<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/NCT01672788</url>
  </required_header>
  <id_info>
    <org_study_id>1276.7</org_study_id>
    <secondary_id>2012-002277-65</secondary_id>
    <nct_id>NCT01672788</nct_id>
  </id_info>
  <brief_title>Demonstration of Bioequivalence of Empagliflozin and Metformin Given in One Tablet Compared to the Intake of Single Tablets</brief_title>
  <official_title>Bioequivalence of Empagliflozin/Metformin (850 mg) Fixed Dose Combination Tablets Compared to Single Tablets Administered Together in Healthy Male and Female Volunteers Under Fed Conditions (an Open-label, Randomised, Single-dose, Four-way Crossover Study)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <brief_summary>
    <textblock>
      The primary objective of this trial is to establish bioequivalence of two FDC tablets and the&#xD;
      single tablets when administered together after a high fat high caloric meal.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">November 2012</completion_date>
  <primary_completion_date type="Actual">November 2012</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Empa: Area Under the Curve 0 to Infinity (AUC0-∞)</measure>
    <time_frame>1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration</time_frame>
    <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Metformin: Area Under the Curve 0 to Infinity (AUC0-∞)</measure>
    <time_frame>1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration</time_frame>
    <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Empa: Maximum Measured Concentration (Cmax)</measure>
    <time_frame>1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration</time_frame>
    <description>Maximum measured concentration of the analyte in plasma, per period.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Metformin: Maximum Measured Concentration (Cmax)</measure>
    <time_frame>1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration</time_frame>
    <description>Maximum measured concentration of the analyte in plasma, per period.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Empa: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)</measure>
    <time_frame>1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration</time_frame>
    <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metformin: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)</measure>
    <time_frame>1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration</time_frame>
    <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">36</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Test 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>fixed dose combination tablet</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Reference 1</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>empagliflozin tablets and metformin tablet</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Test 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>fixed dose combination tablet</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Reference 2</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>empagliflozin tablet and metformin tablet</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Empagliflozin</intervention_name>
    <description>empagliflozin tablets and metformin tablet</description>
    <arm_group_label>Reference 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Empagliflozin + Metformin</intervention_name>
    <description>fixed dose combination tablet (low)</description>
    <arm_group_label>Test 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>empagliflozin tablets and metformin tablet</description>
    <arm_group_label>Reference 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>empagliflozin tablet and metformin tablet</description>
    <arm_group_label>Reference 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Empagliflozin + Metformin</intervention_name>
    <description>fixed dose combination tablet (low)</description>
    <arm_group_label>Test 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Empagliflozin</intervention_name>
    <description>empagliflozin tablet and metformin tablet</description>
    <arm_group_label>Reference 2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
        1. Healthy male and female subjects&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
        1. Any relevant deviation from healthy conditions&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Boehringer Ingelheim</last_name>
    <role>Study Chair</role>
    <affiliation>Boehringer Ingelheim</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>1276.7.1 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Biberach</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <link>
    <url>http://trials.boehringer-ingelheim.com/</url>
    <description>Related Info</description>
  </link>
  <verification_date>August 2015</verification_date>
  <study_first_submitted>August 22, 2012</study_first_submitted>
  <study_first_submitted_qc>August 22, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 27, 2012</study_first_posted>
  <results_first_submitted>June 26, 2015</results_first_submitted>
  <results_first_submitted_qc>August 4, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">August 31, 2015</results_first_posted>
  <last_update_submitted>August 4, 2015</last_update_submitted>
  <last_update_submitted_qc>August 4, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 31, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
    <mesh_term>Empagliflozin</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>This was an open-label, randomized, 4-way crossover trial. 36 patients were randomised to one of 4 treatment sequences and treated. Each treatment period consisted of a single dose of medication followed by 72 hours of pharmacokinetic sampling, with a washout of at least 7 days between treatment periods.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>T1 / R1 / T2 / R2</title>
          <description>Patients received the 4 treatments in the following order:&#xD;
Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)&#xD;
Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)&#xD;
Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)&#xD;
Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)</description>
        </group>
        <group group_id="P2">
          <title>R1 / T1 / R2 / T2</title>
          <description>Patients received the 4 treatments in the following order:&#xD;
Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)&#xD;
Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)&#xD;
Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)&#xD;
Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)</description>
        </group>
        <group group_id="P3">
          <title>T2 / R2 / T1 / R1</title>
          <description>Patients received the 4 treatments in the following order:&#xD;
Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)&#xD;
Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)&#xD;
Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)&#xD;
Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)</description>
        </group>
        <group group_id="P4">
          <title>R2 / T2 / R1 / T1</title>
          <description>Patients received the 4 treatments in the following order:&#xD;
Empa 5mg Free Dose: Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet) (R2)&#xD;
Empa 5mg Fixed-dose: Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin (T2)&#xD;
Empa 12.5mg Free Dose: Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet) (R1)&#xD;
Empa 12.5mg Fixed-dose: Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin (T1)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Treatment Period 1 (3 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="9"/>
              </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="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout Period 1 (7 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="9"/>
              </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="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Treatment Period 2 (3 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="9"/>
              </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="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout Period 2 (7 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="8"/>
              </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="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</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>
          <title>Treatment Period 3 (3 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="8"/>
              </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="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout Period 3 (7 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="8"/>
              </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="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Treatment Period 4 (3 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="8"/>
              </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="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Overall Study</title>
          <description>Total number of patients randomised and treated in the study. This was an open-label, randomized, 4-way crossover trial. 36 patients were randomised to one of 4 treatment sequences and treated. Each treatment period consisted of a single dose of medication followed by 72hours of pharmacokinetic sampling, with a washout of at least 7 days between treatment periods.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="36"/>
          </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="33.6" spread="9.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Empa: Area Under the Curve 0 to Infinity (AUC0-∞)</title>
        <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
        <time_frame>1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration</time_frame>
        <population>Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications</population>
        <group_list>
          <group group_id="O1">
            <title>Empa 12.5mg Fixed-dose</title>
            <description>Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin</description>
          </group>
          <group group_id="O2">
            <title>Empa 12.5mg Free Dose</title>
            <description>Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)</description>
          </group>
          <group group_id="O3">
            <title>Empa 5mg Fixed-dose</title>
            <description>Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin</description>
          </group>
          <group group_id="O4">
            <title>Empa 5mg Free Dose</title>
            <description>Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)</description>
          </group>
        </group_list>
        <measure>
          <title>Empa: Area Under the Curve 0 to Infinity (AUC0-∞)</title>
          <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
          <population>Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications</population>
          <units>nmol*h/L</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="34"/>
                <count group_id="O3" value="35"/>
                <count group_id="O4" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2560" spread="25.5"/>
                    <measurement group_id="O2" value="2530" spread="29.5"/>
                    <measurement group_id="O3" value="986" spread="26.9"/>
                    <measurement group_id="O4" value="968" spread="23.9"/>
                  </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>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Considered characteristic is empa 12.5mg fixed-dose divided by empa 12.5mg free dose</non_inferiority_desc>
            <param_type>Geometric Mean Ratio</param_type>
            <param_value>101.31</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>10.7</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>96.89</ci_lower_limit>
            <ci_upper_limit>105.93</ci_upper_limit>
            <estimate_desc>Standard deviation is actually the geometric coefficient of variation (gCV)</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Considered characteristic is empa 5mg fixed-dose divided by empa 5mg free dose</non_inferiority_desc>
            <param_type>Geometric Mean Ratio</param_type>
            <param_value>100.30</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>7.0</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>97.40</ci_lower_limit>
            <ci_upper_limit>103.29</ci_upper_limit>
            <estimate_desc>Standard deviation is actually the geometric coefficient of variation (gCV)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Metformin: Area Under the Curve 0 to Infinity (AUC0-∞)</title>
        <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
        <time_frame>1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration</time_frame>
        <population>Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications</population>
        <group_list>
          <group group_id="O1">
            <title>Empa 12.5mg Fixed-dose</title>
            <description>Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin</description>
          </group>
          <group group_id="O2">
            <title>Empa 12.5mg Free Dose</title>
            <description>Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)</description>
          </group>
          <group group_id="O3">
            <title>Empa 5mg Fixed-dose</title>
            <description>Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin</description>
          </group>
          <group group_id="O4">
            <title>Empa 5mg Free Dose</title>
            <description>Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)</description>
          </group>
        </group_list>
        <measure>
          <title>Metformin: Area Under the Curve 0 to Infinity (AUC0-∞)</title>
          <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
          <population>Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications</population>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="34"/>
                <count group_id="O3" value="35"/>
                <count group_id="O4" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8640" spread="18.0"/>
                    <measurement group_id="O2" value="8450" spread="24.4"/>
                    <measurement group_id="O3" value="8520" spread="23.8"/>
                    <measurement group_id="O4" value="8560" spread="25.8"/>
                  </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>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Considered characteristic is empa 12.5mg fixed-dose divided by empa 12.5mg free dose.</non_inferiority_desc>
            <param_type>Geometric Mean Ratio</param_type>
            <param_value>101.61</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>8.8</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>97.94</ci_lower_limit>
            <ci_upper_limit>105.41</ci_upper_limit>
            <estimate_desc>Standard deviation is actually the gCV</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Considered characteristic is empa 5mg fixed-dose divided by empa 5mg free dose.</non_inferiority_desc>
            <param_type>Geometric Mean Ratio</param_type>
            <param_value>98.56</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>10.8</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>94.24</ci_lower_limit>
            <ci_upper_limit>103.08</ci_upper_limit>
            <estimate_desc>Standard deviation is actually the gCV</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Empa: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)</title>
        <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
        <time_frame>1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration</time_frame>
        <population>Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications</population>
        <group_list>
          <group group_id="O1">
            <title>Empa 12.5mg Fixed-dose</title>
            <description>Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin</description>
          </group>
          <group group_id="O2">
            <title>Empa 12.5mg Free Dose</title>
            <description>Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)</description>
          </group>
          <group group_id="O3">
            <title>Empa 5mg Fixed-dose</title>
            <description>Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin</description>
          </group>
          <group group_id="O4">
            <title>Empa 5mg Free Dose</title>
            <description>Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)</description>
          </group>
        </group_list>
        <measure>
          <title>Empa: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)</title>
          <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
          <population>Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications</population>
          <units>nmol*h/L</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="34"/>
                <count group_id="O3" value="35"/>
                <count group_id="O4" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2520" spread="25.1"/>
                    <measurement group_id="O2" value="2490" spread="29.3"/>
                    <measurement group_id="O3" value="963" spread="27.1"/>
                    <measurement group_id="O4" value="946" spread="24.2"/>
                  </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>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Considered characteristic is empa 12.5mg fixed-dose divided by empa 12.5mg free dose</non_inferiority_desc>
            <param_type>Geometric Mean Ratio</param_type>
            <param_value>101.20</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>10.4</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>96.89</ci_lower_limit>
            <ci_upper_limit>105.71</ci_upper_limit>
            <estimate_desc>Standard deviation is actually the geometric coefficient of variation (gCV)</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Considered characteristic is empa 5mg fixed-dose divided by empa 5mg free dose</non_inferiority_desc>
            <param_type>Geometric Mean Ratio</param_type>
            <param_value>100.31</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>7.0</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>97.41</ci_lower_limit>
            <ci_upper_limit>103.30</ci_upper_limit>
            <estimate_desc>Standard deviation is actually the gCV</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Empa: Maximum Measured Concentration (Cmax)</title>
        <description>Maximum measured concentration of the analyte in plasma, per period.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
        <time_frame>1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration</time_frame>
        <population>Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications</population>
        <group_list>
          <group group_id="O1">
            <title>Empa 12.5mg Fixed-dose</title>
            <description>Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin</description>
          </group>
          <group group_id="O2">
            <title>Empa 12.5mg Free Dose</title>
            <description>Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)</description>
          </group>
          <group group_id="O3">
            <title>Empa 5mg Fixed-dose</title>
            <description>Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin</description>
          </group>
          <group group_id="O4">
            <title>Empa 5mg Free Dose</title>
            <description>Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)</description>
          </group>
        </group_list>
        <measure>
          <title>Empa: Maximum Measured Concentration (Cmax)</title>
          <description>Maximum measured concentration of the analyte in plasma, per period.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
          <population>Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications</population>
          <units>nmol/L</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="34"/>
                <count group_id="O3" value="35"/>
                <count group_id="O4" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="266" spread="20.3"/>
                    <measurement group_id="O2" value="258" spread="21.3"/>
                    <measurement group_id="O3" value="103" spread="22.1"/>
                    <measurement group_id="O4" value="101" spread="24.4"/>
                  </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>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Considered characteristic is empa 12.5mg fixed-dose divided by empa 12.5mg free dose</non_inferiority_desc>
            <param_type>Geometric Mean Ratio</param_type>
            <param_value>102.70</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>9.4</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>98.75</ci_lower_limit>
            <ci_upper_limit>106.81</ci_upper_limit>
            <estimate_desc>Standard deviation is actually the geometric coefficient of variation (gCV)</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Considered characteristic is empa 5mg fixed-dose divided by empa 5mg free dose</non_inferiority_desc>
            <param_type>Geometric Mean Ratio</param_type>
            <param_value>100.97</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>12.3</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>95.94</ci_lower_limit>
            <ci_upper_limit>106.27</ci_upper_limit>
            <estimate_desc>Standard deviation is actually the gCV</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Metformin: Maximum Measured Concentration (Cmax)</title>
        <description>Maximum measured concentration of the analyte in plasma, per period.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
        <time_frame>1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration</time_frame>
        <population>Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications</population>
        <group_list>
          <group group_id="O1">
            <title>Empa 12.5mg Fixed-dose</title>
            <description>Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin</description>
          </group>
          <group group_id="O2">
            <title>Empa 12.5mg Free Dose</title>
            <description>Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)</description>
          </group>
          <group group_id="O3">
            <title>Empa 5mg Fixed-dose</title>
            <description>Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin</description>
          </group>
          <group group_id="O4">
            <title>Empa 5mg Free Dose</title>
            <description>Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)</description>
          </group>
        </group_list>
        <measure>
          <title>Metformin: Maximum Measured Concentration (Cmax)</title>
          <description>Maximum measured concentration of the analyte in plasma, per period.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
          <population>Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications</population>
          <units>ng/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="34"/>
                <count group_id="O3" value="35"/>
                <count group_id="O4" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1080" spread="16.4"/>
                    <measurement group_id="O2" value="1080" spread="19.6"/>
                    <measurement group_id="O3" value="1090" spread="16.5"/>
                    <measurement group_id="O4" value="1100" spread="17.5"/>
                  </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>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Considered characteristic is empa 12.5mg fixed-dose divided by empa 12.5mg free dose .</non_inferiority_desc>
            <param_type>Geometric Mean Ratio</param_type>
            <param_value>99.64</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>10.5</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>95.39</ci_lower_limit>
            <ci_upper_limit>104.09</ci_upper_limit>
            <estimate_desc>Standard deviation is actually the geometric coefficient of variation (gCV)</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Considered characteristic is empa 5mg fixed-dose divided by empa 5mg free dose.</non_inferiority_desc>
            <param_type>Geometric Mean Ratio</param_type>
            <param_value>97.89</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>10.2</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>93.82</ci_lower_limit>
            <ci_upper_limit>102.15</ci_upper_limit>
            <estimate_desc>Standard deviation is actually the gCV</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Metformin: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)</title>
        <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
        <time_frame>1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration</time_frame>
        <population>Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications</population>
        <group_list>
          <group group_id="O1">
            <title>Empa 12.5mg Fixed-dose</title>
            <description>Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin</description>
          </group>
          <group group_id="O2">
            <title>Empa 12.5mg Free Dose</title>
            <description>Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)</description>
          </group>
          <group group_id="O3">
            <title>Empa 5mg Fixed-dose</title>
            <description>Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin</description>
          </group>
          <group group_id="O4">
            <title>Empa 5mg Free Dose</title>
            <description>Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)</description>
          </group>
        </group_list>
        <measure>
          <title>Metformin: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)</title>
          <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point.&#xD;
In this endpoint, the &quot;Measured values&quot; shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.</description>
          <population>Pharmacokinetic (PK) set: All subjects who took at least 1 dose of investigational treatment, provided at least 1 observation for at least 1 primary PK endpoint, did not have important protocol violations relevant to the evaluation of relative bioavailability, did not vomit at or before 2 times median tmax and did not use restricted medications</population>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="34"/>
                <count group_id="O3" value="35"/>
                <count group_id="O4" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8370" spread="18.1"/>
                    <measurement group_id="O2" value="8190" spread="24.1"/>
                    <measurement group_id="O3" value="8280" spread="23.2"/>
                    <measurement group_id="O4" value="8320" spread="25.2"/>
                  </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>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Considered characteristic is empa 12.5mg fixed-dose divided by empa 12.5mg free dose .</non_inferiority_desc>
            <param_type>Geometric Mean Ratio</param_type>
            <param_value>101.51</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>8.6</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>97.95</ci_lower_limit>
            <ci_upper_limit>105.21</ci_upper_limit>
            <estimate_desc>Standard deviation is actually the geometric coefficient of variation (gCV)</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority or Equivalence</non_inferiority_type>
            <non_inferiority_desc>Considered characteristic is empa 5mg fixed-dose divided by empa 5mg free dose .</non_inferiority_desc>
            <param_type>Geometric Mean Ratio</param_type>
            <param_value>98.57</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>10.1</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>94.50</ci_lower_limit>
            <ci_upper_limit>102.81</ci_upper_limit>
            <estimate_desc>Standard deviation is actually the gCV</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Treatment period and following washout period, up to 35 days</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Empa 12.5mg Fixed-dose</title>
          <description>Fixed-dose tablet of 12.5mg empagliflozin plus 850mg metformin</description>
        </group>
        <group group_id="E2">
          <title>Empa 12.5mg Free Dose</title>
          <description>Free dose combination of 12.5mg empagliflozin (consisting of 1 tablet of 10mg and another of 2.5mg) and 850mg metformin (1 tablet)</description>
        </group>
        <group group_id="E3">
          <title>Empa 5mg Fixed-dose</title>
          <description>Fixed-dose tablet of 5mg empagliflozin plus 850mg metformin</description>
        </group>
        <group group_id="E4">
          <title>Empa 5mg Free Dose</title>
          <description>Free dose combination of 5mg empagliflozin (1 tablet) and 850mg metformin (1 tablet)</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="35"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="36"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MEDDRA 15.1</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="14" subjects_at_risk="35"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="36"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="34"/>
                <counts group_id="E4" subjects_affected="9" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="35"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="36"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="34"/>
                <counts group_id="E4" subjects_affected="7" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="35"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="36"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="35"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="36"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="35"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="36"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="34"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="35"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="36"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="34"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="35"/>
              </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>Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Boehringer Ingelheim Call Center</name_or_title>
      <organization>Boehringer Ingelheim</organization>
      <phone>1-800-243-0127</phone>
      <email>clintriage.rdg@boehringer-ingelheim.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01672788
org study id: 1276.7
secondary id: 2012-002277-65
nct id: NCT01672788
lead sponsor: 
The primary objective of this trial is to establish bioequivalence of two FDC tablets and the
      single tablets when administered together after a high fat high caloric meal.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Empa: Area Under the Curve 0 to Infinity (AUC0-∞)
time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
description: Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
measure: Metformin: Area Under the Curve 0 to Infinity (AUC0-∞)
time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
description: Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
measure: Empa: Maximum Measured Concentration (Cmax)
time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
description: Maximum measured concentration of the analyte in plasma, per period.
In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
measure: Metformin: Maximum Measured Concentration (Cmax)
time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
description: Maximum measured concentration of the analyte in plasma, per period.
In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
measure: Empa: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)
time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
description: Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point.
In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
measure: Metformin: Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)
time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
description: Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point.
In this endpoint, the "Measured values" shows inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities.
arm group label: Test 1
arm group type: Experimental
description: fixed dose combination tablet
arm group label: Reference 1
arm group type: Active Comparator
description: empagliflozin tablets and metformin tablet
arm group label: Test 2
arm group type: Experimental
description: fixed dose combination tablet
arm group label: Reference 2
arm group type: Active Comparator
description: empagliflozin tablet and metformin tablet
intervention type: Drug
intervention name: Empagliflozin
description: empagliflozin tablets and metformin tablet
arm group label: Reference 1
intervention type: Drug
intervention name: Empagliflozin + Metformin
description: fixed dose combination tablet (low)
arm group label: Test 2
intervention type: Drug
intervention name: Metformin
description: empagliflozin tablets and metformin tablet
arm group label: Reference 1
intervention type: Drug
intervention name: Metformin
description: empagliflozin tablet and metformin tablet
arm group label: Reference 2
intervention type: Drug
intervention name: Empagliflozin + Metformin
description: fixed dose combination tablet (low)
arm group label: Test 1
intervention type: Drug
intervention name: Empagliflozin
description: empagliflozin tablet and metformin tablet
arm group label: Reference 2
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Boehringer Ingelheim
role: Study Chair
affiliation: Boehringer Ingelheim
facility: 
country: Germany
url: http://trials.boehringer-ingelheim.com/
description: Related Info
responsible party type: Sponsor
mesh term: Metformin
mesh term: Empagliflozin
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 