<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/NCT02220725</url>
  </required_header>
  <id_info>
    <org_study_id>14-504</org_study_id>
    <nct_id>NCT02220725</nct_id>
  </id_info>
  <brief_title>A Study in Older Subject to Evaluate the Safety and Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Rivaroxaban</brief_title>
  <official_title>A Phase 3 Randomized, Double-blind, Placebo-controlled Study in Older Subjects to Assess Safety and the Reversal of Rivaroxaban Anticoagulation With Intravenously Administered Andexanet Alpha</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Portola Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Alexion</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the ability of Andexanet Alfa to reverse the&#xD;
      anticoagulation effect of Rivaroxaban.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>May 2014</start_date>
  <completion_date type="Actual">August 2015</completion_date>
  <primary_completion_date type="Actual">August 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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II)</measure>
    <time_frame>Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)</time_frame>
    <description>In Part 1, the primary endpoint was percent change from baseline in anti-fXa activity at the nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minutes or +5 minutes time point following the end of the bolus. In Part 2, the primary endpoint was the percent change from baseline in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion. The baseline for the primary endpoint in both parts was the anti-fXa activity just prior to administration of andexanet, 4 hours following the Day 4 dose of rivaroxaban. Anti-fXa activity was measured by a modified chromogenic assay.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficacy: Percent Change in Anti-fXa Activity (Part II)</measure>
    <time_frame>Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part II)</time_frame>
    <description>The percent change from baseline in anti-fXa activity at the nadir, following the bolus, when nadir was defined as the smaller value for anti-fXa activity at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part II). Baseline was the last assessment obtained prior to the first dose of andexanet or placebo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir</measure>
    <time_frame>Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)</time_frame>
    <description>Number of participants with ≥80% reduction in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part I) or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) {Part II]. Baseline was the last assessment obtained prior to the first dose of andexanet or placebo</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy: Change From Baseline in Free Rivaroxaban Concentration at the Nadir</measure>
    <time_frame>Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)</time_frame>
    <description>Change from baseline in free rivaroxaban concentration (ng/mL) at the nadir, when nadir was defined as the smaller value for free rivaroxaban at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part I) or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. Free plasma concentrations of rivaroxaban was determined using a validated method that involved analysis of citrated human plasma with high-throughput equilibrium dialysis followed by liquid chromatography mass spectrometry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II]</measure>
    <time_frame>Baseline to +2 minutes or +10 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)</time_frame>
    <description>Change in ETP from baseline to its peak, where peak was defined as the largest value for ETP between the +2 minute time point and the +10 minute time point after the end of the andexanet bolus (inclusive) {Part I] or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. Baseline was the last assessment obtained prior to the first dose of andexanet or placebo. ETP was measured using a tissue factor-initiated thrombin generation assay.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population)</measure>
    <time_frame>Baseline to +2 minutes or +10 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)</time_frame>
    <description>Number of participants with ETP above the lower limit of the normal range at its peak, between the +2 minute time point and the +10 minute time point after the end of the andexanet bolus (inclusive) [Part I] or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. ETP was measured using a tissue factor-initiated thrombin generation assay</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">80</enrollment>
  <condition>Bleeding</condition>
  <arm_group>
    <arm_group_label>Andexanet 800mg bolus (Part I)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Andexanet (antidote) - 800 mg bolus</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Andexanet 800mg + 960mg (Part II)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>800 mg bolus + 960 mg infusion (8 mg/min)</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Andexanet</intervention_name>
    <arm_group_label>Andexanet 800mg + 960mg (Part II)</arm_group_label>
    <arm_group_label>Andexanet 800mg bolus (Part I)</arm_group_label>
    <other_name>Andexanet alpha</other_name>
    <other_name>PRT4445</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Andexanet 800mg + 960mg (Part II)</arm_group_label>
    <arm_group_label>Andexanet 800mg bolus (Part I)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Reasonably healthy men and women aged 50 to 75&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of abnormal bleeding, active bleeding or risk factors for bleeding&#xD;
&#xD;
          -  History of thrombosis or risk factors for thrombosis&#xD;
&#xD;
          -  History of adult asthma or use of inhaled medications&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Vandana Mathur, M.D.</last_name>
    <role>Study Director</role>
    <affiliation>Portola Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>West Coast Clinical Trials</name>
      <address>
        <city>Cypress</city>
        <state>California</state>
        <zip>90630</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>August 18, 2014</study_first_submitted>
  <study_first_submitted_qc>August 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 20, 2014</study_first_posted>
  <results_first_submitted>May 18, 2018</results_first_submitted>
  <results_first_submitted_qc>August 27, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">September 25, 2018</results_first_posted>
  <disposition_first_submitted>September 19, 2017</disposition_first_submitted>
  <disposition_first_submitted_qc>September 19, 2017</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">September 27, 2017</disposition_first_posted>
  <last_update_submitted>February 8, 2023</last_update_submitted>
  <last_update_submitted_qc>February 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Andexanet alpha</keyword>
  <keyword>Anticoagulation</keyword>
  <keyword>Antidote</keyword>
  <keyword>Rivaroxaban</keyword>
  <keyword>Anti-fXa inhibitor</keyword>
  <keyword>PRT4445</keyword>
  <keyword>Xarelto</keyword>
  <keyword>Reversal agent</keyword>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Subject recruitment occurred at investigative site in the US between May 2014 through June 2015</recruitment_details>
      <pre_assignment_details>Rivaroxaban was administered orally at 20 mg once daily for 4 days followed by andexanet as a bolus (800 mg; Part I) or as a bolus followed by an infusion (800 mg bolus followed by 8 mg/min infusion for 120 minutes, 1760 mg total dose; Part II). Bolus was started 4 hours after the last rivaroxaban dose.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo (Part I)</title>
          <description>Vehicle Control</description>
        </group>
        <group group_id="P2">
          <title>Andexanet (Part I)</title>
          <description>800 mg bolus</description>
        </group>
        <group group_id="P3">
          <title>Placebo (Part II)</title>
          <description>Vehicle Control</description>
        </group>
        <group group_id="P4">
          <title>Andexanet (Part II)</title>
          <description>800 mg bolus + 960 mg infusion (8 mg/min)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="27"/>
                <participants group_id="P3" count="13"/>
                <participants group_id="P4" count="26"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="27"/>
                <participants group_id="P3" count="13"/>
                <participants group_id="P4" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</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="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</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>
              <title>Withdrawal by Subject</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>41 and 39 subjects were randomized in Part I and Part II of study, respectively</population>
      <group_list>
        <group group_id="B1">
          <title>Placebo (Part I)</title>
          <description>Vehicle Control</description>
        </group>
        <group group_id="B2">
          <title>Andexanet (Part I)</title>
          <description>800 mg bolus</description>
        </group>
        <group group_id="B3">
          <title>Placebo (Part II)</title>
          <description>Vehicle Control</description>
        </group>
        <group group_id="B4">
          <title>Andexanet (Part II)</title>
          <description>800 mg bolus + 960 mg infusion (8 mg/min)</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="14"/>
            <count group_id="B2" value="27"/>
            <count group_id="B3" value="13"/>
            <count group_id="B4" value="26"/>
            <count group_id="B5" value="80"/>
          </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="54.4" spread="3.84"/>
                    <measurement group_id="B2" value="55.6" spread="3.79"/>
                    <measurement group_id="B3" value="58.1" spread="5.45"/>
                    <measurement group_id="B4" value="57.0" spread="5.08"/>
                    <measurement group_id="B5" value="56.2" spread="4.61"/>
                  </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="6"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="11"/>
                    <measurement group_id="B5" value="32"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="15"/>
                    <measurement group_id="B5" value="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II)</title>
        <description>In Part 1, the primary endpoint was percent change from baseline in anti-fXa activity at the nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minutes or +5 minutes time point following the end of the bolus. In Part 2, the primary endpoint was the percent change from baseline in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion. The baseline for the primary endpoint in both parts was the anti-fXa activity just prior to administration of andexanet, 4 hours following the Day 4 dose of rivaroxaban. Anti-fXa activity was measured by a modified chromogenic assay.</description>
        <time_frame>Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)</time_frame>
        <population>Modified Intent-to-Treat Population included all subjects receiving andexanet/placebo with anti-fXa activity baseline value at ≥1 timepoints: 2 or 5 minute after the end of the bolus (Part I; N = 41); 110 minute during continuous infusion, 2 minute before or 5 minute after the end of continuous infusion (Part II; N = 39).</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo (Part I)</title>
            <description>Placebo was administered intravenously (IV) as a bolus (Part I). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O2">
            <title>Andexanet (Part I)</title>
            <description>Andexanet administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) (Part 1). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O3">
            <title>Placebo (Part II)</title>
            <description>Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O4">
            <title>Andexanet (Part II)</title>
            <description>Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) followed by a continuous infusion of 960 mg at 8 mg/minute for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban).</description>
          </group>
        </group_list>
        <measure>
          <title>Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II)</title>
          <description>In Part 1, the primary endpoint was percent change from baseline in anti-fXa activity at the nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minutes or +5 minutes time point following the end of the bolus. In Part 2, the primary endpoint was the percent change from baseline in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion. The baseline for the primary endpoint in both parts was the anti-fXa activity just prior to administration of andexanet, 4 hours following the Day 4 dose of rivaroxaban. Anti-fXa activity was measured by a modified chromogenic assay.</description>
          <population>Modified Intent-to-Treat Population included all subjects receiving andexanet/placebo with anti-fXa activity baseline value at ≥1 timepoints: 2 or 5 minute after the end of the bolus (Part I; N = 41); 110 minute during continuous infusion, 2 minute before or 5 minute after the end of continuous infusion (Part II; N = 39).</population>
          <units>Percent change in anti-fXa activity</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="27"/>
                <count group_id="O3" value="13"/>
                <count group_id="O4" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-18.39" spread="14.662"/>
                    <measurement group_id="O2" value="-92.22" spread="10.697"/>
                    <measurement group_id="O3" value="-44.75" spread="11.749"/>
                    <measurement group_id="O4" value="-96.72" spread="1.838"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>2-sided test exact Wilcoxon rank-sum tes</method>
            <param_type>Hodges-Lehman estimate of shift</param_type>
            <param_value>-70.14</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-85.43</ci_lower_limit>
            <ci_upper_limit>-65.91</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>2-sided test exact Wilcoxon rank-sum tes</method>
            <param_type>Hodges-Lehman estimate of shift</param_type>
            <param_value>-51.87</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-57.95</ci_lower_limit>
            <ci_upper_limit>-47.03</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Efficacy: Percent Change in Anti-fXa Activity (Part II)</title>
        <description>The percent change from baseline in anti-fXa activity at the nadir, following the bolus, when nadir was defined as the smaller value for anti-fXa activity at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part II). Baseline was the last assessment obtained prior to the first dose of andexanet or placebo</description>
        <time_frame>Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part II)</time_frame>
        <population>mITT; 41 and 39 subjects who received andexanet or placebo were included in the pharmacodynamics (PD) analysis in Part I and II, respectively.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo (Part II)</title>
            <description>Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O2">
            <title>Andexanet (Part II)</title>
            <description>Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) followed by a continuous infusion of 960 mg at 8 mg/minute for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban).</description>
          </group>
        </group_list>
        <measure>
          <title>Efficacy: Percent Change in Anti-fXa Activity (Part II)</title>
          <description>The percent change from baseline in anti-fXa activity at the nadir, following the bolus, when nadir was defined as the smaller value for anti-fXa activity at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part II). Baseline was the last assessment obtained prior to the first dose of andexanet or placebo</description>
          <population>mITT; 41 and 39 subjects who received andexanet or placebo were included in the pharmacodynamics (PD) analysis in Part I and II, respectively.</population>
          <units>Percent change in anti-fXa activity</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-23.62" spread="10.309"/>
                    <measurement group_id="O2" value="-95.34" spread="1.611"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>2-sided test exact Wilcoxon rank-sum tes</method>
            <param_type>Hodges-Lehman estimate of shift</param_type>
            <param_value>-74.45</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-78.92</ci_lower_limit>
            <ci_upper_limit>-64.45</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir</title>
        <description>Number of participants with ≥80% reduction in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part I) or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) {Part II]. Baseline was the last assessment obtained prior to the first dose of andexanet or placebo</description>
        <time_frame>Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)</time_frame>
        <population>mITT; 41 and 39 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo (Part I)</title>
            <description>Placebo was administered intravenously (IV) as a bolus (Part I). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O2">
            <title>Andexanet (Part I)</title>
            <description>Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) (Part 1). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O3">
            <title>Placebo (Part II)</title>
            <description>Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O4">
            <title>Andexanet (Part II)</title>
            <description>Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) followed by a continuous infusion of 960 mg at 8 mg/minute for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban).</description>
          </group>
        </group_list>
        <measure>
          <title>Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir</title>
          <description>Number of participants with ≥80% reduction in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part I) or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) {Part II]. Baseline was the last assessment obtained prior to the first dose of andexanet or placebo</description>
          <population>mITT; 41 and 39 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="27"/>
                <count group_id="O3" value="13"/>
                <count group_id="O4" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="26"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Efficacy: Change From Baseline in Free Rivaroxaban Concentration at the Nadir</title>
        <description>Change from baseline in free rivaroxaban concentration (ng/mL) at the nadir, when nadir was defined as the smaller value for free rivaroxaban at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part I) or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. Free plasma concentrations of rivaroxaban was determined using a validated method that involved analysis of citrated human plasma with high-throughput equilibrium dialysis followed by liquid chromatography mass spectrometry.</description>
        <time_frame>Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)</time_frame>
        <population>54 subjects who received rivaroxaban were included in the rivaroxaban pharmacokinetics (PK) analysis</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo (Part I)</title>
            <description>Placebo was administered intravenously (IV) as a bolus (Part I). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O2">
            <title>Andexanet (Part I)</title>
            <description>Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) (Part 1). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O3">
            <title>Placebo (Part II)</title>
            <description>Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O4">
            <title>Andexanet (Part II)</title>
            <description>Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) followed by a continuous infusion of 960 mg at 8 mg/minute for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban).</description>
          </group>
        </group_list>
        <measure>
          <title>Efficacy: Change From Baseline in Free Rivaroxaban Concentration at the Nadir</title>
          <description>Change from baseline in free rivaroxaban concentration (ng/mL) at the nadir, when nadir was defined as the smaller value for free rivaroxaban at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part I) or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. Free plasma concentrations of rivaroxaban was determined using a validated method that involved analysis of citrated human plasma with high-throughput equilibrium dialysis followed by liquid chromatography mass spectrometry.</description>
          <population>54 subjects who received rivaroxaban were included in the rivaroxaban pharmacokinetics (PK) analysis</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="27"/>
                <count group_id="O3" value="13"/>
                <count group_id="O4" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.155" spread="2.8914"/>
                    <measurement group_id="O2" value="-23.347" spread="6.2229"/>
                    <measurement group_id="O3" value="-12.063" spread="5.2510"/>
                    <measurement group_id="O4" value="-30.296" spread="8.1451"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>2-sided test exact Wilcoxon rank-sum tes</method>
            <param_type>Hodges-Lehmann Estimate of Shift</param_type>
            <param_value>-18.00</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-23.05</ci_lower_limit>
            <ci_upper_limit>-12.73</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II]</title>
        <description>Change in ETP from baseline to its peak, where peak was defined as the largest value for ETP between the +2 minute time point and the +10 minute time point after the end of the andexanet bolus (inclusive) {Part I] or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. Baseline was the last assessment obtained prior to the first dose of andexanet or placebo. ETP was measured using a tissue factor-initiated thrombin generation assay.</description>
        <time_frame>Baseline to +2 minutes or +10 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)</time_frame>
        <population>mITT; 41 and 39 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo (Part I)</title>
            <description>Placebo was administered intravenously (IV) as a bolus (Part I). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O2">
            <title>Andexanet (Part I)</title>
            <description>Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) (Part 1). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O3">
            <title>Placebo (Part II)</title>
            <description>Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O4">
            <title>Andexanet (Part II)</title>
            <description>Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) followed by a continuous infusion of 960 mg at 8 mg/minute for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban).</description>
          </group>
        </group_list>
        <measure>
          <title>Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II]</title>
          <description>Change in ETP from baseline to its peak, where peak was defined as the largest value for ETP between the +2 minute time point and the +10 minute time point after the end of the andexanet bolus (inclusive) {Part I] or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. Baseline was the last assessment obtained prior to the first dose of andexanet or placebo. ETP was measured using a tissue factor-initiated thrombin generation assay.</description>
          <population>mITT; 41 and 39 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively.</population>
          <units>nmol/min</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="27"/>
                <count group_id="O3" value="13"/>
                <count group_id="O4" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="173.861" spread="104.2528"/>
                    <measurement group_id="O2" value="1314.193" spread="331.1670"/>
                    <measurement group_id="O3" value="264.424" spread="140.6792"/>
                    <measurement group_id="O4" value="1510.368" spread="344.7691"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>2-sided test exact Wilcoxon rank-sum tes</method>
            <param_type>Hodges-Lehman estimate of shift</param_type>
            <param_value>1142.66</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1006.10</ci_lower_limit>
            <ci_upper_limit>1281.40</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>2-sided test exact Wilcoxon rank-sum tes</method>
            <param_type>Hodges-Lehman estimate of shift</param_type>
            <param_value>1205.05</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1034.17</ci_lower_limit>
            <ci_upper_limit>1400.79</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population)</title>
        <description>Number of participants with ETP above the lower limit of the normal range at its peak, between the +2 minute time point and the +10 minute time point after the end of the andexanet bolus (inclusive) [Part I] or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. ETP was measured using a tissue factor-initiated thrombin generation assay</description>
        <time_frame>Baseline to +2 minutes or +10 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)</time_frame>
        <population>mITT; 41 and 39 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo (Part I)</title>
            <description>Placebo was administered intravenously (IV) as a bolus (Part I). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O2">
            <title>Andexanet (Part I)</title>
            <description>Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) (Part 1). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O3">
            <title>Placebo (Part II)</title>
            <description>Placebo was administered IV as a bolus followed by a continuous infusion for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban)</description>
          </group>
          <group group_id="O4">
            <title>Andexanet (Part II)</title>
            <description>Andexanet was administered IV as a bolus of 800 mg at a target rate of approximately 30 mg/minute (over approximately 27 minutes) followed by a continuous infusion of 960 mg at 8 mg/minute for 120 minutes (Part II). The bolus was started 4 hours after the last rivaroxaban dose (at the approximate steady state Cmax for rivaroxaban).</description>
          </group>
        </group_list>
        <measure>
          <title>Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population)</title>
          <description>Number of participants with ETP above the lower limit of the normal range at its peak, between the +2 minute time point and the +10 minute time point after the end of the andexanet bolus (inclusive) [Part I] or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. ETP was measured using a tissue factor-initiated thrombin generation assay</description>
          <population>mITT; 41 and 39 subjects who received andexanet or placebo were included in the PD analysis in Part I and II, respectively.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="27"/>
                <count group_id="O3" value="13"/>
                <count group_id="O4" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="26"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>~8 to 12 weeks</time_frame>
      <desc>The Safety Analysis Population consisted of all subjects randomized and treated with study drug (andexanet or placebo)</desc>
      <group_list>
        <group group_id="E1">
          <title>Placebo (Part I)</title>
          <description>Vehicle Control</description>
        </group>
        <group group_id="E2">
          <title>Andexanet (Part I)</title>
          <description>800 mg bolus</description>
        </group>
        <group group_id="E3">
          <title>Placebo (Part II)</title>
          <description>Vehicle Control</description>
        </group>
        <group group_id="E4">
          <title>Andexanet (Part II)</title>
          <description>800 mg bolus + 960 mg infusion (8 mg/min)</description>
        </group>
      </group_list>
      <serious_events>
        <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="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 15.0</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="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="27"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="13"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Infusion Related Reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="27"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle Spasms</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="26"/>
              </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>Conducted in healthy volunteers at Clinical Research Organization.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Head of Clinical Development</name_or_title>
      <organization>Portola Pharmaceuticals, Inc.</organization>
      <phone>650-246-7000</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/NCT02220725
org study id: 14-504
nct id: NCT02220725
lead sponsor: 
has dmc: Yes
The purpose of this study is to evaluate the ability of Andexanet Alfa to reverse the
      anticoagulation effect of Rivaroxaban.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Efficacy: Percent Change From Baseline in Anti-fXa Activity at the Nadir (Parts I and II)
time frame: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)
description: In Part 1, the primary endpoint was percent change from baseline in anti-fXa activity at the nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minutes or +5 minutes time point following the end of the bolus. In Part 2, the primary endpoint was the percent change from baseline in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion. The baseline for the primary endpoint in both parts was the anti-fXa activity just prior to administration of andexanet, 4 hours following the Day 4 dose of rivaroxaban. Anti-fXa activity was measured by a modified chromogenic assay.
measure: Efficacy: Percent Change in Anti-fXa Activity (Part II)
time frame: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part II)
description: The percent change from baseline in anti-fXa activity at the nadir, following the bolus, when nadir was defined as the smaller value for anti-fXa activity at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part II). Baseline was the last assessment obtained prior to the first dose of andexanet or placebo
measure: Efficacy: Number of Participants With ≥80% Reduction in the Anti-fXa Activity From Baseline to Nadir
time frame: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)
description: Number of participants with ≥80% reduction in anti-fXa activity from its baseline to nadir, when nadir was defined as the smaller value for anti-fXa activity at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part I) or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) {Part II]. Baseline was the last assessment obtained prior to the first dose of andexanet or placebo
measure: Efficacy: Change From Baseline in Free Rivaroxaban Concentration at the Nadir
time frame: Baseline to +2 minutes or +5 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)
description: Change from baseline in free rivaroxaban concentration (ng/mL) at the nadir, when nadir was defined as the smaller value for free rivaroxaban at the +2 minute or +5 minute time point after the completion of the andexanet bolus (Part I) or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. Free plasma concentrations of rivaroxaban was determined using a validated method that involved analysis of citrated human plasma with high-throughput equilibrium dialysis followed by liquid chromatography mass spectrometry.
measure: Efficacy: Change in Thrombin Generation (ETP) From Baseline to Its Peak [Parts I and II]
time frame: Baseline to +2 minutes or +10 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)
description: Change in ETP from baseline to its peak, where peak was defined as the largest value for ETP between the +2 minute time point and the +10 minute time point after the end of the andexanet bolus (inclusive) {Part I] or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. Baseline was the last assessment obtained prior to the first dose of andexanet or placebo. ETP was measured using a tissue factor-initiated thrombin generation assay.
measure: Efficacy: Number of Participants With Thrombin Generation (ETP) Above the Lower Limit of the Derived Normal Range at Its Peak (mITT Population)
time frame: Baseline to +2 minutes or +10 minutes following the end of andexanet/placebo bolus (Part I), or 10 minutes prior to end of andexanet/placebo continuous infusion or 5 minutes after the end of andexanet/placebo continuous infusion (Part II)
description: Number of participants with ETP above the lower limit of the normal range at its peak, between the +2 minute time point and the +10 minute time point after the end of the andexanet bolus (inclusive) [Part I] or between the 110-minute time point (10 minutes prior to the end of the continuous infusion) and the 5-minute time point after the end of the continuous infusion (inclusive) [Part II]. ETP was measured using a tissue factor-initiated thrombin generation assay
arm group label: Andexanet 800mg bolus (Part I)
arm group type: Experimental
description: Andexanet (antidote) - 800 mg bolus
arm group label: Andexanet 800mg + 960mg (Part II)
arm group type: Experimental
description: 800 mg bolus + 960 mg infusion (8 mg/min)
intervention type: Biological
intervention name: Andexanet
arm group label: Andexanet 800mg + 960mg (Part II)
arm group label: Andexanet 800mg bolus (Part I)
other name: Andexanet alpha
other name: PRT4445
intervention type: Other
intervention name: Placebo
arm group label: Andexanet 800mg + 960mg (Part II)
arm group label: Andexanet 800mg bolus (Part I)
criteria: 
gender: All
minimum age: 50 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Vandana Mathur, M.D.
role: Study Director
affiliation: Portola Pharmaceuticals
facility: 
country: United States
responsible party type: Sponsor
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 