<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/NCT03836677</url>
  </required_header>
  <id_info>
    <org_study_id>D5980C00019</org_study_id>
    <nct_id>NCT03836677</nct_id>
  </id_info>
  <brief_title>A Study to Evaluate the Effects of BGF and GFF on Specific Image Based Airway Volumes and Resistance in Subjects With Moderate to Severe COPD</brief_title>
  <official_title>A Randomized, Double-blind, Two Treatment, Two Period, Chronic Dosing (4 Weeks), Crossover, Multi-center Pilot Study to Evaluate the Effects of Budesonide/Glycopyrronium/Formoterol Fumarate and Glycopyrronium/Formoterol Fumarate on Specific Image Based Airway Volumes and Resistance in Subjects With Moderate to Severe COPD</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>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomised, controlled, two period cross-over, 4 weeks chronic dosing, study to&#xD;
      evaluate the effects of Budesonide/Glycopyrronium/Formoterol Fumarate (BGF) and&#xD;
      Glycopyrronium/Formoterol Fumarate (GFF) on airway dimensions.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a randomised, controlled, two period cross-over, 4 weeks chronic dosing, study to&#xD;
      evaluate the effects of Budesonide/Glycopyrronium/Formoterol Fumarate (BGF), and&#xD;
      Glycopyrronium/Formoterol Fumarate (GFF), on specific image based airway volumes and&#xD;
      resistance in subjects with moderate to severe Chronic Obstructive Pulmonary Disease. In this&#xD;
      study, airway dimension parameters will be calculated for each of the active compounds.&#xD;
&#xD;
      This imaging methodology will allow an assessment of the extent of airway changes using a&#xD;
      triple combination of Budesonide/Glycopyrronium/Formoterol Fumarate (BGF) and the dual&#xD;
      combination Glycopyrronium/Formoterol Fumarate (GFF).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 26, 2019</start_date>
  <completion_date type="Actual">November 11, 2019</completion_date>
  <primary_completion_date type="Actual">November 11, 2019</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Specific Image-based Airway Volume (siVaw)</measure>
    <time_frame>Baseline, Day 29</time_frame>
    <description>Specific image-based airway volume (SiVaw) measured in mL/L. Average across lobes, adjusted for lobe volume. Reported as ratio to baseline.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Specific Image-based Airway Resistance (siRaw)</measure>
    <time_frame>Baseline, Day 29</time_frame>
    <description>Specific image-based airway resistance (siRaw) measured in kPa∙s. Average across lobes, adjusted for lobe volume. Reported as ratio to baseline.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Image-based Airway Volume (iVaw)</measure>
    <time_frame>Baseline, Day 29</time_frame>
    <description>Image-based Airway Volume (iVaw) measured in mL. Average across lobes, without adjustment for lobe volume. Reported as ratio to baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Image-based Airway Resistance (iRaw)</measure>
    <time_frame>Baseline, 29 Days</time_frame>
    <description>Image-based airway resistance (iRaw) measured in kPa∙s/L. Average across lobes, without adjustment for lobe volume. Reported as ratio to baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forced Expiratory Volume in One Second (Post-dose FEV1).</measure>
    <time_frame>Baseline 29 Days</time_frame>
    <description>Change from baseline in Forced Expiratory Volume in One Second (Post-dose FEV1).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional Residual Capacity (FRC)</measure>
    <time_frame>Baseline, Day 29</time_frame>
    <description>Change from baseline in Functional residual capacity (FRC).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">23</enrollment>
  <condition>Chronic Obstructive Pulmonary Disease (COPD)</condition>
  <arm_group>
    <arm_group_label>BGF-GFF</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject first treated with Budesonide/Glycopyrronium/Formoterol Fumarate followed by a washout period then treated with Glycopyrronium/Formoterol Fumarate</description>
  </arm_group>
  <arm_group>
    <arm_group_label>GFF-BGF</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject first treated with Glycopyrronium/Formoterol Fumarate followed by a washout period then treated with Budesonide/Glycopyrronium/Formoterol Fumarate</description>
  </arm_group>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>BGF</intervention_name>
    <description>Treatment with Budesonide/Glycopyrronium/FormoterolFumarate</description>
    <arm_group_label>BGF-GFF</arm_group_label>
    <arm_group_label>GFF-BGF</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>GFF</intervention_name>
    <description>Treatment with Glycopyrronium/Formoterol Fumarate</description>
    <arm_group_label>BGF-GFF</arm_group_label>
    <arm_group_label>GFF-BGF</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Subject must be 40 years to ≤80 years of age inclusive, at the time of signing the informed&#xD;
        consent form at Visit 1.&#xD;
&#xD;
          -  COPD Diagnosis: Subjects with an established clinical history of COPD&#xD;
&#xD;
          -  Screening clinical laboratory tests must be acceptable to the Investigator.&#xD;
&#xD;
          -  Screening ECG must be acceptable to the Investigator&#xD;
&#xD;
          -  Individual Compliance: Subjects must be willing to remain at the study center as&#xD;
             required per protocol to complete all visit assessments&#xD;
&#xD;
          -  Patients should be on scheduled maintenance treatment with one or more inhaled&#xD;
             bronchodilator therapies.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  As judged by the investigator, any evidence of significant diseases other than COPD,&#xD;
             i.e., disease or condition which, in the investigator's opinion makes it undesirable&#xD;
             for the subject to participate in the trial.&#xD;
&#xD;
          -  Spirometry Performance:&#xD;
&#xD;
               1. Subjects who cannot perform acceptable spirometry, i.e., meet ATS/ERS&#xD;
                  acceptability criteria.&#xD;
&#xD;
               2. Repeatability: Subjects who cannot perform technically acceptable spirometry in&#xD;
                  accordance with ATS repeatability criteria&#xD;
&#xD;
          -  Cancer: Subjects who have cancer that has not been in complete remission for at least&#xD;
             five years.&#xD;
&#xD;
          -  Substance Abuse: Subjects, who in the opinion of the Investigator, significantly abuse&#xD;
             alcohol or drugs&#xD;
&#xD;
          -  Subjects who in the opinion of the investigator are unable to abstain from prohibited&#xD;
             medications including LABA/LAMAs/ICS&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Erpent</city>
        <zip>5101</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Eindhoven</city>
        <zip>5623 EJ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Groningen</city>
        <zip>9713 GZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Zutphen</city>
        <zip>7207 AE</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Netherlands</country>
  </location_countries>
  <link>
    <url>https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&amp;amp;parentIdentifier=D5980C00019&amp;amp;attachmentIdentifier=a5d5dc54-7197-4031-9e83-0480baeaa3f2&amp;amp;fileName=d5980c00019-sap-ed-2_Redacted.pdf&amp;amp;versionIdentifier=</url>
    <description>Statistical Analysis Plan (SAP)</description>
  </link>
  <link>
    <url>https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&amp;amp;parentIdentifier=D5980C00019&amp;amp;attachmentIdentifier=603a22eb-76ce-4e33-af2d-84d7b45e7bb8&amp;amp;fileName=d5980c00019-csp-v3_Redacted-v1.pdf&amp;amp;versionIdentifier=</url>
    <description>CSP</description>
  </link>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>September 24, 2018</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 11, 2019</study_first_posted>
  <results_first_submitted>November 10, 2020</results_first_submitted>
  <results_first_submitted_qc>January 25, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">February 11, 2021</results_first_posted>
  <last_update_submitted>January 25, 2021</last_update_submitted>
  <last_update_submitted_qc>January 25, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 11, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>COPD</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
  </condition_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>July 5, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/77/NCT03836677/Prot_001.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>August 26, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/77/NCT03836677/SAP_002.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This study randomized 23 subjects at 4 study centers (1 center in Belgium and 3 centers in the Netherlands) from Feb 2019 to Nov 2019.</recruitment_details>
      <pre_assignment_details>Subjects were randomized into 1 of 2 treatment sequences. Sequence 1 received BGF MDI in Period 1 followed by GFF MDI in Period 2. Sequence 2 received GFF MDI in Period 1 followed by BGF MDI in Period 2.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>BGF MDI/GFF MDI</title>
          <description>Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation followed by Washout and then Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
        </group>
        <group group_id="P2">
          <title>GFF MDI/BGF MDI</title>
          <description>Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation followed by Washout and then Budesonide/Glycopyrronium/Formoterol Metered Dose Inhalation</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Period 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Washout</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Period 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Severe non-compliance to protocol</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>ITT Population - all subjects who were randomized to treatment.</population>
      <group_list>
        <group group_id="B1">
          <title>Overall Study</title>
          <description>ITT Population</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="23"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <description>ITT Population</description>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="64.9" spread="7.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <description>ITT Population</description>
          <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_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <description>ITT Population</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Specific Image-based Airway Volume (siVaw)</title>
        <description>Specific image-based airway volume (SiVaw) measured in mL/L. Average across lobes, adjusted for lobe volume. Reported as ratio to baseline.</description>
        <time_frame>Baseline, Day 29</time_frame>
        <population>ITT Population</population>
        <group_list>
          <group group_id="O1">
            <title>BGF MDI</title>
            <description>Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
          </group>
          <group group_id="O2">
            <title>GFF MDI</title>
            <description>Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
          </group>
        </group_list>
        <measure>
          <title>Specific Image-based Airway Volume (siVaw)</title>
          <description>Specific image-based airway volume (SiVaw) measured in mL/L. Average across lobes, adjusted for lobe volume. Reported as ratio to baseline.</description>
          <population>ITT Population</population>
          <units>Ratio to baseline</units>
          <param>Geometric Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.72" lower_limit="1.38" upper_limit="2.13"/>
                    <measurement group_id="O2" value="1.53" lower_limit="1.28" upper_limit="1.83"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>Statistical significance assessed using Hochberg's procedure applied across primary endpoints within each treatment.</p_value_desc>
            <method>t-test, 2 sided</method>
            <method_desc>Within-group comparison to baseline using paired test</method_desc>
            <param_type>Geometric Mean ratio to baseline</param_type>
            <param_value>1.72</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.38</ci_lower_limit>
            <ci_upper_limit>2.13</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>Statistical significance assessed using Hochberg's procedure applied across primary endpoints within each treatment.</p_value_desc>
            <method>t-test, 2 sided</method>
            <method_desc>Within-group comparison to baseline using paired test.</method_desc>
            <param_type>Geometric mean ratio to baseline</param_type>
            <param_value>1.53</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.28</ci_lower_limit>
            <ci_upper_limit>1.83</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Specific Image-based Airway Resistance (siRaw)</title>
        <description>Specific image-based airway resistance (siRaw) measured in kPa∙s. Average across lobes, adjusted for lobe volume. Reported as ratio to baseline.</description>
        <time_frame>Baseline, Day 29</time_frame>
        <population>ITT Population</population>
        <group_list>
          <group group_id="O1">
            <title>BGF MDI</title>
            <description>Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
          </group>
          <group group_id="O2">
            <title>GFF MDI</title>
            <description>Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
          </group>
        </group_list>
        <measure>
          <title>Specific Image-based Airway Resistance (siRaw)</title>
          <description>Specific image-based airway resistance (siRaw) measured in kPa∙s. Average across lobes, adjusted for lobe volume. Reported as ratio to baseline.</description>
          <population>ITT Population</population>
          <units>Ratio to baseline</units>
          <param>Geometric Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.50" lower_limit="0.39" upper_limit="0.63"/>
                    <measurement group_id="O2" value="0.52" lower_limit="0.40" upper_limit="0.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>Statistical significance assessed using Hochberg's procedure applied across primary endpoints within each treatment.</p_value_desc>
            <method>t-test, 2 sided</method>
            <method_desc>Within-group comparison to baseline using paired test</method_desc>
            <param_type>Geometric mean ratio to baseline</param_type>
            <param_value>0.50</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.39</ci_lower_limit>
            <ci_upper_limit>0.63</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>Statistical significance assessed using Hochberg's procedure applied across primary endpoints within each treatment.</p_value_desc>
            <method>t-test, 2 sided</method>
            <method_desc>Within-group comparison to baseline using paired test</method_desc>
            <param_type>Geometric mean ratio to baseline</param_type>
            <param_value>0.52</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.40</ci_lower_limit>
            <ci_upper_limit>0.67</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Image-based Airway Volume (iVaw)</title>
        <description>Image-based Airway Volume (iVaw) measured in mL. Average across lobes, without adjustment for lobe volume. Reported as ratio to baseline.</description>
        <time_frame>Baseline, Day 29</time_frame>
        <population>ITT Population</population>
        <group_list>
          <group group_id="O1">
            <title>BGF MDI</title>
            <description>Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
          </group>
          <group group_id="O2">
            <title>GFF MDI</title>
            <description>Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
          </group>
        </group_list>
        <measure>
          <title>Image-based Airway Volume (iVaw)</title>
          <description>Image-based Airway Volume (iVaw) measured in mL. Average across lobes, without adjustment for lobe volume. Reported as ratio to baseline.</description>
          <population>ITT Population</population>
          <units>Ratio to baseline</units>
          <param>Geometric Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.70" lower_limit="1.37" upper_limit="2.11"/>
                    <measurement group_id="O2" value="1.51" lower_limit="1.26" upper_limit="1.80"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>Within-group comparison to baseline using paired test</method_desc>
            <param_type>Geometric mean ratio to baseline</param_type>
            <param_value>1.70</param_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>1.37</ci_lower_limit>
            <ci_upper_limit>2.11</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0001</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>Within-group comparison to baseline using paired test</method_desc>
            <param_type>Geometric mean ratio to baseline</param_type>
            <param_value>1.51</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.26</ci_lower_limit>
            <ci_upper_limit>1.80</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Image-based Airway Resistance (iRaw)</title>
        <description>Image-based airway resistance (iRaw) measured in kPa∙s/L. Average across lobes, without adjustment for lobe volume. Reported as ratio to baseline.</description>
        <time_frame>Baseline, 29 Days</time_frame>
        <population>ITT Population</population>
        <group_list>
          <group group_id="O1">
            <title>BGF MDI</title>
            <description>Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
          </group>
          <group group_id="O2">
            <title>GFF MDI</title>
            <description>Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
          </group>
        </group_list>
        <measure>
          <title>Image-based Airway Resistance (iRaw)</title>
          <description>Image-based airway resistance (iRaw) measured in kPa∙s/L. Average across lobes, without adjustment for lobe volume. Reported as ratio to baseline.</description>
          <population>ITT Population</population>
          <units>Ratio to baseline</units>
          <param>Geometric Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.50" lower_limit="0.40" upper_limit="0.63"/>
                    <measurement group_id="O2" value="0.52" lower_limit="0.40" upper_limit="0.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>Within-group comparison to baseline using paired test</method_desc>
            <param_type>Geometric mean ratio to baseline</param_type>
            <param_value>0.50</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.40</ci_lower_limit>
            <ci_upper_limit>0.63</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>Within-group comparison to baseline using paired test</method_desc>
            <param_type>Geometric mean ratio to baseline</param_type>
            <param_value>0.52</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.40</ci_lower_limit>
            <ci_upper_limit>0.68</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Forced Expiratory Volume in One Second (Post-dose FEV1).</title>
        <description>Change from baseline in Forced Expiratory Volume in One Second (Post-dose FEV1).</description>
        <time_frame>Baseline 29 Days</time_frame>
        <population>ITT Population</population>
        <group_list>
          <group group_id="O1">
            <title>BGF MDI</title>
            <description>Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
          </group>
          <group group_id="O2">
            <title>GFF MDI</title>
            <description>Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
          </group>
        </group_list>
        <measure>
          <title>Forced Expiratory Volume in One Second (Post-dose FEV1).</title>
          <description>Change from baseline in Forced Expiratory Volume in One Second (Post-dose FEV1).</description>
          <population>ITT Population</population>
          <units>L</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.346" lower_limit="0.182" upper_limit="0.509"/>
                    <measurement group_id="O2" value="0.273" lower_limit="0.140" upper_limit="0.405"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0003</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>Within-group comparison to baseline using paired test.</method_desc>
            <param_type>Mean Change from Baseline</param_type>
            <param_value>0.346</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.182</ci_lower_limit>
            <ci_upper_limit>0.509</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0004</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>Within-group comparison to baseline using paired test.</method_desc>
            <param_type>Mean Change from Baseline</param_type>
            <param_value>0.273</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.140</ci_lower_limit>
            <ci_upper_limit>0.405</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Functional Residual Capacity (FRC)</title>
        <description>Change from baseline in Functional residual capacity (FRC).</description>
        <time_frame>Baseline, Day 29</time_frame>
        <population>ITT Population</population>
        <group_list>
          <group group_id="O1">
            <title>BGF MDI</title>
            <description>Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
          </group>
          <group group_id="O2">
            <title>GFF MDI</title>
            <description>Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
          </group>
        </group_list>
        <measure>
          <title>Functional Residual Capacity (FRC)</title>
          <description>Change from baseline in Functional residual capacity (FRC).</description>
          <population>ITT Population</population>
          <units>L</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="22"/>
                <count group_id="O2" value="21"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.28" lower_limit="-0.77" upper_limit="0.21"/>
                    <measurement group_id="O2" value="-0.50" lower_limit="-0.81" upper_limit="-0.18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.2515</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>Within-group comparison to baseline using paired test.</method_desc>
            <param_type>Mean ratio to baseline</param_type>
            <param_value>-0.28</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.77</ci_lower_limit>
            <ci_upper_limit>0.21</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0040</p_value>
            <method>t-test, 2 sided</method>
            <method_desc>Within-group comparison to baseline using paired test.</method_desc>
            <param_type>Mean ratio to baseline</param_type>
            <param_value>-0.50</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.81</ci_lower_limit>
            <ci_upper_limit>-0.18</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected from visit 2 throughout the treatment period and including the follow-up period telephone call.</time_frame>
      <desc>The Safety Population was defined as all subjects who were randomized to treatment and received at least one dose of study treatment. Serious adverse events were collected visit 2 throughout the treatment period and including the follow-up period telephone call.</desc>
      <group_list>
        <group group_id="E1">
          <title>BGF MDI</title>
          <description>Budoesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
        </group>
        <group group_id="E2">
          <title>GFF MDI</title>
          <description>Glycopyrronium/Formoterol Fumarate Metered Dose Inhalation</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Colon cancer</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <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="22"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="23"/>
              </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 only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>AstraZeneca AB</name_or_title>
      <organization>AstraZeneca AB</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/NCT03836677
org study id: D5980C00019
nct id: NCT03836677
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This is a randomised, controlled, two period cross-over, 4 weeks chronic dosing, study to
      evaluate the effects of Budesonide/Glycopyrronium/Formoterol Fumarate (BGF) and
      Glycopyrronium/Formoterol Fumarate (GFF) on airway dimensions.
This is a randomised, controlled, two period cross-over, 4 weeks chronic dosing, study to
      evaluate the effects of Budesonide/Glycopyrronium/Formoterol Fumarate (BGF), and
      Glycopyrronium/Formoterol Fumarate (GFF), on specific image based airway volumes and
      resistance in subjects with moderate to severe Chronic Obstructive Pulmonary Disease. In this
      study, airway dimension parameters will be calculated for each of the active compounds.

      This imaging methodology will allow an assessment of the extent of airway changes using a
      triple combination of Budesonide/Glycopyrronium/Formoterol Fumarate (BGF) and the dual
      combination Glycopyrronium/Formoterol Fumarate (GFF).
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Specific Image-based Airway Volume (siVaw)
time frame: Baseline, Day 29
description: Specific image-based airway volume (SiVaw) measured in mL/L. Average across lobes, adjusted for lobe volume. Reported as ratio to baseline.
measure: Specific Image-based Airway Resistance (siRaw)
time frame: Baseline, Day 29
description: Specific image-based airway resistance (siRaw) measured in kPa∙s. Average across lobes, adjusted for lobe volume. Reported as ratio to baseline.
measure: Image-based Airway Volume (iVaw)
time frame: Baseline, Day 29
description: Image-based Airway Volume (iVaw) measured in mL. Average across lobes, without adjustment for lobe volume. Reported as ratio to baseline.
measure: Image-based Airway Resistance (iRaw)
time frame: Baseline, 29 Days
description: Image-based airway resistance (iRaw) measured in kPa∙s/L. Average across lobes, without adjustment for lobe volume. Reported as ratio to baseline.
measure: Forced Expiratory Volume in One Second (Post-dose FEV1).
time frame: Baseline 29 Days
description: Change from baseline in Forced Expiratory Volume in One Second (Post-dose FEV1).
measure: Functional Residual Capacity (FRC)
time frame: Baseline, Day 29
description: Change from baseline in Functional residual capacity (FRC).
arm group label: BGF-GFF
arm group type: Experimental
description: Subject first treated with Budesonide/Glycopyrronium/Formoterol Fumarate followed by a washout period then treated with Glycopyrronium/Formoterol Fumarate
arm group label: GFF-BGF
arm group type: Experimental
description: Subject first treated with Glycopyrronium/Formoterol Fumarate followed by a washout period then treated with Budesonide/Glycopyrronium/Formoterol Fumarate
intervention type: Combination Product
intervention name: BGF
description: Treatment with Budesonide/Glycopyrronium/FormoterolFumarate
arm group label: BGF-GFF
arm group label: GFF-BGF
intervention type: Combination Product
intervention name: GFF
description: Treatment with Glycopyrronium/Formoterol Fumarate
arm group label: BGF-GFF
arm group label: GFF-BGF
criteria: 
gender: All
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
country: Belgium
country: Netherlands
url: https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&amp;parentIdentifier=D5980C00019&amp;attachmentIdentifier=a5d5dc54-7197-4031-9e83-0480baeaa3f2&amp;fileName=d5980c00019-sap-ed-2_Redacted.pdf&amp;versionIdentifier=
description: Statistical Analysis Plan (SAP)
url: https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&amp;parentIdentifier=D5980C00019&amp;attachmentIdentifier=603a22eb-76ce-4e33-af2d-84d7b45e7bb8&amp;fileName=d5980c00019-csp-v3_Redacted-v1.pdf&amp;versionIdentifier=
description: CSP
responsible party type: Sponsor
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 