<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/NCT02191865</url>
  </required_header>
  <id_info>
    <org_study_id>1199.200</org_study_id>
    <secondary_id>2014-000690-39</secondary_id>
    <nct_id>NCT02191865</nct_id>
  </id_info>
  <brief_title>Nintedanib in Volunteers With Hepatic Impairment Compared With Healthy Volunteers</brief_title>
  <official_title>Pharmacokinetics, Safety and Tolerability of Nintedanib Single Oral Dose in Male and Female Patients With Different Degrees of Hepatic Impairment (Child-Pugh Classification A and B) as Compared With Nintedanib Administration to Male and Female Healthy Subjects (a Non-blinded, Parallel Group Study of Phase I)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <brief_summary>
    <textblock>
      The primary objective of this study is to investigate the effect of mild (Child-Pugh A, score&#xD;
      5-6) and moderate (Child-Pugh B, score 7-9) hepatic impairment on the pharmacokinetics,&#xD;
      safety and tolerability of nintedanib, in comparison with a control group with normal hepatic&#xD;
      function following oral administration of nintedanib as single dose.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>July 2014</start_date>
  <completion_date type="Actual">January 2015</completion_date>
  <primary_completion_date type="Actual">December 2014</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>AUC (0-inf) of Nintedanib</measure>
    <time_frame>Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration</time_frame>
    <description>AUC (0-inf) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 extrapolated to infinity)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cmax of Nintedanib</measure>
    <time_frame>Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration</time_frame>
    <description>Cmax (Maximum measured concentration of the Nintedanib in plasma)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>AUC (0-tz) of Nintedanib</measure>
    <time_frame>Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration</time_frame>
    <description>AUC (0-tz) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 to the last quantifiable drug plasma concentration)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number (%) of Subjects With Drug-related Adverse Events (AEs)</measure>
    <time_frame>(AEs) during the 'on-treatment' period (from administration of trial medication until the end of the 28-day residual effect period); Up to 29 days</time_frame>
    <description>Number (%) of subjects with drug-related Adverse events (AEs)</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>Hepatic Insufficiency</condition>
  <arm_group>
    <arm_group_label>Mild liver impairment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with mild hepatic impaired function (Child-Pugh A)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Moderate liver impairment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with moderate hepatic impaired function (Child-Pugh B)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy volunteers</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Healthy control subjects</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nintedanib</intervention_name>
    <description>Soft gelatine capsule</description>
    <arm_group_label>Moderate liver impairment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nintedanib</intervention_name>
    <description>Soft gelatine capsule</description>
    <arm_group_label>Mild liver impairment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nintedanib</intervention_name>
    <description>Soft gelatine capsule</description>
    <arm_group_label>Healthy volunteers</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
        Healthy subjects:&#xD;
&#xD;
          -  Male or female subject, healthy according to the investigator's judgement based on a&#xD;
             complete medical history, including a physical examination, vital signs (BP, PR),&#xD;
             12-lead ECG, and clinical laboratory&#xD;
&#xD;
          -  Age of 18 to 79 years at screening visit&#xD;
&#xD;
        Hepatically impaired patients as determined by a hepatologist/ gastroenterologist:&#xD;
&#xD;
          -  A documented diagnosis of the impaired hepatic function, determined by&#xD;
             hepatologist/gastroenterologist/specialist for internal medicine, must be available in&#xD;
             the patient´s source data.&#xD;
&#xD;
          -  Male or female chronic hepatically impaired patient as determined by screening results&#xD;
             and classified as Child-Pugh A (Child-Pugh score of 5-6 points) or as Child-Pugh B&#xD;
             (Child-Pugh score of 7-9 points). Hepatic insufficiency must be diagnosed at least 3&#xD;
             months before screening.&#xD;
&#xD;
          -  Age of 18 to 79 years at screening visit&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
        Healthy subjects:&#xD;
&#xD;
          -  Any finding in the medical examination (including BP, PR or ECG) deviating from normal&#xD;
             and judged as clinically relevant by the investigator&#xD;
&#xD;
          -  Any laboratory value outside the reference range at screening visit that the&#xD;
             investigator considers to be of clinical relevance&#xD;
&#xD;
          -  Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic,&#xD;
             immunological or hormonal disorders judged as clinically relevant by the investigator&#xD;
&#xD;
          -  Surgery of the gastrointestinal tract that could interfere with kinetics of the trial&#xD;
             medication based on the investigator´s judgment&#xD;
&#xD;
          -  Women who are breast feeding or of child-bearing potential not using a highly&#xD;
             effective method of birth control for at least one month prior to inclusion and at&#xD;
             least 3 month after administration of trial medication.&#xD;
&#xD;
        Hepatically impaired patients as determined by a hepatologist/gastroenterologist:&#xD;
&#xD;
          -  Medical disorder, condition or history of such that would impair the patient's ability&#xD;
             to participate or complete this study in the opinion of the investigator or the&#xD;
             sponsor&#xD;
&#xD;
          -  Patients with significant diseases other than underlying diagnose of hepatic&#xD;
             impairment and concomitant diseases related to it. A significant disease is defined as&#xD;
             a disease which in the opinion of the investigator:&#xD;
&#xD;
               -  put the patient at risk because of participation in the study&#xD;
&#xD;
               -  may influence the results of the study&#xD;
&#xD;
               -  is not in a stable condition&#xD;
&#xD;
          -  Surgery of the gastrointestinal tract that could interfere with the kinetics of the&#xD;
             trial medication based on the investigator´s judgment&#xD;
&#xD;
          -  Women who are breast feeding or of child-bearing potential not using a highly&#xD;
             effective method of birth control for at least one month prior to inclusion and at&#xD;
             least 3 month after administration of trial medication&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>79 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>1199.200.49001 Boehringer Ingelheim Investigational Site</name>
      <address>
        <city>Kiel</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>December 2015</verification_date>
  <study_first_submitted>July 14, 2014</study_first_submitted>
  <study_first_submitted_qc>July 14, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 16, 2014</study_first_posted>
  <results_first_submitted>December 21, 2015</results_first_submitted>
  <results_first_submitted_qc>December 21, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">February 1, 2016</results_first_posted>
  <last_update_submitted>December 21, 2015</last_update_submitted>
  <last_update_submitted_qc>December 21, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 1, 2016</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>Hepatic Insufficiency</mesh_term>
    <mesh_term>Liver Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nintedanib</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Healthy subjects were to be matched to subjects with hepatic impairment ((Child-Pugh A, score 5 or 6),(Child-Pugh B, score 7 to 9)) by age (±10 years), body weight (±10%), sex, race, and smoking habits (current vs. ex- and never smokers).</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Child Pugh A</title>
          <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).&#xD;
Subjects were dosed in a 3 plus 5 design, where a subgroup of 3 subjects was dosed and safety was evaluated formally at a safety meeting prior to dosing the remaining 5 subjects in the group.</description>
        </group>
        <group group_id="P2">
          <title>Child Pugh B</title>
          <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).&#xD;
Subjects were dosed in a 3 plus 5 design, where a subgroup of 3 subjects was dosed and safety was evaluated formally at a safety meeting prior to dosing the remaining 5 subjects in the group.</description>
        </group>
        <group group_id="P3">
          <title>Healthy</title>
          <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in subjects with normal hepatic function.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="17"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="17"/>
              </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_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Treated set: The treated set (TS) included all subjects who were dispensed study medication and were documented to have taken atleast one dose of investigational treatment.</population>
      <group_list>
        <group group_id="B1">
          <title>Child Pugh A</title>
          <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).&#xD;
Subjects were dosed in a 3 plus 5 design, where a subgroup of 3 subjects was dosed and safety was evaluated formally at a safety meeting prior to dosing the remaining 5 subjects in the group.</description>
        </group>
        <group group_id="B2">
          <title>Child Pugh B</title>
          <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).&#xD;
Subjects were dosed in a 3 plus 5 design, where a subgroup of 3 subjects was dosed and safety was evaluated formally at a safety meeting prior to dosing the remaining 5 subjects in the group.</description>
        </group>
        <group group_id="B3">
          <title>Healthy</title>
          <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in subjects with normal hepatic function.</description>
        </group>
        <group group_id="B4">
          <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="8"/>
            <count group_id="B2" value="8"/>
            <count group_id="B3" value="17"/>
            <count group_id="B4" value="33"/>
          </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="60.6" spread="8.1"/>
                    <measurement group_id="B2" value="56.6" spread="6.5"/>
                    <measurement group_id="B3" value="57.6" spread="8.4"/>
                    <measurement group_id="B4" value="58.1" spread="7.8"/>
                  </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="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>AUC (0-inf) of Nintedanib</title>
        <description>AUC (0-inf) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 extrapolated to infinity)</description>
        <time_frame>Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration</time_frame>
        <population>Pharmacokinetic set (PKS): The PKS included all subjects of the TS who provided at least 1 observation for at least 1 primary PK endpoint, which was judged as PK evaluable and was not affected by important protocol violation(s) relevant to the evaluation of PK.</population>
        <group_list>
          <group group_id="O1">
            <title>Child-Pugh A</title>
            <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).</description>
          </group>
          <group group_id="O2">
            <title>Child-Pugh B</title>
            <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).</description>
          </group>
          <group group_id="O3">
            <title>Healthy Matched Child-Pugh A</title>
            <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in healthy control subjects matched with hepatic (Child pugh A) impaired subjects</description>
          </group>
          <group group_id="O4">
            <title>Healthy Matched Child-Pugh B</title>
            <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in healthy control subjects matched with hepatic (Child pugh B) impaired subjects .</description>
          </group>
        </group_list>
        <measure>
          <title>AUC (0-inf) of Nintedanib</title>
          <description>AUC (0-inf) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 extrapolated to infinity)</description>
          <population>Pharmacokinetic set (PKS): The PKS included all subjects of the TS who provided at least 1 observation for at least 1 primary PK endpoint, which was judged as PK evaluable and was not affected by important protocol violation(s) relevant to the evaluation of PK.</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="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="200" spread="87.7"/>
                    <measurement group_id="O2" value="674" spread="66.3"/>
                    <measurement group_id="O3" value="92.7" spread="58.5"/>
                    <measurement group_id="O4" value="77.8" spread="38.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The statistical model used for the analysis of AUC (0-inf) was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>ratio of the geometric means</param_type>
            <param_value>215.39</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>73.5</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>120.71</ci_lower_limit>
            <ci_upper_limit>384.32</ci_upper_limit>
            <estimate_desc>Ratio of Child Pugh A (Test): Healthy Child Pugh A (Reference). The Standard deviation is the Intra-individual gCV</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The statistical model used for the analysis of AUC (0-inf) was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Ratio of geometric means</param_type>
            <param_value>867.13</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>45.9</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>572.93</ci_lower_limit>
            <ci_upper_limit>1312.41</ci_upper_limit>
            <estimate_desc>Ratio of Child Pugh B (Test): Healthy Child Pugh B (Reference). The Standard deviation is the Intra-individual gCV</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Cmax of Nintedanib</title>
        <description>Cmax (Maximum measured concentration of the Nintedanib in plasma)</description>
        <time_frame>Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration</time_frame>
        <population>Pharmacokinetic set (PKS): The PKS included all subjects of the TS who provided at least 1 observation for at least 1 primary PK endpoint, which was judged as PK evaluable and was not affected by important protocol violation(s) relevant to the evaluation of PK.</population>
        <group_list>
          <group group_id="O1">
            <title>Child-Pugh A</title>
            <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).</description>
          </group>
          <group group_id="O2">
            <title>Child-Pugh B</title>
            <description>Oral administration of 1 soft gelatin capsule of 100 mg Nintedanib with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).</description>
          </group>
          <group group_id="O3">
            <title>Healthy Matched Child-Pugh A</title>
            <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in healthy control subjects matched with hepatic (Child pugh A) impaired subjects</description>
          </group>
          <group group_id="O4">
            <title>Healthy Matched Child-Pugh B</title>
            <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in healthy control subjects matched with hepatic (Child pugh B) impaired subjects .</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax of Nintedanib</title>
          <description>Cmax (Maximum measured concentration of the Nintedanib in plasma)</description>
          <population>Pharmacokinetic set (PKS): The PKS included all subjects of the TS who provided at least 1 observation for at least 1 primary PK endpoint, which was judged as PK evaluable and was not affected by important protocol violation(s) relevant to the evaluation of PK.</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="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.5" spread="68.4"/>
                    <measurement group_id="O2" value="59.4" spread="87.0"/>
                    <measurement group_id="O3" value="9.25" spread="54.1"/>
                    <measurement group_id="O4" value="7.81" spread="49.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The statistical model used for the analysis of Cmax was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>ratio of the geometric means</param_type>
            <param_value>221.76</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>61.4</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>134.73</ci_lower_limit>
            <ci_upper_limit>365.01</ci_upper_limit>
            <estimate_desc>Ratio of Child Pugh A (Test): Healthy Child Pugh A (Reference). The Standard deviation is the Intra-individual gCV</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The statistical model used for the analysis of Cmax was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Ratio of geometric means</param_type>
            <param_value>761.01</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>69.1</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>439.01</ci_lower_limit>
            <ci_upper_limit>1319.18</ci_upper_limit>
            <estimate_desc>Ratio of Child Pugh B (Test): Healthy Child Pugh B (Reference). The Standard deviation is the Intra-individual gCV</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC (0-tz) of Nintedanib</title>
        <description>AUC (0-tz) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 to the last quantifiable drug plasma concentration)</description>
        <time_frame>Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration</time_frame>
        <population>Pharmacokinetic set (PKS): The PKS included all subjects of the TS who provided at least 1 observation for at least 1 primary PK endpoint, which was judged as PK evaluable and was not affected by important protocol violation(s) relevant to the evaluation of PK.</population>
        <group_list>
          <group group_id="O1">
            <title>Child-Pugh A</title>
            <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).</description>
          </group>
          <group group_id="O2">
            <title>Child-Pugh B</title>
            <description>Oral administration of 1 soft gelatin capsule of 100 mg Nintedanib with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).</description>
          </group>
          <group group_id="O3">
            <title>Healthy Matched Child-Pugh A</title>
            <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in healthy control subjects matched with hepatic (Child pugh A) impaired subjects</description>
          </group>
          <group group_id="O4">
            <title>Healthy Matched Child-Pugh B</title>
            <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in healthy control subjects matched with hepatic (Child pugh B) impaired subjects .</description>
          </group>
        </group_list>
        <measure>
          <title>AUC (0-tz) of Nintedanib</title>
          <description>AUC (0-tz) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 to the last quantifiable drug plasma concentration)</description>
          <population>Pharmacokinetic set (PKS): The PKS included all subjects of the TS who provided at least 1 observation for at least 1 primary PK endpoint, which was judged as PK evaluable and was not affected by important protocol violation(s) relevant to the evaluation of PK.</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="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="193" spread="89.5"/>
                    <measurement group_id="O2" value="652" spread="66.2"/>
                    <measurement group_id="O3" value="89.2" spread="59.6"/>
                    <measurement group_id="O4" value="74.8" spread="38.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>The statistical model used for the analysis of AUC (0-tz) was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>ratio of the geometric means</param_type>
            <param_value>216.79</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>75.0</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>120.37</ci_lower_limit>
            <ci_upper_limit>390.45</ci_upper_limit>
            <estimate_desc>Ratio of Child Pugh A (Test): Healthy Child Pugh A (Reference). The Standard deviation is the Intra-individual gCV</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>The statistical model used for the analysis of AUC (0-tz) was an ANOVA (analysis of variance) model on the logarithmic scale. Observations from a subject with hepatic impairment and the matched healthy control subject were analysed as a matched pair.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Ratio of geometric means</param_type>
            <param_value>870.74</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>45.7</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>576.36</ci_lower_limit>
            <ci_upper_limit>1315.49</ci_upper_limit>
            <estimate_desc>Ratio of Child Pugh B (Test): Healthy Child Pugh B (Reference). The Standard deviation is the Intra-individual gCV</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number (%) of Subjects With Drug-related Adverse Events (AEs)</title>
        <description>Number (%) of subjects with drug-related Adverse events (AEs)</description>
        <time_frame>(AEs) during the 'on-treatment' period (from administration of trial medication until the end of the 28-day residual effect period); Up to 29 days</time_frame>
        <population>TS</population>
        <group_list>
          <group group_id="O1">
            <title>Child-Pugh A</title>
            <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).</description>
          </group>
          <group group_id="O2">
            <title>Child-Pugh B</title>
            <description>Oral administration of 1 soft gelatin capsule of 100 mg Nintedanib with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).</description>
          </group>
          <group group_id="O3">
            <title>Healthy</title>
            <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in subjects with normal hepatic function.</description>
          </group>
        </group_list>
        <measure>
          <title>Number (%) of Subjects With Drug-related Adverse Events (AEs)</title>
          <description>Number (%) of subjects with drug-related Adverse events (AEs)</description>
          <population>TS</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
                <count group_id="O2" value="8"/>
                <count group_id="O3" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0"/>
                    <measurement group_id="O2" value="37.5"/>
                    <measurement group_id="O3" value="17.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>AEs during the 'on-treatment' period (from administration of trial medication until the end of the 28-day residual effect period); up to 29 days</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Child Pugh A</title>
          <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with mild hepatic impairment (Child-Pugh A).</description>
        </group>
        <group group_id="E2">
          <title>Child Pugh B</title>
          <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in patients with moderate hepatic impairment (Child-Pugh B).</description>
        </group>
        <group group_id="E3">
          <title>Healthy</title>
          <description>Oral administration of 1 soft gelatin capsule of Nintedanib 100 mg with 240 ml of water under fed conditions in subjects with normal hepatic function.</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="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 17.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Skin irritation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Boehringer Ingelheim Call Center</name_or_title>
      <organization>Boehringer Ingelheim</organization>
      <phone>800-243-0127 ext +1</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/NCT02191865
org study id: 1199.200
secondary id: 2014-000690-39
nct id: NCT02191865
lead sponsor: 
The primary objective of this study is to investigate the effect of mild (Child-Pugh A, score
      5-6) and moderate (Child-Pugh B, score 7-9) hepatic impairment on the pharmacokinetics,
      safety and tolerability of nintedanib, in comparison with a control group with normal hepatic
      function following oral administration of nintedanib as single dose.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: AUC (0-inf) of Nintedanib
time frame: Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration
description: AUC (0-inf) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 extrapolated to infinity)
measure: Cmax of Nintedanib
time frame: Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration
description: Cmax (Maximum measured concentration of the Nintedanib in plasma)
measure: AUC (0-tz) of Nintedanib
time frame: Pre-dose and 1 hour (h), 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 36h, 48h, 72h, 96h, 120h, 144h and 168h after drug administration
description: AUC (0-tz) (Area under the concentration-time curve of the Nintedanib in plasma over the time interval from 0 to the last quantifiable drug plasma concentration)
measure: Number (%) of Subjects With Drug-related Adverse Events (AEs)
time frame: (AEs) during the 'on-treatment' period (from administration of trial medication until the end of the 28-day residual effect period); Up to 29 days
description: Number (%) of subjects with drug-related Adverse events (AEs)
arm group label: Mild liver impairment
arm group type: Experimental
description: Patients with mild hepatic impaired function (Child-Pugh A)
arm group label: Moderate liver impairment
arm group type: Experimental
description: Patients with moderate hepatic impaired function (Child-Pugh B)
arm group label: Healthy volunteers
arm group type: Experimental
description: Healthy control subjects
intervention type: Drug
intervention name: Nintedanib
description: Soft gelatine capsule
arm group label: Moderate liver impairment
intervention type: Drug
intervention name: Nintedanib
description: Soft gelatine capsule
arm group label: Mild liver impairment
intervention type: Drug
intervention name: Nintedanib
description: Soft gelatine capsule
arm group label: Healthy volunteers
criteria: 
gender: All
minimum age: 18 Years
maximum age: 79 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: Hepatic Insufficiency
mesh term: Liver Failure
mesh term: Nintedanib
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 