<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/NCT01691482</url>
  </required_header>
  <id_info>
    <org_study_id>114956</org_study_id>
    <nct_id>NCT01691482</nct_id>
  </id_info>
  <brief_title>A Study to Look at Day to Day Changes in Lung Function in COPD Subjects Taking Albuterol/Salbutamol and Ipratropium</brief_title>
  <official_title>A 4-Week Randomized Cross-Over Study to Evaluate Daily Lung Function Following the Administration of Albuterol/Salbutamol and Ipratropium in Subjects With Chronic Obstructive Pulmonary Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>GlaxoSmithKline</source>
  <brief_summary>
    <textblock>
      The objective of this study is to assess the daily variation in bronchodilator response to an&#xD;
      inhaled short acting beta2-agonist (albuterol/salbutamol) and an inhaled short acting&#xD;
      anticholinergic (ipratropium) individually and when used in combination in subjects with&#xD;
      COPD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Beta2-agonist and anticholinergics are a principle component of the pharmacologic management&#xD;
      of chronic obstructive pulmonary disease COPD. It has been demonstrated that the combination&#xD;
      of a short acting beta2-agonist and a short acting anticholinergic yields greater efficacy as&#xD;
      measured by FEV1 when compared with the response to the individual short acting&#xD;
      bronchodilators. However, daily bronchial response to these agents is poorly understood. It&#xD;
      is also poorly understood how the variation in magnitude of the response to the individual&#xD;
      agents and how the variation in response for one agent coincides with the variation in&#xD;
      response to the other agent. This study will seek to define the pattern of response of each&#xD;
      individual agent and the relationship between them. The study will also explore if the&#xD;
      combination of the two agents leads to less variation in response compared to the individual&#xD;
      agents. This is a randomized, open label, two period cross-over study. Eligible subjects will&#xD;
      be randomized to a sequence of either albuterol/salbutamol via metered-dose inhaler (MDI)&#xD;
      followed by ipratropium via MDI or the same dose of each bronchodilator given in the opposite&#xD;
      order. Each study period will consist of 10 clinic visits to be conducted over 10 to 14 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>July 23, 2012</start_date>
  <completion_date type="Actual">October 22, 2012</completion_date>
  <primary_completion_date type="Actual">October 1, 2012</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Variability in Daily FEV1, Estimated by Coefficient of Variation</measure>
    <time_frame>up to 10 days</time_frame>
    <description>FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily FEV1 was measured as the fluctuation around the mean FEV1 data collected from Day 1 to Day 10. Variability was measured by the coefficient of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is the difference between the maximum and minimum FEV1 values.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values)</measure>
    <time_frame>up to 10 days</time_frame>
    <description>FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily FEV1 was measured as the fluctuation around the mean FEV1 data collected from Day 1 to Day 10. Variability was measured by the coefficient of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is half the difference between the maximum and minimum FEV1 values.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The Maximal Bronchodilator Response for the First Administered Agent</measure>
    <time_frame>up to 10 days</time_frame>
    <description>The maximal bronchodilator response for the first administered agent is defined as the FEV1 (the maximal amount of air that can be forcefully exhaled in one second) 1 hour post-dose of the first bronchodilator minus the pre-dose. The maximal bronchodilator response for the second agent is defined as the FEV1 1 hour post-dose of the second bronchodilator minus the FEV1 at 1 hour post-dose of the first bronchodilator. The maximal bronchodilator response for the combination is defined as the FEV1 (the maximal amount of air that can be forcefully exhaled in one second) at 1 hour post-administration of the second bronchodilator minus the corresponding pre-dose FEV1. Derived FEV1 response is FEV1 change from 0 hours (0H) for the first agent assessment (at 1 hour [1H]); change from 1H for the second agent assessment (at 2 hours [2H]); and change from 0H for the combination assessment (at 2H). Data were adjusted for FEV1, smoking status, and center.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Days for Which Participants Achieved a &gt;=12% and 200 Milliliter (mL) Increase From Baseline in FEV1</measure>
    <time_frame>up to 35 days</time_frame>
    <description>FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL</measure>
    <time_frame>up to 35 days</time_frame>
    <description>FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation</measure>
    <time_frame>up to 10 days</time_frame>
    <description>IC is the the total amount of air that can be drawn into the lungs after normal expiration. During each study period, pre- and post-bronchodilator spirometry for evaluation of IC was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily IC was measured as the fluctuation around the mean IC data collected from Day 1 to Day 10. Variability was measured by the coefficent of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is the difference between the maximum and minimum IC values.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum)</measure>
    <time_frame>up to 10 days</time_frame>
    <description>IC is the the total amount of air that can be drawn into the lungs after normal expiration. During each study period, pre- and post-bronchodilator spirometry for evaluation of IC was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily IC was measured as the fluctuation around the mean IC data collected from Day 1 to Day 10. Variability was measured by the coefficent of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is half the difference between the maximum and minimum IC values.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">56</enrollment>
  <condition>Pulmonary Disease, Chronic Obstructive</condition>
  <arm_group>
    <arm_group_label>Albuterol/salbutamol followed by ipratropium</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects will recieve daily albuterol/salbutamol followed by ipratropium which will be adminstered one hour after adminstration of albuterol/salbutamol</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ipratropium followed by albuterol/salbutamol</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects will recieve daily ipratropium followed by albuterol/salbutamol which will be adminstered one hour after adminstration of ipratropium</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Albuterol/salbutamol</intervention_name>
    <description>Albuterol/salbutamol (daily)</description>
    <arm_group_label>Albuterol/salbutamol followed by ipratropium</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipratropium</intervention_name>
    <description>Ipratropium (daily)</description>
    <arm_group_label>Ipratropium followed by albuterol/salbutamol</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects must give their signed and dated written informed consent to participate.&#xD;
&#xD;
          -  Subjects 40 years of age or older at Visit 1.&#xD;
&#xD;
          -  Male or female subjects .&#xD;
&#xD;
          -  An established clinical history of COPD.&#xD;
&#xD;
          -  Current or former cigarette smokers with a history of cigarette smoking of &gt;=10&#xD;
             pack-years at Visit 1.&#xD;
&#xD;
          -  A post-albuterol/salbutamol FEV1/FVC ratio of &lt;0.70 and a post-albuterol/salbutamol&#xD;
             FEV1 of &gt;=30 and &lt;= 70% of predicted normal values at Visit 1 calculated using NHANES&#xD;
             III reference equations .&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A current diagnosis of asthma&#xD;
&#xD;
          -  Women who are pregnant of lactating or are planning on becoming pregnant during the&#xD;
             study.&#xD;
&#xD;
          -  Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1.&#xD;
&#xD;
          -  Participation in pulmonary rehabilitation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>GSK Clinical Trials</last_name>
    <role>Study Director</role>
    <affiliation>GlaxoSmithKline</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Spartanburg</city>
        <state>South Carolina</state>
        <zip>29303</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Manchester</city>
        <zip>M23 9LT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.clinicalstudydatarequest.com</url>
    <description>Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.</description>
  </link>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>September 20, 2012</study_first_submitted>
  <study_first_submitted_qc>September 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 24, 2012</study_first_posted>
  <results_first_submitted>June 12, 2013</results_first_submitted>
  <results_first_submitted_qc>November 7, 2013</results_first_submitted_qc>
  <results_first_posted type="Estimate">December 25, 2013</results_first_posted>
  <last_update_submitted>June 18, 2018</last_update_submitted>
  <last_update_submitted_qc>June 18, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 20, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Albuterol</mesh_term>
    <mesh_term>Ipratropium</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.</ipd_description>
  </patient_data>
  <study_docs>
    <study_doc>
      <doc_id>114956</doc_id>
      <doc_type>Statistical Analysis Plan</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
    <study_doc>
      <doc_id>114956</doc_id>
      <doc_type>Dataset Specification</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
    <study_doc>
      <doc_id>114956</doc_id>
      <doc_type>Clinical Study Report</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
    <study_doc>
      <doc_id>114956</doc_id>
      <doc_type>Annotated Case Report Form</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
    <study_doc>
      <doc_id>114956</doc_id>
      <doc_type>Informed Consent Form</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
    <study_doc>
      <doc_id>114956</doc_id>
      <doc_type>Study Protocol</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
    <study_doc>
      <doc_id>114956</doc_id>
      <doc_type>Individual Participant Data Set</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
  </study_docs>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>This was a randomized, open-label, two-period cross-over study to evaluate the daily bronchodilator response to albuterol/salbutamol and ipratropium individually and in combination in participants with chronic obstructive pulmonary disease.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>A/S Then Ipratropium in TP1; Ipratropium Then A/S in TP2</title>
          <description>Participants received albuterol (4 puffs; 90 micrograms [µg] per puff)/salbutamol (A/S) (4 puffs; 100 µg per puff) followed by ipratropium (4 puffs; 20 µg per puff) via a metered-dose inhaler (MDI) during treatment period 1 (TP1) then, ipratropium followed by A/S at the same doses via an MDI in treatment period 2 (TP2).</description>
        </group>
        <group group_id="P2">
          <title>Ipratropium Then A/S in TP1; A/S Then Ipratropium in TP2</title>
          <description>Participants received Ipratropium (4 puffs; 20 µg per puff) followed by albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) (A/S) via a MDI in TP1, then A/S followed by ipratropium at the same doses via an MDI in TP2.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Treatment Period 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="28"/>
                <participants group_id="P2" count="28"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="28"/>
                <participants group_id="P2" count="28"/>
              </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>Treatment Period 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="28"/>
                <participants group_id="P2" count="28"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="27"/>
                <participants group_id="P2" count="26"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
              </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>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>All Randomized Participants</title>
          <description>All participants randomized to receive a sequence of either salbutamol (4 puffs; 100 µg per puff) via an MDI and albuterol (4 puffs; 90 µg per puff) followed by ipratropium (4 puffs; 20 µg per puff) via an MDI in TP1 and the same dose of each bronchodilator given in the opposite order in TP2, or ipratropium followed by albuterol/salbutamol in TP1 and the same dose of each bronchodilator given in the opposite order in TP2</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="56"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="60.3" spread="7.42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="35"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                  </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>African American/African Heritage</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Variability in Daily FEV1, Estimated by Coefficient of Variation</title>
        <description>FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily FEV1 was measured as the fluctuation around the mean FEV1 data collected from Day 1 to Day 10. Variability was measured by the coefficient of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is the difference between the maximum and minimum FEV1 values.</description>
        <time_frame>up to 10 days</time_frame>
        <population>Efficacy Population: participants in the Intent-to-Treat Population (all participants who were randomized and received at least one bronchodilator in the treatment period) who completed pre- and post- bronchodilator assessments for at least 17 visits, with no more than 3 consecutive missing days</population>
        <group_list>
          <group group_id="O1">
            <title>Albuterol/Salbutamol Followed by Ipratropium</title>
            <description>All participants randomized to receive a sequence of albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) via an MDI followed by ipratropium (4 puffs; 20 µg per puff) via an MDI in either TP1 or TP2.</description>
          </group>
          <group group_id="O2">
            <title>Ipratropium Followed by Albuterol/Salbutamol</title>
            <description>All participants randomized to receive a sequence of ipratropium (4 puffs; 20 µg per puff) via an MDI followed by albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) via an MDI in either TP1 or TP2</description>
          </group>
        </group_list>
        <measure>
          <title>Variability in Daily FEV1, Estimated by Coefficient of Variation</title>
          <description>FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily FEV1 was measured as the fluctuation around the mean FEV1 data collected from Day 1 to Day 10. Variability was measured by the coefficient of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is the difference between the maximum and minimum FEV1 values.</description>
          <population>Efficacy Population: participants in the Intent-to-Treat Population (all participants who were randomized and received at least one bronchodilator in the treatment period) who completed pre- and post- bronchodilator assessments for at least 17 visits, with no more than 3 consecutive missing days</population>
          <units>Liters</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="55"/>
                <count group_id="O2" value="55"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Pre-dose/non-bronchodilator</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.081" spread="0.0394"/>
                    <measurement group_id="O2" value="0.079" spread="0.0372"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Albuterol/Salbutamol (A/S) alone, 1 hour</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.059" spread="0.0276"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium as the first bronchodilator; thus, data were not collected for albuterol/salbutamol (A/S) at this time point.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>A/S followed by ipratropium, 2 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.054" spread="0.0232"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium followed by A/S; thus, data were not collected for A/S followed by ipratropium.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium alone, 1 hour</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S as the first bronchodilator; thus, data were not collected for ipratropium at this time point.</measurement>
                    <measurement group_id="O2" value="0.072" spread="0.0406"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium followed by A/S, 2 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S followed by ipratropium; thus, data were not collected for ipratropium followed by A/S.</measurement>
                    <measurement group_id="O2" value="0.063" spread="0.0327"/>
                  </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>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.058</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0046</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.049</ci_lower_limit>
            <ci_upper_limit>0.067</ci_upper_limit>
            <estimate_desc>Treatment: A/S alone. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), FEV1 Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.071</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0046</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.062</ci_lower_limit>
            <ci_upper_limit>0.080</ci_upper_limit>
            <estimate_desc>Treatment: ipratropium alone. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), FEV1 Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.053</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0046</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.044</ci_lower_limit>
            <ci_upper_limit>0.062</ci_upper_limit>
            <estimate_desc>Treatment: A+I. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), FEV1 Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Slope</param_type>
            <param_value>0.062</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0046</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.053</ci_lower_limit>
            <ci_upper_limit>0.071</ci_upper_limit>
            <estimate_desc>Treatment: I+A. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), FEV1 Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>The Maximal Bronchodilator Response for the First Administered Agent</title>
        <description>The maximal bronchodilator response for the first administered agent is defined as the FEV1 (the maximal amount of air that can be forcefully exhaled in one second) 1 hour post-dose of the first bronchodilator minus the pre-dose. The maximal bronchodilator response for the second agent is defined as the FEV1 1 hour post-dose of the second bronchodilator minus the FEV1 at 1 hour post-dose of the first bronchodilator. The maximal bronchodilator response for the combination is defined as the FEV1 (the maximal amount of air that can be forcefully exhaled in one second) at 1 hour post-administration of the second bronchodilator minus the corresponding pre-dose FEV1. Derived FEV1 response is FEV1 change from 0 hours (0H) for the first agent assessment (at 1 hour [1H]); change from 1H for the second agent assessment (at 2 hours [2H]); and change from 0H for the combination assessment (at 2H). Data were adjusted for FEV1, smoking status, and center.</description>
        <time_frame>up to 10 days</time_frame>
        <population>Efficacy Population</population>
        <group_list>
          <group group_id="O1">
            <title>All Randomized Participants</title>
            <description>All participants randomized to receive a sequence of either salbutamol (4 puffs; 100 µg per puff) via an MDI and albuterol (4 puffs; 90 µg per puff) followed by ipratropium (4 puffs; 20 µg per puff) via an MDI in TP1 and the same dose of each bronchodilator given in the opposite order in TP2, or ipratropium followed by albuterol/salbutamol in TP1 and the same dose of each bronchodilator given in the opposite order in TP2</description>
          </group>
        </group_list>
        <measure>
          <title>The Maximal Bronchodilator Response for the First Administered Agent</title>
          <description>The maximal bronchodilator response for the first administered agent is defined as the FEV1 (the maximal amount of air that can be forcefully exhaled in one second) 1 hour post-dose of the first bronchodilator minus the pre-dose. The maximal bronchodilator response for the second agent is defined as the FEV1 1 hour post-dose of the second bronchodilator minus the FEV1 at 1 hour post-dose of the first bronchodilator. The maximal bronchodilator response for the combination is defined as the FEV1 (the maximal amount of air that can be forcefully exhaled in one second) at 1 hour post-administration of the second bronchodilator minus the corresponding pre-dose FEV1. Derived FEV1 response is FEV1 change from 0 hours (0H) for the first agent assessment (at 1 hour [1H]); change from 1H for the second agent assessment (at 2 hours [2H]); and change from 0H for the combination assessment (at 2H). Data were adjusted for FEV1, smoking status, and center.</description>
          <population>Efficacy Population</population>
          <units>Liters</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="55"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>First agent, albuterol/salbutamol (A/S)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.269" spread="0.0174"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>First agent, ipratropium</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.243" spread="0.0174"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Second agent, A/S</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.094" spread="0.0123"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Second agent, ipratropium</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.094" spread="0.0123"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>A/S followed by ipratropium</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.363" spread="0.0200"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium followed by A/S</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.337" spread="0.0200"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Days for Which Participants Achieved a &gt;=12% and 200 Milliliter (mL) Increase From Baseline in FEV1</title>
        <description>FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours).</description>
        <time_frame>up to 35 days</time_frame>
        <population>Efficacy Population</population>
        <group_list>
          <group group_id="O1">
            <title>Albuterol/Salbutamol Followed by Ipratropium</title>
            <description>All participants randomized to receive a sequence of albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) via an MDI followed by ipratropium (4 puffs; 20 µg per puff) via an MDI in either TP1 or TP2.</description>
          </group>
          <group group_id="O2">
            <title>Ipratropium Follwed by Albuterol/Salbutamol</title>
            <description>All participants randomized to receive a sequence of ipratropium (4 puffs; 20 µg per puff) via an MDI followed by albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) via an MDI in either TP1 or TP2</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Days for Which Participants Achieved a &gt;=12% and 200 Milliliter (mL) Increase From Baseline in FEV1</title>
          <description>FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours).</description>
          <population>Efficacy Population</population>
          <units>percentage of days</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="55"/>
                <count group_id="O2" value="55"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Albuterol/Salbutamol (A/S) alone, 1 hour</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="58.4" spread="38.26"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium as the first bronchodilator; thus, data were not collected for albuterol/salbutamol (A/S) at this time point.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>A/S followed by ipratropium, 2 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="71.7" spread="35.51"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium followed by A/S; thus, data were not collected for A/S followed by ipratropium.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium alone, 1 hour</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S as the first bronchodilator; thus, data were not collected for ipratropium at this time point.</measurement>
                    <measurement group_id="O2" value="55.4" spread="39.34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium followed by A/S, 2 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S followed by ipratropium; thus, data were not collected for ipratropium followed by A/S.</measurement>
                    <measurement group_id="O2" value="69.1" spread="36.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL</title>
        <description>FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours).</description>
        <time_frame>up to 35 days</time_frame>
        <population>Efficacy Population</population>
        <group_list>
          <group group_id="O1">
            <title>Albuterol/Salbutamol Followed by Ipratropium</title>
            <description>All participants randomized to receive a sequence of albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) via an MDI followed by ipratropium (4 puffs; 20 µg per puff) via an MDI in either TP1 or TP2.</description>
          </group>
          <group group_id="O2">
            <title>Ipratropium Follwed by Albuterol/Salbutamol</title>
            <description>All participants randomized to receive a sequence of ipratropium (4 puffs; 20 µg per puff) via an MDI followed by albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) via an MDI in either TP1 or TP2</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL</title>
          <description>FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours).</description>
          <population>Efficacy Population</population>
          <units>percentage of days</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="55"/>
                <count group_id="O2" value="55"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>A/S alone, 1 hour, 100 mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="81.6" spread="31.35"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium as the first bronchodilator; thus, data were not collected for albuterol/salbutamol (A/S) at this time point.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>A/S followed by ipratropium, 2 hours, 100 mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="85.2" spread="29.92"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium followed by A/S; thus, data were not collected for A/S followed by ipratropium.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium alone, 1 hour, 100 mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S as the first bronchodilator; thus, data were not collected for ipratropium at this time point.</measurement>
                    <measurement group_id="O2" value="72.9" spread="38.06"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium followed by A/S, 2 hours, 100 mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S followed by ipratropium; thus, data were not collected for ipratropium followed by A/S.</measurement>
                    <measurement group_id="O2" value="81.2" spread="33.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>A/S alone, 1 hour, 200 mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="59.2" spread="38.20"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium as the first bronchodilator; thus, data were not collected for albuterol/salbutamol (A/S) at this time point.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>A/S followed by ipratropium, 2 hours, 200 mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="72.7" spread="35.25"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium followed by A/S; thus, data were not collected for A/S followed by ipratropium.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium alone, 1 hour, 200 mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S as the first bronchodilator; thus, data were not collected for ipratropium at this time point.</measurement>
                    <measurement group_id="O2" value="56.0" spread="39.54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium followed by A/S, 2 hours, 200 mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S followed by ipratropium; thus, data were not collected for ipratropium followed by A/S.</measurement>
                    <measurement group_id="O2" value="70.5" spread="36.23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>A/S alone, 1 hour, 250 mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45.9" spread="38.85"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium as the first bronchodilator; thus, data were not collected for albuterol/salbutamol (A/S) at this time point.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>A/S followed by ipratropium, 2 hours, 250 mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="64.0" spread="39.08"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium followed by A/S; thus, data were not collected for A/S followed by ipratropium.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium alone, 1 hour, 250 mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S as the first bronchodilator; thus, data were not collected for ipratropium at this time point.</measurement>
                    <measurement group_id="O2" value="45.8" spread="36.94"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium followed by A/S, 2 hours, 250 mL</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S followed by ipratropium; thus, data were not collected for ipratropium followed by A/S.</measurement>
                    <measurement group_id="O2" value="59.6" spread="38.19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values)</title>
        <description>FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily FEV1 was measured as the fluctuation around the mean FEV1 data collected from Day 1 to Day 10. Variability was measured by the coefficient of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is half the difference between the maximum and minimum FEV1 values.</description>
        <time_frame>up to 10 days</time_frame>
        <population>Efficacy Population</population>
        <group_list>
          <group group_id="O1">
            <title>Albuterol/Salbutamol Followed by Ipratropium</title>
            <description>All participants randomized to receive a sequence of albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) via an MDI followed by ipratropium (4 puffs; 20 µg per puff) via an MDI in either TP1 or TP2.</description>
          </group>
          <group group_id="O2">
            <title>Ipratropium Followed by Albuterol/Salbutamol</title>
            <description>All participants randomized to receive a sequence of ipratropium (4 puffs; 20 µg per puff) via an MDI followed by albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) via an MDI in either TP1 or TP2</description>
          </group>
        </group_list>
        <measure>
          <title>Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values)</title>
          <description>FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily FEV1 was measured as the fluctuation around the mean FEV1 data collected from Day 1 to Day 10. Variability was measured by the coefficient of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is half the difference between the maximum and minimum FEV1 values.</description>
          <population>Efficacy Population</population>
          <units>Liters</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="55"/>
                <count group_id="O2" value="55"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Pre-dose/non-bronchodilator</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.136" spread="0.0627"/>
                    <measurement group_id="O2" value="0.135" spread="0.0780"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Albuterol/Salbutamol (A/S) alone, 1 hour</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.125" spread="0.0525"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium as the first bronchodilator; thus, data were not collected for albuterol/salbutamol (A/S) at this time point.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>A/S followed by ipratropium, 2 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.122" spread="0.0542"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium followed by A/S; thus, data were not collected for A/S followed by ipratropium.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium alone, 1 hour</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S as the first bronchodilator; thus, data were not collected for ipratropium at this time point.</measurement>
                    <measurement group_id="O2" value="0.145" spread="0.0805"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium followed by A/S, 2 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S followed by ipratropium; thus, data were not collected for ipratropium followed by A/S.</measurement>
                    <measurement group_id="O2" value="0.137" spread="0.0726"/>
                  </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>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.058</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0046</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.049</ci_lower_limit>
            <ci_upper_limit>0.067</ci_upper_limit>
            <estimate_desc>Treatment: A/S alone. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), FEV1 Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.071</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0046</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.062</ci_lower_limit>
            <ci_upper_limit>0.080</ci_upper_limit>
            <estimate_desc>Treatment: ipratropium alone. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), FEV1 Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.053</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0046</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.044</ci_lower_limit>
            <ci_upper_limit>0.062</ci_upper_limit>
            <estimate_desc>Treatment: A+I. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), FEV1 Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.062</param_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.053</ci_lower_limit>
            <ci_upper_limit>0.071</ci_upper_limit>
            <estimate_desc>Treatment: I+A. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), FEV1 Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation</title>
        <description>IC is the the total amount of air that can be drawn into the lungs after normal expiration. During each study period, pre- and post-bronchodilator spirometry for evaluation of IC was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily IC was measured as the fluctuation around the mean IC data collected from Day 1 to Day 10. Variability was measured by the coefficent of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is the difference between the maximum and minimum IC values.</description>
        <time_frame>up to 10 days</time_frame>
        <population>Efficacy Population</population>
        <group_list>
          <group group_id="O1">
            <title>Albuterol/Salbutamol Followed by Ipratropium</title>
            <description>All participants randomized to receive a sequence of albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) via an MDI followed by ipratropium (4 puffs; 20 µg per puff) via an MDI in either TP1 or TP2.</description>
          </group>
          <group group_id="O2">
            <title>Ipratropium Followed by Albuterol/Salbutamol</title>
            <description>All participants randomized to receive a sequence of ipratropium (4 puffs; 20 µg per puff) via an MDI followed by albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) via an MDI in either TP1 or TP2</description>
          </group>
        </group_list>
        <measure>
          <title>Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation</title>
          <description>IC is the the total amount of air that can be drawn into the lungs after normal expiration. During each study period, pre- and post-bronchodilator spirometry for evaluation of IC was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily IC was measured as the fluctuation around the mean IC data collected from Day 1 to Day 10. Variability was measured by the coefficent of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is the difference between the maximum and minimum IC values.</description>
          <population>Efficacy Population</population>
          <units>Liters</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="55"/>
                <count group_id="O2" value="55"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Pre-dose/non-bronchodilator</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.078" spread="0.0305"/>
                    <measurement group_id="O2" value="0.083" spread="0.0374"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Albuterol/Salbutamol (A/S) alone, 1 hour</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.069" spread="0.0310"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium as the first bronchodilator; thus, data were not collected for albuterol/salbutamol (A/S) at this time point.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>A/S followed by ipratropium (A+I), 2 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.070" spread="0.0373"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium followed by A/S; thus, data were not collected for A/S followed by ipratropium.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium alone, 1 hour</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S as the first bronchodilator; thus, data were not collected for ipratropium at this time point.</measurement>
                    <measurement group_id="O2" value="0.072" spread="0.0353"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium followed by A/S (I+A), 2 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S followed by ipratropium; thus, data were not collected for ipratropium followed by A/S.</measurement>
                    <measurement group_id="O2" value="0.066" spread="0.0307"/>
                  </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>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.067</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0045</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.058</ci_lower_limit>
            <ci_upper_limit>0.076</ci_upper_limit>
            <estimate_desc>Treatment: A/S alone. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), IC Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.070</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0045</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.061</ci_lower_limit>
            <ci_upper_limit>0.079</ci_upper_limit>
            <estimate_desc>Treatment: ipratropium alone. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), IC Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.069</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0045</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.060</ci_lower_limit>
            <ci_upper_limit>0.078</ci_upper_limit>
            <estimate_desc>Treatment: A+I. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), IC Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.064</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0045</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.055</ci_lower_limit>
            <ci_upper_limit>0.073</ci_upper_limit>
            <estimate_desc>Treatment: I+A. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), IC Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum)</title>
        <description>IC is the the total amount of air that can be drawn into the lungs after normal expiration. During each study period, pre- and post-bronchodilator spirometry for evaluation of IC was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily IC was measured as the fluctuation around the mean IC data collected from Day 1 to Day 10. Variability was measured by the coefficent of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is half the difference between the maximum and minimum IC values.</description>
        <time_frame>up to 10 days</time_frame>
        <population>Efficacy Population</population>
        <group_list>
          <group group_id="O1">
            <title>Albuterol/Salbutamol Followed by Ipratropium</title>
            <description>All participants randomized to receive a sequence of albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) via an MDI followed by ipratropium (4 puffs; 20 µg per puff) via an MDI in either TP1 or TP2.</description>
          </group>
          <group group_id="O2">
            <title>Ipratropium Followed by Albuterol/Salbutamol</title>
            <description>All participants randomized to receive a sequence of ipratropium (4 puffs; 20 µg per puff) via an MDI followed by albuterol (4 puffs; 90 µg per puff)/salbutamol (4 puffs; 100 µg per puff) via an MDI in either TP1 or TP2</description>
          </group>
        </group_list>
        <measure>
          <title>Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum)</title>
          <description>IC is the the total amount of air that can be drawn into the lungs after normal expiration. During each study period, pre- and post-bronchodilator spirometry for evaluation of IC was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily IC was measured as the fluctuation around the mean IC data collected from Day 1 to Day 10. Variability was measured by the coefficent of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is half the difference between the maximum and minimum IC values.</description>
          <population>Efficacy Population</population>
          <units>Liters</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="55"/>
                <count group_id="O2" value="55"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Pre-dose/non-bronchodilator</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.225" spread="0.1017"/>
                    <measurement group_id="O2" value="0.236" spread="0.1166"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Albuterol/Salbutamol (A/S) alone, 1 hour</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.229" spread="0.1004"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium as the first bronchodilator; thus, data were not collected for albuterol/salbutamol (A/S) at this time point.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>A/S followed by ipratropium, 2 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.233" spread="0.1132"/>
                    <measurement group_id="O2" value="NA" spread="NA">Participants in this treatment arm received ipratropium followed by A/S; thus, data were not collected for A/S followed by ipratropium.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium alone, 1 hour</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S as the first bronchodilator; thus, data were not collected for ipratropium at this time point.</measurement>
                    <measurement group_id="O2" value="0.235" spread="0.1026"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ipratropium followed by A/S, 2 hours</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Participants in this treatment arm received A/S followed by ipratropium; thus, data were not collected for ipratropium followed by A/S.</measurement>
                    <measurement group_id="O2" value="0.221" spread="0.1066"/>
                  </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>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.228</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0140</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.200</ci_lower_limit>
            <ci_upper_limit>0.255</ci_upper_limit>
            <estimate_desc>Treatment: A/S alone. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), IC Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.231</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0140</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.203</ci_lower_limit>
            <ci_upper_limit>0.258</ci_upper_limit>
            <estimate_desc>Treatment: ipratropium alone. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), IC Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.232</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0140</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.204</ci_lower_limit>
            <ci_upper_limit>0.259</ci_upper_limit>
            <estimate_desc>Treatment: A+I. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), IC Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <param_type>Adjusted Mean</param_type>
            <param_value>0.217</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.0140</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_lower_limit>0.190</ci_lower_limit>
            <ci_upper_limit>0.245</ci_upper_limit>
            <estimate_desc>Treatment: I+A. A mixed model analysis, with period, treatment (A+I, I+A, Albuterol alone, Ipratropium alone), IC Baseline, smoking status at Screening, and center fitted as fixed effects and participant as a random effect was used.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>All Randomized Participants</title>
          <description>All participants randomized to receive a sequence of either salbutamol (4 puffs; 100 µg per puff) via an MDI and albuterol (4 puffs; 90 µg per puff) followed by ipratropium (4 puffs; 20 µg per puff) via an MDI in TP1 and the same dose of each bronchodilator given in the opposite order in TP2, or ipratropium followed by albuterol/salbutamol in TP1 and the same dose of each bronchodilator given in the opposite order in TP2</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA</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="16" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chest discomfort</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bacterial infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Herpes zoster</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Excoriation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Muscle strain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Radius fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Tooth fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Joint swelling</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </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="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Increased upper airway secretion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Painful respiration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </event>
              <event>
                <sub_title>Sneezing</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="56"/>
              </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>GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>GSK Response Center</name_or_title>
      <organization>GlaxoSmithKline</organization>
      <phone>866-435-7343</phone>
    </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/NCT01691482
org study id: 114956
nct id: NCT01691482
lead sponsor: 
The objective of this study is to assess the daily variation in bronchodilator response to an
      inhaled short acting beta2-agonist (albuterol/salbutamol) and an inhaled short acting
      anticholinergic (ipratropium) individually and when used in combination in subjects with
      COPD.
Beta2-agonist and anticholinergics are a principle component of the pharmacologic management
      of chronic obstructive pulmonary disease COPD. It has been demonstrated that the combination
      of a short acting beta2-agonist and a short acting anticholinergic yields greater efficacy as
      measured by FEV1 when compared with the response to the individual short acting
      bronchodilators. However, daily bronchial response to these agents is poorly understood. It
      is also poorly understood how the variation in magnitude of the response to the individual
      agents and how the variation in response for one agent coincides with the variation in
      response to the other agent. This study will seek to define the pattern of response of each
      individual agent and the relationship between them. The study will also explore if the
      combination of the two agents leads to less variation in response compared to the individual
      agents. This is a randomized, open label, two period cross-over study. Eligible subjects will
      be randomized to a sequence of either albuterol/salbutamol via metered-dose inhaler (MDI)
      followed by ipratropium via MDI or the same dose of each bronchodilator given in the opposite
      order. Each study period will consist of 10 clinic visits to be conducted over 10 to 14 days.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Variability in Daily FEV1, Estimated by Coefficient of Variation
time frame: up to 10 days
description: FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily FEV1 was measured as the fluctuation around the mean FEV1 data collected from Day 1 to Day 10. Variability was measured by the coefficient of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is the difference between the maximum and minimum FEV1 values.
measure: Variability in Daily FEV1, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum Values)
time frame: up to 10 days
description: FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily FEV1 was measured as the fluctuation around the mean FEV1 data collected from Day 1 to Day 10. Variability was measured by the coefficient of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is half the difference between the maximum and minimum FEV1 values.
measure: The Maximal Bronchodilator Response for the First Administered Agent
time frame: up to 10 days
description: The maximal bronchodilator response for the first administered agent is defined as the FEV1 (the maximal amount of air that can be forcefully exhaled in one second) 1 hour post-dose of the first bronchodilator minus the pre-dose. The maximal bronchodilator response for the second agent is defined as the FEV1 1 hour post-dose of the second bronchodilator minus the FEV1 at 1 hour post-dose of the first bronchodilator. The maximal bronchodilator response for the combination is defined as the FEV1 (the maximal amount of air that can be forcefully exhaled in one second) at 1 hour post-administration of the second bronchodilator minus the corresponding pre-dose FEV1. Derived FEV1 response is FEV1 change from 0 hours (0H) for the first agent assessment (at 1 hour [1H]); change from 1H for the second agent assessment (at 2 hours [2H]); and change from 0H for the combination assessment (at 2H). Data were adjusted for FEV1, smoking status, and center.
measure: Percentage of Days for Which Participants Achieved a >=12% and 200 Milliliter (mL) Increase From Baseline in FEV1
time frame: up to 35 days
description: FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours).
measure: Percentage of Days for Which Participants Achieved a Threshold Increase From Baseline in FEV1 of 100 mL, 200 mL, and 250 mL
time frame: up to 35 days
description: FEV1 is the maximal amount of air that can be forcefully exhaled in one second. During each study period, pre- and post-bronchodilator spirometry for evaluation of FEV1 was performed at study visits as follows: approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours).
measure: Variability in Daily Inspiratory Capacity (IC), Estimated by Coefficient of Variation
time frame: up to 10 days
description: IC is the the total amount of air that can be drawn into the lungs after normal expiration. During each study period, pre- and post-bronchodilator spirometry for evaluation of IC was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily IC was measured as the fluctuation around the mean IC data collected from Day 1 to Day 10. Variability was measured by the coefficent of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is the difference between the maximum and minimum IC values.
measure: Variability in Daily IC, Estimated by Half Range (i.e., Half the Difference Between Maximum and Minimum)
time frame: up to 10 days
description: IC is the the total amount of air that can be drawn into the lungs after normal expiration. During each study period, pre- and post-bronchodilator spirometry for evaluation of IC was performed at study visits as follows: prior to administration of the first short-acting bronchodilator, approximately 1 hour after administration of the first bronchodilator (1 hour), and approximately 1 hour after administration of the second short-acting bronchodilator (2 hours). Variability in daily IC was measured as the fluctuation around the mean IC data collected from Day 1 to Day 10. Variability was measured by the coefficent of variation (CV) and the half range. The CV is the dispersion of the data around the mean, whereas the half range method is half the difference between the maximum and minimum IC values.
arm group label: Albuterol/salbutamol followed by ipratropium
arm group type: Active Comparator
description: Subjects will recieve daily albuterol/salbutamol followed by ipratropium which will be adminstered one hour after adminstration of albuterol/salbutamol
arm group label: Ipratropium followed by albuterol/salbutamol
arm group type: Active Comparator
description: Subjects will recieve daily ipratropium followed by albuterol/salbutamol which will be adminstered one hour after adminstration of ipratropium
intervention type: Drug
intervention name: Albuterol/salbutamol
description: Albuterol/salbutamol (daily)
arm group label: Albuterol/salbutamol followed by ipratropium
intervention type: Drug
intervention name: Ipratropium
description: Ipratropium (daily)
arm group label: Ipratropium followed by albuterol/salbutamol
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
last name: GSK Clinical Trials
role: Study Director
affiliation: GlaxoSmithKline
facility: 
facility: 
country: United Kingdom
country: United States
url: https://www.clinicalstudydatarequest.com
description: Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.
responsible party type: Sponsor
mesh term: Lung Diseases
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Albuterol
mesh term: Ipratropium
sharing ipd: Yes
ipd description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
study doc: 
study doc: 
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participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 