<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/NCT01679613</url>
  </required_header>
  <id_info>
    <org_study_id>1199.161</org_study_id>
    <secondary_id>2012-001009-26</secondary_id>
    <nct_id>NCT01679613</nct_id>
  </id_info>
  <brief_title>Investigation of Drug-drug Interaction of Nintedanib and Ketoconazole in Healthy Male Volunteers</brief_title>
  <official_title>Relative Bioavailability of Nintedanib Given Alone and in Combination With Ketoconazole at Steady State in Healthy Male Volunteers (an Open-label, Randomised, Two-way Cross-over Clinical Phase I Study)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <brief_summary>
    <textblock>
      The objective of the current study is to investigate the relative bioavailability of a single&#xD;
      dose of nintedanib low or high dose with and without coadministration of ketoconazole at&#xD;
      steady state&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">November 2012</completion_date>
  <primary_completion_date type="Actual">November 2012</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area Under the Curve From 0 Extrapolated to Infinity (AUC0-∞)</measure>
    <time_frame>1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration</time_frame>
    <description>AUC0-∞ represents the Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity&#xD;
For this endpoint, the &quot;measured values&quot; show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Measured Concentration (Cmax)</measure>
    <time_frame>1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration</time_frame>
    <description>Cmax represents the maximum concentration of nintedanib in plasma&#xD;
For this endpoint, the &quot;measured values&quot; show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Area Under the Curve From 0 to the Last Quantifiable Concentration (AUC0-tz)</measure>
    <time_frame>1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration</time_frame>
    <description>AUC0-tz represents the area under the plasma concentration-time curve of nintedanib from time 0 to the last quantifiable nintedanib plasma concentration.&#xD;
For this endpoint, the &quot;measured values&quot; show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>1 Nintedanib (Reference)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>single dose, oral with 240 ml water</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2 Nintedanib + Ketoconazole (Test)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nintedanib single dose, Ketoconazole steady state, oral with 240 ml water</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3 Nintedanib (Reference)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>single dose, oral with 240 ml water</description>
  </arm_group>
  <arm_group>
    <arm_group_label>4 Nintedanib + Ketoconazole (Test)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nintedanib single dose, Ketoconazole steady state, oral with 240 ml water</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nintedanib</intervention_name>
    <description>low or medium dose depending on pilot part</description>
    <arm_group_label>3 Nintedanib (Reference)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nintedanib</intervention_name>
    <description>low dose oral administration</description>
    <arm_group_label>1 Nintedanib (Reference)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketoconazole</intervention_name>
    <description>oral administration</description>
    <arm_group_label>2 Nintedanib + Ketoconazole (Test)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nintedanib</intervention_name>
    <description>low dose oral administration</description>
    <arm_group_label>2 Nintedanib + Ketoconazole (Test)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nintedanib</intervention_name>
    <description>low or medium dose depending on pilot part</description>
    <arm_group_label>4 Nintedanib + Ketoconazole (Test)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketoconazole</intervention_name>
    <description>oral administration</description>
    <arm_group_label>4 Nintedanib + Ketoconazole (Test)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
        1. healthy male subjects&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
        1. Any relevant deviation from healthy conditions&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Boehringer Ingelheim</last_name>
    <role>Study Chair</role>
    <affiliation>Boehringer Ingelheim</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>1199.161.1 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Biberach</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <link>
    <url>http://trials.boehringer-ingelheim.com</url>
    <description>Related Info</description>
  </link>
  <verification_date>November 2014</verification_date>
  <study_first_submitted>September 3, 2012</study_first_submitted>
  <study_first_submitted_qc>September 5, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 6, 2012</study_first_posted>
  <results_first_submitted>November 14, 2014</results_first_submitted>
  <results_first_submitted_qc>November 26, 2014</results_first_submitted_qc>
  <results_first_posted type="Estimate">November 27, 2014</results_first_posted>
  <last_update_submitted>November 26, 2014</last_update_submitted>
  <last_update_submitted_qc>November 26, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">November 27, 2014</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>Ketoconazole</mesh_term>
    <mesh_term>Nintedanib</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>This was a randomised, open-label trial with a 2-way cross-over Pilot part, followed by a 2-way cross-over Main part. Subjects participated either in the Pilot part with 2 treatment sequences (A_B and B_A) or in the Main part with treatment sequences (C_D and D_C) with wash-out period of at least 14 days between each sequence.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Nintedanib (Pilot Part)/ Nintedanib+Ketoconazole (Pilot Part)</title>
          <description>Nintedanib 50mg was given as a single dose (Treatment A). Following a wash out period of at least 14 days, ketoconazole 400mg was given once daily for three days and nintedanib 50 mg was given as a single dose 1 hour (h) after the ketoconazole administration with ketoconazole under steady-state conditions (Treatment B)</description>
        </group>
        <group group_id="P2">
          <title>Nintedanib+Ketoconazole (Pilot Part)/ Nintedanib (Pilot Part)</title>
          <description>Ketoconazole 400mg was given once daily for three days and nintedanib 50 mg was given as a single dose 1 hour (h) after the ketoconazole administration with ketoconazole under steady-state conditions (Treatment B). Following a wash out period of at least 14 days, nintedanib 50mg was given as a single dose (Treatment A).</description>
        </group>
        <group group_id="P3">
          <title>Nintedanib (Main Part)/ Nintedanib+Ketoconazole (Main Part)</title>
          <description>Based on the results from the Pilot part, nintedanib 50mg was given as a single dose (Treatment C). Following a wash out period of at least 14 days, ketoconazole 400mg was given once daily for 3 days followed by administration of nintedanib 50mg as a single dose 1h after administration of ketoconazole, based on the results from the Pilot part. Nintedanib administration was done under steady state ketoconazole (Treatment D)</description>
        </group>
        <group group_id="P4">
          <title>Nintedanib+Ketoconazole (Main Part)/ Nintedanib (Main Part)</title>
          <description>Ketoconazole 400mg was given once daily for 3 days followed by administration of nintedanib 50mg as a single dose 1h after administration of ketoconazole, based on the results from the Pilot part. Nintedanib administration was done under steady state ketoconazole (Treatment D). Following a wash out period of at least 14 days, nintedanib 50mg was given as a single dose, based on the results from the Pilot part (Treatment C).</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="13"/>
                <participants group_id="P4" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Received Nintedanib (Pilot)</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Received Nintedanib+Ketoconazole (Pilot)</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4">One subject received only ketoconazole not nintedanib</participants>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Received Nintedanib (Main)</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="13"/>
                <participants group_id="P4" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Received Nintedanib+Ketoconazole (Main)</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="13">Two subjects received only ketoconazole not nintedanib</participants>
                <participants group_id="P4" count="13">Two subjects received only ketoconazole not nintedanib</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="11"/>
                <participants group_id="P4" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>other than stated above</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The treated set (TS) includes all subjects who were dispensed study medication and were documented to have taken at least one dose of study medication (nintedanib or ketoconazole).</population>
      <group_list>
        <group group_id="B1">
          <title>Overall Study</title>
          <description>This was a randomised, open-label trial in healthy male subjects with a 2-way cross-over Pilot part, followed by a 2-way cross-over Main part. Subjects participated either in the Pilot part with 2 treatments (A and B) given in 1 of the 2 treatment sequences (A_B and B_A) or in the Main part with also 2 treatments (C and D) given in 1 of the 2 treatment sequences (C_D and D_C). Nintedanib administrations of the 2 respective treatments (A and B or C and D) were to be separated by a wash-out period of at least 14 days. The Pilot part was separated from the Main part by at least 3 weeks to allow for interim analysis</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="34"/>
          </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="35.9" spread="10.7"/>
                  </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="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Curve From 0 Extrapolated to Infinity (AUC0-∞)</title>
        <description>AUC0-∞ represents the Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity&#xD;
For this endpoint, the &quot;measured values&quot; show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities</description>
        <time_frame>1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration</time_frame>
        <population>The treated set (TS) includes all subjects who were dispensed study medication and were documented to have taken at least one dose of study medication (nintedanib or ketoconazole).</population>
        <group_list>
          <group group_id="O1">
            <title>Nintedanib</title>
            <description>In both parts (Pilot and Main) 50 mg of nintedanib were given as a single dose on Day 1.&#xD;
In the Main part, alternatively, a single dose of 100mg could have been given. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.</description>
          </group>
          <group group_id="O2">
            <title>Nintedanib + Ketoconazole</title>
            <description>In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2 and 50 mg nintedanib were given as a single dose 1 h after the ketoconazole administration on Day 1, with ketoconazole under steady-state conditions.&#xD;
In the Main part, alternatively, a single dose of 100mg could have been given 1 h after the ketoconazole administration or 4 h before the ketoconazole administration on Day 1. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Curve From 0 Extrapolated to Infinity (AUC0-∞)</title>
          <description>AUC0-∞ represents the Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity&#xD;
For this endpoint, the &quot;measured values&quot; show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities</description>
          <population>The treated set (TS) includes all subjects who were dispensed study medication and were documented to have taken at least one dose of study medication (nintedanib or ketoconazole).</population>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38.6" spread="42.5"/>
                    <measurement group_id="O2" value="61.3" spread="40.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>1.0000</p_value>
            <p_value_desc>p-value for ratio outside interval 0.8 - 1.25</p_value_desc>
            <method>ANOVA</method>
            <method_desc>The model includes fixed effects for sequence, period, and treatment. Subjects within sequences is included as random effect.</method_desc>
            <param_type>Geometric Mean Ratio in percentage</param_type>
            <param_value>160.48</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>17.9</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>148.245</ci_lower_limit>
            <ci_upper_limit>173.736</ci_upper_limit>
            <estimate_desc>Ratio calculated as nintedanib+ketoconazole divided by nintedanib (in %).&#xD;
The standard deviation is actually the geometric coefficient of variation (gCV).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Measured Concentration (Cmax)</title>
        <description>Cmax represents the maximum concentration of nintedanib in plasma&#xD;
For this endpoint, the &quot;measured values&quot; show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities</description>
        <time_frame>1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration</time_frame>
        <population>TS</population>
        <group_list>
          <group group_id="O1">
            <title>Nintedanib</title>
            <description>In both parts (Pilot and Main) 50 mg of nintedanib were given as a single dose on Day 1.&#xD;
In the Main part, alternatively, a single dose of 100mg could have been given. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.</description>
          </group>
          <group group_id="O2">
            <title>Nintedanib + Ketoconazole</title>
            <description>In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2 and 50 mg nintedanib were given as a single dose 1 h after the ketoconazole administration on Day 1, with ketoconazole under steady-state conditions.&#xD;
In the Main part, alternatively, a single dose of 100mg could have been given 1 h after the ketoconazole administration or 4 h before the ketoconazole administration on Day 1. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Measured Concentration (Cmax)</title>
          <description>Cmax represents the maximum concentration of nintedanib in plasma&#xD;
For this endpoint, the &quot;measured values&quot; show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities</description>
          <population>TS</population>
          <units>ng/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.19" spread="71.0"/>
                    <measurement group_id="O2" value="7.13" spread="44.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>1.0000</p_value>
            <p_value_desc>p-value for ratio outside interval 0.8 - 1.25</p_value_desc>
            <method>ANOVA</method>
            <method_desc>The model includes fixed effects for sequence, period, and treatment. Subjects within sequences is included as random effect.</method_desc>
            <param_type>Geometric Mean Ratio in percentage</param_type>
            <param_value>179.62</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>29.9</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>157.557</ci_lower_limit>
            <ci_upper_limit>204.779</ci_upper_limit>
            <estimate_desc>The standard deviation is actually the gCV (in %).&#xD;
Ratio calculated as nintedanib+ketoconazole divided by nintedanib</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Area Under the Curve From 0 to the Last Quantifiable Concentration (AUC0-tz)</title>
        <description>AUC0-tz represents the area under the plasma concentration-time curve of nintedanib from time 0 to the last quantifiable nintedanib plasma concentration.&#xD;
For this endpoint, the &quot;measured values&quot; show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities</description>
        <time_frame>1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration</time_frame>
        <population>TS</population>
        <group_list>
          <group group_id="O1">
            <title>Nintedanib</title>
            <description>In both parts (Pilot and Main) 50 mg of nintedanib were given as a single dose on Day 1.&#xD;
In the Main part, alternatively, a single dose of 100mg could have been given. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.</description>
          </group>
          <group group_id="O2">
            <title>Nintedanib + Ketoconazole</title>
            <description>In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2 and 50 mg nintedanib were given as a single dose 1 h after the ketoconazole administration on Day 1, with ketoconazole under steady-state conditions.&#xD;
In the Main part, alternatively, a single dose of 100mg could have been given 1 h after the ketoconazole administration or 4 h before the ketoconazole administration on Day 1. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Curve From 0 to the Last Quantifiable Concentration (AUC0-tz)</title>
          <description>AUC0-tz represents the area under the plasma concentration-time curve of nintedanib from time 0 to the last quantifiable nintedanib plasma concentration.&#xD;
For this endpoint, the &quot;measured values&quot; show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities</description>
          <population>TS</population>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="35.7" spread="47.8"/>
                    <measurement group_id="O2" value="59.4" spread="40.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>1.000</p_value>
            <p_value_desc>p-value for ratio outside interval 0.8 to 1.25</p_value_desc>
            <method>ANOVA</method>
            <method_desc>The model includes fixed effects for sequence, period, and treatment. Subjects within sequences is included as random effect.</method_desc>
            <param_type>Geometric Mean Ratio in percentage</param_type>
            <param_value>168.09</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>17.9</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>155.252</ci_lower_limit>
            <ci_upper_limit>181.981</ci_upper_limit>
            <estimate_desc>The standard deviation is actually the gCV.&#xD;
Ratio calculated as nintedanib+ketoconazole divided by nintedanib (in %).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From the first trial drug administration until 18 days after the last trial drug administration, up to 32 days.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Ketoconazole</title>
          <description>In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2</description>
        </group>
        <group group_id="E2">
          <title>Nintedanib</title>
          <description>In both parts (Pilot and Main) 50 mg of nintedanib were given as a single dose on Day 1.&#xD;
In the Main part, alternatively, a single dose of 100mg could have been given. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.</description>
        </group>
        <group group_id="E3">
          <title>Nintedanib + Ketoconazole</title>
          <description>In both parts (Pilot and Main) of the study 400 mg ketoconazole were given once daily for 3 days starting on Day -2 and 50 mg nintedanib were given as a single dose 1 h after the ketoconazole administration on Day 1, with ketoconazole under steady-state conditions.&#xD;
In the Main part, alternatively, a single dose of 100mg could have been given 1 h after the ketoconazole administration or 4 h before the ketoconazole administration on Day 1. The chosen dosing scheme depended on the increase in nintedanib exposure due to ketoconazole co-administration observed in the Pilot part.</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="34"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
                <counts group_id="E3" 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 15.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="31"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="31"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
                <counts group_id="E3" subjects_affected="2" 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="2" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="31"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="29"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Boehringer Ingelheim Call Center</name_or_title>
      <organization>Boehringer Ingelheim 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/NCT01679613
org study id: 1199.161
secondary id: 2012-001009-26
nct id: NCT01679613
lead sponsor: 
The objective of the current study is to investigate the relative bioavailability of a single
      dose of nintedanib low or high dose with and without coadministration of ketoconazole at
      steady state
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Area Under the Curve From 0 Extrapolated to Infinity (AUC0-∞)
time frame: 1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration
description: AUC0-∞ represents the Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity
For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities
measure: Maximum Measured Concentration (Cmax)
time frame: 1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration
description: Cmax represents the maximum concentration of nintedanib in plasma
For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities
measure: Area Under the Curve From 0 to the Last Quantifiable Concentration (AUC0-tz)
time frame: 1 hour (h) before drug administration and 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 10h, 12h, 15h, 24h, 36h, 48h and 72h after the drug administration
description: AUC0-tz represents the area under the plasma concentration-time curve of nintedanib from time 0 to the last quantifiable nintedanib plasma concentration.
For this endpoint, the "measured values" show inter-individual variabilities, whereas the statistical analyses show intra-individual variabilities
arm group label: 1 Nintedanib (Reference)
arm group type: Experimental
description: single dose, oral with 240 ml water
arm group label: 2 Nintedanib + Ketoconazole (Test)
arm group type: Experimental
description: Nintedanib single dose, Ketoconazole steady state, oral with 240 ml water
arm group label: 3 Nintedanib (Reference)
arm group type: Experimental
description: single dose, oral with 240 ml water
arm group label: 4 Nintedanib + Ketoconazole (Test)
arm group type: Experimental
description: Nintedanib single dose, Ketoconazole steady state, oral with 240 ml water
intervention type: Drug
intervention name: Nintedanib
description: low or medium dose depending on pilot part
arm group label: 3 Nintedanib (Reference)
intervention type: Drug
intervention name: Nintedanib
description: low dose oral administration
arm group label: 1 Nintedanib (Reference)
intervention type: Drug
intervention name: Ketoconazole
description: oral administration
arm group label: 2 Nintedanib + Ketoconazole (Test)
intervention type: Drug
intervention name: Nintedanib
description: low dose oral administration
arm group label: 2 Nintedanib + Ketoconazole (Test)
intervention type: Drug
intervention name: Nintedanib
description: low or medium dose depending on pilot part
arm group label: 4 Nintedanib + Ketoconazole (Test)
intervention type: Drug
intervention name: Ketoconazole
description: oral administration
arm group label: 4 Nintedanib + Ketoconazole (Test)
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Boehringer Ingelheim
role: Study Chair
affiliation: Boehringer Ingelheim
facility: 
country: Germany
url: http://trials.boehringer-ingelheim.com
description: Related Info
responsible party type: Sponsor
mesh term: Ketoconazole
mesh term: Nintedanib
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 