<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/NCT02233790</url>
  </required_header>
  <id_info>
    <org_study_id>ISSBRIL0209</org_study_id>
    <nct_id>NCT02233790</nct_id>
  </id_info>
  <brief_title>Ticagrelor and Clopidogrel on Reperfusion in Patients With AMI</brief_title>
  <official_title>Comparison of Ticagrelor and Clopidogrel on Reperfusion in Patients With AMI Undergoing PPCI Evaluated by SPECT</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>First Hospital of China Medical University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>First Hospital of China Medical University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The patients with acute myocardial infarction (AMI) present high mortality and morbidity&#xD;
      rate,even treated with stenting in the blocked heart vessels.&#xD;
&#xD;
      The appearance of no-reflow is common after re-opening of the blocked vessel. The no-reflow&#xD;
      were commonly attributed to tiny blockage in coronary micro-vasculature by thrombus and spasm&#xD;
      of the micro-vessel during stenting.&#xD;
&#xD;
      An agent with more effective anti-clotting and micro-vessel dilation would be helpful to&#xD;
      solve the issue of no-reflow. Ticagrelor was demonstrated to be a potent platelet inhibitor&#xD;
      and a potent micro-vessel dilator which can influence metabolism of adenosine, a endogenous&#xD;
      potent small vessel dilator.&#xD;
&#xD;
      This study is to test the effectiveness of ticagrelor on improving reperfusion and minimizing&#xD;
      the myocardial infarct size after PPCI in patients with AMI.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The patients with acute myocardial infarction (AMI) present high mortality and morbidity&#xD;
      rate, and also have malignant prognosis even if they could survive. The mortality and&#xD;
      prognosis has been improved markedly because of the treatment with primary percutaneous&#xD;
      coronary intervention (PPCI). However, the issue of no-reflow after revascularization has not&#xD;
      been solved yet. The mechanisms of no-reflow in human being were regarded mainly as&#xD;
      micro-embolism in coronary micro-circulation with thrombus or debris from atherosclerotic&#xD;
      plaque, coronary micro-vasculature spasm and other conditions.&#xD;
&#xD;
      Therefore, an agent with potent antithrombotic and micro-vasculature dilation function would&#xD;
      be more effective on prevention of no-reflow after coronary revascularization. Ticagrelor was&#xD;
      demonstrated to be a potent platelet inhibitor and a potent micro-vessel dilator which can&#xD;
      influence metabolism of adenosine.&#xD;
&#xD;
      Ticagrelor can inhibit adenosine uptake in vitro and subsequently augments cardiac blood flow&#xD;
      in a canine model of reactive hypoxia- or adenosine-induced blood flow increases. In a dog&#xD;
      coronary thrombosis model, ticagrelor blocks ADP-induced platelet activation and aggregation;&#xD;
      prevents platelet-mediated thrombosis; prolongs reperfusion time and reduces re-occlusion and&#xD;
      cyclic flow variation; and significantly decreases infarct size and rapidly restores&#xD;
      myocardial tissue perfusion. These findings suggest that ticagrelor may have additional&#xD;
      benefits in patients with acute coronary syndrome beyond inhibition of platelet aggregation,&#xD;
      which is advantageous to the dilation of microcirculation and improvement of myocardial&#xD;
      perfusion. AMISTAD study shows that: adenosine reperfusion therapy can reduce 33% of the&#xD;
      infarction area assessed by single-photon emission computed tomography (SPECT) detection.&#xD;
      AMISTAD- 2 study showed that: adenosine early reperfusion therapy can reduce the composite&#xD;
      end point of death and heart failure events. Additionally, ticagrelor is a non-precursor&#xD;
      agent, playing a role directly on platelet inhibition.&#xD;
&#xD;
      Myocardial perfusion imaging with SPECT is among the most widely used and well-established&#xD;
      noninvasive tools for the diagnosis of ischemic coronary disease. It has been shown to have a&#xD;
      high sensitivity and specificity in identifying patients with coronary artery disease and to&#xD;
      be accurate in identifying areas of prior myocardial infarction.&#xD;
&#xD;
      Given the evidence (from PLATO trial) of greater IPA with ticagrelor than clopidogrel,&#xD;
      similar risk of major bleeding and probable effect of micro-vasculature dilation due to&#xD;
      adenosine, ticagrelor will improve the reperfusion and decrease the infarct size&#xD;
      significantly.&#xD;
&#xD;
      This study is to test the effectiveness of ticagrelor on improving reperfusion and minimizing&#xD;
      the myocardial infarct size after PPCI in patients with AMI. Also, it is to evaluate the&#xD;
      safety of ticagrelor in patients with AMI.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>December 2014</start_date>
  <completion_date type="Anticipated">December 2016</completion_date>
  <primary_completion_date type="Anticipated">September 2016</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>myocardial infarcted size</measure>
    <time_frame>1 week</time_frame>
    <description>To evaluate the infarcted size on Day 7 after PPCI by SPECT.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>elevated ST segment resolution</measure>
    <time_frame>1 hour and 24 hours</time_frame>
    <description>To observe the elevated ST segment resolution at 1 h and 24 h after PPCI;</description>
  </secondary_outcome>
  <other_outcome>
    <measure>severe brachycardia arrhythmia</measure>
    <time_frame>1 month</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">600</enrollment>
  <condition>Myocardial Infarction</condition>
  <condition>No-Reflow Phenomenon</condition>
  <arm_group>
    <arm_group_label>Ticagrelor</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Clopidogrel</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ticagrelor</intervention_name>
    <description>a loading dose of 180mg pre-PCI, and then 90 mg twice daily for 1 Month within the study. Thereafter, the patients will take clopidogrel if Ticagrelor is not available on the market.</description>
    <arm_group_label>Ticagrelor</arm_group_label>
    <other_name>Brilinta</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clopidogrel</intervention_name>
    <description>Clopidogrel 75 mg once daily after a loading dose of 300 mg pre-PCI.</description>
    <arm_group_label>Clopidogrel</arm_group_label>
    <other_name>Plavix</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Provision of informed consent prior to any study specific procedures&#xD;
&#xD;
          -  Patients with acute ST-segment elevation myocardial infarction, an onset of symptoms&#xD;
             presented within 12 hours. Two criteria have to be met: persistent ST-segment&#xD;
             elevation of at least 0.1 mV in at least two contiguous leads or a new left&#xD;
             bundle-branch block, and the intention to perform primary PCI&#xD;
&#xD;
          -  Patients must agree to undergo all protocol-required follow-up examinations and not to&#xD;
             participate any other clinical trials within the duration of this study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any contraindication against the use of clopidogrel or ticagrelor&#xD;
&#xD;
          -  Fibrinolytic therapy within 24 hours before randomization&#xD;
&#xD;
          -  Stroke within the previous 6 months or intracranial hemorrhage at any time before&#xD;
             randomization&#xD;
&#xD;
          -  Any other concomitant severe organic or systemic disorder, such as severe liver&#xD;
             (ALT&gt;3×ULN )or renal disease(creatinin&gt;5.0mg/dl or 442μmol/L), etc.&#xD;
&#xD;
          -  A need for oral anticoagulation therapy&#xD;
&#xD;
          -  An increased risk of bradycardia or atrial-ventricle block&#xD;
&#xD;
          -  Concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer&#xD;
&#xD;
          -  Pregnant women or breast-feeding, or planning to become pregnant while enrolled in&#xD;
             this study&#xD;
&#xD;
          -  Subject has any condition for which, in the opinion of the investigator, participation&#xD;
             would not be in the best interest of the subject (eg, compromise the well-being) or&#xD;
             that could prevent, limit, or confound the protocol-specified assessments&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Yingxian Sun, Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>First Hospital of China Medical University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Yingxian Sun, Dr.</last_name>
    <phone>0086-24-83282688</phone>
    <email>sunyingxian12@126.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Wen Tian, Dr.</last_name>
    <phone>0086-24-83282300</phone>
    <email>dr.wentian@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>The First Hospital of China Medical University</name>
      <address>
        <city>Shenyang</city>
        <state>Liaoning</state>
        <zip>110001</zip>
        <country>China</country>
      </address>
    </facility>
    <contact>
      <last_name>Jianhua Tong, Master</last_name>
      <phone>0086-24-83282837</phone>
      <email>yykyk@vip.163.com</email>
    </contact>
    <investigator>
      <last_name>Wen Tian, Dr.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Mahaffey KW, Puma JA, Barbagelata NA, DiCarli MF, Leesar MA, Browne KF, Eisenberg PR, Bolli R, Casas AC, Molina-Viamonte V, Orlandi C, Blevins R, Gibbons RJ, Califf RM, Granger CB. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial. J Am Coll Cardiol. 1999 Nov 15;34(6):1711-20. doi: 10.1016/s0735-1097(99)00418-0.</citation>
    <PMID>10577561</PMID>
  </reference>
  <reference>
    <citation>Steg PG, James S, Harrington RA, Ardissino D, Becker RC, Cannon CP, Emanuelsson H, Finkelstein A, Husted S, Katus H, Kilhamn J, Olofsson S, Storey RF, Weaver WD, Wallentin L; PLATO Study Group. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation. 2010 Nov 23;122(21):2131-41. doi: 10.1161/CIRCULATIONAHA.109.927582. Epub 2010 Nov 8.</citation>
    <PMID>21060072</PMID>
  </reference>
  <reference>
    <citation>Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R, Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy D, Wilson V, Ledley GS, Storey RF. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009 Dec 22;120(25):2577-85. doi: 10.1161/CIRCULATIONAHA.109.912550. Epub 2009 Nov 18.</citation>
    <PMID>19923168</PMID>
  </reference>
  <reference>
    <citation>Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW; AMISTAD-II Investigators. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol. 2005 Jun 7;45(11):1775-80. doi: 10.1016/j.jacc.2005.02.061.</citation>
    <PMID>15936605</PMID>
  </reference>
  <verification_date>September 2014</verification_date>
  <study_first_submitted>September 4, 2014</study_first_submitted>
  <study_first_submitted_qc>September 5, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 8, 2014</study_first_posted>
  <last_update_submitted>September 5, 2014</last_update_submitted>
  <last_update_submitted_qc>September 5, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 8, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>First Hospital of China Medical University</investigator_affiliation>
    <investigator_full_name>Yingxian Sun</investigator_full_name>
    <investigator_title>Director, Department of cardiology</investigator_title>
  </responsible_party>
  <keyword>Myocardial infarction</keyword>
  <keyword>No-Reflow Phenomenon</keyword>
  <keyword>Ticagrelor</keyword>
  <keyword>Clopidogrel</keyword>
  <keyword>Single-Photon Emission Computerized Tomography</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Myocardial Infarction</mesh_term>
    <mesh_term>Infarction</mesh_term>
    <mesh_term>No-Reflow Phenomenon</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Clopidogrel</mesh_term>
    <mesh_term>Ticagrelor</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/NCT02233790
org study id: ISSBRIL0209
nct id: NCT02233790
lead sponsor: 
collaborator: 
has dmc: Yes
The patients with acute myocardial infarction (AMI) present high mortality and morbidity
      rate,even treated with stenting in the blocked heart vessels.

      The appearance of no-reflow is common after re-opening of the blocked vessel. The no-reflow
      were commonly attributed to tiny blockage in coronary micro-vasculature by thrombus and spasm
      of the micro-vessel during stenting.

      An agent with more effective anti-clotting and micro-vessel dilation would be helpful to
      solve the issue of no-reflow. Ticagrelor was demonstrated to be a potent platelet inhibitor
      and a potent micro-vessel dilator which can influence metabolism of adenosine, a endogenous
      potent small vessel dilator.

      This study is to test the effectiveness of ticagrelor on improving reperfusion and minimizing
      the myocardial infarct size after PPCI in patients with AMI.
The patients with acute myocardial infarction (AMI) present high mortality and morbidity
      rate, and also have malignant prognosis even if they could survive. The mortality and
      prognosis has been improved markedly because of the treatment with primary percutaneous
      coronary intervention (PPCI). However, the issue of no-reflow after revascularization has not
      been solved yet. The mechanisms of no-reflow in human being were regarded mainly as
      micro-embolism in coronary micro-circulation with thrombus or debris from atherosclerotic
      plaque, coronary micro-vasculature spasm and other conditions.

      Therefore, an agent with potent antithrombotic and micro-vasculature dilation function would
      be more effective on prevention of no-reflow after coronary revascularization. Ticagrelor was
      demonstrated to be a potent platelet inhibitor and a potent micro-vessel dilator which can
      influence metabolism of adenosine.

      Ticagrelor can inhibit adenosine uptake in vitro and subsequently augments cardiac blood flow
      in a canine model of reactive hypoxia- or adenosine-induced blood flow increases. In a dog
      coronary thrombosis model, ticagrelor blocks ADP-induced platelet activation and aggregation;
      prevents platelet-mediated thrombosis; prolongs reperfusion time and reduces re-occlusion and
      cyclic flow variation; and significantly decreases infarct size and rapidly restores
      myocardial tissue perfusion. These findings suggest that ticagrelor may have additional
      benefits in patients with acute coronary syndrome beyond inhibition of platelet aggregation,
      which is advantageous to the dilation of microcirculation and improvement of myocardial
      perfusion. AMISTAD study shows that: adenosine reperfusion therapy can reduce 33% of the
      infarction area assessed by single-photon emission computed tomography (SPECT) detection.
      AMISTAD- 2 study showed that: adenosine early reperfusion therapy can reduce the composite
      end point of death and heart failure events. Additionally, ticagrelor is a non-precursor
      agent, playing a role directly on platelet inhibition.

      Myocardial perfusion imaging with SPECT is among the most widely used and well-established
      noninvasive tools for the diagnosis of ischemic coronary disease. It has been shown to have a
      high sensitivity and specificity in identifying patients with coronary artery disease and to
      be accurate in identifying areas of prior myocardial infarction.

      Given the evidence (from PLATO trial) of greater IPA with ticagrelor than clopidogrel,
      similar risk of major bleeding and probable effect of micro-vasculature dilation due to
      adenosine, ticagrelor will improve the reperfusion and decrease the infarct size
      significantly.

      This study is to test the effectiveness of ticagrelor on improving reperfusion and minimizing
      the myocardial infarct size after PPCI in patients with AMI. Also, it is to evaluate the
      safety of ticagrelor in patients with AMI.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: myocardial infarcted size
time frame: 1 week
description: To evaluate the infarcted size on Day 7 after PPCI by SPECT.
measure: elevated ST segment resolution
time frame: 1 hour and 24 hours
description: To observe the elevated ST segment resolution at 1 h and 24 h after PPCI;
measure: severe brachycardia arrhythmia
time frame: 1 month
arm group label: Ticagrelor
arm group type: Experimental
arm group label: Clopidogrel
arm group type: Active Comparator
intervention type: Drug
intervention name: Ticagrelor
description: a loading dose of 180mg pre-PCI, and then 90 mg twice daily for 1 Month within the study. Thereafter, the patients will take clopidogrel if Ticagrelor is not available on the market.
arm group label: Ticagrelor
other name: Brilinta
intervention type: Drug
intervention name: Clopidogrel
description: Clopidogrel 75 mg once daily after a loading dose of 300 mg pre-PCI.
arm group label: Clopidogrel
other name: Plavix
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Yingxian Sun, Dr.
role: Principal Investigator
affiliation: First Hospital of China Medical University
last name: Yingxian Sun, Dr.
phone: 0086-24-83282688
email: sunyingxian12@126.com
last name: Wen Tian, Dr.
phone: 0086-24-83282300
email: dr.wentian@gmail.com
facility: 
contact: 
investigator: 
country: China
citation: Mahaffey KW, Puma JA, Barbagelata NA, DiCarli MF, Leesar MA, Browne KF, Eisenberg PR, Bolli R, Casas AC, Molina-Viamonte V, Orlandi C, Blevins R, Gibbons RJ, Califf RM, Granger CB. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial. J Am Coll Cardiol. 1999 Nov 15;34(6):1711-20. doi: 10.1016/s0735-1097(99)00418-0.
PMID: 10577561
citation: Steg PG, James S, Harrington RA, Ardissino D, Becker RC, Cannon CP, Emanuelsson H, Finkelstein A, Husted S, Katus H, Kilhamn J, Olofsson S, Storey RF, Weaver WD, Wallentin L; PLATO Study Group. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation. 2010 Nov 23;122(21):2131-41. doi: 10.1161/CIRCULATIONAHA.109.927582. Epub 2010 Nov 8.
PMID: 21060072
citation: Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R, Antonino MJ, Patil SB, Karunakaran A, Kereiakes DJ, Parris C, Purdy D, Wilson V, Ledley GS, Storey RF. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009 Dec 22;120(25):2577-85. doi: 10.1161/CIRCULATIONAHA.109.912550. Epub 2009 Nov 18.
PMID: 19923168
citation: Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW; AMISTAD-II Investigators. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol. 2005 Jun 7;45(11):1775-80. doi: 10.1016/j.jacc.2005.02.061.
PMID: 15936605
responsible party type: Principal Investigator
investigator affiliation: First Hospital of China Medical University
investigator full name: Yingxian Sun
investigator title: Director, Department of cardiology
mesh term: Myocardial Infarction
mesh term: Infarction
mesh term: No-Reflow Phenomenon
mesh term: Clopidogrel
mesh term: Ticagrelor