<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/NCT03829046</url>
  </required_header>
  <id_info>
    <org_study_id>GCO 18-1412</org_study_id>
    <secondary_id>20167719</secondary_id>
    <nct_id>NCT03829046</nct_id>
  </id_info>
  <brief_title>The Effects of Evolocumab in Patients With Diabetes and Atherosclerotic Vascular Disease</brief_title>
  <official_title>The Effects of Evolocumab on Endothelial and Inflammatory Biocellular Markers in Patients With Diabetes and Atherosclerotic Vascular Disease (METCHNIKOFF)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Robert Rosenson</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Toronto</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Michigan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Icahn School of Medicine at Mount Sinai</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Experimental models have linked lipid lowering therapies with systemic inflammation; however,&#xD;
      relatively little is known about this network in clinical populations and specifically how it&#xD;
      changes with PCSK9 inhibition. The eligible subjects will have 6 visits in 13 to 16 weeks and&#xD;
      will have Repatha/placebo 140mg subcutaneous every 4 weeks for 3 times since randomization&#xD;
      visit, blood tests will be done in each visit to evaluate the effects of evolocumab upon&#xD;
      biocellular markers potentially altered by PCSK9 inhibition in a population of type 2&#xD;
      diabetes patients with microvascular dysfunction.&#xD;
&#xD;
      Primary Aims:&#xD;
&#xD;
      Determine the ACUTE and SHORT-TERM effects of PCSK9 inhibition with evolocumab on biocellular&#xD;
      markers of inflammation, immune mediated thrombosis and rheology. The data from this trial&#xD;
      will be used to support a clinical trial to assess the role of PCSK9 inhibition in type 2&#xD;
      diabetes patients with cardiac microvascular dysfunction.&#xD;
&#xD;
      Secondary Aims:&#xD;
&#xD;
        1. To define the association between PCSK 9 concentrations and immune-related phenotype.&#xD;
&#xD;
        2. To define the association between Lp(a) concentrations, oxidized phospholipids (OxPL),&#xD;
           ApoB, biocellular markers of inflammation, tissue factor and immunothrombosis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Multi-center, double-blind, randomized, placebo-controlled, parallel group Phase IV study&#xD;
      with two treatment arms: evolocumab SC 420 mg/dL QM or matching placebo. The population will&#xD;
      include 40 participants with documented Atherosclerotic Vascular Disease (CAD, Stroke, PAD)&#xD;
      and type 2 diabetes who receive treatment with maximal tolerated statin therapy and stable&#xD;
      doses of anti-hyperglycemic therapy.&#xD;
&#xD;
      Subjects will be followed for 12 weeks during the treatment phase, maintaining the&#xD;
      double-blind throughout. Assessments of ACUTE and SHORT-TERM effects of PCSK9 inhibition with&#xD;
      evolocumab on biocellular markers of endothelial function will be measured at baseline, Week&#xD;
      2, and Week 12. Safety assessments will be undertaken at each study visit.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 3, 2019</start_date>
  <completion_date type="Actual">November 15, 2021</completion_date>
  <primary_completion_date type="Actual">November 15, 2021</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>
    <intervention_model_description>A multi-center, double-blind, randomized, placebo-controlled, parallel group Phase IV study with two treatment arms: evolocumab SC 420 mg/dL QM or matching placebo. The identity of the treatments will be concealed by the use of matching placebo to the study drug that are identical in packaging, labeling, appearance and schedule of administration.</intervention_model_description>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>The identity of the treatments will be concealed by the use of matching placebo to the study drug that are identical in packaging, labeling, appearance and schedule of administration.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Adverse Events</measure>
    <time_frame>up to 12 weeks</time_frame>
    <description>Safety as measured by number of adverse events, defined as any untoward medical occurrence in a subject who has been administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Seattle Angina Questionnaire</measure>
    <time_frame>12 weeks</time_frame>
    <description>The Seattle Angina Questionnaire is a quality-of-life measure for patients with coronary artery disease. The SAQ is a self-report instrument with 19 items that yields five subscale scores: physical limitation, angina stability, angina frequency, treatment satisfaction, and disease perception. The possible range of scores for each of the five subscales is 0 to 100, with higher scores indicating better quality of life. There is no summary score generated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MDA Level</measure>
    <time_frame>12 weeks</time_frame>
    <description>Malondialdehyde levels to measure oxidative stress</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MPO Level</measure>
    <time_frame>12 weeks</time_frame>
    <description>Myeloperoxidase level to measure inflammation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IL-6 Level</measure>
    <time_frame>12 weeks</time_frame>
    <description>Interleukin-6 levels to measure cytokines</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IL-18 Level</measure>
    <time_frame>12 weeks</time_frame>
    <description>Interleukin-8 levels to measure cytokines</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TNF-α Level</measure>
    <time_frame>12 weeks</time_frame>
    <description>Tumor necrosis factor alpha levels to measure cytokines</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PECAM Level</measure>
    <time_frame>12 weeks</time_frame>
    <description>Platelet endothelial cell adhesion molecule levels to measure vascular endothelial activation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICAM Level</measure>
    <time_frame>12 weeks</time_frame>
    <description>Intercellular adhesion molecule levels to measure vascular endothelial activation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>VCAM Level</measure>
    <time_frame>12 weeks</time_frame>
    <description>Vascular cell adhesion molecule levels to measure vascular endothelial activation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alpha5/Beta3 Activation Levels</measure>
    <time_frame>12 weeks</time_frame>
    <description>Alpha 5/Beta 3 levels to measure vascular endothelial activation</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">41</enrollment>
  <condition>Atherosclerotic Vascular Disease</condition>
  <condition>Type2 Diabetes</condition>
  <condition>Microvascular Dysfunction</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo SC QM</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Evolocumab</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Evolocumab SC 420mg/dL QM</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>12 weeks of treatment</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Evolocumab</intervention_name>
    <description>12 weeks of treatment</description>
    <arm_group_label>Evolocumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects ≥18 years of age signing of informed consent;&#xD;
&#xD;
          -  A history of clinical ASCVD, which is defined as: acute coronary syndrome, or a&#xD;
             history of MI, stable or unstable angina, coronary or other arterial&#xD;
             revascularization, stroke, transient ischemic attack (TIA), or peripheral arterial&#xD;
             disease presumed to be of atherosclerotic origin;&#xD;
&#xD;
          -  Clinical diagnosis of type 2 diabetes according to ADA/ CDA guidelines;&#xD;
&#xD;
          -  Subject on stable dose of maximally-tolerated statin therapy for ≥4 weeks prior to&#xD;
             screening and LDL-c ≥70mg/dL. For subjects whose maximally tolerated dose of statin is&#xD;
             no type or dose (i.e. determined to be statin intolerant by primary investigator),&#xD;
             background lipid-lowering therapy is not required;&#xD;
&#xD;
          -  Fasting triglycerides ≤400mg/dL (4.52mmol/L) by central laboratory at screening;&#xD;
&#xD;
          -  Willing and able to comply with scheduled visits, treatment plan, laboratory tests and&#xD;
             other trial procedures;&#xD;
&#xD;
          -  Abnormal urinary Albumin Creatinine Ratio (ACR) as defined by an ACR ≥2;&#xD;
&#xD;
          -  Subject tolerates screening placebo injection.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Personal or family history of hereditary muscular disorders;&#xD;
&#xD;
          -  NYHA III or IV heart failure, or last know left ventricular ejection fraction (LVEF)&#xD;
             &lt;30%;&#xD;
&#xD;
          -  Uncontrolled serious cardiac arrhythmia defined as recurrent and highly symptomatic&#xD;
             ventricular tachycardia, atrial fibrillation with rapid ventricular response, or&#xD;
             supraventricular tachycardia that are not controlled by medications, in the past 6&#xD;
             weeks prior to randomization;&#xD;
&#xD;
          -  Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI),&#xD;
             coronary artery graft (CABG) or stroke within 3 months prior to randomization;&#xD;
&#xD;
          -  Planned cardiac surgery or revascularization;&#xD;
&#xD;
          -  Moderate to severe renal dysfunction, defined as an estimated glomerular filtration&#xD;
             rate (eGFR) &lt;30mL/min/1.73m2 at screening;&#xD;
&#xD;
          -  Type 1 diabetes, poorly controlled type 2 diabetes (HbA1c &gt;10%), newly diagnosed type&#xD;
             2 diabetes (within 6 months of randomization), or laboratory evidence of diabetes&#xD;
             during screening (fasting serum glucose ≥126mg/dL [7.0mmol/L] or HbA1c ≥6.5% without&#xD;
             prior diagnosis of diabetes;&#xD;
&#xD;
          -  Uncontrolled hypertension, defined as sitting systolic blood pressure (SBP) &gt;160mmHg&#xD;
             or diastolic BP (DBP) &gt;100mmHg;&#xD;
&#xD;
          -  Subject who has taken a cholesterol easter transfer protein (CETP) inhibitor in the&#xD;
             last 12 months prior to LDL-c screening, such as: anacetrapib, dalcetrapib or&#xD;
             evacetrapib;&#xD;
&#xD;
          -  Treatment in the last 3 months prior to LDL-c screening with any of the following&#xD;
             drugs: systemic cyclosporine, systemic steroids (e.g. IV, intramuscular [IM], or PO)&#xD;
             (Note: hormone replacement therapy is permitted), vitamin A derivatives and retinol&#xD;
             derivatives for the treatment of dermatologic conditions (e.g. Accutane); (Note:&#xD;
             vitamin A in a multivitamin preparation is permitted). Topical retinol prescription&#xD;
             and non-prescription derivatives or creams are permitted;&#xD;
&#xD;
          -  Uncontrolled hypothyroidism or hyperthyroidism as defined by thyroid stimulating&#xD;
             hormone (TSH) &lt;1.0 time the lower limit of normal or &gt;1.5 times the ULN, respectively,&#xD;
             at screening. Potential subjects with TSH &lt;1.0 time the lower limit of normal due to&#xD;
             thyroid replacement therapy is not considered an exclusion;&#xD;
&#xD;
          -  Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase&#xD;
             (AST) or alanine aminotransferase (ALT) &gt;3 times the ULN as determined by central&#xD;
             laboratory analysis at screening;&#xD;
&#xD;
          -  Known active infection or major hematologic, renal metabolic, gastrointestinal or&#xD;
             endocrine dysfunction in the judgment of the investigator;&#xD;
&#xD;
          -  Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months prior to&#xD;
             randomization;&#xD;
&#xD;
          -  Unreliability as a study participant based on the investigator's (or designee's)&#xD;
             knowledge of the subject (e.g. alcohol or other drug abuse);&#xD;
&#xD;
          -  Currently enrolled in another investigational device or drug study, or less than 30&#xD;
             days since ending another investigational device or drug study(s), or receiving other&#xD;
             investigational agent(s);&#xD;
&#xD;
          -  Female subject who has either (1) not used at least 1 highly effective method of&#xD;
             contraception for at least 1 month prior to screening or (2) is not willing to use&#xD;
             such a method during treatment and for an additional 15 weeks after the end of&#xD;
             treatment, unless the subject is sterilized or postmenopausal;&#xD;
&#xD;
          -  Subject who is pregnant or breast feeding, or planning to become pregnant during&#xD;
             treatment and/ or within 15 weeks after the end of treatment;&#xD;
&#xD;
          -  Use of PCSK9 inhibitor within 10 weeks from screening;&#xD;
&#xD;
          -  Subject who has any kind of disorder that, in the opinion of the investigator, may&#xD;
             compromise the ability of the subject to give written informed consent and/or to&#xD;
             comply with all required study procedures;&#xD;
&#xD;
          -  Malignancy except non-melanoma skin cancers, cervical or breast ductal carcinoma in&#xD;
             situ within the last 5 years;&#xD;
&#xD;
          -  Subject who has known sensitivity to any of the products or components to be&#xD;
             administered during dosing;&#xD;
&#xD;
          -  Subject who is likely to not be available to complete all protocol-required study&#xD;
             visits or procedures, and/or to comply with all required study procedures to the best&#xD;
             of the subject and investigator's knowledge;&#xD;
&#xD;
          -  History or evidence of any other clinically significant disorder, condition or disease&#xD;
             (with the exception of those outlined above) that, in the opinion of the principal&#xD;
             investigator would pose a risk to subject or interfere with the study evaluation,&#xD;
             procedures or completion;&#xD;
&#xD;
          -  Blood donation 4 weeks prior to screening, or stated intention to donate blood or&#xD;
             blood products during the period of the study or within one month following completion&#xD;
             of the study;&#xD;
&#xD;
          -  Subjects who have participated in other studies within 30 days prior to screening, or&#xD;
             have five times the plasma half-life (if known) of the investigational drug, whichever&#xD;
             is longer;&#xD;
&#xD;
          -  BMI&gt;40kg/m2.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Both: male and female</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Robert Rosenson, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Icahn School of Medicine at Mount Sinai</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Kim A Connelly, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>St. Michael's Hospital at University of Toronto</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Icahn School of Medicine at Mount Sinai</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Michael's - University of Toronto</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5B1W8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.nature.com/articles/nature01323</url>
    <description>Inflammation in atherosclerosis</description>
  </link>
  <link>
    <url>https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361218/</url>
    <description>Hemodynamic Shear Stress via ROS Modulates PCSK9 Expression in Human Vascular Endothelial and Smooth Muscle Cells and Along the Mouse Aorta.</description>
  </link>
  <link>
    <url>https://www.ncbi.nlm.nih.gov/pubmed/26333678</url>
    <description>Local effects of human PCSK9 on the atherosclerotic lesion.</description>
  </link>
  <reference>
    <citation>Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol. 2015 Feb;15(2):104-16. doi: 10.1038/nri3793.</citation>
    <PMID>25614320</PMID>
  </reference>
  <reference>
    <citation>Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol. 2007 Jun 26;49(25):2379-93. doi: 10.1016/j.jacc.2007.02.059. Epub 2007 Jun 8.</citation>
    <PMID>17599600</PMID>
  </reference>
  <reference>
    <citation>Dai G, Kaazempur-Mofrad MR, Natarajan S, Zhang Y, Vaughn S, Blackman BR, Kamm RD, Garcia-Cardena G, Gimbrone MA Jr. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14871-6. doi: 10.1073/pnas.0406073101. Epub 2004 Oct 4.</citation>
    <PMID>15466704</PMID>
  </reference>
  <reference>
    <citation>Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. Arterioscler Thromb Vasc Biol. 1998 May;18(5):677-85. doi: 10.1161/01.atv.18.5.677.</citation>
    <PMID>9598824</PMID>
  </reference>
  <reference>
    <citation>Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation. 2010 Jun 8;121(22):2437-45. doi: 10.1161/CIRCULATIONAHA.109.916346. No abstract available.</citation>
    <PMID>20530020</PMID>
  </reference>
  <reference>
    <citation>Chang HN, Leroueil PR, Selwa K, Gasper CJ, Tsuchida RE, Wang JJ, McHugh WM, Cornell TT, Baker JR Jr, Goonewardena SN. Profiling inflammatory responses with microfluidic immunoblotting. PLoS One. 2013 Nov 27;8(11):e81889. doi: 10.1371/journal.pone.0081889. eCollection 2013.</citation>
    <PMID>24312374</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>February 1, 2019</study_first_submitted>
  <study_first_submitted_qc>February 1, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 4, 2019</study_first_posted>
  <results_first_submitted>January 24, 2023</results_first_submitted>
  <results_first_submitted_qc>March 6, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">March 8, 2023</results_first_posted>
  <last_update_submitted>March 6, 2023</last_update_submitted>
  <last_update_submitted_qc>March 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Icahn School of Medicine at Mount Sinai</investigator_affiliation>
    <investigator_full_name>Robert Rosenson</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>PCSK9 inhibition</keyword>
  <keyword>Evolocumab</keyword>
  <keyword>Inflammatory Signals</keyword>
  <keyword>Circulating monocyte subsets</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vascular Diseases</mesh_term>
    <mesh_term>Atherosclerosis</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Evolocumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>This is a pilot study and all data from this trial will be used to support a bigger clinical trial to assess the role of PCSK9 inhibition in type 2 diabetes patients with cardiac microvascular dysfunction.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 9, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/46/NCT03829046/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>July 27, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/46/NCT03829046/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Placebo</title>
          <description>Placebo SC QM x 12 weeks of treatment</description>
        </group>
        <group group_id="P2">
          <title>Evolocumab</title>
          <description>Evolocumab SC 420mg/dL QM x 12 weeks of treatment</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
                <participants group_id="P2" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <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="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Placebo</title>
          <description>Placebo SC QM x 12 weeks of treatment</description>
        </group>
        <group group_id="B2">
          <title>Evolocumab</title>
          <description>Evolocumab SC 420mg/dL QM x 12 weeks of treatment</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="19"/>
            <count group_id="B2" value="21"/>
            <count group_id="B3" value="40"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <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="63.9" spread="9.3"/>
                    <measurement group_id="B2" value="65.9" spread="7.7"/>
                    <measurement group_id="B3" value="65.7" spread="8.2"/>
                  </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="11"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</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_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="1"/>
                    <measurement group_id="B3" value="1"/>
                  </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="11"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="19"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Smoking</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Current</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Former</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Never smoker</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Diabetes</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Hypertension</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cardiovascular Disease (CVD)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Coronary Artery Disease (CAD)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Carotid Disease</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Peripheral Artery Disease (PAD)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Family History</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Premature CAD</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No premature CAD</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Medication Use</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Antihypertensive</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Antidiabetics</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>High intensity Statins</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Low to moderate intensity Statins</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>No Statin (Statin intolerance)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cholesterol Panel</title>
          <description>Total Cholesterol, Low-density Lipoprotein - cholesterol (LDL-C), High-density Lipoprotein - cholesterol (HDL), Triglycerides (TG)</description>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <title>Total Cholesterol</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="189.9" spread="39.1"/>
                    <measurement group_id="B2" value="180.0" spread="34.7"/>
                    <measurement group_id="B3" value="184.7" spread="36.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LDL-C</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="114.2" spread="30.4"/>
                    <measurement group_id="B2" value="107.7" spread="32.0"/>
                    <measurement group_id="B3" value="110.8" spread="30.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>HDL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="51.6" spread="17.8"/>
                    <measurement group_id="B2" value="44.9" spread="11.9"/>
                    <measurement group_id="B3" value="48.1" spread="15.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Triglycerides</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="129.2" spread="56.0"/>
                    <measurement group_id="B2" value="145.0" spread="59.2"/>
                    <measurement group_id="B3" value="137.5" spread="56.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Albumin</title>
          <units>g/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4.4" spread="0.3"/>
                    <measurement group_id="B2" value="4.4" spread="0.3"/>
                    <measurement group_id="B3" value="4.4" spread="0.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Fibrinogen</title>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="329.9" spread="80.6"/>
                    <measurement group_id="B2" value="317.5" spread="131.1"/>
                    <measurement group_id="B3" value="323.4" spread="107.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>HbA1c (glycated hemoglobin)</title>
          <units>percentage of hgb coated with glucose</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7.0" spread="1.2"/>
                    <measurement group_id="B2" value="7.0" spread="1.1"/>
                    <measurement group_id="B3" value="7.0" spread="1.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Adverse Events</title>
        <description>Safety as measured by number of adverse events, defined as any untoward medical occurrence in a subject who has been administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.</description>
        <time_frame>up to 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo SC QM x 12 weeks of treatment</description>
          </group>
          <group group_id="O2">
            <title>Evolocumab</title>
            <description>Evolocumab SC 420mg/dL QM x 12 weeks of treatment</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Adverse Events</title>
          <description>Safety as measured by number of adverse events, defined as any untoward medical occurrence in a subject who has been administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.</description>
          <units>events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                    <measurement group_id="O2" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Seattle Angina Questionnaire</title>
        <description>The Seattle Angina Questionnaire is a quality-of-life measure for patients with coronary artery disease. The SAQ is a self-report instrument with 19 items that yields five subscale scores: physical limitation, angina stability, angina frequency, treatment satisfaction, and disease perception. The possible range of scores for each of the five subscales is 0 to 100, with higher scores indicating better quality of life. There is no summary score generated.</description>
        <time_frame>12 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>MDA Level</title>
        <description>Malondialdehyde levels to measure oxidative stress</description>
        <time_frame>12 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>MPO Level</title>
        <description>Myeloperoxidase level to measure inflammation</description>
        <time_frame>12 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>IL-6 Level</title>
        <description>Interleukin-6 levels to measure cytokines</description>
        <time_frame>12 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>IL-18 Level</title>
        <description>Interleukin-8 levels to measure cytokines</description>
        <time_frame>12 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>TNF-α Level</title>
        <description>Tumor necrosis factor alpha levels to measure cytokines</description>
        <time_frame>12 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>PECAM Level</title>
        <description>Platelet endothelial cell adhesion molecule levels to measure vascular endothelial activation</description>
        <time_frame>12 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>ICAM Level</title>
        <description>Intercellular adhesion molecule levels to measure vascular endothelial activation</description>
        <time_frame>12 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>VCAM Level</title>
        <description>Vascular cell adhesion molecule levels to measure vascular endothelial activation</description>
        <time_frame>12 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Alpha5/Beta3 Activation Levels</title>
        <description>Alpha 5/Beta 3 levels to measure vascular endothelial activation</description>
        <time_frame>12 weeks</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>12 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Placebo SC QM x 12 weeks of treatment</description>
        </group>
        <group group_id="E2">
          <title>Evolocumab</title>
          <description>Evolocumab SC 420mg/dL QM x 12 weeks of treatment</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <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="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Hospital Admission- Unsuccessful PTA</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Acute Osteomyelitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Cervical Stenosis of Spine</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Seizure Type activity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Ataxia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Exertional Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Critical limb ischemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Chest Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>weird taste in mouth right after injection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>patient felt disoriented and confused after first injection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>drowsy right after injections</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>stomach cramps</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>reduced appetite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>worsening memory</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Flu-like Symptoms</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin itching</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>pinch at injection site when consumes greasy food</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>pain under breast on and off</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="21"/>
              </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>Dr. Qinzhong Chen</name_or_title>
      <organization>Icahn School of Medicine at Mount Sinai</organization>
      <phone>212-659-8864</phone>
      <email>qinzhong.chen@mssm.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/NCT03829046
org study id: GCO 18-1412
secondary id: 20167719
nct id: NCT03829046
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Experimental models have linked lipid lowering therapies with systemic inflammation; however,
      relatively little is known about this network in clinical populations and specifically how it
      changes with PCSK9 inhibition. The eligible subjects will have 6 visits in 13 to 16 weeks and
      will have Repatha/placebo 140mg subcutaneous every 4 weeks for 3 times since randomization
      visit, blood tests will be done in each visit to evaluate the effects of evolocumab upon
      biocellular markers potentially altered by PCSK9 inhibition in a population of type 2
      diabetes patients with microvascular dysfunction.

      Primary Aims:

      Determine the ACUTE and SHORT-TERM effects of PCSK9 inhibition with evolocumab on biocellular
      markers of inflammation, immune mediated thrombosis and rheology. The data from this trial
      will be used to support a clinical trial to assess the role of PCSK9 inhibition in type 2
      diabetes patients with cardiac microvascular dysfunction.

      Secondary Aims:

        1. To define the association between PCSK 9 concentrations and immune-related phenotype.

        2. To define the association between Lp(a) concentrations, oxidized phospholipids (OxPL),
           ApoB, biocellular markers of inflammation, tissue factor and immunothrombosis.
Multi-center, double-blind, randomized, placebo-controlled, parallel group Phase IV study
      with two treatment arms: evolocumab SC 420 mg/dL QM or matching placebo. The population will
      include 40 participants with documented Atherosclerotic Vascular Disease (CAD, Stroke, PAD)
      and type 2 diabetes who receive treatment with maximal tolerated statin therapy and stable
      doses of anti-hyperglycemic therapy.

      Subjects will be followed for 12 weeks during the treatment phase, maintaining the
      double-blind throughout. Assessments of ACUTE and SHORT-TERM effects of PCSK9 inhibition with
      evolocumab on biocellular markers of endothelial function will be measured at baseline, Week
      2, and Week 12. Safety assessments will be undertaken at each study visit.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: A multi-center, double-blind, randomized, placebo-controlled, parallel group Phase IV study with two treatment arms: evolocumab SC 420 mg/dL QM or matching placebo. The identity of the treatments will be concealed by the use of matching placebo to the study drug that are identical in packaging, labeling, appearance and schedule of administration.
primary purpose: Supportive Care
masking: Triple (Participant, Care Provider, Investigator)
masking description: The identity of the treatments will be concealed by the use of matching placebo to the study drug that are identical in packaging, labeling, appearance and schedule of administration.
measure: Number of Adverse Events
time frame: up to 12 weeks
description: Safety as measured by number of adverse events, defined as any untoward medical occurrence in a subject who has been administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
measure: Seattle Angina Questionnaire
time frame: 12 weeks
description: The Seattle Angina Questionnaire is a quality-of-life measure for patients with coronary artery disease. The SAQ is a self-report instrument with 19 items that yields five subscale scores: physical limitation, angina stability, angina frequency, treatment satisfaction, and disease perception. The possible range of scores for each of the five subscales is 0 to 100, with higher scores indicating better quality of life. There is no summary score generated.
measure: MDA Level
time frame: 12 weeks
description: Malondialdehyde levels to measure oxidative stress
measure: MPO Level
time frame: 12 weeks
description: Myeloperoxidase level to measure inflammation
measure: IL-6 Level
time frame: 12 weeks
description: Interleukin-6 levels to measure cytokines
measure: IL-18 Level
time frame: 12 weeks
description: Interleukin-8 levels to measure cytokines
measure: TNF-α Level
time frame: 12 weeks
description: Tumor necrosis factor alpha levels to measure cytokines
measure: PECAM Level
time frame: 12 weeks
description: Platelet endothelial cell adhesion molecule levels to measure vascular endothelial activation
measure: ICAM Level
time frame: 12 weeks
description: Intercellular adhesion molecule levels to measure vascular endothelial activation
measure: VCAM Level
time frame: 12 weeks
description: Vascular cell adhesion molecule levels to measure vascular endothelial activation
measure: Alpha5/Beta3 Activation Levels
time frame: 12 weeks
description: Alpha 5/Beta 3 levels to measure vascular endothelial activation
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo SC QM
arm group label: Evolocumab
arm group type: Active Comparator
description: Evolocumab SC 420mg/dL QM
intervention type: Drug
intervention name: Placebo
description: 12 weeks of treatment
arm group label: Placebo
intervention type: Drug
intervention name: Evolocumab
description: 12 weeks of treatment
arm group label: Evolocumab
criteria: 
gender: All
gender based: Yes
gender description: Both: male and female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Robert Rosenson, MD
role: Principal Investigator
affiliation: Icahn School of Medicine at Mount Sinai
last name: Kim A Connelly, MD
role: Principal Investigator
affiliation: St. Michael's Hospital at University of Toronto
facility: 
facility: 
country: Canada
country: United States
url: https://www.nature.com/articles/nature01323
description: Inflammation in atherosclerosis
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361218/
description: Hemodynamic Shear Stress via ROS Modulates PCSK9 Expression in Human Vascular Endothelial and Smooth Muscle Cells and Along the Mouse Aorta.
url: https://www.ncbi.nlm.nih.gov/pubmed/26333678
description: Local effects of human PCSK9 on the atherosclerotic lesion.
citation: Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol. 2015 Feb;15(2):104-16. doi: 10.1038/nri3793.
PMID: 25614320
citation: Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol. 2007 Jun 26;49(25):2379-93. doi: 10.1016/j.jacc.2007.02.059. Epub 2007 Jun 8.
PMID: 17599600
citation: Dai G, Kaazempur-Mofrad MR, Natarajan S, Zhang Y, Vaughn S, Blackman BR, Kamm RD, Garcia-Cardena G, Gimbrone MA Jr. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14871-6. doi: 10.1073/pnas.0406073101. Epub 2004 Oct 4.
PMID: 15466704
citation: Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. Arterioscler Thromb Vasc Biol. 1998 May;18(5):677-85. doi: 10.1161/01.atv.18.5.677.
PMID: 9598824
citation: Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation. 2010 Jun 8;121(22):2437-45. doi: 10.1161/CIRCULATIONAHA.109.916346. No abstract available.
PMID: 20530020
citation: Chang HN, Leroueil PR, Selwa K, Gasper CJ, Tsuchida RE, Wang JJ, McHugh WM, Cornell TT, Baker JR Jr, Goonewardena SN. Profiling inflammatory responses with microfluidic immunoblotting. PLoS One. 2013 Nov 27;8(11):e81889. doi: 10.1371/journal.pone.0081889. eCollection 2013.
PMID: 24312374
responsible party type: Sponsor-Investigator
investigator affiliation: Icahn School of Medicine at Mount Sinai
investigator full name: Robert Rosenson
investigator title: Professor
mesh term: Vascular Diseases
mesh term: Atherosclerosis
mesh term: Diabetes Mellitus
mesh term: Evolocumab
sharing ipd: Undecided
ipd description: This is a pilot study and all data from this trial will be used to support a bigger clinical trial to assess the role of PCSK9 inhibition in type 2 diabetes patients with cardiac microvascular dysfunction.
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 