<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/NCT01703286</url>
  </required_header>
  <id_info>
    <org_study_id>1218.105</org_study_id>
    <secondary_id>2012-003317-33</secondary_id>
    <nct_id>NCT01703286</nct_id>
  </id_info>
  <brief_title>Trial to Assess the Influence of 4 Weeks' Treatment With Linagliptin as Compared to Glimepiride and Placebo on Endothelial Function in Patients With Type 2 Diabetes Using FMD (Flow-Mediated Vasodilation)</brief_title>
  <official_title>Randomized, Three Period Cross Over, Double Blind, Double Dummy Study in Type 2 Diabetic Patients to Assess the Endothelial Effects of Linagliptin, Glimepiride and Placebo Therapy for 28 Days ('ENDOTHELINA')</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 general aim of the present study is to investigate the impact of 4 weeks treatment with&#xD;
      linagliptin (5 mg) on endothelial function in patients with type 2 diabetes mellitus. In the&#xD;
      current trial this effect of linagliptin treatment on endothelial function will be compared&#xD;
      against both the sulfonylurea glimepiride and against placebo, which has not been tested in a&#xD;
      trial before; as also is the case for other DPP-4 inhibitors.&#xD;
&#xD;
      Besides placebo, glimepiride was chosen as a comparator, as it is one compound of the second&#xD;
      most used oral antidiabetic drug class.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">January 2014</completion_date>
  <primary_completion_date type="Actual">January 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>Double</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 28</measure>
    <time_frame>baseline and day 28 for each treatment arm</time_frame>
    <description>Endothelial function under fasted condition was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Flow Mediated Vasodilation (FMD) 2 h Post Meal on Day 28</measure>
    <time_frame>baseline and day 28 for each treatment arm</time_frame>
    <description>Endothelial function 2 hours post meal was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in 2 Hours Post Meal Endothelial Independent Vasodilation (EIDV) on Day 28</measure>
    <time_frame>baseline and day 28 for each treatment arm</time_frame>
    <description>Endothelial function 2h post-meal was measured by endothelial independent vasodilation (EIDV). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients With Adverse Events</measure>
    <time_frame>up to 20 weeks</time_frame>
    <description>Number of patients with any adverse events</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">42</enrollment>
  <condition>Diabetes Mellitus, Type 2</condition>
  <arm_group>
    <arm_group_label>Linagliptin 5mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>given once daily over 28 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Glimepiride</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>given once daily in 1mg dosis over 7 days, following a titration step to 2mg and application for 21 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>given once daily over 28 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo matching Glimepiride</description>
    <arm_group_label>Linagliptin 5mg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Linagliptin</intervention_name>
    <description>given once daily for 28 days</description>
    <arm_group_label>Linagliptin 5mg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo matching Linagliptin</description>
    <arm_group_label>Glimepiride</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo matching Linagliptin</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo matching Glimepiride</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Glimepiride</intervention_name>
    <description>1 mg for 7 days followed by uptitration to 2 mg (given for following 21 days)</description>
    <arm_group_label>Glimepiride</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          1. Type 2 diabetic male and female patients according to the following criteria:&#xD;
&#xD;
             Based upon a complete medical history and clinical laboratory tests&#xD;
&#xD;
          2. Age &gt;= 18 and Age &lt;= 65 years&#xD;
&#xD;
          3. Body mass index &gt;= 25 &lt;= 35 kg/m2&#xD;
&#xD;
          4. HbA1c &lt;= 7.5%&#xD;
&#xD;
          5. Treatment with metformin (=1500 mg daily) for &lt;= 3 months&#xD;
&#xD;
          6. Signed and dated written informed consent prior to admission to the study in&#xD;
             accordance with GCP and the local legislation.&#xD;
&#xD;
             For female patients of childbearing potential:&#xD;
&#xD;
          7. Use of acceptable method of contraception (Pearl-Index &lt;1).&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Treatment with any glucose-lowering drug except for metformin within prior 3 months.&#xD;
&#xD;
          2. Any finding of the medical examination (including blood pressure, pulse rate and&#xD;
             electrocardiogram) deviating from normal and of clinical relevance.&#xD;
&#xD;
          3. Any evidence of a clinically relevant acute concomitant disease&#xD;
&#xD;
          4. History of cardiovascular disease (e.g. coronary artery disease history of acute&#xD;
             myocard infarction or stroke, peripheral vascular disease).&#xD;
&#xD;
          5. History of major diabetic complications (e.g. nephropathy, retinopathy)&#xD;
&#xD;
          6. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, immunological or&#xD;
             hormonal disorders (except: hypertension treated with angiotensin receptor blocker or&#xD;
             angiotensin-converting-enzyme inhibitors, hyperlipidemia with statin therapy, thyroid&#xD;
             hormone replacement therapy, all stable for at least three months prior to screening).&#xD;
&#xD;
          7. Surgery of the gastrointestinal tract (except appendectomy).&#xD;
&#xD;
          8. Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or&#xD;
             neurological disorders.&#xD;
&#xD;
          9. History of relevant orthostatic hypotension, fainting spells or blackouts.&#xD;
&#xD;
         10. Chronic or relevant acute infections.&#xD;
&#xD;
         11. History of relevant allergy/hypersensitivity (including allergy to drug or its&#xD;
             excipients).&#xD;
&#xD;
         12. Intake of drugs with a long half-life (&gt; 24 hours) within at least one month or less&#xD;
             than 10 half-lives of the respective drug prior to administration or during the trial.&#xD;
&#xD;
         13. Participation in another trial with an investigational drug within one month prior to&#xD;
             administration or during the trial.&#xD;
&#xD;
         14. Smoker (&gt;= 1 cigarettes or &gt;= 1 cigars or &gt;= 1 pipes/day).&#xD;
&#xD;
         15. Alcohol abuse (more than 60 g/day).&#xD;
&#xD;
         16. Drug abuse.&#xD;
&#xD;
         17. Blood donation (more than 100 mL within four weeks prior to administration or during&#xD;
             the trial).&#xD;
&#xD;
         18. Excessive physical activities (within one week prior to administration or during the&#xD;
             trial).&#xD;
&#xD;
         19. Any laboratory value outside the reference range that is of clinical relevance.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Boehringer Ingelheim</last_name>
    <role>Study Chair</role>
    <affiliation>Boehringer Ingelheim</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>1218.105.001 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Neuss</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 2015</verification_date>
  <study_first_submitted>October 1, 2012</study_first_submitted>
  <study_first_submitted_qc>October 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 10, 2012</study_first_posted>
  <results_first_submitted>January 12, 2015</results_first_submitted>
  <results_first_submitted_qc>January 12, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">January 19, 2015</results_first_posted>
  <last_update_submitted>January 12, 2015</last_update_submitted>
  <last_update_submitted_qc>January 12, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 19, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glimepiride</mesh_term>
    <mesh_term>Linagliptin</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Pbo/ G1-4/ L 5</title>
          <description>Placebo tablet once daily over 28 days/ Glimepiride 1 tablet (1 mg) once daily for 7 days followed by uptitration to 2 to 4 mg once daily within next 21 days/ Linagliptin 1 tablet (5 mg) once daily for 28 days</description>
        </group>
        <group group_id="P2">
          <title>L 5/ G 1-4/ Pbo</title>
          <description>Linagliptin 1 tablet (5 mg) once daily for 28 days/ Glimepiride 1 tablet (1 mg) once daily for 7 days followed by uptitration to 2 to 4 mg once daily within next 21 days/ Placebo tablet once daily over 28 days</description>
        </group>
        <group group_id="P3">
          <title>G 1-4/ L 5/ Pbo</title>
          <description>Glimepiride 1 tablet (1 mg) once daily for 7 days followed by uptitration to 2 to 4 mg once daily within next 21 days/ Linagliptin 1 tablet (5 mg) once daily for 28 days/ Placebo tablet once daily over 28 days</description>
        </group>
        <group group_id="P4">
          <title>G1-4/ Pbo/ L 5</title>
          <description>Glimepiride 1 tablet (1 mg) once daily for 7 days followed by uptitration to 2 to 4 mg once daily within next 21 days/ Placebo tablet once daily over 28 days/ Linagliptin 1 tablet (5 mg) once daily for 28 days</description>
        </group>
        <group group_id="P5">
          <title>Pbo/ L 5/ G1-4</title>
          <description>Placebo tablet once daily over 28 days/ Linagliptin 1 tablet (5 mg) once daily for 28 days/ Glimepiride 1 tablet (1 mg) once daily for 7 days followed by uptitration to 2 to 4 mg once daily within next 21 days</description>
        </group>
        <group group_id="P6">
          <title>L 5/ Pbo/ G1-4/</title>
          <description>Linagliptin 1 tablet (5 mg) once daily for 28 days/ Placebo tablet once daily over 28 days/ Glimepiride 1 tablet (1 mg) once daily for 7 days followed by uptitration to 2 to 4 mg once daily within next 21 days</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Period 1 Including Washout</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="7"/>
                <participants group_id="P4" count="7"/>
                <participants group_id="P5" count="7"/>
                <participants group_id="P6" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="7"/>
                <participants group_id="P4" count="6"/>
                <participants group_id="P5" count="7"/>
                <participants group_id="P6" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" 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="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Period 2 Including Washout</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="7"/>
                <participants group_id="P4" count="6"/>
                <participants group_id="P5" count="7"/>
                <participants group_id="P6" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="7"/>
                <participants group_id="P4" count="5"/>
                <participants group_id="P5" count="7"/>
                <participants group_id="P6" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Period 3 Including Washout</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="7"/>
                <participants group_id="P4" count="5"/>
                <participants group_id="P5" count="7"/>
                <participants group_id="P6" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="7"/>
                <participants group_id="P4" count="5"/>
                <participants group_id="P5" count="7"/>
                <participants group_id="P6" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>TS (treated set) - included all patients who were dispensed trial medication and were documented to have taken at least 1 dose of trial drug.</population>
      <group_list>
        <group group_id="B1">
          <title>Total Participants</title>
          <description>All study participants</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="42"/>
          </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="60.3" spread="6.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 28</title>
        <description>Endothelial function under fasted condition was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.</description>
        <time_frame>baseline and day 28 for each treatment arm</time_frame>
        <population>Efficacy set (ES)- included all patients of the TS who provided at least 1 observation for at least 1 primary, secondary, or other efficacy endpoint without important protocol violations relevant for the statistical evaluation of these endpoints.</population>
        <group_list>
          <group group_id="O1">
            <title>Linagliptin 5 mg</title>
            <description>Linagliptin: 1 tablet (5 mg) once daily for 28 days</description>
          </group>
          <group group_id="O2">
            <title>Glimepiride 1-4 mg</title>
            <description>Glimepiride: 1 tablet (1 mg) once daily for 7 days followed by uptitration to 2 to 4 mg once daily within next 21 days</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Placebo: matching Linagliptin or Glimepiride tablet once daily over 28 days</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 28</title>
          <description>Endothelial function under fasted condition was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.</description>
          <population>Efficacy set (ES)- included all patients of the TS who provided at least 1 observation for at least 1 primary, secondary, or other efficacy endpoint without important protocol violations relevant for the statistical evaluation of these endpoints.</population>
          <units>percentage</units>
          <param>Geometric Mean</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="39"/>
                <count group_id="O2" value="41"/>
                <count group_id="O3" value="39"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.885" lower_limit="0.695" upper_limit="1.128"/>
                    <measurement group_id="O2" value="1.002" lower_limit="0.795" upper_limit="1.262"/>
                    <measurement group_id="O3" value="1.002" lower_limit="0.786" upper_limit="1.277"/>
                  </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>
            <p_value>0.5403</p_value>
            <method>ANOVA</method>
            <param_type>Geometric mean ratio (net)</param_type>
            <param_value>0.884</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.633</ci_lower_limit>
            <ci_upper_limit>1.235</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.5402</p_value>
            <method>ANOVA</method>
            <param_type>Geometric mean ratio (net)</param_type>
            <param_value>0.884</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.632</ci_lower_limit>
            <ci_upper_limit>1.235</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.9989</p_value>
            <method>ANOVA</method>
            <param_type>Geometric mean ratio (net)</param_type>
            <param_value>1.000</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.715</ci_lower_limit>
            <ci_upper_limit>1.397</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Flow Mediated Vasodilation (FMD) 2 h Post Meal on Day 28</title>
        <description>Endothelial function 2 hours post meal was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.</description>
        <time_frame>baseline and day 28 for each treatment arm</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Linagliptin 5 mg</title>
            <description>Linagliptin: 1 tablet (5 mg) once daily for 28 days</description>
          </group>
          <group group_id="O2">
            <title>Glimepiride 1-4 mg</title>
            <description>Glimepiride: 1 tablet (1 mg) once daily for 7 days followed by uptitration to 2 to 4 mg once daily within next 21 days</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Placebo: matching Linagliptin or Glimepiride tablet once daily over 28 days</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Flow Mediated Vasodilation (FMD) 2 h Post Meal on Day 28</title>
          <description>Endothelial function 2 hours post meal was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.</description>
          <units>Percentage</units>
          <param>Geometric Mean</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="41"/>
                <count group_id="O3" value="39"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.262" lower_limit="0.968" upper_limit="1.646"/>
                    <measurement group_id="O2" value="1.045" lower_limit="0.815" upper_limit="1.339"/>
                    <measurement group_id="O3" value="1.009" lower_limit="0.777" upper_limit="1.311"/>
                  </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>
            <p_value>0.3885</p_value>
            <method>ANOVA</method>
            <param_type>Geometric mean ratio (net)</param_type>
            <param_value>1.208</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.840</ci_lower_limit>
            <ci_upper_limit>1.738</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.3105</p_value>
            <method>ANOVA</method>
            <param_type>Geometric mean ratio (net)</param_type>
            <param_value>1.251</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.868</ci_lower_limit>
            <ci_upper_limit>1.801</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.8749</p_value>
            <method>ANOVA</method>
            <param_type>Geometric mean ratio (net)</param_type>
            <param_value>1.035</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.721</ci_lower_limit>
            <ci_upper_limit>1.485</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in 2 Hours Post Meal Endothelial Independent Vasodilation (EIDV) on Day 28</title>
        <description>Endothelial function 2h post-meal was measured by endothelial independent vasodilation (EIDV). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.</description>
        <time_frame>baseline and day 28 for each treatment arm</time_frame>
        <population>Efficacy set (ES)- included all patients of the TS who provided at least 1 observation for at least 1 primary, secondary, or other efficacy endpoint without important protocol violations relevant for the statistical evaluation of these endpoints.</population>
        <group_list>
          <group group_id="O1">
            <title>Linagliptin 5 mg</title>
            <description>Linagliptin: 1 tablet (5 mg) once daily for 28 days</description>
          </group>
          <group group_id="O2">
            <title>Glimepiride 1-4 mg</title>
            <description>Glimepiride: 1 tablet (1 mg) once daily for 7 days followed by uptitration to 2 to 4 mg once daily within next 21 days</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Placebo: matching Linagliptin or Glimepiride tablet once daily over 28 days</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in 2 Hours Post Meal Endothelial Independent Vasodilation (EIDV) on Day 28</title>
          <description>Endothelial function 2h post-meal was measured by endothelial independent vasodilation (EIDV). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.</description>
          <population>Efficacy set (ES)- included all patients of the TS who provided at least 1 observation for at least 1 primary, secondary, or other efficacy endpoint without important protocol violations relevant for the statistical evaluation of these endpoints.</population>
          <units>percentage</units>
          <param>Mean</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="39"/>
                <count group_id="O2" value="41"/>
                <count group_id="O3" value="39"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.003" lower_limit="0.945" upper_limit="1.061"/>
                    <measurement group_id="O2" value="1.053" lower_limit="0.998" upper_limit="1.108"/>
                    <measurement group_id="O3" value="0.981" lower_limit="0.923" upper_limit="1.039"/>
                  </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>
            <p_value>0.2982</p_value>
            <method>ANOVA</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-0.050</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.048</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.130</ci_lower_limit>
            <ci_upper_limit>0.030</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.6601</p_value>
            <method>ANOVA</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>0.021</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.048</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.059</ci_lower_limit>
            <ci_upper_limit>0.101</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.1412</p_value>
            <method>ANOVA</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>0.072</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.048</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.009</ci_lower_limit>
            <ci_upper_limit>0.152</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients With Adverse Events</title>
        <description>Number of patients with any adverse events</description>
        <time_frame>up to 20 weeks</time_frame>
        <population>Treated set (TS)</population>
        <group_list>
          <group group_id="O1">
            <title>Linagliptin 5 mg</title>
            <description>Linagliptin: 1 tablet (5 mg) once daily for 28 days</description>
          </group>
          <group group_id="O2">
            <title>Glimepiride 1-4 mg</title>
            <description>Glimepiride: 1 tablet (1 mg) once daily for 7 days followed by uptitration to 2 to 4 mg once daily within next 21 days</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Placebo: matching Linagliptin or Glimepiride tablet once daily over 28 days</description>
          </group>
          <group group_id="O4">
            <title>REP - Linagliptin 5 mg</title>
            <description>Residual effect period - Linagliptin 5 mg</description>
          </group>
          <group group_id="O5">
            <title>REP - Glimepiride 1-4 mg</title>
            <description>Residual effect period - Glimepiride 1-4 mg</description>
          </group>
          <group group_id="O6">
            <title>Rep - Placebo</title>
            <description>Residual effect period - Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With Adverse Events</title>
          <description>Number of patients with any adverse events</description>
          <population>Treated set (TS)</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="41"/>
                <count group_id="O3" value="40"/>
                <count group_id="O4" value="40"/>
                <count group_id="O5" value="41"/>
                <count group_id="O6" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11"/>
                    <measurement group_id="O2" value="25"/>
                    <measurement group_id="O3" value="14"/>
                    <measurement group_id="O4" value="4"/>
                    <measurement group_id="O5" value="7"/>
                    <measurement group_id="O6" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>28 days treatment period + 7 days residual effect period</time_frame>
      <desc>The adverse events occurred during residual effect period (REP) were included in the frequencies.</desc>
      <group_list>
        <group group_id="E1">
          <title>Linagliptin 5 mg</title>
          <description>Linagliptin: 1 tablet (5 mg) once daily for 28 days</description>
        </group>
        <group group_id="E2">
          <title>Glimepiride 1-4 mg</title>
          <description>Glimepiride: 1 tablet (1 mg) once daily for 7 days followed by uptitration to 2 to 4 mg once daily within next 21 days</description>
        </group>
        <group group_id="E3">
          <title>Placebo</title>
          <description>Placebo: matching Linagliptin or Glimepiride given once daily over 28 days</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="40"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MEDDRA 16.1</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="6" subjects_at_risk="40"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="40"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="40"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="40"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="40"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="40"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Boehringer Ingelheim Call Center</name_or_title>
      <organization>Boehringer Ingelheim Pharmaceuticals</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/NCT01703286
org study id: 1218.105
secondary id: 2012-003317-33
nct id: NCT01703286
lead sponsor: 
collaborator: 
The general aim of the present study is to investigate the impact of 4 weeks treatment with
      linagliptin (5 mg) on endothelial function in patients with type 2 diabetes mellitus. In the
      current trial this effect of linagliptin treatment on endothelial function will be compared
      against both the sulfonylurea glimepiride and against placebo, which has not been tested in a
      trial before; as also is the case for other DPP-4 inhibitors.

      Besides placebo, glimepiride was chosen as a comparator, as it is one compound of the second
      most used oral antidiabetic drug class.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double
measure: Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 28
time frame: baseline and day 28 for each treatment arm
description: Endothelial function under fasted condition was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.
measure: Change From Baseline in Flow Mediated Vasodilation (FMD) 2 h Post Meal on Day 28
time frame: baseline and day 28 for each treatment arm
description: Endothelial function 2 hours post meal was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.
measure: Change From Baseline in 2 Hours Post Meal Endothelial Independent Vasodilation (EIDV) on Day 28
time frame: baseline and day 28 for each treatment arm
description: Endothelial function 2h post-meal was measured by endothelial independent vasodilation (EIDV). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.
measure: Number of Patients With Adverse Events
time frame: up to 20 weeks
description: Number of patients with any adverse events
arm group label: Linagliptin 5mg
arm group type: Experimental
description: given once daily over 28 days
arm group label: Glimepiride
arm group type: Active Comparator
description: given once daily in 1mg dosis over 7 days, following a titration step to 2mg and application for 21 days
arm group label: Placebo
arm group type: Placebo Comparator
description: given once daily over 28 days
intervention type: Drug
intervention name: Placebo
description: Placebo matching Glimepiride
arm group label: Linagliptin 5mg
intervention type: Drug
intervention name: Linagliptin
description: given once daily for 28 days
arm group label: Linagliptin 5mg
intervention type: Drug
intervention name: Placebo
description: Placebo matching Linagliptin
arm group label: Glimepiride
intervention type: Drug
intervention name: Placebo
description: Placebo matching Linagliptin
arm group label: Placebo
intervention type: Drug
intervention name: Placebo
description: Placebo matching Glimepiride
arm group label: Placebo
intervention type: Drug
intervention name: Glimepiride
description: 1 mg for 7 days followed by uptitration to 2 mg (given for following 21 days)
arm group label: Glimepiride
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
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: Diabetes Mellitus, Type 2
mesh term: Glimepiride
mesh term: Linagliptin
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 