<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/NCT02189837</url>
  </required_header>
  <id_info>
    <org_study_id>20130194</org_study_id>
    <secondary_id>FLOREY</secondary_id>
    <nct_id>NCT02189837</nct_id>
  </id_info>
  <brief_title>Effects on Lipoprotein Metabolism From PCSK9 Inhibition Utilizing a Monoclonal Antibody</brief_title>
  <acronym>FLOREY</acronym>
  <official_title>Double-blind, Randomized, Placebo-controlled, Single Site Study to Evaluate the Effects of Evolocumab (AMG 145) Treatment, Alone and in Combination With Atorvastatin, on Lipoprotein Kinetics</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Amgen</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Amgen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized, double-blind, placebo-controlled trial to evaluate the effect of&#xD;
      evolocumab, atorvastatin, and combination therapy on lipoprotein kinetics.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 8, 2014</start_date>
  <completion_date type="Actual">March 5, 2015</completion_date>
  <primary_completion_date type="Actual">February 13, 2015</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percent Change From Baseline in Low-density Lipoprotein (LDL) Apolipoprotein B-100 Fractional Catabolic Rate (FCR)</measure>
    <time_frame>Baseline (5 days prior to Day 1) and Day 50; plasma samples for fasting lipids were obtained at 0, 5, 10, 20, 30, 40, and 60 min, as well as at 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours, and 2, 3, 4 and 5 days after D3-leucine administration.</time_frame>
    <description>The fractional catabolic rate (the percentage of apolipoprotein B-100 in LDL which is replaced, transferred or lost per unit of time) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. LDL particles were isolated from plasma by sequential ultracentrifugation, and isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percent Change From Baseline in LDL-C at Day 50</measure>
    <time_frame>Baseline and Day 50</time_frame>
    <description>LDL-C was measured using ultrcentrifugation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent Change From Baseline in LDL Apolipoprotein B-100 Production Rate (PR)</measure>
    <time_frame>Baseline and Day 50</time_frame>
    <description>The production rate of apolipoprotein B-100 in LDL was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. LDL particles were isolated from plasma by sequential ultracentrifugation and isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate the production rate.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent Change From Baseline in Lipoprotein (a) Fractional Catabolic Rate (FCR)</measure>
    <time_frame>Baseline (5 days prior to Day 1) and Day 50; plasma samples for fasting lipids were obtained at 0, 5, 10, 20, 30, 40, and 60 min, as well as at 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours, and 2, 3, 4 and 5 days after D3-leucine administration.</time_frame>
    <description>The fractional catabolic rate (the percentage of lipoprotein(a) (Lp[a]) which is replaced, transferred or lost per unit of time) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. Lp(a) was isolated from plasma using an immunoprecipitation method employing immunomagnetic beads and polyacrylamide gel electrophoresis. Isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent Change From Baseline in Lipoprotein(a) Production Rate (PR)</measure>
    <time_frame>Baseline and Day 50</time_frame>
    <description>The production rate of lipoprotein(a) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. Lp(a) was isolated from plasma using an immunoprecipitation method employing immunomagnetic beads and polyacrylamide gel electrophoresis. Isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">89</enrollment>
  <condition>Primary Hyperlipidemia and Mixed Dyslipidemia</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Atorvastatin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Evolocumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Evolocumab and Atorvastatin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Evolocumab</intervention_name>
    <description>Administered by subcutaneous injection</description>
    <arm_group_label>Evolocumab</arm_group_label>
    <arm_group_label>Evolocumab and Atorvastatin</arm_group_label>
    <other_name>AMG 145</other_name>
    <other_name>Repatha</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atorvastatin</intervention_name>
    <description>Administered by mouth</description>
    <arm_group_label>Atorvastatin</arm_group_label>
    <arm_group_label>Evolocumab and Atorvastatin</arm_group_label>
    <other_name>LIPITOR®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo to Evolocumab</intervention_name>
    <description>Administered by subcutaneous injection</description>
    <arm_group_label>Atorvastatin</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo to Atorvastatin</intervention_name>
    <description>Administered by mouth</description>
    <arm_group_label>Evolocumab</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Fasting LDL-C at screening ≥ 100 mg/dL and ≤ 190 mg/dL&#xD;
&#xD;
          -  Fasting triglycerides ≤ 150 mg/dL&#xD;
&#xD;
          -  Body mass index (BMI) between 18.0 and 32.0 kg/m^2&#xD;
&#xD;
          -  Framingham cardiac risk score 10% or less&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Treatment with a lipid-regulating drug or over the counter supplement in the last 3&#xD;
             months prior to screening&#xD;
&#xD;
          -  History of coronary heart disease (CHD) or CHD equivalent&#xD;
&#xD;
          -  Uncontrolled hypertension&#xD;
&#xD;
          -  Diabetes mellitus&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>MD</last_name>
    <role>Study Director</role>
    <affiliation>Amgen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Adelaide</city>
        <state>South Australia</state>
        <zip>5000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Nedlands</city>
        <state>Western Australia</state>
        <zip>6009</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <link>
    <url>http://www.amgentrials.com</url>
    <description>AmgenTrials clinical trials website</description>
  </link>
  <reference>
    <citation>Watts GF, Chan DC, Dent R, Somaratne R, Wasserman SM, Scott R, Burrows S, R Barrett PH. Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism. Circulation. 2017 Jan 24;135(4):338-351. doi: 10.1161/CIRCULATIONAHA.116.025080. Epub 2016 Dec 9.</citation>
    <PMID>27941065</PMID>
  </reference>
  <reference>
    <citation>Watts GF, Chan DC, Somaratne R, Wasserman SM, Scott R, Marcovina SM, Barrett PHR. Controlled study of the effect of proprotein convertase subtilisin-kexin type 9 inhibition with evolocumab on lipoprotein(a) particle kinetics. Eur Heart J. 2018 Jul 14;39(27):2577-2585. doi: 10.1093/eurheartj/ehy122. Erratum In: Eur Heart J. 2019 Jan 1;40(1):58.</citation>
    <PMID>29566128</PMID>
  </reference>
  <reference>
    <citation>Chan DC, Watts GF, Somaratne R, Wasserman SM, Scott R, Barrett PHR. Comparative Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibition and Statins on Postprandial Triglyceride-Rich Lipoprotein Metabolism. Arterioscler Thromb Vasc Biol. 2018 Jul;38(7):1644-1655. doi: 10.1161/ATVBAHA.118.310882. Epub 2018 Jun 7.</citation>
    <PMID>29880491</PMID>
  </reference>
  <verification_date>September 2018</verification_date>
  <study_first_submitted>July 8, 2014</study_first_submitted>
  <study_first_submitted_qc>July 11, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 15, 2014</study_first_posted>
  <results_first_submitted>June 6, 2016</results_first_submitted>
  <results_first_submitted_qc>July 20, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">August 31, 2016</results_first_posted>
  <disposition_first_submitted>January 5, 2016</disposition_first_submitted>
  <disposition_first_submitted_qc>January 5, 2016</disposition_first_submitted_qc>
  <disposition_first_posted type="Estimate">February 5, 2016</disposition_first_posted>
  <last_update_submitted>September 6, 2018</last_update_submitted>
  <last_update_submitted_qc>September 6, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 3, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Raised cholesterol</keyword>
  <keyword>Cholesterol</keyword>
  <keyword>Elevated Cholesterol</keyword>
  <keyword>Hyperlipidemias</keyword>
  <keyword>Dyslipidemias</keyword>
  <keyword>Lipid Metabolism Disorders</keyword>
  <keyword>Metabolic Diseases</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dyslipidemias</mesh_term>
    <mesh_term>Hyperlipidemias</mesh_term>
    <mesh_term>Hyperlipoproteinemias</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atorvastatin</mesh_term>
    <mesh_term>Evolocumab</mesh_term>
    <mesh_term>Antibodies, Monoclonal</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This study was conducted at 2 centers in Australia. The first participant was enrolled on 08 July 2014, and the last participant enrolled on 15 December 2014.</recruitment_details>
      <pre_assignment_details>Participants who met eligibility criteria underwent an initial 4 week run-in period of dietary stabilization before randomization. Randomization was stratified based on screening low-density lipoprotein (LDL-C) concentration (&lt; 130 mg/dL vs ≥ 130 mg/dL)</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo</title>
          <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
        </group>
        <group group_id="P2">
          <title>Atorvastatin</title>
          <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
        </group>
        <group group_id="P3">
          <title>Evolocumab</title>
          <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
        </group>
        <group group_id="P4">
          <title>Evolocumab and Atorvastatin</title>
          <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
                <participants group_id="P2" count="23"/>
                <participants group_id="P3" count="23"/>
                <participants group_id="P4" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Received Treatment</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="22"/>
                <participants group_id="P3" count="22"/>
                <participants group_id="P4" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="22"/>
                <participants group_id="P3" count="20"/>
                <participants group_id="P4" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="2"/>
              </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="1"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Sponsor Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The full analysis set includes all randomized participants who received any study drug.</population>
      <group_list>
        <group group_id="B1">
          <title>Placebo</title>
          <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
        </group>
        <group group_id="B2">
          <title>Atorvastatin</title>
          <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
        </group>
        <group group_id="B3">
          <title>Evolocumab</title>
          <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
        </group>
        <group group_id="B4">
          <title>Evolocumab and Atorvastatin</title>
          <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
        </group>
        <group group_id="B5">
          <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="21"/>
            <count group_id="B2" value="22"/>
            <count group_id="B3" value="22"/>
            <count group_id="B4" value="20"/>
            <count group_id="B5" value="85"/>
          </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="33.9" spread="12.7"/>
                    <measurement group_id="B2" value="30.4" spread="7.4"/>
                    <measurement group_id="B3" value="33.5" spread="11.6"/>
                    <measurement group_id="B4" value="31.0" spread="9.8"/>
                    <measurement group_id="B5" value="32.2" spread="10.5"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="22"/>
                    <measurement group_id="B4" value="20"/>
                    <measurement group_id="B5" value="85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>American Indian or Alaska Native</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black or African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Native Hawaiian or Other Pacific Islander</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="20"/>
                    <measurement group_id="B4" value="14"/>
                    <measurement group_id="B5" value="73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Mixed Race</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Screening LDL-C Level</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>&lt; 130 mg/dL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="8"/>
                    <measurement group_id="B5" value="35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 130 mg/dL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="13"/>
                    <measurement group_id="B4" value="12"/>
                    <measurement group_id="B5" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>LDL-C Concentration</title>
          <description>LDL-C was measured using ultracentrifugation</description>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="118.1" spread="18.1"/>
                    <measurement group_id="B2" value="123.2" spread="21.3"/>
                    <measurement group_id="B3" value="118.2" spread="18.4"/>
                    <measurement group_id="B4" value="116.5" spread="23.7"/>
                    <measurement group_id="B5" value="119.1" spread="20.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percent Change From Baseline in Low-density Lipoprotein (LDL) Apolipoprotein B-100 Fractional Catabolic Rate (FCR)</title>
        <description>The fractional catabolic rate (the percentage of apolipoprotein B-100 in LDL which is replaced, transferred or lost per unit of time) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. LDL particles were isolated from plasma by sequential ultracentrifugation, and isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.</description>
        <time_frame>Baseline (5 days prior to Day 1) and Day 50; plasma samples for fasting lipids were obtained at 0, 5, 10, 20, 30, 40, and 60 min, as well as at 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours, and 2, 3, 4 and 5 days after D3-leucine administration.</time_frame>
        <population>Efficacy Analysis Set including all randomized and dosed participants who completed baseline and Day 50 measurements.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Atorvastatin</title>
            <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O3">
            <title>Evolocumab</title>
            <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O4">
            <title>Evolocumab and Atorvastatin</title>
            <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change From Baseline in Low-density Lipoprotein (LDL) Apolipoprotein B-100 Fractional Catabolic Rate (FCR)</title>
          <description>The fractional catabolic rate (the percentage of apolipoprotein B-100 in LDL which is replaced, transferred or lost per unit of time) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. LDL particles were isolated from plasma by sequential ultracentrifugation, and isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.</description>
          <population>Efficacy Analysis Set including all randomized and dosed participants who completed baseline and Day 50 measurements.</population>
          <units>percent change</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="22"/>
                <count group_id="O3" value="20"/>
                <count group_id="O4" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.07" spread="26.06"/>
                    <measurement group_id="O2" value="74.13" spread="24.84"/>
                    <measurement group_id="O3" value="83.70" spread="26.06"/>
                    <measurement group_id="O4" value="310.48" spread="26.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The superiority of evolocumab monotherapy to placebo was tested using a 2-sided p-value at a significance level of 0.05.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.018</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>LS Mean Treatment Difference</param_type>
            <param_value>88.76</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>36.67</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>15.73</ci_lower_limit>
            <ci_upper_limit>161.80</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The treatment effect of evolocumab plus atorvastatin compared with placebo plus atorvastatin was estimated and a nominal p-value is provided.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>LS Mean Treatment Difference</param_type>
            <param_value>236.35</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>36.32</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>164.02</ci_lower_limit>
            <ci_upper_limit>308.69</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>To assess whether the treatment effect of evolocumab compared with placebo depended on being administered alone or combined with atorvastatin, the interaction was tested, i.e., the difference between the treatment difference versus the respective placebo group for the evolocumab+atorvastatin group and the evolocumab group was calculated.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.005</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>Treatment Effect</param_type>
            <param_value>147.59</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>51.61</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>44.80</ci_lower_limit>
            <ci_upper_limit>250.38</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Change From Baseline in LDL-C at Day 50</title>
        <description>LDL-C was measured using ultrcentrifugation.</description>
        <time_frame>Baseline and Day 50</time_frame>
        <population>Efficacy Analysis Set with available data at both time points</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Atorvastatin</title>
            <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O3">
            <title>Evolocumab</title>
            <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O4">
            <title>Evolocumab and Atorvastatin</title>
            <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change From Baseline in LDL-C at Day 50</title>
          <description>LDL-C was measured using ultrcentrifugation.</description>
          <population>Efficacy Analysis Set with available data at both time points</population>
          <units>percent change</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="22"/>
                <count group_id="O3" value="18"/>
                <count group_id="O4" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.65" spread="3.09"/>
                    <measurement group_id="O2" value="-45.25" spread="2.86"/>
                    <measurement group_id="O3" value="-57.79" spread="3.15"/>
                    <measurement group_id="O4" value="-83.19" spread="3.24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>LS Mean Treatment Difference</param_type>
            <param_value>-57.14</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>4.40</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>-65.91</ci_lower_limit>
            <ci_upper_limit>-48.38</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>LS Mean Treatment Difference</param_type>
            <param_value>-37.95</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>4.31</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-46.55</ci_lower_limit>
            <ci_upper_limit>-29.34</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.003</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>Treatment Effect</param_type>
            <param_value>19.20</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>6.15</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>6.93</ci_lower_limit>
            <ci_upper_limit>31.47</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Change From Baseline in LDL Apolipoprotein B-100 Production Rate (PR)</title>
        <description>The production rate of apolipoprotein B-100 in LDL was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. LDL particles were isolated from plasma by sequential ultracentrifugation and isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate the production rate.</description>
        <time_frame>Baseline and Day 50</time_frame>
        <population>Efficacy Analysis Set</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Atorvastatin</title>
            <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O3">
            <title>Evolocumab</title>
            <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O4">
            <title>Evolocumab and Atorvastatin</title>
            <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change From Baseline in LDL Apolipoprotein B-100 Production Rate (PR)</title>
          <description>The production rate of apolipoprotein B-100 in LDL was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. LDL particles were isolated from plasma by sequential ultracentrifugation and isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate the production rate.</description>
          <population>Efficacy Analysis Set</population>
          <units>percent change</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="22"/>
                <count group_id="O3" value="20"/>
                <count group_id="O4" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.80" spread="7.40"/>
                    <measurement group_id="O2" value="-3.27" spread="7.05"/>
                    <measurement group_id="O3" value="-20.45" spread="7.40"/>
                    <measurement group_id="O4" value="-35.93" spread="7.57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.11</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>LS Mean Treatment Difference</param_type>
            <param_value>-16.65</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>10.41</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-37.37</ci_lower_limit>
            <ci_upper_limit>4.08</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.002</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>LS Mean Treatment Difference</param_type>
            <param_value>-32.66</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>10.31</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-53.19</ci_lower_limit>
            <ci_upper_limit>-12.13</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.28</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>Treatment Effect</param_type>
            <param_value>-16.01</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>14.65</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-45.18</ci_lower_limit>
            <ci_upper_limit>13.16</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Change From Baseline in Lipoprotein (a) Fractional Catabolic Rate (FCR)</title>
        <description>The fractional catabolic rate (the percentage of lipoprotein(a) (Lp[a]) which is replaced, transferred or lost per unit of time) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. Lp(a) was isolated from plasma using an immunoprecipitation method employing immunomagnetic beads and polyacrylamide gel electrophoresis. Isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.</description>
        <time_frame>Baseline (5 days prior to Day 1) and Day 50; plasma samples for fasting lipids were obtained at 0, 5, 10, 20, 30, 40, and 60 min, as well as at 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours, and 2, 3, 4 and 5 days after D3-leucine administration.</time_frame>
        <population>Efficacy Analysis Set with available data</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Atorvastatin</title>
            <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O3">
            <title>Evolocumab</title>
            <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O4">
            <title>Evolocumab and Atorvastatin</title>
            <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change From Baseline in Lipoprotein (a) Fractional Catabolic Rate (FCR)</title>
          <description>The fractional catabolic rate (the percentage of lipoprotein(a) (Lp[a]) which is replaced, transferred or lost per unit of time) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. Lp(a) was isolated from plasma using an immunoprecipitation method employing immunomagnetic beads and polyacrylamide gel electrophoresis. Isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.</description>
          <population>Efficacy Analysis Set with available data</population>
          <units>percent change</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="17"/>
                <count group_id="O3" value="14"/>
                <count group_id="O4" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.49" spread="9.17"/>
                    <measurement group_id="O2" value="25.52" spread="8.92"/>
                    <measurement group_id="O3" value="5.37" spread="9.81"/>
                    <measurement group_id="O4" value="64.57" spread="9.23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The superiority of evolocumab monotherapy to placebo was tested using a 2-sided p-value at a significance level of 0.05.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.87</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>LS Mean Treatment Difference</param_type>
            <param_value>-2.12</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>13.40</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-28.94</ci_lower_limit>
            <ci_upper_limit>24.70</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The treatment effect of evolocumab plus atorvastatin compared with placebo plus atorvastatin was estimated and a nominal p-value is provided.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.003</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>LS Mean Treatment Difference</param_type>
            <param_value>39.06</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>12.76</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>13.52</ci_lower_limit>
            <ci_upper_limit>64.59</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>To assess whether the treatment effect of evolocumab compared with placebo depended on being administered alone or combined with atorvastatin, the interaction was tested, i.e., the difference between the treatment difference versus the respective placebo group for the evolocumab+atorvastatin group and the evolocumab group was calculated.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.030</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>Treatment Effect</param_type>
            <param_value>41.18</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>18.50</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>4.15</ci_lower_limit>
            <ci_upper_limit>78.20</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Change From Baseline in Lipoprotein(a) Production Rate (PR)</title>
        <description>The production rate of lipoprotein(a) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. Lp(a) was isolated from plasma using an immunoprecipitation method employing immunomagnetic beads and polyacrylamide gel electrophoresis. Isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.</description>
        <time_frame>Baseline and Day 50</time_frame>
        <population>Efficacy Analysis Set with available data</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Atorvastatin</title>
            <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O3">
            <title>Evolocumab</title>
            <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
          </group>
          <group group_id="O4">
            <title>Evolocumab and Atorvastatin</title>
            <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change From Baseline in Lipoprotein(a) Production Rate (PR)</title>
          <description>The production rate of lipoprotein(a) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. Lp(a) was isolated from plasma using an immunoprecipitation method employing immunomagnetic beads and polyacrylamide gel electrophoresis. Isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.</description>
          <population>Efficacy Analysis Set with available data</population>
          <units>percent change</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="17"/>
                <count group_id="O3" value="14"/>
                <count group_id="O4" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.52" spread="7.94"/>
                    <measurement group_id="O2" value="-6.88" spread="7.72"/>
                    <measurement group_id="O3" value="-35.91" spread="8.49"/>
                    <measurement group_id="O4" value="16.40" spread="7.99"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.001</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>LS Mean Treatment Difference</param_type>
            <param_value>-39.43</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>11.60</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-62.66</ci_lower_limit>
            <ci_upper_limit>-16.21</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.039</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>LS Mean Treatment Difference</param_type>
            <param_value>23.28</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>11.05</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.16</ci_lower_limit>
            <ci_upper_limit>45.40</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>ANCOVA</method>
            <method_desc>Model includes terms for the 2 factors in the factorial design (placebo or evolocumab and oral placebo or statin), their interaction, and LDL-C level.</method_desc>
            <param_type>Treatment Effect</param_type>
            <param_value>62.72</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>16.02</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>30.65</ci_lower_limit>
            <ci_upper_limit>94.79</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From first dose of study drug until day 73</time_frame>
      <desc>Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.</desc>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
        </group>
        <group group_id="E2">
          <title>Atorvastatin</title>
          <description>Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
        </group>
        <group group_id="E3">
          <title>Evolocumab</title>
          <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.</description>
        </group>
        <group group_id="E4">
          <title>Evolocumab and Atorvastatin</title>
          <description>Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 17.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Liver injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 17.1</default_vocab>
        <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="5" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="10" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood creatine phosphokinase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="22"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="22"/>
                <counts group_id="E4" subjects_affected="7" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Study Director</name_or_title>
      <organization>Amgen Inc.</organization>
      <phone>866-572-6436</phone>
    </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/NCT02189837
org study id: 20130194
secondary id: FLOREY
nct id: NCT02189837
lead sponsor: 
has dmc: No
This is a randomized, double-blind, placebo-controlled trial to evaluate the effect of
      evolocumab, atorvastatin, and combination therapy on lipoprotein kinetics.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Percent Change From Baseline in Low-density Lipoprotein (LDL) Apolipoprotein B-100 Fractional Catabolic Rate (FCR)
time frame: Baseline (5 days prior to Day 1) and Day 50; plasma samples for fasting lipids were obtained at 0, 5, 10, 20, 30, 40, and 60 min, as well as at 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours, and 2, 3, 4 and 5 days after D3-leucine administration.
description: The fractional catabolic rate (the percentage of apolipoprotein B-100 in LDL which is replaced, transferred or lost per unit of time) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. LDL particles were isolated from plasma by sequential ultracentrifugation, and isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.
measure: Percent Change From Baseline in LDL-C at Day 50
time frame: Baseline and Day 50
description: LDL-C was measured using ultrcentrifugation.
measure: Percent Change From Baseline in LDL Apolipoprotein B-100 Production Rate (PR)
time frame: Baseline and Day 50
description: The production rate of apolipoprotein B-100 in LDL was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. LDL particles were isolated from plasma by sequential ultracentrifugation and isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate the production rate.
measure: Percent Change From Baseline in Lipoprotein (a) Fractional Catabolic Rate (FCR)
time frame: Baseline (5 days prior to Day 1) and Day 50; plasma samples for fasting lipids were obtained at 0, 5, 10, 20, 30, 40, and 60 min, as well as at 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours, and 2, 3, 4 and 5 days after D3-leucine administration.
description: The fractional catabolic rate (the percentage of lipoprotein(a) (Lp[a]) which is replaced, transferred or lost per unit of time) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. Lp(a) was isolated from plasma using an immunoprecipitation method employing immunomagnetic beads and polyacrylamide gel electrophoresis. Isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.
measure: Percent Change From Baseline in Lipoprotein(a) Production Rate (PR)
time frame: Baseline and Day 50
description: The production rate of lipoprotein(a) was measured at Baseline and Day 50 over 5 consecutive days using the stable isotope tracer, D3-leucine. Lp(a) was isolated from plasma using an immunoprecipitation method employing immunomagnetic beads and polyacrylamide gel electrophoresis. Isotopic enrichment was determined using gas chromatography-mass spectrometry. Mathematical modelling of the protein enrichment data was used to estimate protein catabolism.
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.
arm group label: Atorvastatin
arm group type: Active Comparator
description: Participants received placebo subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.
arm group label: Evolocumab
arm group type: Experimental
description: Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and placebo tablets once a day for up to 8 weeks.
arm group label: Evolocumab and Atorvastatin
arm group type: Experimental
description: Participants received 420 mg evolocumab by subcutaneous injection once every 2 weeks on days 1, 15, 29 and 43 and 80 mg atorvastatin orally once a day for up to 8 weeks.
intervention type: Biological
intervention name: Evolocumab
description: Administered by subcutaneous injection
arm group label: Evolocumab
arm group label: Evolocumab and Atorvastatin
other name: AMG 145
other name: Repatha
intervention type: Drug
intervention name: Atorvastatin
description: Administered by mouth
arm group label: Atorvastatin
arm group label: Evolocumab and Atorvastatin
other name: LIPITOR®
intervention type: Drug
intervention name: Placebo to Evolocumab
description: Administered by subcutaneous injection
arm group label: Atorvastatin
arm group label: Placebo
intervention type: Drug
intervention name: Placebo to Atorvastatin
description: Administered by mouth
arm group label: Evolocumab
arm group label: Placebo
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: MD
role: Study Director
affiliation: Amgen
facility: 
facility: 
country: Australia
url: http://www.amgentrials.com
description: AmgenTrials clinical trials website
citation: Watts GF, Chan DC, Dent R, Somaratne R, Wasserman SM, Scott R, Burrows S, R Barrett PH. Factorial Effects of Evolocumab and Atorvastatin on Lipoprotein Metabolism. Circulation. 2017 Jan 24;135(4):338-351. doi: 10.1161/CIRCULATIONAHA.116.025080. Epub 2016 Dec 9.
PMID: 27941065
citation: Watts GF, Chan DC, Somaratne R, Wasserman SM, Scott R, Marcovina SM, Barrett PHR. Controlled study of the effect of proprotein convertase subtilisin-kexin type 9 inhibition with evolocumab on lipoprotein(a) particle kinetics. Eur Heart J. 2018 Jul 14;39(27):2577-2585. doi: 10.1093/eurheartj/ehy122. Erratum In: Eur Heart J. 2019 Jan 1;40(1):58.
PMID: 29566128
citation: Chan DC, Watts GF, Somaratne R, Wasserman SM, Scott R, Barrett PHR. Comparative Effects of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibition and Statins on Postprandial Triglyceride-Rich Lipoprotein Metabolism. Arterioscler Thromb Vasc Biol. 2018 Jul;38(7):1644-1655. doi: 10.1161/ATVBAHA.118.310882. Epub 2018 Jun 7.
PMID: 29880491
responsible party type: Sponsor
mesh term: Dyslipidemias
mesh term: Hyperlipidemias
mesh term: Hyperlipoproteinemias
mesh term: Atorvastatin
mesh term: Evolocumab
mesh term: Antibodies, Monoclonal
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 