<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/NCT01700322</url>
  </required_header>
  <id_info>
    <org_study_id>CTH-C1</org_study_id>
    <nct_id>NCT01700322</nct_id>
  </id_info>
  <brief_title>Endothelium, Stenting, and Antiplatelet Therapy (EST) - Clopidogrel, Prasugrel, Ticagrelor Study</brief_title>
  <acronym>EST</acronym>
  <official_title>Effects of Clopidogrel vs Prasugel vs Ticagrelor on Endothelial Function, Inflammatory and Oxidative Stress Parameters and Platelet Function in Patients Undergoing Coronary Artery Stenting. A Randomised, Prospective Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johannes Gutenberg University Mainz</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Johannes Gutenberg University Mainz</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Endothelial dysfunction is an important predictor - and a determinant - of adverse clinical&#xD;
      outcome. Endothelial function is impaired by coronary artery stenting, a stud from our group&#xD;
      has shown that it can be improved by platelet inhibition using clopidogrel. However,&#xD;
      clopidogrel unresponsiveness is a known problem, and it has been show that the endothelial&#xD;
      effects of clopidogrel tend to wane upon prolonged treatment. Whether a more effective&#xD;
      anti-platelet therapy is able to prevent/improve not only thrombotic events but also&#xD;
      endothelial dysfunction, with potential positive impact on clinical outcome in patients&#xD;
      undergoing coronary artery stenting, is an important hypothesis that needs to be further&#xD;
      investigated. To date, evidence regarding &quot;ancillary&quot; (non-platelet-dependent) effects of&#xD;
      antiaggregant drugs is very limited. For instance, while their antiplatelet effects, and&#xD;
      their beneficial effects in patients with acute coronary syndromes, have been clearly&#xD;
      demonstrated in multicentric trials, it remains to be shown whether these drugs also protect&#xD;
      endothelial function. Interestingly, some authors suggest that the mortality benefit observed&#xD;
      in the PLATO study is at least in part independent of direct antiplatelet effects. No study,&#xD;
      to date, has tested the effects of prasugrel and/or ticagrelor on endothelial function. With&#xD;
      the present trial, the investigators plan to test the effect of clopidogrel, prasugrel and&#xD;
      ticagrelor on endothelial function before and up to 4 weeks after coronary artery stenting.&#xD;
      This study will provide important pathophysiologic insight on the relationship between&#xD;
      platelet aggregation and endothelial function, two parameters that have been shown to&#xD;
      influence patients' prognosis.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">September 2016</completion_date>
  <primary_completion_date type="Actual">July 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>Basic Science</primary_purpose>
    <masking>Single (Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in FMD</measure>
    <time_frame>baseline and 1 month</time_frame>
    <description>The primary endpoint is the change in flow-mediated dilation (FMD) (comparison before treatment versus after treatment and stenting) in the three study groups. The mean FMD across the three measurements (1 day, 1 week, 1 month) performed after coronary artery stenting will be compared to the FMD value before drug administration and stenting.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>FMD 2 hours after loading dose</measure>
    <time_frame>baseline and 2 hours after loading dose</time_frame>
    <description>Change in FMD 2 hours after the administration of the study drug</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>L-FMC at 2 hours after the loading dose</measure>
    <time_frame>baseline and 2 hours</time_frame>
    <description>change in L-FMC at two hours after the loading dose</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>L-FMC 1 month after loading dose</measure>
    <time_frame>baseline and 1 day after stenting</time_frame>
    <description>change in flow-mediated constriction (L-FMC) (comparison before treatment versus after treatment and stenting) in the three study groups. The mean L-FMC across the three measurements (1 day, 1 week, 1 month) performed after coronary artery stenting will be compared to the value before drug administration and stenting</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability</measure>
    <time_frame>from baseline to 1 month after enrollment</time_frame>
    <description>Number of patients with adverse events.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">126</enrollment>
  <condition>Coronary Artery Disease</condition>
  <arm_group>
    <arm_group_label>Ticagrelor</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Ticagrelor 180mg oral loading dose and 90mg b.i.d for 30 days following coronary artery stenting</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Clopidogrel</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Clopidogrel 600mg loading dose + 75 mg once a day for 30 days following coronary artery stenting.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prasugrel</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Prasugrel 60mg oral loading dose followed by 10mg once a day for 30 days following coronary artery stenting</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Coronary stenting</intervention_name>
    <description>All patients will receive a drug eluting stent as clinically indicated.</description>
    <arm_group_label>Clopidogrel</arm_group_label>
    <arm_group_label>Prasugrel</arm_group_label>
    <arm_group_label>Ticagrelor</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ticagrelor</intervention_name>
    <description>Ticagrelor 180mg oral loading dose and 90mg b.i.d for 30 days following coronary artery stenting</description>
    <arm_group_label>Ticagrelor</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clopidogrel</intervention_name>
    <description>Clopidogrel 600mg loading dose + 75 mg once a day for 30 days following coronary artery stenting.</description>
    <arm_group_label>Clopidogrel</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prasugrel</intervention_name>
    <description>Prasugrel 60mg oral loading dose followed by 10mg once a day for 30 days following coronary artery stenting</description>
    <arm_group_label>Prasugrel</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  - 18-75 years old consecutive patients undergoing coronary angiography and stenting at&#xD;
             the University Medical Centre Mainz&#xD;
&#xD;
          -  A coronary lesion (and patient) amenable to treatment with drug eluting stent&#xD;
&#xD;
          -  Ability of subject to understand character and individual consequences of clinical&#xD;
             trial&#xD;
&#xD;
          -  Signed and dated informed consent of the subject must be available before start of any&#xD;
             specific trial procedures.&#xD;
&#xD;
          -  Negative pregnancy test of women with childbearing potential&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects presenting 1 or more of the following criteria will not be enrolled in the&#xD;
             trial:&#xD;
&#xD;
          -  Patients with elevated (&gt; 5 times upper normal limit) C-reactive protein level prior&#xD;
             to stenting&#xD;
&#xD;
          -  Patients in whom therapy with long-acting nitrates cannot be suspended prior to&#xD;
             endothelial function measurements&#xD;
&#xD;
          -  An acute coronary syndrome treated with coronary stenting within the last 4 weeks&#xD;
&#xD;
          -  Patients with known inflammatory/infective diseases&#xD;
&#xD;
          -  Patients with severe extracardiac diseases limiting life expectancy&#xD;
&#xD;
          -  Known heart failure (LV-EF ≤ 40% AND NYHA III-IV)&#xD;
&#xD;
          -  PCI or coronary By-Pass surgery within the last 4 weeks, pre-existing ongoing&#xD;
             treatment with any of the study treatments.&#xD;
&#xD;
          -  History of cerebrovascular events (stroke)&#xD;
&#xD;
          -  Known renal dysfunction (serum creatinine ≥ 1.8mg/dl in women, ≥ 2.0mg/dl in men)&#xD;
&#xD;
          -  Serum potassium &gt; 5.5mmol/l&#xD;
&#xD;
          -  Known hepatic impairment (AST, ALT &gt; 3 times upper limit of normal)&#xD;
&#xD;
          -  Changes in the ß-blocker, statin or ACE or angiotensin-receptor blocker inhibitor&#xD;
             treatment within the past 2 weeks&#xD;
&#xD;
          -  Pregnancy and lactation, inadequate contraception&#xD;
&#xD;
          -  Body weight &lt; 60kg&#xD;
&#xD;
          -  Active bleeding&#xD;
&#xD;
          -  Therapy with CYP3A4 inhibitors (ketoconazole, protease inhibitors, macrolide&#xD;
             antibiotics)&#xD;
&#xD;
          -  Therapy with anticoagulants: phenprocoumone, warfarin, dabigatran, rivaroxaban&#xD;
&#xD;
          -  History of hypersensitivity to any of the investigational medicinal products or to any&#xD;
             drug with similar chemical structure or to any excipient present in the pharmaceutical&#xD;
             form of the investigational medicinal product.&#xD;
&#xD;
          -  Ongoing participation in other clinical trials or within the last 3 months, or ongoing&#xD;
             therapy with one of the study medications.&#xD;
&#xD;
          -  Medical or psychological condition that would not permit completion of the trial or&#xD;
             signing of informed consent.&#xD;
&#xD;
          -  Patients with acute ST-elevation myocardial infarction&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Thomas Munzel, MD Prof.</last_name>
    <role>Study Chair</role>
    <affiliation>University Medical Center Mainz</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>2 Medical Clinic</name>
      <address>
        <city>Mainz</city>
        <zip>55131</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>September 2016</verification_date>
  <study_first_submitted>September 4, 2012</study_first_submitted>
  <study_first_submitted_qc>October 3, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 4, 2012</study_first_posted>
  <last_update_submitted>September 4, 2016</last_update_submitted>
  <last_update_submitted_qc>September 4, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 7, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Johannes Gutenberg University Mainz</investigator_affiliation>
    <investigator_full_name>Tommaso Gori</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Coronary artery disease</keyword>
  <keyword>coronary stenting</keyword>
  <keyword>platelet aggregation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Myocardial Ischemia</mesh_term>
    <mesh_term>Coronary Disease</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>
    <mesh_term>Prasugrel Hydrochloride</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/NCT01700322
org study id: CTH-C1
nct id: NCT01700322
lead sponsor: 
has dmc: Yes
Endothelial dysfunction is an important predictor - and a determinant - of adverse clinical
      outcome. Endothelial function is impaired by coronary artery stenting, a stud from our group
      has shown that it can be improved by platelet inhibition using clopidogrel. However,
      clopidogrel unresponsiveness is a known problem, and it has been show that the endothelial
      effects of clopidogrel tend to wane upon prolonged treatment. Whether a more effective
      anti-platelet therapy is able to prevent/improve not only thrombotic events but also
      endothelial dysfunction, with potential positive impact on clinical outcome in patients
      undergoing coronary artery stenting, is an important hypothesis that needs to be further
      investigated. To date, evidence regarding "ancillary" (non-platelet-dependent) effects of
      antiaggregant drugs is very limited. For instance, while their antiplatelet effects, and
      their beneficial effects in patients with acute coronary syndromes, have been clearly
      demonstrated in multicentric trials, it remains to be shown whether these drugs also protect
      endothelial function. Interestingly, some authors suggest that the mortality benefit observed
      in the PLATO study is at least in part independent of direct antiplatelet effects. No study,
      to date, has tested the effects of prasugrel and/or ticagrelor on endothelial function. With
      the present trial, the investigators plan to test the effect of clopidogrel, prasugrel and
      ticagrelor on endothelial function before and up to 4 weeks after coronary artery stenting.
      This study will provide important pathophysiologic insight on the relationship between
      platelet aggregation and endothelial function, two parameters that have been shown to
      influence patients' prognosis.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Single (Investigator)
measure: Change in FMD
time frame: baseline and 1 month
description: The primary endpoint is the change in flow-mediated dilation (FMD) (comparison before treatment versus after treatment and stenting) in the three study groups. The mean FMD across the three measurements (1 day, 1 week, 1 month) performed after coronary artery stenting will be compared to the FMD value before drug administration and stenting.
measure: FMD 2 hours after loading dose
time frame: baseline and 2 hours after loading dose
description: Change in FMD 2 hours after the administration of the study drug
measure: L-FMC at 2 hours after the loading dose
time frame: baseline and 2 hours
description: change in L-FMC at two hours after the loading dose
measure: L-FMC 1 month after loading dose
time frame: baseline and 1 day after stenting
description: change in flow-mediated constriction (L-FMC) (comparison before treatment versus after treatment and stenting) in the three study groups. The mean L-FMC across the three measurements (1 day, 1 week, 1 month) performed after coronary artery stenting will be compared to the value before drug administration and stenting
measure: Safety and tolerability
time frame: from baseline to 1 month after enrollment
description: Number of patients with adverse events.
arm group label: Ticagrelor
arm group type: Active Comparator
description: Ticagrelor 180mg oral loading dose and 90mg b.i.d for 30 days following coronary artery stenting
arm group label: Clopidogrel
arm group type: Active Comparator
description: Clopidogrel 600mg loading dose + 75 mg once a day for 30 days following coronary artery stenting.
arm group label: Prasugrel
arm group type: Active Comparator
description: Prasugrel 60mg oral loading dose followed by 10mg once a day for 30 days following coronary artery stenting
intervention type: Procedure
intervention name: Coronary stenting
description: All patients will receive a drug eluting stent as clinically indicated.
arm group label: Clopidogrel
arm group label: Prasugrel
arm group label: Ticagrelor
intervention type: Drug
intervention name: Ticagrelor
description: Ticagrelor 180mg oral loading dose and 90mg b.i.d for 30 days following coronary artery stenting
arm group label: Ticagrelor
intervention type: Drug
intervention name: Clopidogrel
description: Clopidogrel 600mg loading dose + 75 mg once a day for 30 days following coronary artery stenting.
arm group label: Clopidogrel
intervention type: Drug
intervention name: Prasugrel
description: Prasugrel 60mg oral loading dose followed by 10mg once a day for 30 days following coronary artery stenting
arm group label: Prasugrel
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Thomas Munzel, MD Prof.
role: Study Chair
affiliation: University Medical Center Mainz
facility: 
country: Germany
responsible party type: Principal Investigator
investigator affiliation: Johannes Gutenberg University Mainz
investigator full name: Tommaso Gori
investigator title: Professor
mesh term: Coronary Artery Disease
mesh term: Myocardial Ischemia
mesh term: Coronary Disease
mesh term: Clopidogrel
mesh term: Ticagrelor
mesh term: Prasugrel Hydrochloride