<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/NCT03259490</url>
  </required_header>
  <id_info>
    <org_study_id>1361-0003</org_study_id>
    <secondary_id>2017-000425-12</secondary_id>
    <nct_id>NCT03259490</nct_id>
  </id_info>
  <brief_title>This Study Tests Whether Taking the Medicines Empagliflozin, Linagliptin, and Metformin Together in 1 Pill is the Same as Taking Them in Separate Pills. The Study is Done in Healthy Men and Women and Measures the Amount of Each Medicine in the Blood</brief_title>
  <official_title>Bioequivalence of a Fixed Dose Combination Tablet of Empagliflozin/Linagliptin/Metformin Extended Release Compared to the Free Combination of Empagliflozin, Linagliptin, and Metformin Extended Release Tablets Following Oral Administration in Healthy Male and Female Subjects (an Open-label, Randomised, Single-dose, Two-period, Two-sequence Crossover Study)</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>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To establish the bioequivalence of one fixed dose combination (FDC) tablet of&#xD;
      empagliflozin/linagliptin/metformin extended release (XR) versus the free combination of&#xD;
      empagliflozin tablet, linagliptin tablet, and metformin XR tablets administered as a single&#xD;
      dose under fed conditions&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 31, 2017</start_date>
  <completion_date type="Actual">November 13, 2017</completion_date>
  <primary_completion_date type="Actual">November 13, 2017</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>Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) for Empagliflozin</measure>
    <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</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 (AUC0-tz) for empagliflozin.&#xD;
Plasma concentrations and/or parameters of a subject were to be considered as non-evaluable,if for example:&#xD;
The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subjects experiencing emesis)&#xD;
A predose concentration was &gt;5% Cmax value of that subject&#xD;
Missing samples/concentration data at important phases of pharmacokinetic (PK) disposition curve.&#xD;
Pharmacokinetic parameter set (PKS): This subject set included all subjects in the treated set (TS) who provided at least one primary or secondary PK parameter that was not excluded according to the description above. Thus, a subject was to be included in the PKS even if he/she contributed only one PK parameter value for one period to the statistical assessment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC0-tz for Metformin.</measure>
    <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
    <description>AUC0-tz for metformin.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) for Linagliptin</measure>
    <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
    <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 72 hours (AUC0-72) for Linagliptin</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)</measure>
    <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
    <description>Maximum measured concentration of the empagliflozin in plasma (Cmax)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cmax for Metformin in Plasma</measure>
    <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
    <description>Cmax for metformin in plasma.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cmax for Linagliptin in Plasma</measure>
    <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
    <description>Cmax for linagliptin in plasma.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Empagliflozin (AUC(0-∞)</measure>
    <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
    <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin (AUC(0-∞)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(0-∞) for Metformin</measure>
    <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
    <description>AUC(0-∞) for Metformin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(0-∞) for Linagliptin</measure>
    <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
    <description>AUC(0-∞) for Linagliptin</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Test Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>High dose empagliflozin/linagliptin/metformin XR fixed dose combination tablet</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Reference Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single tablets of empagliflozin + linagliptin + metformin XR</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Empagliflozin/linagliptin/metformin HCl</intervention_name>
    <description>Once daily</description>
    <arm_group_label>Test Treatment</arm_group_label>
    <other_name>TRIJARDY® XR</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Empagliflozin</intervention_name>
    <description>Once daily</description>
    <arm_group_label>Reference Treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Linagliptin</intervention_name>
    <description>Once daily</description>
    <arm_group_label>Reference Treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin HCl</intervention_name>
    <description>Once daily</description>
    <arm_group_label>Reference Treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy male or female subjects according to the assessment of the investigator, based&#xD;
             on a complete medical history including a physical examination, vital signs (Blood&#xD;
             Pressure (BP), Pulse Rate (PR)), 12-lead Electrocardiogram (ECG), and clinical&#xD;
             laboratory tests&#xD;
&#xD;
          -  Age of 18 to 55 years (incl.)&#xD;
&#xD;
          -  BMI of 18.5 to 29.9 kg/m2 (incl.)&#xD;
&#xD;
          -  Signed and dated written informed consent prior to admission to the study in&#xD;
             accordance with Good Clinical Practice (GCP) and local legislation&#xD;
&#xD;
          -  Female subjects of childbearing potential willing to use adequate contraception.&#xD;
&#xD;
          -  Further inclusion criteria apply&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any finding in the medical examination (including Blood Pressure (BP), Pulse Rate&#xD;
             (PR), or Electrocardiogram (ECG)) is deviating from normal and judged as clinically&#xD;
             relevant by the investigator&#xD;
&#xD;
          -  Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg,&#xD;
             diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the&#xD;
             range of 45 to 90 beats per minute (BPM)&#xD;
&#xD;
          -  Any laboratory value outside the reference range that the investigator considers to be&#xD;
             of clinical relevance&#xD;
&#xD;
          -  Any evidence of a concomitant disease judged as clinically relevant by the&#xD;
             investigator&#xD;
&#xD;
          -  Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic,&#xD;
             immunological, or hormonal disorders&#xD;
&#xD;
          -  Diseases of the central nervous system (including but not limited to any kind of&#xD;
             seizures or stroke), and other relevant neurological or psychiatric disorders&#xD;
&#xD;
          -  Further exclusion criteria apply&#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>
  <location>
    <facility>
      <name>Humanpharmakologisches Zentrum Biberach</name>
      <address>
        <city>Biberach</city>
        <zip>88397</zip>
        <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>February 2020</verification_date>
  <study_first_submitted>August 22, 2017</study_first_submitted>
  <study_first_submitted_qc>August 22, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 23, 2017</study_first_posted>
  <results_first_submitted>February 6, 2020</results_first_submitted>
  <results_first_submitted_qc>February 6, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">February 21, 2020</results_first_posted>
  <last_update_submitted>February 25, 2020</last_update_submitted>
  <last_update_submitted_qc>February 25, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 5, 2020</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>
    <mesh_term>Linagliptin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 28, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/90/NCT03259490/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 8, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/90/NCT03259490/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>It was planned to include healthy male and female subjects in this randomised, open label study. They were recruited from the volunteers' pool of the study site.</recruitment_details>
      <pre_assignment_details>This trial was a two-way crossover study. All subjects received the 2 treatments in randomised order.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Test/ Reference (TR)</title>
          <description>Subjects were orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast.</description>
        </group>
        <group group_id="P2">
          <title>Reference/ Test (RT)</title>
          <description>Subjects were orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Period 1</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="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Period 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Treated set (TS): This subject set included all subjects who were documented to have received one dose of study drug.</population>
      <group_list>
        <group group_id="B1">
          <title>Test/ Reference (TR)</title>
          <description>Subjects were orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast.</description>
        </group>
        <group group_id="B2">
          <title>Reference/ Test (RT)</title>
          <description>Subjects were orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast.</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>
          <population>TS</population>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="37.1" spread="12.2"/>
                    <measurement group_id="B2" value="43.5" spread="8.0"/>
                    <measurement group_id="B3" value="40.3" spread="10.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <population>TS</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <description>Ethnicity was not reported in this trial</description>
          <population>TS</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) for Empagliflozin</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 (AUC0-tz) for empagliflozin.&#xD;
Plasma concentrations and/or parameters of a subject were to be considered as non-evaluable,if for example:&#xD;
The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subjects experiencing emesis)&#xD;
A predose concentration was &gt;5% Cmax value of that subject&#xD;
Missing samples/concentration data at important phases of pharmacokinetic (PK) disposition curve.&#xD;
Pharmacokinetic parameter set (PKS): This subject set included all subjects in the treated set (TS) who provided at least one primary or secondary PK parameter that was not excluded according to the description above. Thus, a subject was to be included in the PKS even if he/she contributed only one PK parameter value for one period to the statistical assessment.</description>
        <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
        <population>PKS</population>
        <group_list>
          <group group_id="O1">
            <title>Empagliflozin/Linagliptin/Metformin FDC (Test)</title>
            <description>Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
          <group group_id="O2">
            <title>Empagliflozin/Linagliptin/Metformin FC (Reference)</title>
            <description>Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) for Empagliflozin</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 (AUC0-tz) for empagliflozin.&#xD;
Plasma concentrations and/or parameters of a subject were to be considered as non-evaluable,if for example:&#xD;
The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subjects experiencing emesis)&#xD;
A predose concentration was &gt;5% Cmax value of that subject&#xD;
Missing samples/concentration data at important phases of pharmacokinetic (PK) disposition curve.&#xD;
Pharmacokinetic parameter set (PKS): This subject set included all subjects in the treated set (TS) who provided at least one primary or secondary PK parameter that was not excluded according to the description above. Thus, a subject was to be included in the PKS even if he/she contributed only one PK parameter value for one period to the statistical assessment.</description>
          <population>PKS</population>
          <units>nanomoles*hours/ litres (nmol*h/L)</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5656.07" spread="1.04"/>
                    <measurement group_id="O2" value="5488.31" spread="1.04"/>
                  </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>
            <groups_desc>The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Adjusted gmean ratio T/R (%)</param_type>
            <param_value>103.06</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>5.8</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>100.36</ci_lower_limit>
            <ci_upper_limit>105.83</ci_upper_limit>
            <estimate_desc>The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>AUC0-tz for Metformin.</title>
        <description>AUC0-tz for metformin.</description>
        <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
        <population>PKS</population>
        <group_list>
          <group group_id="O1">
            <title>Empagliflozin/Linagliptin/Metformin FDC (Test)</title>
            <description>Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
          <group group_id="O2">
            <title>Empagliflozin/Linagliptin/Metformin FC (Reference)</title>
            <description>Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
        </group_list>
        <measure>
          <title>AUC0-tz for Metformin.</title>
          <description>AUC0-tz for metformin.</description>
          <population>PKS</population>
          <units>nanogram*hours/ millilitres (ng*h/mL)</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12455.82" spread="1.05"/>
                    <measurement group_id="O2" value="12412.57" spread="1.05"/>
                  </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>
            <groups_desc>The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Adjusted gmean ratio T/R (%)</param_type>
            <param_value>100.35</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>9.5</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>96.11</ci_lower_limit>
            <ci_upper_limit>104.77</ci_upper_limit>
            <estimate_desc>The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) for Linagliptin</title>
        <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 72 hours (AUC0-72) for Linagliptin</description>
        <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
        <population>PKS</population>
        <group_list>
          <group group_id="O1">
            <title>Empagliflozin/Linagliptin/Metformin FDC (Test)</title>
            <description>Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
          <group group_id="O2">
            <title>Empagliflozin/Linagliptin/Metformin FC (Reference)</title>
            <description>Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) for Linagliptin</title>
          <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 72 hours (AUC0-72) for Linagliptin</description>
          <population>PKS</population>
          <units>nmol*h/L</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="238.84" spread="1.04"/>
                    <measurement group_id="O2" value="238.11" spread="1.04"/>
                  </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>
            <groups_desc>The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Adjusted gmean ratio T/R (%)</param_type>
            <param_value>100.31</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>8.2</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>96.65</ci_lower_limit>
            <ci_upper_limit>104.10</ci_upper_limit>
            <estimate_desc>The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)</title>
        <description>Maximum measured concentration of the empagliflozin in plasma (Cmax)</description>
        <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
        <population>PKS</population>
        <group_list>
          <group group_id="O1">
            <title>Empagliflozin/Linagliptin/Metformin FDC (Test)</title>
            <description>Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
          <group group_id="O2">
            <title>Empagliflozin/Linagliptin/Metformin FC (Reference)</title>
            <description>Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)</title>
          <description>Maximum measured concentration of the empagliflozin in plasma (Cmax)</description>
          <population>PKS</population>
          <units>nmol/L</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="540.01" spread="1.04"/>
                    <measurement group_id="O2" value="540.26" spread="1.04"/>
                  </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>
            <groups_desc>The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Adjusted gmean ratio T/R (%)</param_type>
            <param_value>99.95</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>12.4</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>94.52</ci_lower_limit>
            <ci_upper_limit>105.70</ci_upper_limit>
            <estimate_desc>The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Cmax for Metformin in Plasma</title>
        <description>Cmax for metformin in plasma.</description>
        <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
        <population>PKS</population>
        <group_list>
          <group group_id="O1">
            <title>Empagliflozin/Linagliptin/Metformin FDC (Test)</title>
            <description>Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
          <group group_id="O2">
            <title>Empagliflozin/Linagliptin/Metformin FC (Reference)</title>
            <description>Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax for Metformin in Plasma</title>
          <description>Cmax for metformin in plasma.</description>
          <population>PKS</population>
          <units>ng/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1237.16" spread="1.04"/>
                    <measurement group_id="O2" value="1147.88" spread="1.04"/>
                  </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>
            <groups_desc>The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Adjusted gmean ratio T/R (%)</param_type>
            <param_value>107.78</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>11.0</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>102.52</ci_lower_limit>
            <ci_upper_limit>113.31</ci_upper_limit>
            <estimate_desc>The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Cmax for Linagliptin in Plasma</title>
        <description>Cmax for linagliptin in plasma.</description>
        <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
        <population>PKS</population>
        <group_list>
          <group group_id="O1">
            <title>Empagliflozin/Linagliptin/Metformin FDC (Test)</title>
            <description>Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
          <group group_id="O2">
            <title>Empagliflozin/Linagliptin/Metformin FC (Reference)</title>
            <description>Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax for Linagliptin in Plasma</title>
          <description>Cmax for linagliptin in plasma.</description>
          <population>PKS</population>
          <units>nmol/L</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.69" spread="1.04"/>
                    <measurement group_id="O2" value="5.86" spread="1.04"/>
                  </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>
            <groups_desc>The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Adjusted gmean ratio T/R (%)</param_type>
            <param_value>97.17</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>10.6</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>92.63</ci_lower_limit>
            <ci_upper_limit>101.93</ci_upper_limit>
            <estimate_desc>The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Empagliflozin (AUC(0-∞)</title>
        <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin (AUC(0-∞)</description>
        <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
        <population>PKS</population>
        <group_list>
          <group group_id="O1">
            <title>Empagliflozin/Linagliptin/Metformin FDC (Test)</title>
            <description>Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
          <group group_id="O2">
            <title>Empagliflozin/Linagliptin/Metformin FC (Reference)</title>
            <description>Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Empagliflozin (AUC(0-∞)</title>
          <description>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin (AUC(0-∞)</description>
          <population>PKS</population>
          <units>nmol*h/L</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5727.20" spread="1.04"/>
                    <measurement group_id="O2" value="5554.37" spread="1.04"/>
                  </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>
            <groups_desc>The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Adjusted gmean ratio T/R (%)</param_type>
            <param_value>103.11</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>5.9</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>100.38</ci_lower_limit>
            <ci_upper_limit>105.92</ci_upper_limit>
            <estimate_desc>The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(0-∞) for Metformin</title>
        <description>AUC(0-∞) for Metformin</description>
        <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
        <population>PKS</population>
        <group_list>
          <group group_id="O1">
            <title>Empagliflozin/Linagliptin/Metformin FDC (Test)</title>
            <description>Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
          <group group_id="O2">
            <title>Empagliflozin/Linagliptin/Metformin FC (Reference)</title>
            <description>Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(0-∞) for Metformin</title>
          <description>AUC(0-∞) for Metformin</description>
          <population>PKS</population>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12745.62" spread="1.05"/>
                    <measurement group_id="O2" value="12724.27" spread="1.05"/>
                  </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>
            <groups_desc>The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Adjusted gmean ratio T/R (%)</param_type>
            <param_value>100.17</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>10.1</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>95.68</ci_lower_limit>
            <ci_upper_limit>104.86</ci_upper_limit>
            <estimate_desc>The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(0-∞) for Linagliptin</title>
        <description>AUC(0-∞) for Linagliptin</description>
        <time_frame>Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose</time_frame>
        <population>PKS</population>
        <group_list>
          <group group_id="O1">
            <title>Empagliflozin/Linagliptin/Metformin FDC (Test)</title>
            <description>Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
          <group group_id="O2">
            <title>Empagliflozin/Linagliptin/Metformin FC (Reference)</title>
            <description>Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(0-∞) for Linagliptin</title>
          <description>AUC(0-∞) for Linagliptin</description>
          <population>PKS</population>
          <units>nmol*h/L</units>
          <param>Geometric Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="29"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="384.27" spread="1.05"/>
                    <measurement group_id="O2" value="394.95" spread="1.05"/>
                  </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>
            <groups_desc>The assessment of bioequivalence was based upon two-sided 90% confidence intervals (CIs) for the ratios of the geometric means (test/reference) for the endpoints using an acceptance range of 80.00 to 125.00%.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>Adjusted gmean ratio T/R (%)</param_type>
            <param_value>97.30</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>13.2</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>91.65</ci_lower_limit>
            <ci_upper_limit>103.29</ci_upper_limit>
            <estimate_desc>The standard deviation is actually intra-individual geometric co-efficient of variation (gCV)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP); up to 50 days</time_frame>
      <desc>REP for the combined treatment with empagliflozin, linagliptin, and metformin, when measurable drug levels or pharmacodynamic effects were still likely to be present, was defined as 7 days after the last administration of trial medication.</desc>
      <group_list>
        <group group_id="E1">
          <title>Empagliflozin/Linagliptin/Metformin FDC (Test)</title>
          <description>Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast</description>
        </group>
        <group group_id="E2">
          <title>Empagliflozin/Linagliptin/Metformin FC (Reference)</title>
          <description>Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="29"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 20.1</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="11" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Oral herpes</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="29"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="29"/>
              </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/NCT03259490
org study id: 1361-0003
secondary id: 2017-000425-12
nct id: NCT03259490
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
To establish the bioequivalence of one fixed dose combination (FDC) tablet of
      empagliflozin/linagliptin/metformin extended release (XR) versus the free combination of
      empagliflozin tablet, linagliptin tablet, and metformin XR tablets administered as a single
      dose under fed conditions
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) for Empagliflozin
time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose
description: Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) for empagliflozin.
Plasma concentrations and/or parameters of a subject were to be considered as non-evaluable,if for example:
The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subjects experiencing emesis)
A predose concentration was >5% Cmax value of that subject
Missing samples/concentration data at important phases of pharmacokinetic (PK) disposition curve.
Pharmacokinetic parameter set (PKS): This subject set included all subjects in the treated set (TS) who provided at least one primary or secondary PK parameter that was not excluded according to the description above. Thus, a subject was to be included in the PKS even if he/she contributed only one PK parameter value for one period to the statistical assessment.
measure: AUC0-tz for Metformin.
time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose
description: AUC0-tz for metformin.
measure: Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) for Linagliptin
time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose
description: Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 72 hours (AUC0-72) for Linagliptin
measure: Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)
time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose
description: Maximum measured concentration of the empagliflozin in plasma (Cmax)
measure: Cmax for Metformin in Plasma
time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose
description: Cmax for metformin in plasma.
measure: Cmax for Linagliptin in Plasma
time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose
description: Cmax for linagliptin in plasma.
measure: Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Empagliflozin (AUC(0-∞)
time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose
description: Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin (AUC(0-∞)
measure: AUC(0-∞) for Metformin
time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose
description: AUC(0-∞) for Metformin
measure: AUC(0-∞) for Linagliptin
time frame: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose
description: AUC(0-∞) for Linagliptin
arm group label: Test Treatment
arm group type: Experimental
description: High dose empagliflozin/linagliptin/metformin XR fixed dose combination tablet
arm group label: Reference Treatment
arm group type: Experimental
description: Single tablets of empagliflozin + linagliptin + metformin XR
intervention type: Drug
intervention name: Empagliflozin/linagliptin/metformin HCl
description: Once daily
arm group label: Test Treatment
other name: TRIJARDY® XR
intervention type: Drug
intervention name: Empagliflozin
description: Once daily
arm group label: Reference Treatment
intervention type: Drug
intervention name: Linagliptin
description: Once daily
arm group label: Reference Treatment
intervention type: Drug
intervention name: Metformin HCl
description: Once daily
arm group label: Reference Treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Germany
url: http://trials.boehringer-ingelheim.com/
description: Related Info
responsible party type: Sponsor
mesh term: Metformin
mesh term: Empagliflozin
mesh term: Linagliptin
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 