet inhibitory effects of ticagrelor might not&#xD;
      be possible within 24 hours of stopping the drug, it should be possible in the days that&#xD;
      follow. This has not been examined. Accordingly, we propose to perform a study in which we&#xD;
      systematically evaluate inhibition of ADP mediated platelet activation, a reliable measure of&#xD;
      ticagrelor's antiplatelet activity, when donor platelets are added to the platelets of&#xD;
      subjects treated with ticagrelor at time intervals up to 96 hours after their last dose.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>January 2017</start_date>
  <completion_date type="Anticipated">January 2018</completion_date>
  <primary_completion_date type="Anticipated">December 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Reversal of platelet inhibition</measure>
    <time_frame>5 days</time_frame>
    <description>The primary outcome is to measure the efficacy of untreated platelets in reversing the platelet inhibition due to ticagrelor in combination with aspirin by ex vivo mixing studies. Increase in platelet aggregation will be measured by light transmission aggregometry after stimulation by adenosine diphosphate, arachidonic acid, and collagen.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Timing of reversal of platelet inhibition</measure>
    <time_frame>5 days</time_frame>
    <description>The secondary outcome measure is to determine the time point post cessation at which untreated donor platelets reverse the antiplatelet effect of ticagrelor in combination with aspirin.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>Ticagrelor</condition>
  <condition>Aspirin</condition>
  <condition>Platelet Dysfunction Due to Drugs</condition>
  <condition>Transfusion</condition>
  <arm_group>
    <arm_group_label>Antiplatelet Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be treated with five days of ticagrelor in combination with acetylsalicylic acid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Subjects will not receive antiplatelet treatment and their PRP will be used as the source of untreated platelets in laboratory mixing studies.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Antiplatelet treatment</intervention_name>
    <description>Subjects will be treated with ticagrelor in combination with acetylsalicylic acid for five days. Ticagrelor will be administered at a loading dose of 180 mg, followed by 90 mg twice daily maintenance dose. Acetylsalicylic acid will be administered at a dose of 81 mg daily.</description>
    <arm_group_label>Antiplatelet Treatment</arm_group_label>
    <other_name>Ticagrelor and acetylsalicylic acid</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy subjects&#xD;
&#xD;
          -  At least 18 years of age&#xD;
&#xD;
          -  No history of cardiovascular disease&#xD;
&#xD;
          -  Not taking antiplatelet therapy prior to participation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known thrombocytopenia, other coagulation disorder such as von Willebrand's disease,&#xD;
             haemophilia&#xD;
&#xD;
          -  Allergy or intolerance to ticagrelor or aspirin (if known)&#xD;
&#xD;
          -  Consumption of drugs within the preceding fourteen days that potentially can interfere&#xD;
             with metabolism of ticagrelor through CYP3A4, CYP3A or P-glycoprotein (eg,&#xD;
             ketoconazole, clarithromycin, nefazodone, ritonavir, atazanavir, diltiazem,&#xD;
             amprenavir, aprepitant, erythromycin, fluconazole, verapamil, rifampicin,&#xD;
             dexamethasone, phenytoin, carbamazepine, phenobarbital, cyclosporine, simvastatin,&#xD;
             atorvastatin, tolbutamide, digoxin)21&#xD;
&#xD;
          -  Previous transfusion or pregnancy (because of potential alloimmunisation)&#xD;
&#xD;
          -  Pregnant or trying to conceive, or breastfeeding&#xD;
&#xD;
          -  Unable or unwilling to give written informed consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Population Health Research Institute</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L9L 2X2</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Paul Kruger, MB BS</last_name>
      <phone>9059230285</phone>
      <email>paul.kruger@phri.ca</email>
    </contact>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>December 26, 2016</study_first_submitted>
  <study_first_submitted_qc>December 26, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 29, 2016</study_first_posted>
  <last_update_submitted>April 5, 2017</last_update_submitted>
  <last_update_submitted_qc>April 5, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">April 6, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hamilton Health Sciences Corporation</investigator_affiliation>
    <investigator_full_name>Paul Kruger</investigator_full_name>
    <investigator_title>Dr</investigator_title>
  </responsible_party>
  <keyword>Ticagrelor</keyword>
  <keyword>Acetylsalicylic acid</keyword>
  <keyword>Platelet transfusion</keyword>
  <keyword>Reversal</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aspirin</mesh_term>
    <mesh_term>Ticagrelor</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>March 6, 2018</submitted>
    <returned>October 9, 2018</returned>
  </pending_results>
  <!-- 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/NCT03005704
org study id: PopulationHRI
nct id: NCT03005704
lead sponsor: 
has dmc: No
The specific objective of this study is to investigate the potential for normal platelets to
      reverse the inhibition of platelet aggregation in patients treated with ticagrelor in
      combination with aspirin.
Ticagrelor is one of three commercially available antiplatelet adenosine diphosphate (ADP)
      antagonists (the other two are clopidogrel and prasugrel). They exert their antiplatelet
      effects by binding to P2Y12 receptors on the platelet surface. Ticagrelor is used in
      combination with aspirin to prevent and treat thrombosis in patients with acute coronary
      syndrome, particularly after stent implantation. ADP antagonists are combined with aspirin
      because aspirin blocks platelet aggregation by preventing thromboxane production, and
      blocking two different pathways leads to greater efficacy than either drug used alone. Recent
      clinical trials indicate ticagrelor in combination with aspirin is more effective for
      prevention of thrombotic events in patients with symptomatic coronary artery disease than
      aspirin in combination with clopidogrel, but causes significantly more bleeding. The improved
      efficacy and reduced safety occurs because ticagrelor causes greater inhibition of
      ADP-mediated platelet activation. The latter can be reliably measured in the laboratory.

      Management of patients who bleed while taking an ADP antagonist in combination with aspirin
      is challenging because there is no specific antidote, Platelet transfusion has the potential
      to reverse the effects of clopidogrel or prasugrel and aspirin, but these findings cannot be
      extrapolated to ticagrelor in combination with aspirin because the pharmacokinetic and
      pharmacodynamic effects of ticagrelor differ.

      Aspirin, clopidogrel active metabolite, and prasugrel active metabolite have half-lives of
      15-20 minutes, 30 minutes, and four hours respectively. They are irreversible platelet
      inhibitors which bind to and permanently block platelet function. After their drug
      elimination, new platelets which enter the circulation from megakaryocytes in the bone marrow
      are unaffected. Therefore, after elimination, newly transfused platelets have the potential
      to restore haemostasis. In contrast, ticagrelor, a reversible platelet inhibitor, has a
      longer half-life (7.7 to 14.1 hours). As a result of its longer half-life, newly added
      platelets (both from the bone marrow and transfused platelets) are inhibited by ticagrelor
      for at least 24 hours after the last dose. Therefore, reversing platelet inhibition and
      controlling excessive bleeding associated with ticagrelor by platelet transfusion poses a
      greater challenge than with clopidogrel and prasugrel. Nevertheless, because of its greater
      efficacy, ticagrelor is preferred over clopidogrel in high risk patients.

      Previous studies of platelet transfusion and ev vivo mixing within 24 hours of drug
      administration have shown than the inhibition of ADP-mediated platelet activation by
      clopidogrel and prasugrel, but not ticagrelor can be reversed or modulated by the addition of
      donor platelets. Although reversing the platelet inhibitory effects of ticagrelor might not
      be possible within 24 hours of stopping the drug, it should be possible in the days that
      follow. This has not been examined. Accordingly, we propose to perform a study in which we
      systematically evaluate inhibition of ADP mediated platelet activation, a reliable measure of
      ticagrelor's antiplatelet activity, when donor platelets are added to the platelets of
      subjects treated with ticagrelor at time intervals up to 96 hours after their last dose.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Reversal of platelet inhibition
time frame: 5 days
description: The primary outcome is to measure the efficacy of untreated platelets in reversing the platelet inhibition due to ticagrelor in combination with aspirin by ex vivo mixing studies. Increase in platelet aggregation will be measured by light transmission aggregometry after stimulation by adenosine diphosphate, arachidonic acid, and collagen.
measure: Timing of reversal of platelet inhibition
time frame: 5 days
description: The secondary outcome measure is to determine the time point post cessation at which untreated donor platelets reverse the antiplatelet effect of ticagrelor in combination with aspirin.
arm group label: Antiplatelet Treatment
arm group type: Experimental
description: Subjects will be treated with five days of ticagrelor in combination with acetylsalicylic acid.
arm group label: Control
arm group type: No Intervention
description: Subjects will not receive antiplatelet treatment and their PRP will be used as the source of untreated platelets in laboratory mixing studies.
intervention type: Drug
intervention name: Antiplatelet treatment
description: Subjects will be treated with ticagrelor in combination with acetylsalicylic acid for five days. Ticagrelor will be administered at a loading dose of 180 mg, followed by 90 mg twice daily maintenance dose. Acetylsalicylic acid will be administered at a dose of 81 mg daily.
arm group label: Antiplatelet Treatment
other name: Ticagrelor and acetylsalicylic acid
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
facility: 
status: Recruiting
contact: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: Hamilton Health Sciences Corporation
investigator full name: Paul Kruger
investigator title: Dr
mesh term: Aspirin
mesh term: Ticagrelor
sharing ipd: No
submitted: March 6, 2018
returned: October 9, 2018