<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/NCT03774394</url>
  </required_header>
  <id_info>
    <org_study_id>IRB201801870 -A</org_study_id>
    <nct_id>NCT03774394</nct_id>
  </id_info>
  <brief_title>Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus</brief_title>
  <official_title>Impact of Chronic Kidney Disease (CKD) on Pharmacodynamic Profiles of the P2Y12 Receptor Inhibitor Clopidogrel in the Setting of Type 2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Scott R. MacKenzie Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Florida</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) are at increased risk&#xD;
      of atherothrombotic events. Clopidogrel is the most widely used platelet P2Y12 receptor&#xD;
      inhibitor in patients with coronary artery disease (CAD). However, despite its benefits, many&#xD;
      patients still experience recurrent atherothrombotic events. The proposed study will test the&#xD;
      central hypothesis that in DM patients the presence of CKD reduces clopidogrel-mediated P2Y12&#xD;
      inhibitory effects through synergistic mechanisms, which include upregulation of the P2Y12&#xD;
      signaling pathway and impaired clopidogrel metabolism.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with diabetes mellitus (DM) and coexisting chronic kidney disease (CKD) are at&#xD;
      increased risk of atherothrombotic events, underscoring the importance of secondary&#xD;
      prevention antiplatelet therapy in these high-risk patients. Clopidogrel is the most widely&#xD;
      used platelet P2Y12 receptor inhibitor in patients with coronary artery disease (CAD).&#xD;
      However, despite its clinical benefits, many patients still experience recurrent&#xD;
      atherothrombotic events. This is in part due to the impaired effects of clopidogrel in DM&#xD;
      patients, particularly among those with coexisting CKD. However, underlying mechanism(s)&#xD;
      leading to magnification of impaired clopidogrel response among DM patients with CKD remain&#xD;
      unexplored. The ever growing prevalence of CKD in patients with DM and their high risk of&#xD;
      recurrent events underscores the need to define such mechanism(s) as this may set the basis&#xD;
      for identifying treatment regimens leading to more effective platelet inhibition and&#xD;
      cardiovascular protection in these high-risk patients. The proposed study will test the&#xD;
      central hypothesis that in DM patients the presence of CKD reduces clopidogrel-mediated P2Y12&#xD;
      inhibitory effects through synergistic mechanisms, which include upregulation of the P2Y12&#xD;
      signaling pathway and impaired clopidogrel metabolism. Comprehensive pharmacokinetic and&#xD;
      pharmacodynamic assessments, including ex vivo and in vitro experiments, evaluating the&#xD;
      impact of CKD on antiplatelet drug response in DM patients are proposed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 22, 2019</start_date>
  <completion_date type="Actual">May 31, 2022</completion_date>
  <primary_completion_date type="Actual">May 23, 2022</primary_completion_date>
  <phase>Phase 4</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>Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is &gt;50%</measure>
    <time_frame>6 hours</time_frame>
    <description>Comparison of platelet reactivity measured as PRI assessed by VASP after a 600 mg clopidogrel LD between DM patients with and without CKD</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clopidogrel Active Metabolite Concentration</measure>
    <time_frame>6 hours</time_frame>
    <description>Comparison of clopidogrel active metabolite plasma concentrations by means of AUC</description>
  </secondary_outcome>
  <other_outcome>
    <measure>P2Y12 Reaction Units (PRU) Assessed by VerifyNow. The Cutoff for High Platelet Reactivity is &gt;208.</measure>
    <time_frame>6 hours</time_frame>
    <description>Comparison of platelet reactivity measured as PRU assessed by VerifyNow after a 600 mg clopidogrel LD between DM patients with and without CKD</description>
  </other_outcome>
  <other_outcome>
    <measure>Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is &gt;50%</measure>
    <time_frame>Baseline</time_frame>
    <description>Comparison of of platelet reactivity measured as PRI assessed by VASP after incubation with clopidogrel active metabolite between DM patients with and without CKD</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">61</enrollment>
  <condition>Chronic Kidney Disease (CKD)</condition>
  <condition>Type 2 Diabetes Mellitus (T2DM)</condition>
  <condition>Coronary Artery Disease (CAD)</condition>
  <arm_group>
    <arm_group_label>Diabetes Mellitus patients with Chronic Kidney Disease</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Diabetes Mellitus patients without Chronic Kidney Disease</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clopidogrel</intervention_name>
    <description>Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.</description>
    <arm_group_label>Diabetes Mellitus patients with Chronic Kidney Disease</arm_group_label>
    <arm_group_label>Diabetes Mellitus patients without Chronic Kidney Disease</arm_group_label>
    <other_name>Plavix</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clopidogrel active metabolite</intervention_name>
    <description>In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
    <arm_group_label>Diabetes Mellitus patients with Chronic Kidney Disease</arm_group_label>
    <arm_group_label>Diabetes Mellitus patients without Chronic Kidney Disease</arm_group_label>
    <other_name>Plavix</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Type 2 DM, defined according to ADA definition, on treatment with oral hypoglycemic&#xD;
             agents and/or insulin&#xD;
&#xD;
          -  Angiographically documented CAD&#xD;
&#xD;
          -  On treatment with low-dose aspirin (81mg/day) for ≥30 days as part of standard of&#xD;
             care.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of any antiplatelet therapy (except aspirin) in prior 30 days&#xD;
&#xD;
          -  Use of parenteral or oral anticoagulation&#xD;
&#xD;
          -  Active bleeding&#xD;
&#xD;
          -  High risk of bleeding&#xD;
&#xD;
          -  Clinical indication to be on a P2Y12 receptor inhibitor&#xD;
&#xD;
          -  End-stage renal disease on hemodialysis&#xD;
&#xD;
          -  Any active malignancy&#xD;
&#xD;
          -  Platelet count &lt; 100x106/µl&#xD;
&#xD;
          -  Hemoglobin &lt;9 g/dl&#xD;
&#xD;
          -  Severe known liver disease&#xD;
&#xD;
          -  Hemodynamic instability&#xD;
&#xD;
          -  Known allergy to clopidogrel&#xD;
&#xD;
          -  Pregnant / lactating females (women of childbearing age must use reliable birth&#xD;
             control).&#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_official>
    <last_name>Francesco Franchi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Florida</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Florida Jacksonville</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32209</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>December 11, 2018</study_first_submitted>
  <study_first_submitted_qc>December 11, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 13, 2018</study_first_posted>
  <results_first_submitted>June 29, 2023</results_first_submitted>
  <results_first_submitted_qc>July 24, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">August 21, 2023</results_first_posted>
  <last_update_submitted>July 24, 2023</last_update_submitted>
  <last_update_submitted_qc>July 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>pharmacodynamics (PD)</keyword>
  <keyword>pharmacokinetic (PK)</keyword>
  <keyword>clopidogrel</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Renal Insufficiency, Chronic</mesh_term>
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Myocardial Ischemia</mesh_term>
    <mesh_term>Coronary Disease</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Clopidogrel</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 21, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT03774394/Prot_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Diabetes Mellitus Patients With Chronic Kidney Disease</title>
          <description>Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
        </group>
        <group group_id="P2">
          <title>Diabetes Mellitus Patients Without Chronic Kidney Disease</title>
          <description>Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="31"/>
                <participants group_id="P2" count="30"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="29"/>
                <participants group_id="P2" count="30"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Patient with diabetes and stable coronary artery disease not on a P2Y12 inhibitor.</population>
      <group_list>
        <group group_id="B1">
          <title>Diabetes Mellitus Patients With Chronic Kidney Disease</title>
          <description>Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
        </group>
        <group group_id="B2">
          <title>Diabetes Mellitus Patients Without Chronic Kidney Disease</title>
          <description>Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="31"/>
            <count group_id="B2" value="30"/>
            <count group_id="B3" value="61"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="68.4" spread="10.8"/>
                    <measurement group_id="B2" value="65.2" spread="6.8"/>
                    <measurement group_id="B3" value="66.7" spread="8.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="34"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="24"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="36"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="30"/>
                    <measurement group_id="B3" value="61"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior myocardial infarction</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is &gt;50%</title>
        <description>Comparison of platelet reactivity measured as PRI assessed by VASP after a 600 mg clopidogrel LD between DM patients with and without CKD</description>
        <time_frame>6 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Diabetes Mellitus Patients With Chronic Kidney Disease</title>
            <description>Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
          </group>
          <group group_id="O2">
            <title>Diabetes Mellitus Patients Without Chronic Kidney Disease</title>
            <description>Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
          </group>
        </group_list>
        <measure>
          <title>Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is &gt;50%</title>
          <description>Comparison of platelet reactivity measured as PRI assessed by VASP after a 600 mg clopidogrel LD between DM patients with and without CKD</description>
          <units>PRI%</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="67.5" spread="27.4"/>
                    <measurement group_id="O2" value="67.2" spread="30.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clopidogrel Active Metabolite Concentration</title>
        <description>Comparison of clopidogrel active metabolite plasma concentrations by means of AUC</description>
        <time_frame>6 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Diabetes Mellitus Patients With Chronic Kidney Disease</title>
            <description>Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
          </group>
          <group group_id="O2">
            <title>Diabetes Mellitus Patients Without Chronic Kidney Disease</title>
            <description>Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
          </group>
        </group_list>
        <measure>
          <title>Clopidogrel Active Metabolite Concentration</title>
          <description>Comparison of clopidogrel active metabolite plasma concentrations by means of AUC</description>
          <units>ng*h/mL</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="47.1" lower_limit="32.8" upper_limit="62.7"/>
                    <measurement group_id="O2" value="39.6" lower_limit="19.8" upper_limit="85.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>P2Y12 Reaction Units (PRU) Assessed by VerifyNow. The Cutoff for High Platelet Reactivity is &gt;208.</title>
        <description>Comparison of platelet reactivity measured as PRU assessed by VerifyNow after a 600 mg clopidogrel LD between DM patients with and without CKD</description>
        <time_frame>6 hours</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Diabetes Mellitus Patients With Chronic Kidney Disease</title>
            <description>Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
          </group>
          <group group_id="O2">
            <title>Diabetes Mellitus Patients Without Chronic Kidney Disease</title>
            <description>Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
          </group>
        </group_list>
        <measure>
          <title>P2Y12 Reaction Units (PRU) Assessed by VerifyNow. The Cutoff for High Platelet Reactivity is &gt;208.</title>
          <description>Comparison of platelet reactivity measured as PRU assessed by VerifyNow after a 600 mg clopidogrel LD between DM patients with and without CKD</description>
          <units>PRU</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="164" spread="91"/>
                    <measurement group_id="O2" value="156" spread="92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is &gt;50%</title>
        <description>Comparison of of platelet reactivity measured as PRI assessed by VASP after incubation with clopidogrel active metabolite between DM patients with and without CKD</description>
        <time_frame>Baseline</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Diabetes Mellitus Patients With Chronic Kidney Disease</title>
            <description>Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
          </group>
          <group group_id="O2">
            <title>Diabetes Mellitus Patients Without Chronic Kidney Disease</title>
            <description>Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
          </group>
        </group_list>
        <measure>
          <title>Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is &gt;50%</title>
          <description>Comparison of of platelet reactivity measured as PRI assessed by VASP after incubation with clopidogrel active metabolite between DM patients with and without CKD</description>
          <units>PRI%</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="92.7" spread="5.6"/>
                    <measurement group_id="O2" value="94.4" spread="3.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>24 hours</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Diabetes Mellitus Patients With Chronic Kidney Disease</title>
          <description>Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
        </group>
        <group group_id="E2">
          <title>Diabetes Mellitus Patients Without Chronic Kidney Disease</title>
          <description>Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.&#xD;
Clopidogrel: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.&#xD;
Clopidogrel active metabolite: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="31"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="31"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="31"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Francesco Franchi, MD</name_or_title>
      <organization>University of Florida</organization>
      <phone>+1-904-244-2060</phone>
      <email>francesco.franchi@jax.ufl.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03774394
org study id: IRB201801870 -A
nct id: NCT03774394
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) are at increased risk
      of atherothrombotic events. Clopidogrel is the most widely used platelet P2Y12 receptor
      inhibitor in patients with coronary artery disease (CAD). However, despite its benefits, many
      patients still experience recurrent atherothrombotic events. The proposed study will test the
      central hypothesis that in DM patients the presence of CKD reduces clopidogrel-mediated P2Y12
      inhibitory effects through synergistic mechanisms, which include upregulation of the P2Y12
      signaling pathway and impaired clopidogrel metabolism.
Patients with diabetes mellitus (DM) and coexisting chronic kidney disease (CKD) are at
      increased risk of atherothrombotic events, underscoring the importance of secondary
      prevention antiplatelet therapy in these high-risk patients. Clopidogrel is the most widely
      used platelet P2Y12 receptor inhibitor in patients with coronary artery disease (CAD).
      However, despite its clinical benefits, many patients still experience recurrent
      atherothrombotic events. This is in part due to the impaired effects of clopidogrel in DM
      patients, particularly among those with coexisting CKD. However, underlying mechanism(s)
      leading to magnification of impaired clopidogrel response among DM patients with CKD remain
      unexplored. The ever growing prevalence of CKD in patients with DM and their high risk of
      recurrent events underscores the need to define such mechanism(s) as this may set the basis
      for identifying treatment regimens leading to more effective platelet inhibition and
      cardiovascular protection in these high-risk patients. The proposed study will test the
      central hypothesis that in DM patients the presence of CKD reduces clopidogrel-mediated P2Y12
      inhibitory effects through synergistic mechanisms, which include upregulation of the P2Y12
      signaling pathway and impaired clopidogrel metabolism. Comprehensive pharmacokinetic and
      pharmacodynamic assessments, including ex vivo and in vitro experiments, evaluating the
      impact of CKD on antiplatelet drug response in DM patients are proposed.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is >50%
time frame: 6 hours
description: Comparison of platelet reactivity measured as PRI assessed by VASP after a 600 mg clopidogrel LD between DM patients with and without CKD
measure: Clopidogrel Active Metabolite Concentration
time frame: 6 hours
description: Comparison of clopidogrel active metabolite plasma concentrations by means of AUC
measure: P2Y12 Reaction Units (PRU) Assessed by VerifyNow. The Cutoff for High Platelet Reactivity is >208.
time frame: 6 hours
description: Comparison of platelet reactivity measured as PRU assessed by VerifyNow after a 600 mg clopidogrel LD between DM patients with and without CKD
measure: Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is >50%
time frame: Baseline
description: Comparison of of platelet reactivity measured as PRI assessed by VASP after incubation with clopidogrel active metabolite between DM patients with and without CKD
arm group label: Diabetes Mellitus patients with Chronic Kidney Disease
arm group type: Experimental
description: Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.
arm group label: Diabetes Mellitus patients without Chronic Kidney Disease
arm group type: Active Comparator
description: Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours.
Blood samples collected at baseline will be incubated with clopidogrel active metabolite.
intervention type: Drug
intervention name: Clopidogrel
description: Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.
arm group label: Diabetes Mellitus patients with Chronic Kidney Disease
arm group label: Diabetes Mellitus patients without Chronic Kidney Disease
other name: Plavix
intervention type: Drug
intervention name: Clopidogrel active metabolite
description: In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)
arm group label: Diabetes Mellitus patients with Chronic Kidney Disease
arm group label: Diabetes Mellitus patients without Chronic Kidney Disease
other name: Plavix
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Francesco Franchi, MD
role: Principal Investigator
affiliation: University of Florida
facility: 
country: United States
responsible party type: Sponsor
mesh term: Kidney Diseases
mesh term: Renal Insufficiency, Chronic
mesh term: Coronary Artery Disease
mesh term: Myocardial Ischemia
mesh term: Coronary Disease
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 2
mesh term: Clopidogrel
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 