<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/NCT01703260</url>
  </required_header>
  <id_info>
    <org_study_id>ROF-NASH_205</org_study_id>
    <secondary_id>U1111-1129-5051</secondary_id>
    <nct_id>NCT01703260</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of Roflumilast and Pioglitazone in Treating Adults With Nonalcoholic SteatoHepatitis</brief_title>
  <official_title>A Randomized, Double-Blind, Controlled, Multi-Center Phase 2 Study to Evaluate the Effect of Roflumilast Plus Pioglitazone on Liver Enzymes and Liver Fat Content in Subjects With Nonalcoholic SteatoHepatitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>AstraZeneca</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the effect of roflumilast and pioglitazone therapy&#xD;
      on serum transaminase (ALT) levels in adults with Nonalcoholic SteatoHepatitis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This proof of concept study will evaluate the effect of roflumilast and pioglitazone on&#xD;
      transaminase levels and liver fat content.&#xD;
&#xD;
      Takeda has chosen not to continue this Study, however, randomized subjects were allowed to&#xD;
      complete the study per protocol.&#xD;
&#xD;
      The decision to terminate the study is not related to any safety concerns with either of the&#xD;
      study medications.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Company decision; No safety or efficacy concerns (see detailed description)&#xD;
  </why_stopped>
  <start_date>June 2013</start_date>
  <completion_date type="Actual">September 2014</completion_date>
  <primary_completion_date type="Actual">September 2014</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Amount of Serum Alanine Transaminase (ALT) at Baseline</measure>
    <time_frame>Baseline</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent Change From Baseline in Serum ALT at Month 4</measure>
    <time_frame>Month 4</time_frame>
    <description>The percent change between the serum ALT value collected at Month 4 or final visit relative to baseline.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Amount of Serum Aspartate Transaminase (AST) at Baseline</measure>
    <time_frame>Baseline</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent Change From Baseline in Serum AST at Month 4</measure>
    <time_frame>Month 4</time_frame>
    <description>The percent change between the serum AST value collected at Month 4 or final visit relative to baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Liver Fat Content at Baseline</measure>
    <time_frame>Baseline</time_frame>
    <description>Liver fat content was quantitatively measured by evaluating the percentage of proton density fat fraction (PDFF) from an abdominal magnetic resonance imaging (MRI). On the basis of Couinaud classification (a classification used to describe functional liver anatomy), the liver was divided into 8 segments: caudate, left superolateral, left inferolateral, left superomedial (4a), left inferomedial (4b), right anteroinferior, right posteroinferior, right posterosuperior and right anterosuperior.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Liver Fat Content at Month 4</measure>
    <time_frame>Baseline and Month 4</time_frame>
    <description>Liver fat content was quantitatively measured by evaluating the percentage of PDFF from an abdominal MRI. On the basis of Couinaud classification (a classification used to describe functional liver anatomy), the liver was divided into 8 segments: caudate, left superolateral, left inferolateral, left superomedial (4a), left inferomedial (4b), right anteroinferior, right posteroinferior, right posterosuperior and right anterosuperior.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Nonalcoholic Steatohapatitis</condition>
  <arm_group>
    <arm_group_label>Roflumilast + pioglitazone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Roflumilast dose and pioglitazone dose, orally for up to 4 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Roflumilast</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Roflumilast dose and pioglitazone matching-placebo dose orally for up to 4 months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pioglitazone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pioglitazone dose, orally and roflumilast matching-placebo dose, orally for up to 4 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Roflumilast</intervention_name>
    <description>Roflumilast dose</description>
    <arm_group_label>Roflumilast</arm_group_label>
    <arm_group_label>Roflumilast + pioglitazone</arm_group_label>
    <other_name>Daxas, Daliresp</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pioglitazone</intervention_name>
    <description>Pioglitazone dose</description>
    <arm_group_label>Pioglitazone</arm_group_label>
    <arm_group_label>Roflumilast + pioglitazone</arm_group_label>
    <other_name>Actos</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Pioglitazone placebo-matching dose</description>
    <arm_group_label>Roflumilast</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Roflumilast placebo-matching dose</description>
    <arm_group_label>Pioglitazone</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. In the opinion of the investigator, the patient is capable of understanding and&#xD;
             complying with protocol requirements.&#xD;
&#xD;
          2. The patient or, when applicable, the patient's legally acceptable representative signs&#xD;
             and dates a written, informed consent form and any required privacy authorization&#xD;
             prior to the initiation of any study procedures.&#xD;
&#xD;
          3. Has a historical diagnosis of NASH, established no more than 12 months prior to study&#xD;
             entry based on histology (liver biopsy).&#xD;
&#xD;
          4. Has a NAFLD Activity Score (NAS) of ≥3, with a score of at least 1 in steatosis and&#xD;
             lobular inflammation - the subcomponents of NAS. It is acceptable if the score for&#xD;
             hepatocyte ballooning is &quot;zero&quot;.&#xD;
&#xD;
          5. The subject has a MRI determined liver fat fraction of equal or higher than 7 percent.&#xD;
&#xD;
          6. The subject is female or male and aged 18 to 80 years, inclusive.&#xD;
&#xD;
          7. A male who is nonsterilized and sexually active with a female partner of childbearing&#xD;
             potential agrees to use adequate contraception from signing of informed consent&#xD;
             throughout the duration of the study and for 30 weeks after last dose.&#xD;
&#xD;
          8. A female of childbearing potential who is sexually active with a nonsterilized male&#xD;
             partner agrees to use routinely adequate contraception from signing of informed&#xD;
             consent throughout the duration of the study and for 30 days after last dose.&#xD;
&#xD;
          9. If taking Vitamin E and/or pentoxifylline, the subject has been receiving a stable&#xD;
             dose for 6 months prior to randomization, started Vitamin E and/or pentoxifylline&#xD;
             therapy prior to the qualifying liver biopsy, and agrees to maintain a stable dose&#xD;
             throughout the study when possible.&#xD;
&#xD;
         10. Subject has an ALT level at Screening between 55 and 250 IU/L, inclusive, and between&#xD;
             60 and 250 IU/L at one other occasion during the 6 months prior to Randomization.&#xD;
&#xD;
         11. If taking a statin, should be on stable dose for 6 months prior to screening.&#xD;
&#xD;
         12. If taking angiotensin receptor blockers and fish oil, should be on a stable dose for&#xD;
             at least 3 month prior to screening.&#xD;
&#xD;
         13. If diabetic, the subject is on a stable dose of metformin, dipeptidyl peptidase-4&#xD;
             inhibitor, sulfonylurea or insulin or a combination thereof for at least 3 months&#xD;
             prior to Screening.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. The subject has a history of chronic liver disease other than NASH eg, chronic or&#xD;
             acute hepatitis, Wilson's disease, alcoholic liver diseases or any other non-NASH&#xD;
             active liver disease.&#xD;
&#xD;
          2. Subjects with liver cirrhosis (of any cause) or laboratory or clinical signs of&#xD;
             functional liver failure&#xD;
&#xD;
          3. Clinically relevant abnormal laboratory values suggesting an undiagnosed disease other&#xD;
             than NASH requiring further clinical evaluation (as assessed by the Investigator).&#xD;
&#xD;
          4. The subject has active cancer or a history of a malignant disease (except basal cell&#xD;
             carcinoma) within 5 years prior to Screening or any history of bladder cancer.&#xD;
&#xD;
          5. Subject with a history of weight loss or weight gain of &gt;10 pounds within 6 months&#xD;
             prior to Screening.&#xD;
&#xD;
          6. Subject with a history of bariatric surgery within 5 years prior to Screening.&#xD;
&#xD;
          7. The subject has received any investigational compound within 30 days prior to&#xD;
             Screening or is currently participating in another clinical study.&#xD;
&#xD;
          8. The subject has a history of hypersensitivity or allergies to roflumilast or&#xD;
             pioglitazone including any associated excipients.&#xD;
&#xD;
          9. The subject is required to take excluded medications.&#xD;
&#xD;
         10. The subject has taken oral or injectable glucocorticoids for longer than 7 days within&#xD;
             3 months prior to Screening.&#xD;
&#xD;
         11. The subject has poorly controlled Type 1 or Type 2 diabetes mellitus with an HbA1c&#xD;
             ≥8.5 at Screening or per Investigator judgment.&#xD;
&#xD;
         12. The subject has hepatitis A, B or C.&#xD;
&#xD;
         13. The subject has severe immunological diseases (eg, known HIV infection, multiple&#xD;
             sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy) assessed&#xD;
             at Screening.&#xD;
&#xD;
         14. The subject had a history of diabetic gastroparesis or history of gastric bypass&#xD;
             surgery.&#xD;
&#xD;
         15. The subject had a history of coronary angioplasty, coronary stent placement, coronary&#xD;
             bypass surgery, or myocardial infarction within 6 months prior to Screening.&#xD;
&#xD;
         16. The subject had New York Heart Association heart failure of Class (II-IV) regardless&#xD;
             of therapy.&#xD;
&#xD;
         17. The subject had a diastolic blood pressure greater than 100 mm Hg or a systolic blood&#xD;
             pressure of greater than 160 mm Hg (The mean of the 3 serial BP measurements will be&#xD;
             used to determine subject eligibility).&#xD;
&#xD;
         18. The subject has presence or history of psychotic disorder that may be associated with&#xD;
             suicidal thinking, ideation or behavior. These disorders include, but are not limited&#xD;
             to, depression, psychosis, psychotic disorder, and schizophrenia. Subjects will be&#xD;
             monitored by Columbia-Suicide Severity Rating Scales throughout the duration of the&#xD;
             study.&#xD;
&#xD;
         19. The subject has a history of drug abuse (defined as illicit drug use) or a history of&#xD;
             alcohol abuse (defined as regular or daily consumption of more than 2 alcoholic drinks&#xD;
             per day for women or 3 alcoholic drinks per day for men. One drink is equivalent to a&#xD;
             12-ounce beer, a 4-ounce glass of wine, or a 1-ounce shot of hard liquor.) within 1&#xD;
             year prior to the Screening visit.&#xD;
&#xD;
         20. The subject has a hemoglobin &lt;120 g/L for men and &lt;100 g/L for women.&#xD;
&#xD;
         21. The subject has received pioglitazone or roflumilast in a previous clinical study or&#xD;
             as a therapeutic agent within 1 year prior to screening.&#xD;
&#xD;
         22. If female, the subject is pregnant or lactating or intending to become pregnant&#xD;
             before, during, or within 1 month after participating in this study; or intending to&#xD;
             donate ova during such time period.&#xD;
&#xD;
         23. The subject is an immediate family member, study site employee, or is in a dependent&#xD;
             relationship with a study site employee who is involved in conduct of this study (eg,&#xD;
             spouse, parent, child, sibling) or may consent under duress.&#xD;
&#xD;
         24. The subject has significant results from physical examinations or clinical laboratory&#xD;
             results that, at the discretion of the investigator, would make it difficult to&#xD;
             successfully manage and follow the subject according to the protocol.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>AstraZeneca AstraZeneca</last_name>
    <role>Study Director</role>
    <affiliation>AstraZeneca</affiliation>
  </overall_official>
  <location>
    <facility>
      <address>
        <city>Coronado</city>
        <state>California</state>
        <zip>92118</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Coronado</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Annapolis</city>
        <state>Maryland</state>
        <zip>21401</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2016</verification_date>
  <study_first_submitted>October 2, 2012</study_first_submitted>
  <study_first_submitted_qc>October 6, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 10, 2012</study_first_posted>
  <results_first_submitted>September 21, 2015</results_first_submitted>
  <results_first_submitted_qc>January 26, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">February 23, 2016</results_first_posted>
  <last_update_submitted>December 2, 2016</last_update_submitted>
  <last_update_submitted_qc>December 2, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 1, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Drug therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fatty Liver</mesh_term>
    <mesh_term>Non-alcoholic Fatty Liver Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pioglitazone</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants took part at 11 sites in the United States from 26 April 2013 to 30 September 2014.</recruitment_details>
      <pre_assignment_details>Participants with a historical diagnosis of nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) of greater than or equal to (&gt;=) 3 were enrolled in 1 of 3 treatment groups as follows: roflumilast + pioglitazone; roflumilast only; pioglitazone only.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Roflumilast + Pioglitazone</title>
          <description>Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.</description>
        </group>
        <group group_id="P2">
          <title>Roflumilast Only</title>
          <description>Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.</description>
        </group>
        <group group_id="P3">
          <title>Pioglitazone Only</title>
          <description>Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</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="6"/>
              </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="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <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="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Study Termination</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The randomized set included all participants who were randomized.</population>
      <group_list>
        <group group_id="B1">
          <title>Roflumilast + Pioglitazone</title>
          <description>Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.</description>
        </group>
        <group group_id="B2">
          <title>Roflumilast Only</title>
          <description>Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.</description>
        </group>
        <group group_id="B3">
          <title>Pioglitazone Only</title>
          <description>Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.</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="7"/>
            <count group_id="B2" value="7"/>
            <count group_id="B3" value="6"/>
            <count group_id="B4" value="20"/>
          </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="45.4" spread="9.64"/>
                    <measurement group_id="B2" value="43.9" spread="14.77"/>
                    <measurement group_id="B3" value="42.5" spread="8.67"/>
                    <measurement group_id="B4" value="44.0" spread="10.93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age, Customized</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>18 - 39 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>40 - 59 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>60 - 80 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Gender</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="5"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Hispanic or Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non-Hispanic or Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Multiracial</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Height</title>
          <units>centimeter (cm)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="165.6" spread="15.13"/>
                    <measurement group_id="B2" value="168.7" spread="8.62"/>
                    <measurement group_id="B3" value="174.3" spread="7.50"/>
                    <measurement group_id="B4" value="169.3" spread="11.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Weight</title>
          <units>kilogram (kg)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="102.19" spread="21.041"/>
                    <measurement group_id="B2" value="92.06" spread="20.784"/>
                    <measurement group_id="B3" value="110.15" spread="15.456"/>
                    <measurement group_id="B4" value="101.03" spread="19.887"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body Mass Index (BMI)</title>
          <units>kilogram per square meter(kg/m^2)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="37.18" spread="5.192"/>
                    <measurement group_id="B2" value="32.19" spread="6.189"/>
                    <measurement group_id="B3" value="36.60" spread="7.475"/>
                    <measurement group_id="B4" value="35.26" spread="6.381"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Smoking Classification</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Had Never Smoked</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Current Smoker</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ex-Smoker</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Type 2 Diabetes Mellitus</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Had Diabetes Mellitus</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Did Not Have Diabetes Mellitus</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Amount of Serum Alanine Transaminase (ALT) at Baseline</title>
        <time_frame>Baseline</time_frame>
        <population>Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline assessment available.</population>
        <group_list>
          <group group_id="O1">
            <title>Roflumilast + Pioglitazone</title>
            <description>Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.</description>
          </group>
          <group group_id="O2">
            <title>Roflumilast Only</title>
            <description>Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.</description>
          </group>
          <group group_id="O3">
            <title>Pioglitazone Only</title>
            <description>Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.</description>
          </group>
        </group_list>
        <measure>
          <title>Amount of Serum Alanine Transaminase (ALT) at Baseline</title>
          <population>Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline assessment available.</population>
          <units>international units per liter (IU/L)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="101.7" spread="56.98"/>
                    <measurement group_id="O2" value="83.4" spread="31.63"/>
                    <measurement group_id="O3" value="118.8" spread="36.76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percent Change From Baseline in Serum ALT at Month 4</title>
        <description>The percent change between the serum ALT value collected at Month 4 or final visit relative to baseline.</description>
        <time_frame>Month 4</time_frame>
        <population>Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline and at least 1 post-baseline assessment available.</population>
        <group_list>
          <group group_id="O1">
            <title>Roflumilast + Pioglitazone</title>
            <description>Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.</description>
          </group>
          <group group_id="O2">
            <title>Roflumilast Only</title>
            <description>Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.</description>
          </group>
          <group group_id="O3">
            <title>Pioglitazone Only</title>
            <description>Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change From Baseline in Serum ALT at Month 4</title>
          <description>The percent change between the serum ALT value collected at Month 4 or final visit relative to baseline.</description>
          <population>Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline and at least 1 post-baseline assessment available.</population>
          <units>percent change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-53.89" spread="23.362"/>
                    <measurement group_id="O2" value="-56.22" spread="6.014"/>
                    <measurement group_id="O3" value="-28.86" spread="53.298"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Amount of Serum Aspartate Transaminase (AST) at Baseline</title>
        <time_frame>Baseline</time_frame>
        <population>Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline assessment available.</population>
        <group_list>
          <group group_id="O1">
            <title>Roflumilast + Pioglitazone</title>
            <description>Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.</description>
          </group>
          <group group_id="O2">
            <title>Roflumilast Only</title>
            <description>Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.</description>
          </group>
          <group group_id="O3">
            <title>Pioglitazone Only</title>
            <description>Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.</description>
          </group>
        </group_list>
        <measure>
          <title>Amount of Serum Aspartate Transaminase (AST) at Baseline</title>
          <population>Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline assessment available.</population>
          <units>IU/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="64.0" spread="43.49"/>
                    <measurement group_id="O2" value="44.9" spread="15.25"/>
                    <measurement group_id="O3" value="88.3" spread="73.06"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Change From Baseline in Serum AST at Month 4</title>
        <description>The percent change between the serum AST value collected at Month 4 or final visit relative to baseline.</description>
        <time_frame>Month 4</time_frame>
        <population>Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline and at least 1 post-baseline assessment available.</population>
        <group_list>
          <group group_id="O1">
            <title>Roflumilast + Pioglitazone</title>
            <description>Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.</description>
          </group>
          <group group_id="O2">
            <title>Roflumilast Only</title>
            <description>Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.</description>
          </group>
          <group group_id="O3">
            <title>Pioglitazone Only</title>
            <description>Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change From Baseline in Serum AST at Month 4</title>
          <description>The percent change between the serum AST value collected at Month 4 or final visit relative to baseline.</description>
          <population>Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline and at least 1 post-baseline assessment available.</population>
          <units>percent change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-41.31" spread="36.087"/>
                    <measurement group_id="O2" value="-43.20" spread="7.339"/>
                    <measurement group_id="O3" value="-17.56" spread="45.458"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Liver Fat Content at Baseline</title>
        <description>Liver fat content was quantitatively measured by evaluating the percentage of proton density fat fraction (PDFF) from an abdominal magnetic resonance imaging (MRI). On the basis of Couinaud classification (a classification used to describe functional liver anatomy), the liver was divided into 8 segments: caudate, left superolateral, left inferolateral, left superomedial (4a), left inferomedial (4b), right anteroinferior, right posteroinferior, right posterosuperior and right anterosuperior.</description>
        <time_frame>Baseline</time_frame>
        <population>Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline assessment available.</population>
        <group_list>
          <group group_id="O1">
            <title>Roflumilast + Pioglitazone</title>
            <description>Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.</description>
          </group>
          <group group_id="O2">
            <title>Roflumilast Only</title>
            <description>Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.</description>
          </group>
          <group group_id="O3">
            <title>Pioglitazone Only</title>
            <description>Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.</description>
          </group>
        </group_list>
        <measure>
          <title>Liver Fat Content at Baseline</title>
          <description>Liver fat content was quantitatively measured by evaluating the percentage of proton density fat fraction (PDFF) from an abdominal magnetic resonance imaging (MRI). On the basis of Couinaud classification (a classification used to describe functional liver anatomy), the liver was divided into 8 segments: caudate, left superolateral, left inferolateral, left superomedial (4a), left inferomedial (4b), right anteroinferior, right posteroinferior, right posterosuperior and right anterosuperior.</description>
          <population>Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline assessment available.</population>
          <units>percentage of PDFF</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Caudate; (n= 6, 7, 6)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.233" spread="8.2750"/>
                    <measurement group_id="O2" value="19.107" spread="7.7990"/>
                    <measurement group_id="O3" value="20.117" spread="9.8492"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left superolateral; (n= 6, 6, 6)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.485" spread="8.8080"/>
                    <measurement group_id="O2" value="17.813" spread="7.4410"/>
                    <measurement group_id="O3" value="17.278" spread="7.2225"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left inferolateral; (n= 6, 7, 6)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.385" spread="8.9894"/>
                    <measurement group_id="O2" value="19.747" spread="7.8306"/>
                    <measurement group_id="O3" value="19.153" spread="10.5909"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left superomedial: (n= 6, 7, 6)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.115" spread="9.7126"/>
                    <measurement group_id="O2" value="20.426" spread="7.9170"/>
                    <measurement group_id="O3" value="20.100" spread="9.8688"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left inferomedial: (n= 6, 6, 6)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.553" spread="9.5912"/>
                    <measurement group_id="O2" value="18.977" spread="8.6970"/>
                    <measurement group_id="O3" value="21.530" spread="9.5193"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right anteroinferior: (n= 6, 7, 6)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.478" spread="9.0548"/>
                    <measurement group_id="O2" value="19.994" spread="9.0103"/>
                    <measurement group_id="O3" value="20.742" spread="8.7829"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right posteroinferior: (n= 6, 7, 6)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23.710" spread="8.6478"/>
                    <measurement group_id="O2" value="18.804" spread="6.6882"/>
                    <measurement group_id="O3" value="20.070" spread="9.9727"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right posterosuperior: (n= 6, 7, 6)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23.282" spread="9.5984"/>
                    <measurement group_id="O2" value="18.870" spread="7.5764"/>
                    <measurement group_id="O3" value="19.943" spread="8.9666"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right anterosuperior: (n=6, 7, 6)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23.630" spread="8.7454"/>
                    <measurement group_id="O2" value="19.786" spread="8.5929"/>
                    <measurement group_id="O3" value="21.527" spread="9.6648"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Liver Fat Content at Month 4</title>
        <description>Liver fat content was quantitatively measured by evaluating the percentage of PDFF from an abdominal MRI. On the basis of Couinaud classification (a classification used to describe functional liver anatomy), the liver was divided into 8 segments: caudate, left superolateral, left inferolateral, left superomedial (4a), left inferomedial (4b), right anteroinferior, right posteroinferior, right posterosuperior and right anterosuperior.</description>
        <time_frame>Baseline and Month 4</time_frame>
        <population>Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline and at least 1 post-baseline assessment available.</population>
        <group_list>
          <group group_id="O1">
            <title>Roflumilast + Pioglitazone</title>
            <description>Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.</description>
          </group>
          <group group_id="O2">
            <title>Roflumilast Only</title>
            <description>Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.</description>
          </group>
          <group group_id="O3">
            <title>Pioglitazone Only</title>
            <description>Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Liver Fat Content at Month 4</title>
          <description>Liver fat content was quantitatively measured by evaluating the percentage of PDFF from an abdominal MRI. On the basis of Couinaud classification (a classification used to describe functional liver anatomy), the liver was divided into 8 segments: caudate, left superolateral, left inferolateral, left superomedial (4a), left inferomedial (4b), right anteroinferior, right posteroinferior, right posterosuperior and right anterosuperior.</description>
          <population>Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline and at least 1 post-baseline assessment available.</population>
          <units>percent change in PDFF</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Caudate; (n= 3, 3, 3)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-18.787" spread="11.5646"/>
                    <measurement group_id="O2" value="-11.590" spread="5.5674"/>
                    <measurement group_id="O3" value="-10.287" spread="8.8098"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left superolateral; (n= 6, 6, 6)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-15.170" spread="13.7442"/>
                    <measurement group_id="O2" value="-10.287" spread="1.9695"/>
                    <measurement group_id="O3" value="-8.067" spread="7.6318"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left inferolateral; (n= 3, 3, 3)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-14.290" spread="13.1654"/>
                    <measurement group_id="O2" value="-10.077" spread="2.9030"/>
                    <measurement group_id="O3" value="-8.773" spread="7.0821"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left superomedial: (n= 3, 3, 3)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-14.687" spread="13.6909"/>
                    <measurement group_id="O2" value="-11.177" spread="3.9429"/>
                    <measurement group_id="O3" value="-9.217" spread="8.7999"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Left inferomedial: (n= 3, 3, 3)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-14.107" spread="15.2957"/>
                    <measurement group_id="O2" value="-10.977" spread="5.0052"/>
                    <measurement group_id="O3" value="-9.417" spread="8.9360"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right anteroinferior: (n= 3, 3, 3)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-13.990" spread="13.1266"/>
                    <measurement group_id="O2" value="-10.260" spread="6.9972"/>
                    <measurement group_id="O3" value="-7.693" spread="9.7985"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right posteroinferior: (n=3, 3, 3)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-18.073" spread="13.1470"/>
                    <measurement group_id="O2" value="-9.250" spread="1.6808"/>
                    <measurement group_id="O3" value="-8.790" spread="10.2188"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right posterosuperior: (n=3, 3, 3)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-17.717" spread="13.0691"/>
                    <measurement group_id="O2" value="-9.797" spread="4.4053"/>
                    <measurement group_id="O3" value="-8.113" spread="10.4166"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right anterosuperior: (n=3, 3, 3)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-16.127" spread="13.9820"/>
                    <measurement group_id="O2" value="-9.803" spread="3.3661"/>
                    <measurement group_id="O3" value="-8.647" spread="10.1658"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Treatment-emergent AEs will be defined as any AEs, regardless of relationship to study drug, that occur or worsen after the first dose of double-blinded study drug and no more than 30 days after the last dose of study drug.</time_frame>
      <desc>At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.</desc>
      <group_list>
        <group group_id="E1">
          <title>Roflumilast + Pioglitazone</title>
          <description>Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.</description>
        </group>
        <group group_id="E2">
          <title>Roflumilast Only</title>
          <description>Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.</description>
        </group>
        <group group_id="E3">
          <title>Pioglitazone Only</title>
          <description>Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.</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="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA (17.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Eructation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Liver function test abnormal</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Cow's milk intolerance</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Increased appetite</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Sciatica</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Rhinorrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="6"/>
              </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>The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>AstraZeneca Clinical Study Information Center</name_or_title>
      <organization>AstraZeneca</organization>
      <phone>1-877-240-9479</phone>
      <email>information.center@astrazeneca.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/NCT01703260
org study id: ROF-NASH_205
secondary id: U1111-1129-5051
nct id: NCT01703260
lead sponsor: 
has dmc: No
The purpose of this study is to evaluate the effect of roflumilast and pioglitazone therapy
      on serum transaminase (ALT) levels in adults with Nonalcoholic SteatoHepatitis.
This proof of concept study will evaluate the effect of roflumilast and pioglitazone on
      transaminase levels and liver fat content.

      Takeda has chosen not to continue this Study, however, randomized subjects were allowed to
      complete the study per protocol.

      The decision to terminate the study is not related to any safety concerns with either of the
      study medications.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Amount of Serum Alanine Transaminase (ALT) at Baseline
time frame: Baseline
measure: Percent Change From Baseline in Serum ALT at Month 4
time frame: Month 4
description: The percent change between the serum ALT value collected at Month 4 or final visit relative to baseline.
measure: Amount of Serum Aspartate Transaminase (AST) at Baseline
time frame: Baseline
measure: Percent Change From Baseline in Serum AST at Month 4
time frame: Month 4
description: The percent change between the serum AST value collected at Month 4 or final visit relative to baseline.
measure: Liver Fat Content at Baseline
time frame: Baseline
description: Liver fat content was quantitatively measured by evaluating the percentage of proton density fat fraction (PDFF) from an abdominal magnetic resonance imaging (MRI). On the basis of Couinaud classification (a classification used to describe functional liver anatomy), the liver was divided into 8 segments: caudate, left superolateral, left inferolateral, left superomedial (4a), left inferomedial (4b), right anteroinferior, right posteroinferior, right posterosuperior and right anterosuperior.
measure: Change From Baseline in Liver Fat Content at Month 4
time frame: Baseline and Month 4
description: Liver fat content was quantitatively measured by evaluating the percentage of PDFF from an abdominal MRI. On the basis of Couinaud classification (a classification used to describe functional liver anatomy), the liver was divided into 8 segments: caudate, left superolateral, left inferolateral, left superomedial (4a), left inferomedial (4b), right anteroinferior, right posteroinferior, right posterosuperior and right anterosuperior.
arm group label: Roflumilast + pioglitazone
arm group type: Experimental
description: Roflumilast dose and pioglitazone dose, orally for up to 4 months
arm group label: Roflumilast
arm group type: Experimental
description: Roflumilast dose and pioglitazone matching-placebo dose orally for up to 4 months.
arm group label: Pioglitazone
arm group type: Experimental
description: Pioglitazone dose, orally and roflumilast matching-placebo dose, orally for up to 4 months
intervention type: Drug
intervention name: Roflumilast
description: Roflumilast dose
arm group label: Roflumilast
arm group label: Roflumilast + pioglitazone
other name: Daxas, Daliresp
intervention type: Drug
intervention name: Pioglitazone
description: Pioglitazone dose
arm group label: Pioglitazone
arm group label: Roflumilast + pioglitazone
other name: Actos
intervention type: Drug
intervention name: Placebo
description: Pioglitazone placebo-matching dose
arm group label: Roflumilast
intervention type: Drug
intervention name: Placebo
description: Roflumilast placebo-matching dose
arm group label: Pioglitazone
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: AstraZeneca AstraZeneca
role: Study Director
affiliation: AstraZeneca
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
mesh term: Pioglitazone
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 