<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/NCT02975583</url>
  </required_header>
  <id_info>
    <org_study_id>161925</org_study_id>
    <nct_id>NCT02975583</nct_id>
  </id_info>
  <brief_title>Vorapaxar and Lower Extremity Bypass Grafts</brief_title>
  <official_title>A Double-blind, Randomized, Parallel Design Two Center Study to Compare the Effect of Vorapaxar vs. Placebo on Lower Extremity Vein Graft Maturation, Remodeling, and Function</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      There are no medical therapies indicated for reduction of limb ischemic events. Studies of&#xD;
      dual-antiplatelet therapy with aspirin and clopidogrel versus aspirin alone (CASPAR) as well&#xD;
      as studies of systemic anticoagulation (WAVE) have shown no benefit for either strategy in&#xD;
      the reduction in limb vascular events. Surgical bypass grafting involves harvesting of the&#xD;
      vein, warm ischemia with disruption of vaso vasorum, ischemia-reperfusion, and finally&#xD;
      heightened hemodynamic stress in the new arterial environment. Vein grafts rapidly remodel in&#xD;
      response to the increase in blood flow and pressure in an attempt to normalize them into&#xD;
      physiological range. The investigators have previously identified 3 distinct temporal phases&#xD;
      of the remodeling process: During the first 30 days following implantation is a critical&#xD;
      period of luminal enlargement which appears to be an endothelium-independent process. The&#xD;
      second phase occurs between 1 and 3 months and represents a period of stiffening of the vein&#xD;
      graft indicating synthesis of fibrous proteins. The third period is referred to as&#xD;
      biochemical remodeling wherein the vein recovers clinically measureable endothelial function.&#xD;
      It is likely diabetes mellitus impacts each of these phases. TRA2°P-TIMI 50 demonstrated a&#xD;
      reduction in acute limb ischemic (ALI) events (42% reduction) and urgent peripheral arterial&#xD;
      revascularizations (35% reduction), a finding unique among medical therapies. While the&#xD;
      temporal trend in reduction in ALI events occurred early and late after exposure suggestion&#xD;
      an antithrombotic mechanism, the reduction in elective revascularization occurred later&#xD;
      suggested beneficial effects beyond platelet inhibition. The purpose of this trial is to&#xD;
      study the physiological impact of vorapaxar on lower extremity bypass graft maturation and&#xD;
      function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Peripheral artery disease (PAD) is characterized by atherosclerotic occlusive disease of the&#xD;
      lower extremities. More than 8 million Americans and 200 million people globally have PAD.&#xD;
      Recent data reveal a prevalence of 15% in the MEDICARE population. In populations at risk,&#xD;
      patients with a history of diabetes or cigarette smoking, the risk may rise as high as 30%.&#xD;
      In addition to the heightened risk of myocardial infarction and stroke, PAD increases the&#xD;
      risk of lower extremity claudication and critical limb ischemia. Lower extremity bypass&#xD;
      grafting is an important method of restoring blood flow to the distal limb, reducing symptoms&#xD;
      of claudication, and preventing amputation in patients with severe PAD.&#xD;
&#xD;
      Vorapaxar is a protease activated receptor (PAR)-1 antagonist that inhibits thrombin&#xD;
      activation of the PAR-1 receptor. Vorapaxar has been FDA approved for patients with PAD to&#xD;
      reduce the rate of cardiovascular death, MI, stroke, and urgent coronary revascularization.&#xD;
      It is prohibited in patients with a previous stroke. In addition, patients treated with&#xD;
      vorapaxar were noted to have a significant reduction in the rates of acute limb ischemia.&#xD;
      This study will be a randomized, double blind, placebo-controlled randomized study of&#xD;
      vorapaxar vs. placebo in 80 patients undergoing femoral-popliteal bypass grafting for&#xD;
      Rutherford 3 - 5 disease.&#xD;
&#xD;
      Baseline visit: Informed consent will be signed. Vital signs will be taken and blood drawn&#xD;
      fasting for baseline values.&#xD;
&#xD;
      First visit, pre-surgery: Blood will be drawn for platelet activation testing. A 6 minute&#xD;
      walk test will be performed. Brachial artery reactivity testing will be performed. An&#xD;
      ankle-brachial index will be performed.&#xD;
&#xD;
      30 days: Platelet testing will be performed. 90 days: Limited history and physical exam. 180&#xD;
      days: Limited history and exam, blood draw for biomarkers, brachial artery reactivity&#xD;
      testing. Vein bypass graft reactivity testing.&#xD;
&#xD;
      360 days: 6 minute walk test and ankle brachial index will be performed.&#xD;
&#xD;
      Randomization: The Investigational Pharmacy will create a block randomization. Patients in&#xD;
      the active treatment group will receive vorapaxar 2.08 mg daily or matching placebo.&#xD;
      Treatment will continue for 1 year.&#xD;
&#xD;
      In addition, 20 healthy subjects to serve as a control population to define normal parameters&#xD;
      during a single visit day. The healthy subjects will not be administered vorapaxar or&#xD;
      placebo.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    We could not secure adequate medication&#xD;
  </why_stopped>
  <start_date type="Actual">October 1, 2017</start_date>
  <completion_date type="Actual">January 10, 2018</completion_date>
  <primary_completion_date type="Actual">January 10, 2018</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>Other</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Bypass Graft Flow Mediated Vasodilation under Fasted Conditions using B-mode ultrasonography on Day 180 for each treatment condition.</measure>
    <time_frame>6 Months</time_frame>
    <description>Ultrasonographic evaluation of the graft before and after sphygmomanometric cuff inflation on the calf is performed and the measure of interest is percent increase in vein graft diameter.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 180 [ Time Frame: baseline and day 180 for each treatment arm ]</measure>
    <time_frame>6 Months</time_frame>
    <description>Ultrasonographic evaluation of the graft before and after sphygmomanometric cuff inflation on the arm is performed and the measure of interest is percent increase in brachial artery diameter.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Platelet Activation blood testing</measure>
    <time_frame>30 days</time_frame>
    <description>The investigators will be measuring levels of platelet dilysyl-MDA cross-links 30 days after treatment initiation. Higher levels indicate more platelet activation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Six Minute Walk Test from Baseline to 1 year</measure>
    <time_frame>One year</time_frame>
    <description>The distance walked in a 100 foot hallway in 6 minutes.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Peripheral Artery Disease</condition>
  <arm_group>
    <arm_group_label>Experimental: Vorapaxar</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Drug: Vorapaxar 2.08 mg orally daily for a year Other name: Zontivity</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Comparator: Placebos</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Medication: Matching Placebo Daily tablet</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vorapaxar</intervention_name>
    <description>2.08 mg oral tablet daily</description>
    <arm_group_label>Experimental: Vorapaxar</arm_group_label>
    <other_name>Zontivity</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <description>Placebo oral tablet daily</description>
    <arm_group_label>Placebo Comparator: Placebos</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female, age 35 years or older&#xD;
&#xD;
          -  Atherosclerotic, infrainguinal PAD&#xD;
&#xD;
          -  Rutherford classes 3-5 planned for lower extremity bypass grafting&#xD;
&#xD;
          -  Adequate inflow into the index femoral artery&#xD;
&#xD;
          -  Adequate popliteal, tibial, or pedal revascularization target&#xD;
&#xD;
          -  Willing to comply with protocol, attend follow-up appointments, complete all study&#xD;
             assessments, and provide informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Complete occlusion of the iliac artery&#xD;
&#xD;
          -  Aortoiliac occlusive disease or severe common femoral artery disease&#xD;
&#xD;
          -  Presence of a femoral, popliteal or tibial aneurysm of the index limb&#xD;
&#xD;
          -  Life expectancy less than 2 years&#xD;
&#xD;
          -  A vascular disease prognosis that includes an anticipated above ankle amputation on&#xD;
             index limb within 4 weeks of index procedure&#xD;
&#xD;
          -  Renal dysfunction defined as MDRD eGFR ≤ 30ml/min/173 m2 at the time of screening&#xD;
&#xD;
          -  Currently on dialysis or history of a renal transplant&#xD;
&#xD;
          -  A documented hypercoagulable state&#xD;
&#xD;
          -  Nonatherosclerotic occlusive disease&#xD;
&#xD;
          -  Any prior infrainguinal revascularization&#xD;
&#xD;
          -  Current immunosuppressive medication, chemotherapy or radiation therapy&#xD;
&#xD;
          -  Absolute contraindication to iodinated contrast&#xD;
&#xD;
          -  Women who are pregnant&#xD;
&#xD;
          -  Women who are nursing&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Joshua A Beckman</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University Medical Center</affiliation>
  </overall_official>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>November 18, 2016</study_first_submitted>
  <study_first_submitted_qc>November 22, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 29, 2016</study_first_posted>
  <last_update_submitted>January 23, 2018</last_update_submitted>
  <last_update_submitted_qc>January 23, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 25, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University</investigator_affiliation>
    <investigator_full_name>Joshua Beckman</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Atherosclerosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Peripheral Arterial Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vorapaxar</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There is no plan to share IPD at this time.</ipd_description>
  </patient_data>
  <!-- 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/NCT02975583
org study id: 161925
nct id: NCT02975583
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
There are no medical therapies indicated for reduction of limb ischemic events. Studies of
      dual-antiplatelet therapy with aspirin and clopidogrel versus aspirin alone (CASPAR) as well
      as studies of systemic anticoagulation (WAVE) have shown no benefit for either strategy in
      the reduction in limb vascular events. Surgical bypass grafting involves harvesting of the
      vein, warm ischemia with disruption of vaso vasorum, ischemia-reperfusion, and finally
      heightened hemodynamic stress in the new arterial environment. Vein grafts rapidly remodel in
      response to the increase in blood flow and pressure in an attempt to normalize them into
      physiological range. The investigators have previously identified 3 distinct temporal phases
      of the remodeling process: During the first 30 days following implantation is a critical
      period of luminal enlargement which appears to be an endothelium-independent process. The
      second phase occurs between 1 and 3 months and represents a period of stiffening of the vein
      graft indicating synthesis of fibrous proteins. The third period is referred to as
      biochemical remodeling wherein the vein recovers clinically measureable endothelial function.
      It is likely diabetes mellitus impacts each of these phases. TRA2°P-TIMI 50 demonstrated a
      reduction in acute limb ischemic (ALI) events (42% reduction) and urgent peripheral arterial
      revascularizations (35% reduction), a finding unique among medical therapies. While the
      temporal trend in reduction in ALI events occurred early and late after exposure suggestion
      an antithrombotic mechanism, the reduction in elective revascularization occurred later
      suggested beneficial effects beyond platelet inhibition. The purpose of this trial is to
      study the physiological impact of vorapaxar on lower extremity bypass graft maturation and
      function.
Peripheral artery disease (PAD) is characterized by atherosclerotic occlusive disease of the
      lower extremities. More than 8 million Americans and 200 million people globally have PAD.
      Recent data reveal a prevalence of 15% in the MEDICARE population. In populations at risk,
      patients with a history of diabetes or cigarette smoking, the risk may rise as high as 30%.
      In addition to the heightened risk of myocardial infarction and stroke, PAD increases the
      risk of lower extremity claudication and critical limb ischemia. Lower extremity bypass
      grafting is an important method of restoring blood flow to the distal limb, reducing symptoms
      of claudication, and preventing amputation in patients with severe PAD.

      Vorapaxar is a protease activated receptor (PAR)-1 antagonist that inhibits thrombin
      activation of the PAR-1 receptor. Vorapaxar has been FDA approved for patients with PAD to
      reduce the rate of cardiovascular death, MI, stroke, and urgent coronary revascularization.
      It is prohibited in patients with a previous stroke. In addition, patients treated with
      vorapaxar were noted to have a significant reduction in the rates of acute limb ischemia.
      This study will be a randomized, double blind, placebo-controlled randomized study of
      vorapaxar vs. placebo in 80 patients undergoing femoral-popliteal bypass grafting for
      Rutherford 3 - 5 disease.

      Baseline visit: Informed consent will be signed. Vital signs will be taken and blood drawn
      fasting for baseline values.

      First visit, pre-surgery: Blood will be drawn for platelet activation testing. A 6 minute
      walk test will be performed. Brachial artery reactivity testing will be performed. An
      ankle-brachial index will be performed.

      30 days: Platelet testing will be performed. 90 days: Limited history and physical exam. 180
      days: Limited history and exam, blood draw for biomarkers, brachial artery reactivity
      testing. Vein bypass graft reactivity testing.

      360 days: 6 minute walk test and ankle brachial index will be performed.

      Randomization: The Investigational Pharmacy will create a block randomization. Patients in
      the active treatment group will receive vorapaxar 2.08 mg daily or matching placebo.
      Treatment will continue for 1 year.

      In addition, 20 healthy subjects to serve as a control population to define normal parameters
      during a single visit day. The healthy subjects will not be administered vorapaxar or
      placebo.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Bypass Graft Flow Mediated Vasodilation under Fasted Conditions using B-mode ultrasonography on Day 180 for each treatment condition.
time frame: 6 Months
description: Ultrasonographic evaluation of the graft before and after sphygmomanometric cuff inflation on the calf is performed and the measure of interest is percent increase in vein graft diameter.
measure: Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 180 [ Time Frame: baseline and day 180 for each treatment arm ]
time frame: 6 Months
description: Ultrasonographic evaluation of the graft before and after sphygmomanometric cuff inflation on the arm is performed and the measure of interest is percent increase in brachial artery diameter.
measure: Platelet Activation blood testing
time frame: 30 days
description: The investigators will be measuring levels of platelet dilysyl-MDA cross-links 30 days after treatment initiation. Higher levels indicate more platelet activation.
measure: Change in Six Minute Walk Test from Baseline to 1 year
time frame: One year
description: The distance walked in a 100 foot hallway in 6 minutes.
arm group label: Experimental: Vorapaxar
arm group type: Active Comparator
description: Drug: Vorapaxar 2.08 mg orally daily for a year Other name: Zontivity
arm group label: Placebo Comparator: Placebos
arm group type: Placebo Comparator
description: Medication: Matching Placebo Daily tablet
intervention type: Drug
intervention name: Vorapaxar
description: 2.08 mg oral tablet daily
arm group label: Experimental: Vorapaxar
other name: Zontivity
intervention type: Drug
intervention name: Placebos
description: Placebo oral tablet daily
arm group label: Placebo Comparator: Placebos
other name: Placebo
criteria: 
gender: All
minimum age: 35 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Joshua A Beckman
role: Principal Investigator
affiliation: Vanderbilt University Medical Center
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University
investigator full name: Joshua Beckman
investigator title: Professor of Medicine
mesh term: Peripheral Arterial Disease
mesh term: Vorapaxar
sharing ipd: No
ipd description: There is no plan to share IPD at this time.