<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/NCT02230995</url>
  </required_header>
  <id_info>
    <org_study_id>1276.15</org_study_id>
    <secondary_id>2014-002016-17</secondary_id>
    <nct_id>NCT02230995</nct_id>
  </id_info>
  <brief_title>Bioequivalence of a Fixed Dose Combination Tablet of Empagliflozin/Metformin Extended Release Compared With Mono Compound Tablets in Healthy Subjects</brief_title>
  <official_title>Bioequivalence of a Fixed Dose Combination Tablet of Empagliflozin/Metformin Extended Release (25 mg/1000 mg) Compared With the Free Combination of Empagliflozin and Metformin Extended Release Tablets in Healthy Subjects Following a High-fat, High-caloric Meal (an Open-label, Randomised, Single Dose, Crossover Trial)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Eli Lilly and Company</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <brief_summary>
    <textblock>
      The purpose of this trial is to demonstrate bioequivalence of a newly developed fixed dose&#xD;
      combination (FDC) tablet containing empagliflozin and metformin extended release compared to&#xD;
      the free combination of empagliflozin and metformin extended release under fed conditions.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">October 2014</completion_date>
  <primary_completion_date type="Actual">October 2014</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>AUC0-tz of Empagliflozin in Plasma</measure>
    <time_frame>-1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration</time_frame>
    <description>Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC0-tz of Metformin in Plasma</measure>
    <time_frame>-1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h 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 time of the last quantifiable concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cmax of Empagliflozin in Plasma</measure>
    <time_frame>-1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration</time_frame>
    <description>Maximum measured concentration of empagliflozin in plasma (Cmax)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cmax of Metformin in Plasma</measure>
    <time_frame>-1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration</time_frame>
    <description>Maximum measured concentration of the metformin in plasma</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>AUC0-infinity of Empagliflozin in Plasma</measure>
    <time_frame>-1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration</time_frame>
    <description>Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 extrapolated to infinity (AUC0-infinity)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC0-infinity of Metformin in Plasma</measure>
    <time_frame>-1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h 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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Fixed dose combination</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single dose empagliflozin/metformin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Single tablets combination</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>single doses empagliflozin and metformin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>metformin</intervention_name>
    <description>single dose of metformin given as tablets</description>
    <arm_group_label>Single tablets combination</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>empagliflozin/metformin</intervention_name>
    <description>Single dose empagliflozin/metformin given as fixed-dose combination tablet</description>
    <arm_group_label>Fixed dose combination</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>empagliflozin</intervention_name>
    <description>single dose of empagliflozin given as tablet</description>
    <arm_group_label>Single tablets combination</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
        - Healthy male and female subjects&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
        - Any relevant deviation from healthy condition.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 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>Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Biberach an der Riss</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>January 2017</verification_date>
  <study_first_submitted>August 29, 2014</study_first_submitted>
  <study_first_submitted_qc>August 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 3, 2014</study_first_posted>
  <results_first_submitted>January 19, 2017</results_first_submitted>
  <results_first_submitted_qc>January 19, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">March 9, 2017</results_first_posted>
  <last_update_submitted>January 19, 2017</last_update_submitted>
  <last_update_submitted_qc>January 19, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">March 9, 2017</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, randomised, 2-way crossover trial with 2 treatments (T and R) and 2 treatment sequences (T_R and R_T). Trial drug administrations of the 2 single dose treatments were separated by a washout period of at least 7 days.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Fed 25mg+1000mg FDC/Single</title>
          <description>Subjects received in period 1 a single dose of 25 mg empagliflozin/1000 mg metformin HCl XR (1 FDC tablet) with 240 mL of water after intake of a high-fat, high-caloric meal, followed in period 2 with a single dose of 25 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.&#xD;
2 treatments separated by a wash-out period of at least 7 days.</description>
        </group>
        <group group_id="P2">
          <title>Fed 25mg+1000mg Single/FDC</title>
          <description>Subjects received in period 1 a single dose of 25 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal, followed in period 2 with a single dose of 25 mg empagliflozin/1000 mg metformin HCl XR (1 FDC tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.&#xD;
2 treatments separated by a wash-out period of at least 7 days.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Period 1 + Washout</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Period 2 + Washout</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Fed 25mg+1000mg FDC/Single</title>
          <description>Subjects received in period 1 a single dose of 25 mg empagliflozin/1000 mg metformin HCl XR (1 FDC tablet) with 240 mL of water after intake of a high-fat, high-caloric meal, followed in period 2 with a single dose of 25 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.&#xD;
2 treatments separated by a wash-out period of at least 7 days.</description>
        </group>
        <group group_id="B2">
          <title>Fed 25mg+1000mg Single/FDC</title>
          <description>Subjects received in period 1 a single dose of 25 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal, followed in period 2 with a single dose of 25 mg empagliflozin/1000 mg metformin HCl XR (1 FDC tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.&#xD;
2 treatments separated by a wash-out period of at least 7 days.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="15"/>
            <count group_id="B2" value="15"/>
            <count group_id="B3" value="30"/>
          </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="36.60" spread="9.30"/>
                    <measurement group_id="B2" value="32.00" spread="9.80"/>
                    <measurement group_id="B3" value="34.30" spread="9.70"/>
                  </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="9"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>AUC0-tz of Empagliflozin in Plasma</title>
        <description>Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz)</description>
        <time_frame>-1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration</time_frame>
        <population>PKS set</population>
        <group_list>
          <group group_id="O1">
            <title>Fed 25mg+1000mg FDC</title>
            <description>Subjects received a single dose of 25 mg empagliflozin/1000 mg metformin Hydrochloride (HCl) Extended release (XR) (1 Fixed dose combination (FDC) tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
          </group>
          <group group_id="O2">
            <title>Fed 25mg+1000mg Single</title>
            <description>Subject received a single dose of 25 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC0-tz of Empagliflozin in Plasma</title>
          <description>Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz)</description>
          <population>PKS set</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="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5370" spread="14.9"/>
                    <measurement group_id="O2" value="5470" spread="16.0"/>
                  </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>The assessment of bioequivalence was based on 2-sided 90% confidence intervals (CIs) for the ratios (test to reference treatment) of the adjusted geometric means (gMeans) of the primary endpoints, using an acceptance range of 80.00 to 125.00%.</non_inferiority_desc>
            <p_value>&lt;0.00001</p_value>
            <method>ANOVA</method>
            <method_desc>ANOVA model on the logarithmic scale including random effects for 'subjects within sequences' &amp; fixed effect for 'sequence', 'period' &amp; 'treatment'.</method_desc>
            <param_type>Adjusted gMean ratio</param_type>
            <param_value>98.22</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>5.0</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>96.11</ci_lower_limit>
            <ci_upper_limit>100.39</ci_upper_limit>
            <estimate_desc>Relative bioavailability of empagliflozin was estimated by the ratios of the adjusted gMean of Fed 25mg+1000mg FDC divided by Fed 25mg+1000mg Single. Standard deviation is actually Intra individual geometric coefficient variation (gCV).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>AUC0-tz of Metformin in Plasma</title>
        <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable concentration</description>
        <time_frame>-1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration</time_frame>
        <population>Pharmacokinetic Set (PKS): This analysis set included all treated subjects that provided at least 1 observation for at least 1 primary endpoint without important protocol violations with respect to the statistical evaluation of the pharmacokinetic endpoints.</population>
        <group_list>
          <group group_id="O1">
            <title>Fed 25mg+1000mg FDC</title>
            <description>Subjects received a single dose of 25 mg empagliflozin/1000 mg metformin Hydrochloride (HCl) Extended release (XR) (1 Fixed dose combination (FDC) tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
          </group>
          <group group_id="O2">
            <title>Fed 25mg+1000mg Single</title>
            <description>Subject received a single dose of 25 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC0-tz of Metformin in Plasma</title>
          <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable concentration</description>
          <population>Pharmacokinetic Set (PKS): This analysis set included all treated subjects that provided at least 1 observation for at least 1 primary endpoint without important protocol violations with respect to the statistical evaluation of the pharmacokinetic endpoints.</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="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11000" spread="21.5"/>
                    <measurement group_id="O2" value="10800" spread="22.8"/>
                  </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>The assessment of bioequivalence was based on 2-sided 90% confidence intervals (CIs) for the ratios (test to reference treatment) of the adjusted geometric means (gMeans) of the primary endpoints, using an acceptance range of 80.00 to 125.00%.</non_inferiority_desc>
            <p_value>&lt;0.00001</p_value>
            <method>ANOVA</method>
            <method_desc>ANOVA model on the logarithmic scale including random effects for 'subjects within sequences' &amp; fixed effect for 'sequence', 'period' &amp; 'treatment'.</method_desc>
            <param_type>Adjusted gMean ratio</param_type>
            <param_value>102.14</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>7.9</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>98.65</ci_lower_limit>
            <ci_upper_limit>105.76</ci_upper_limit>
            <estimate_desc>Relative bioavailability of metformin was estimated by the ratios of the adjusted gMean of Fed 25mg+1000mg FDC divided by Fed 25mg+1000mg Single. Standard deviation is actually Intra individual geometric coefficient variation (gCV).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Cmax of Empagliflozin in Plasma</title>
        <description>Maximum measured concentration of empagliflozin in plasma (Cmax)</description>
        <time_frame>-1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration</time_frame>
        <population>PKS set</population>
        <group_list>
          <group group_id="O1">
            <title>Fed 25mg+1000mg FDC</title>
            <description>Subjects received a single dose of 25 mg empagliflozin/1000 mg metformin Hydrochloride (HCl) Extended release (XR) (1 Fixed dose combination (FDC) tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
          </group>
          <group group_id="O2">
            <title>Fed 25mg+1000mg Single</title>
            <description>Subject received a single dose of 25 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax of Empagliflozin in Plasma</title>
          <description>Maximum measured concentration of empagliflozin in plasma (Cmax)</description>
          <population>PKS set</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="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="590" spread="19.9"/>
                    <measurement group_id="O2" value="597" spread="19.5"/>
                  </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>The assessment of bioequivalence was based on 2-sided 90% confidence intervals (CIs) for the ratios (test to reference treatment) of the adjusted geometric means (gMeans) of the primary endpoints, using an acceptance range of 80.00 to 125.00%.</non_inferiority_desc>
            <p_value>&lt;0.00001</p_value>
            <method>ANOVA</method>
            <method_desc>ANOVA model on the logarithmic scale including random effects for 'subjects within sequences' &amp; fixed effect for 'sequence', 'period' &amp; 'treatment'.</method_desc>
            <param_type>Adjusted gMean ratio</param_type>
            <param_value>98.70</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>93.51</ci_lower_limit>
            <ci_upper_limit>104.17</ci_upper_limit>
            <estimate_desc>Relative bioavailability of empagliflozin was estimated by the ratios of the adjusted gMean of Fed 25mg+1000mg FDC divided by Fed 25mg+1000mg Single. Standard deviation is actually Intra individual geometric coefficient variation (gCV).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Cmax of Metformin in Plasma</title>
        <description>Maximum measured concentration of the metformin in plasma</description>
        <time_frame>-1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration</time_frame>
        <population>PKS set</population>
        <group_list>
          <group group_id="O1">
            <title>Fed 25mg+1000mg FDC</title>
            <description>Subjects received a single dose of 25 mg empagliflozin/1000 mg metformin Hydrochloride (HCl) Extended release (XR) (1 Fixed dose combination (FDC) tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
          </group>
          <group group_id="O2">
            <title>Fed 25mg+1000mg Single</title>
            <description>Subject received a single dose of 25 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax of Metformin in Plasma</title>
          <description>Maximum measured concentration of the metformin in plasma</description>
          <population>PKS set</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="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1120" spread="23.0"/>
                    <measurement group_id="O2" value="1060" spread="24.9"/>
                  </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>The assessment of bioequivalence was based on 2-sided 90% confidence intervals (CIs) for the ratios (test to reference treatment) of the adjusted geometric means (gMeans) of the primary endpoints, using an acceptance range of 80.00 to 125.00%.</non_inferiority_desc>
            <p_value>&lt;0.00001</p_value>
            <method>ANOVA</method>
            <method_desc>ANOVA model on the logarithmic scale including random effects for 'subjects within sequences' &amp; fixed effect for 'sequence', 'period' &amp; 'treatment'.</method_desc>
            <param_type>Adjusted gMean ratio</param_type>
            <param_value>105.69</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>10.9</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>100.78</ci_lower_limit>
            <ci_upper_limit>110.84</ci_upper_limit>
            <estimate_desc>Relative bioavailability of metformin was estimated by the ratios of the adjusted gMean of Fed 25mg+1000mg FDC divided by Fed 25mg+1000mg Single. Standard deviation is actually Intra individual geometric coefficient variation (gCV).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC0-infinity of Empagliflozin in Plasma</title>
        <description>Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 extrapolated to infinity (AUC0-infinity)</description>
        <time_frame>-1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration</time_frame>
        <population>PKS set</population>
        <group_list>
          <group group_id="O1">
            <title>Fed 25mg+1000mg FDC</title>
            <description>Subjects received a single dose of 25 mg empagliflozin/1000 mg metformin Hydrochloride (HCl) Extended release (XR) (1 Fixed dose combination (FDC) tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
          </group>
          <group group_id="O2">
            <title>Fed 25mg+1000mg Single</title>
            <description>Subject received a single dose of 25 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC0-infinity of Empagliflozin in Plasma</title>
          <description>Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 extrapolated to infinity (AUC0-infinity)</description>
          <population>PKS set</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="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5460" spread="15.1"/>
                    <measurement group_id="O2" value="5550" spread="16.2"/>
                  </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>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted gMean ratio</param_type>
            <param_value>98.32</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>5.1</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>96.16</ci_lower_limit>
            <ci_upper_limit>100.53</ci_upper_limit>
            <estimate_desc>Relative bioavailability of empagliflozin was estimated by ratios of adjusted geometric means (gMean) of Fed 25mg+1000mg FDC divided by Fed 25mg+1000mg Single. Standard deviation is actually Intra individual geometric coefficient variation (gCV).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC0-infinity of Metformin in Plasma</title>
        <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.</description>
        <time_frame>-1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration</time_frame>
        <population>PKS set</population>
        <group_list>
          <group group_id="O1">
            <title>Fed 25mg+1000mg FDC</title>
            <description>Subjects received a single dose of 25 mg empagliflozin/1000 mg metformin Hydrochloride (HCl) Extended release (XR) (1 Fixed dose combination (FDC) tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
          </group>
          <group group_id="O2">
            <title>Fed 25mg+1000mg Single</title>
            <description>Subject received a single dose of 25 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC0-infinity of Metformin in Plasma</title>
          <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.</description>
          <population>PKS set</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="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11500" spread="20.2"/>
                    <measurement group_id="O2" value="11000" spread="22.7"/>
                  </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 or Other</non_inferiority_type>
            <param_type>Adjusted gMean ratio</param_type>
            <param_value>104.66</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>7.3</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>101.36</ci_lower_limit>
            <ci_upper_limit>108.07</ci_upper_limit>
            <estimate_desc>Relative bioavailability of metformin was estimated by the ratios of the adjusted geometric means (gMean) of Fed 25mg+1000mg FDC divided by Fed 25mg+1000mg Single. Standard deviation is actually Intra individual geometric coefficient variation (gCV).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From first drug administration up to 13 days after last drug administration, ie., upto 20 days.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Fed 25mg+1000mg FDC</title>
          <description>Subjects received a single dose of 25 mg empagliflozin/1000 mg metformin Hydrochloride (HCl) Extended release (XR) (1 Fixed dose combination (FDC) tablet) with 240 mL of water after intake of a high-fat, high-caloric meal.</description>
        </group>
        <group group_id="E2">
          <title>Fed 25mg+1000mg Single</title>
          <description>Subject received a single dose of 25 mg empagliflozin (1 tablet) together with 1000 mg metformin HCl XR (2 tablets) with 240 mL of water after intake of a high-fat, high-caloric meal.</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="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>17.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>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/NCT02230995
org study id: 1276.15
secondary id: 2014-002016-17
nct id: NCT02230995
lead sponsor: 
collaborator: 
The purpose of this trial is to demonstrate bioequivalence of a newly developed fixed dose
      combination (FDC) tablet containing empagliflozin and metformin extended release compared to
      the free combination of empagliflozin and metformin extended release under fed conditions.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: AUC0-tz of Empagliflozin in Plasma
time frame: -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
description: Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz)
measure: AUC0-tz of Metformin in Plasma
time frame: -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
description: Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable concentration
measure: Cmax of Empagliflozin in Plasma
time frame: -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
description: Maximum measured concentration of empagliflozin in plasma (Cmax)
measure: Cmax of Metformin in Plasma
time frame: -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
description: Maximum measured concentration of the metformin in plasma
measure: AUC0-infinity of Empagliflozin in Plasma
time frame: -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
description: Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 extrapolated to infinity (AUC0-infinity)
measure: AUC0-infinity of Metformin in Plasma
time frame: -1:00 hour(h) before the drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 5:00h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration
description: Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity.
arm group label: Fixed dose combination
arm group type: Experimental
description: Single dose empagliflozin/metformin
arm group label: Single tablets combination
arm group type: Active Comparator
description: single doses empagliflozin and metformin
intervention type: Drug
intervention name: metformin
description: single dose of metformin given as tablets
arm group label: Single tablets combination
intervention type: Drug
intervention name: empagliflozin/metformin
description: Single dose empagliflozin/metformin given as fixed-dose combination tablet
arm group label: Fixed dose combination
intervention type: Drug
intervention name: empagliflozin
description: single dose of empagliflozin given as tablet
arm group label: Single tablets combination
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 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: 