<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/NCT03227445</url>
  </required_header>
  <id_info>
    <org_study_id>206901</org_study_id>
    <nct_id>NCT03227445</nct_id>
  </id_info>
  <brief_title>Comparative Study of ELLIPTA Dry Powder Inhaler (DPI) Versus DISKUS DPI Used With HandiHaler DPI in Subjects With Chronic Obstructive Pulmonary Disease (COPD)</brief_title>
  <official_title>A Randomized, Open-label, Cross-over, Placebo Inhaler Study to Evaluate the Correct Use of ELLIPTA™ Dry Powder Inhaler (DPI) Compared to DISKUS™ DPI Used in Combination With HandiHaler DPI in Participants With Chronic Obstructive Pulmonary Disease (COPD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>GlaxoSmithKline</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This randomized, cross over study aims to find out the benefits of delivering triple therapy&#xD;
      using a single ELLIPTA® DPI (fixed-dose combination triple therapy) versus delivering triple&#xD;
      therapy using two different types of inhalers (open triple therapy) including DISKUS® with&#xD;
      HandiHaler® to subjects with COPD. Correct inhaler use, critical errors and performance&#xD;
      attributes will also be assessed. Approximately 240 subjects with COPD will be randomized in&#xD;
      the study. The study will be conducted in 3 visits and will be completed in approximately 56&#xD;
      days. At Visit 1 (Day 1) and Visit 2 (Day 28) subjects will be randomized to receive a&#xD;
      placebo ELLIPTA inhaler once daily (QD) or a placebo DISKUS twice daily (BID) with placebo&#xD;
      HandiHaler QD inhaler in 1:1 ratio in a cross-over manner for the study period (28 days for&#xD;
      each period). At Visit 3 (Day 56), subjects will be asked to complete preference&#xD;
      questionnaire 1 or 2. There will be no active treatment and subjects will continue to take&#xD;
      their own prescribed COPD maintenance and rescue medication during the entire study period.&#xD;
      ELLIPTA and DISKUS are the registered trademarks of GlaxoSmithKline group of companies.&#xD;
      HandiHaler is the registered trademark of Boehringer Ingelheim group of companies.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 20, 2017</start_date>
  <completion_date type="Actual">January 4, 2018</completion_date>
  <primary_completion_date type="Actual">January 4, 2018</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>
    <intervention_model_description>Subjects will be randomized to receive a placebo ELLIPTA inhaler QD or a placebo DISKUS BID with placebo HandiHaler QD inhaler at Visit 1 and Visit 2 in a cross-over manner followed by Preference Questionnaire 1 or 2</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>This will an open-label study and blinding will not be performed.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Participants With Zero Errors After 28 Days of Inhaler Use in Each Treatment Phase (Primary Estimand: Hypothetical)</measure>
    <time_frame>Up to Day 56</time_frame>
    <description>A checklist for correct use of each inhaler was developed in Patient Instruction Leaflets (PIL's). Participants were guided by trained health care provider (HCP) to demonstrate correct use of inhaler. Baseline assessment was conducted when participant initially dispensed the inhaler. Second assessment was conducted after each 28day dosing period. Correct Use Check list was completed by HCP at each visit. Primary hypothetical estimand is the estimate of treatment effect of all participants who stayed on their randomized study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. Participants could attend visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. Participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage of Participants With Atleast One Error After 28 Days of Inhaler Use in Each Treatment Phase (Primary Estimand: Hypothetical)</measure>
    <time_frame>Up to Day 56</time_frame>
    <description>Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage of Participants With Atleast One Error After 28 Days of Inhaler Use in Each Treatment Phase (Supplementary Estimand: Composite)</measure>
    <time_frame>Up to Day 56</time_frame>
    <description>Supplementary estimand estimated the composite effect of initial randomized treatment. A sensitivity analysis using the Cochran-Mantel-Haenszel test was performed on participants with discordant results. Participants who withdrew during period 2 were included in the analysis using early withdrawal data where available or imputation otherwise. Participants who experienced an intercurrent event in Period 1 were excluded from the analysis.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage of Participants With Zero Errors After 28 Days of Inhaler Use in Each Treatment Phase(Supplementary Estimand: Composite)</measure>
    <time_frame>Up to Day 56</time_frame>
    <description>Supplementary estimand estimated the composite effect of initial randomized treatment. The analysis was performed using stratified exact logistic model. Participants were included in the model as fixed strata, treatment option was included in the exact statement and period included as fixed effects. Participants who withdrew during period 2 were included in the analysis using early withdrawal data where available or imputation otherwise. Participants who experienced an intercurrent event in Period 1 were excluded from the analysis.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Errors by Type for Each Inhaler After 28 Days of Use in Each Treatment Phase (Primary Estimand: Hypothetical)</measure>
    <time_frame>Up to Day 56</time_frame>
    <description>The occurrence of each type of error for each inhaler (ELLIPTA, DISKUS or HANDIHALER) were evaluated based on the information collected in Correct Use Checklists. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence &amp; did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups &amp; experienced no intercurrent events were included. The number of error is reported as NA for the type of error which was not applicable to the particular inhaler type</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Errors Per Participant for Each Treatment Group After 28 Days of Use (Primary Estimand: Hypothetical)</measure>
    <time_frame>Up to Day 56</time_frame>
    <description>Participants were provided with PIL explaining correct use of inhaler. Overall error includes both critical and non-critical errors. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Errors Per Participant for Each Treatment Group After 28 Days of Use</measure>
    <time_frame>Day 1 and Day 28 of each treatment group</time_frame>
    <description>Assessment of errors was conducted by HCP trained in the correct inhaler use of the three inhalers based on the checklist of errors. The median number of overall errors made by per participant was assessed for ELLIPTA and DISKUS + HandiHaler both on Day 1 and Day 28 for each treatment group. The difference was calculated by subtracting values of Day 28 from Day1 for each treatment regimen. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Errors for Each Treatment Group in Participants With One or More Errors After 28 Days of Use (Primary Estimand: Hypothetical)</measure>
    <time_frame>Up to Day 56</time_frame>
    <description>Participants were provided with the PIL, explaining correct use of the inhaler. Overall error includes both critical and non-critical errors. Assessment of errors was conducted by HCP trained in the correct inhaler use of the three inhalers based on the checklist of errors. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Errors for Each Treatment Group in Participants With One or More Errors After 28 Days of Use</measure>
    <time_frame>Day 1 and Day 28 of each treatment group</time_frame>
    <description>Assessment of errors was conducted by health care professionals trained in the correct inhaler use of the three inhalers based on the checklist of errors. The median of overall errors made by each participant was assessed for ELLIPTA and DISKUS + HandiHaler both on Day 1 and Day 28. The difference was calculated by subtracting values of Day 28 from Day1 for each treatment regimen. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Zero Critical Errors After 28 Days of Each Treatment Group Use (Primary Estimand: Hypothetical)</measure>
    <time_frame>Up to Day 56</time_frame>
    <description>A checklist for correct use of each inhaler was developed based on the steps identified in the PIL. A critical error was defined as an error that was most likely to result in no, or a significantly reduced amount, of medication being inhaled by the participant. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Atleast One Critical Error After 28 Days of Each Treatment Group Use (Primary Estimand: Hypothetical)</measure>
    <time_frame>Up to Day 56</time_frame>
    <description>A critical error was defined as an error that was most likely to result in no, or a significantly reduced amount, of medication being inhaled by the participant. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Atleast One Critical Error After 28 Days of Each Treatment Group Use (Supplementary Estimand: Composite)</measure>
    <time_frame>Up to Day 56</time_frame>
    <description>Supplementary estimand estimated the composite effect of initial randomized treatment. A sensitivity analysis using the Cochran-Mantel-Haenszel test was performed on participants with discordant results. Participants who withdrew during period 2 were included in the analysis using early withdrawal data where available or imputation otherwise. Participants who experienced an intercurrent event in Period 1 were excluded from the analysis.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">240</enrollment>
  <condition>Pulmonary Disease, Chronic Obstructive</condition>
  <arm_group>
    <arm_group_label>Treatment sequence A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Eligible subjects will use ELLIPTA DPI QD for 28 days in Period 1 followed by DISKUS BID with HandiHaler QD use for 28 days in Period 2. These subjects will then be asked to complete preference questionnaire 1 at Visit 3 (Day 56).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment sequence B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Eligible subjects will use ELLIPTA DPI QD for 28 days in Period 1 followed by DISKUS BID with HandiHaler QD use for 28 days in Period 2. These subjects will then be asked to complete preference questionnaire 2 at Visit 3 (Day 56).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment sequence C</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Eligible subjects will use DISKUS BID with HandiHaler QD for 28 days in Period 1 followed by ELLIPTA DPI QD use for 28 days in Period 2. These subjects will then be asked to complete preference questionnaire 1 at Visit 3 (Day 56).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment sequence D</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Eligible subjects will use DISKUS BID with HandiHaler QD for 28 days in Period 1 followed by ELLIPTA DPI QD use for 28 days in Period 2. These subjects will then be asked to complete preference questionnaire 2 at Visit 3 (Day 56).</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>ELLIPTA placebo DPI</intervention_name>
    <description>ELLIPTA is a dry powder inhaler used via oral route. It will be a placebo DPI with two strips with 30 blisters per strip. First strip will contain lactose monohydrate and the second strip will contain lactose monohydrate blended with magnesium stearate.</description>
    <arm_group_label>Treatment sequence A</arm_group_label>
    <arm_group_label>Treatment sequence B</arm_group_label>
    <arm_group_label>Treatment sequence C</arm_group_label>
    <arm_group_label>Treatment sequence D</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>DISKUS placebo DPI</intervention_name>
    <description>DISKUS is a dry powder inhaler used via oral route. It will be a placebo DPI with one blister strip that will contain lactose monohydrate.</description>
    <arm_group_label>Treatment sequence A</arm_group_label>
    <arm_group_label>Treatment sequence B</arm_group_label>
    <arm_group_label>Treatment sequence C</arm_group_label>
    <arm_group_label>Treatment sequence D</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>HandiHaler placebo DPI</intervention_name>
    <description>HandiHaler is a dry powder inhaler used via oral route. It will be a DPI with placebo capsules that will contain lactose monohydrate.</description>
    <arm_group_label>Treatment sequence A</arm_group_label>
    <arm_group_label>Treatment sequence B</arm_group_label>
    <arm_group_label>Treatment sequence C</arm_group_label>
    <arm_group_label>Treatment sequence D</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Inhaler preference questionnaires</intervention_name>
    <description>Preference questionnaires will be given to subjects to understand the inhaler preference. There will be 2 types of questionnaire, preference questionnaires 1 and 2, which will be randomized at visit 3 (Day 56).</description>
    <arm_group_label>Treatment sequence A</arm_group_label>
    <arm_group_label>Treatment sequence B</arm_group_label>
    <arm_group_label>Treatment sequence C</arm_group_label>
    <arm_group_label>Treatment sequence D</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects must be capable of giving signed informed consent.&#xD;
&#xD;
          -  Subjects must have a diagnosis of COPD with a documented history of COPD for at least&#xD;
             12 months, in accordance with the definition by the American Thoracic Society/European&#xD;
             Respiratory Society.&#xD;
&#xD;
          -  Subjects must be 40 years of age inclusive, at the time of signing the informed&#xD;
             consent.&#xD;
&#xD;
          -  Male or female subjects will be included. Females must not be pregnant or planning&#xD;
             pregnancy during the study or not lactating.&#xD;
&#xD;
          -  Subjects must have a documented post albuterol forced expiratory volume in one second&#xD;
             (FEV1)/ forced vital capacity (FVC) ratio &lt;0.70 and FEV1 &lt;=70% of predicted obtained&#xD;
             within two years of Visit 1.&#xD;
&#xD;
          -  Current or former (defined as subjects who have quit smoking for at least 3 months&#xD;
             prior to Screening/Visit 1) cigarette smokers with a &gt; 10 pack-year smoking history&#xD;
             [Number of pack-years = (number of cigarettes per day/20) x number of years smoked&#xD;
             (example, 10 pack-years is equal to 20 cigarettes per day for 10 years, or 10&#xD;
             cigarettes per day for 20 years].&#xD;
&#xD;
          -  All subjects should be currently receiving maintenance treatment for COPD for at least&#xD;
             4 weeks prior to Randomization/Visit 1 and evaluated as unlikely to change COPD&#xD;
             treatment within 4 weeks of Visit 1.&#xD;
&#xD;
          -  All subjects should be able to stay on their prescribed maintenance COPD inhaler (s)&#xD;
             without change throughout the entire treatment period.&#xD;
&#xD;
          -  Subjects must be able to read, comprehend, and record information in English.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects must not have a current diagnosis of asthma.&#xD;
&#xD;
          -  Subjects must not have used the ELLIPTA, DISKUS, or HandiHaler inhalers in the 12&#xD;
             months prior to Visit 1.&#xD;
&#xD;
          -  Subjects must not be receiving their current COPD medications with the ELLIPTA,&#xD;
             DISKUS, or HandiHaler inhalers.&#xD;
&#xD;
          -  Subjects must not be receiving only inhaled short-acting beta-adrenergic agonists,&#xD;
             i.e., albuterol as their daily COPD therapy (as needed or regularly scheduled).&#xD;
&#xD;
          -  Subjects must not have experienced more than 1 COPD exacerbation which required&#xD;
             hospitalization in the 12 months prior to Visit 1.&#xD;
&#xD;
          -  Subjects must not have a known or suspected history of alcohol or drug abuse within&#xD;
             the last 2 years.&#xD;
&#xD;
          -  Subjects must not have a history of hypersensitivity to any component of the study&#xD;
             inhalers (example, lactose, magnesium stearate). In addition, subjects with a history&#xD;
             of severe milk protein allergy that, in the opinion of the study physician,&#xD;
             contraindicates participation will also be excluded.&#xD;
&#xD;
          -  Subjects with other respiratory disorders, including active tuberculosis, active lung&#xD;
             cancer, sarcoidosis, lung fibrosis, pulmonary hypertension, or pulmonary disease&#xD;
             (including but not confined to asthma, bronchiectasis with the need for treatment,&#xD;
             cystic fibrosis, and bronchopulmonary dysplasia), interstitial lung diseases or other&#xD;
             active pulmonary diseases.&#xD;
&#xD;
          -  Subjects with historical, or current evidence of clinically significant or rapidly&#xD;
             progressing or unstable cardiovascular, neurological, renal, hepatic, immunological,&#xD;
             endocrine (including uncontrolled diabetes or thyroid disease) or hematological&#xD;
             abnormalities that are uncontrolled. Significant is defined as any disease that, in&#xD;
             the opinion of the investigator, would put the safety of the participant at risk&#xD;
             through participation, or which would affect the analysis if the disease/condition&#xD;
             exacerbated during the study will be excluded.&#xD;
&#xD;
          -  Subjects with history of psychiatric disease, intellectual impairment, poor motivation&#xD;
             or other conditions that will limit the validity of informed consent to participate in&#xD;
             the study will be excluded.&#xD;
&#xD;
          -  Subjects at risk of non-compliance, or unable to comply with the study procedures, or&#xD;
             unable to continue their current medications.&#xD;
&#xD;
          -  Subjects who have received an investigational drug and/or medical device/inhaler&#xD;
             within 30 days of entry into this study (Screening/Visit 1), or within five drug&#xD;
             half-lives of the investigational drug, whichever is longer.&#xD;
&#xD;
          -  Subjects will not be eligible for this study if he/she is an immediate family member&#xD;
             of the participating investigator, sub investigator, study coordinator, or employee of&#xD;
             the participating investigator.&#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>Orlando</city>
        <state>Florida</state>
        <zip>32825</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Natchitoches</city>
        <state>Louisiana</state>
        <zip>71457</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Saint Charles</city>
        <state>Missouri</state>
        <zip>63301</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28207</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Gastonia</city>
        <state>North Carolina</state>
        <zip>28054</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Monroe</city>
        <state>North Carolina</state>
        <zip>28112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Mooresville</city>
        <state>North Carolina</state>
        <zip>28117</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Canton</city>
        <state>Ohio</state>
        <zip>44718</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Dayton</city>
        <state>Ohio</state>
        <zip>45419</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73120</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Medford</city>
        <state>Oregon</state>
        <zip>97504</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Anderson</city>
        <state>South Carolina</state>
        <zip>29621</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Greenville</city>
        <state>South Carolina</state>
        <zip>29615</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Rock Hill</city>
        <state>South Carolina</state>
        <zip>29732</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <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>Richmond</city>
        <state>Virginia</state>
        <zip>23225</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>Richmond</city>
        <state>Virginia</state>
        <zip>23229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Kerwin EM, Spangenthal S, Zvarich M, Millar V, Jain R, Collison K, Sharma R. ELLIPTA Versus DISKUS plus HandiHaler in COPD: A Randomized, Open-Label, Crossover Study in a Clinical Trial Setting. Chronic Obstr Pulm Dis. 2020 Apr;7(2):118-129. doi: 10.15326/jcopdf.7.2.2019.0153.</citation>
    <PMID>32324983</PMID>
  </reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>July 19, 2017</study_first_submitted>
  <study_first_submitted_qc>July 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 24, 2017</study_first_posted>
  <results_first_submitted>January 4, 2019</results_first_submitted>
  <results_first_submitted_qc>December 20, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">January 9, 2020</results_first_posted>
  <last_update_submitted>June 26, 2020</last_update_submitted>
  <last_update_submitted_qc>June 26, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 8, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>DISKUS</keyword>
  <keyword>HandiHaler</keyword>
  <keyword>COPD</keyword>
  <keyword>Placebo</keyword>
  <keyword>Cross-over</keyword>
  <keyword>Dry powder inhaler</keyword>
  <keyword>ELLIPTA</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>IPD for this study will be made available via the Clinical Study Data Request site.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>IPD is available via the Clinical Study Data Request site (click on the link provided below)</ipd_time_frame>
    <ipd_access_criteria>Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.</ipd_access_criteria>
    <ipd_url>https://clinicalstudydatarequest.com/Posting.aspx?ID=20372</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>May 17, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/45/NCT03227445/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 28, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/45/NCT03227445/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This is a randomized, multi-center, open-label study comparing placebo ELLIPTA with placebo DISKUS + HandiHaler to assess correct inhaler use in participants with Chronic Obstructive Pulmonary Disease (COPD). A total of 17 centers across United States participated in the study.</recruitment_details>
      <pre_assignment_details>Out of 240 randomized participants (par), 239 entered the study as 1 par was randomized in error. In order to minimize potential bias the order of placebo devices &amp; order of responses, in preference questionnaire (PQ), was randomized in a crossover design. All par on study received placebo only &amp; participant flow reflects this as the only treatment</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>ELLIPTA/DISKUS+HANDIHALER/Q1</title>
          <description>Participants received placebo via ELLIPTA dry powder inhaler (DPI) in period 1 and DISKUS DPI + HandiHaler in period 2, followed by preference questionnaire (PQ) version 1. There was no active treatment and participants continued to take their own prescribed COPD medication and rescue medications for the duration of the study</description>
        </group>
        <group group_id="P2">
          <title>ELLIPTA/DISKUS+HANDIHALER/Q2</title>
          <description>Participants received placebo via ELLIPTA DPI in period 1 and DISKUS DPI + HandiHaler in period 2, followed by PQ2. There was no active treatment and participants continued to take their own prescribed COPD medication and rescue medications for the duration of the study</description>
        </group>
        <group group_id="P3">
          <title>DISKUS+HANDIHALER/ELLIPTA/Q1</title>
          <description>Participants received placebo via DISKUS DPI + HandiHaler in period 1 and ELLIPTA DPI in period 2, followed by PQ1. There was no active treatment and participants continued to take their own prescribed COPD medication and rescue medications for the duration of the study</description>
        </group>
        <group group_id="P4">
          <title>DISKUS+HANDIHALER/ELLIPTA/Q2</title>
          <description>Participants received placebo via DISKUS DPI + HandiHaler in period 1 and ELLIPTA DPI in period 2, followed by PQ2. There was no active treatment and participants continued to take their own prescribed COPD medication and rescue medications for the duration of the study</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Period 1 (28 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="60"/>
                <participants group_id="P2" count="59"/>
                <participants group_id="P3" count="60"/>
                <participants group_id="P4" count="60"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="58"/>
                <participants group_id="P2" count="57"/>
                <participants group_id="P3" count="59"/>
                <participants group_id="P4" count="58"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" 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="1"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" 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="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Period 2 (28 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="58"/>
                <participants group_id="P2" count="57"/>
                <participants group_id="P3" count="59"/>
                <participants group_id="P4" count="58"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="57"/>
                <participants group_id="P2" count="56"/>
                <participants group_id="P3" count="57"/>
                <participants group_id="P4" count="55"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" 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 Study Participants</title>
          <description>Participants received placebo via ELLIPTA dry powder inhaler (DPI) or DISKUS DPI in combination with HandiHaler DPI based on the following treatment sequences: Treatment Sequence A (ELLIPTA in period 1 and DISKUS + HandiHaler in period 2, followed by PQ 1.); Treatment Sequence B (ELLIPTA in period 1 and DISKUS + HandiHaler in period 2, followed by PQ2); Treatment Sequence C (DISKUS + HandiHaler in period 1 and ELLIPTA in period 2, followed by PQ1); or Treatment Sequence D (DISKUS + HandiHaler in period 1 and ELLIPTA in period 2, followed by PQ2). Participants continued to take their own prescribed COPD medication and rescue medications for the entire 56-day study period.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="239"/>
          </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="65.9" spread="8.25"/>
                  </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="108"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="131"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Count of Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>African American/African Heritage</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White - Arabic/North African Heritage</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White - White/Caucasian/European Heritage</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="213"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Participants With Zero Errors After 28 Days of Inhaler Use in Each Treatment Phase (Primary Estimand: Hypothetical)</title>
        <description>A checklist for correct use of each inhaler was developed in Patient Instruction Leaflets (PIL's). Participants were guided by trained health care provider (HCP) to demonstrate correct use of inhaler. Baseline assessment was conducted when participant initially dispensed the inhaler. Second assessment was conducted after each 28day dosing period. Correct Use Check list was completed by HCP at each visit. Primary hypothetical estimand is the estimate of treatment effect of all participants who stayed on their randomized study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. Participants could attend visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. Participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included</description>
        <time_frame>Up to Day 56</time_frame>
        <population>Intent-to-treat (ITT) Population comprised of all randomized participants, excluding those who were randomized in error, and did not have at least one error assessment at Visit 1. Only those participants with data available at specified time point were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>ELLIPTA</title>
            <description>Participants were randomized to use placebo via ELLIPTA in either period 1 or 2.</description>
          </group>
          <group group_id="O2">
            <title>DISKUS + HANDIHALER</title>
            <description>Participants were randomized to use placebo via DISKUS + HANDIHALER in period 1 or 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Zero Errors After 28 Days of Inhaler Use in Each Treatment Phase (Primary Estimand: Hypothetical)</title>
          <description>A checklist for correct use of each inhaler was developed in Patient Instruction Leaflets (PIL's). Participants were guided by trained health care provider (HCP) to demonstrate correct use of inhaler. Baseline assessment was conducted when participant initially dispensed the inhaler. Second assessment was conducted after each 28day dosing period. Correct Use Check list was completed by HCP at each visit. Primary hypothetical estimand is the estimate of treatment effect of all participants who stayed on their randomized study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. Participants could attend visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. Participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included</description>
          <population>Intent-to-treat (ITT) Population comprised of all randomized participants, excluding those who were randomized in error, and did not have at least one error assessment at Visit 1. Only those participants with data available at specified time point were analyzed.</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="217"/>
                <count group_id="O2" value="217"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="96"/>
                    <measurement group_id="O2" value="87"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>stratified exact logistic model</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>6.88</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.97</ci_lower_limit>
            <ci_upper_limit>54.28</ci_upper_limit>
            <estimate_desc>Participants included in the model as fixed strata, treatment option was included in the exact statement and period included as fixed effects.</estimate_desc>
            <other_analysis_desc>There are three intercurrent events identified which could impact upon the estimand of interest:&#xD;
The participant could withdraw from randomised study device sequence and therefore withdraw from the study&#xD;
The participant could change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER; these subjects should have been withdrawn from the study according to the protocol.&#xD;
The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol.&#xD;
Rescue Medication use and change to maintenance COPD medication which is not delivered via ELLIPTA, DISKUS or HANDIHALER are not considered intercurrent events</other_analysis_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Errors by Type for Each Inhaler After 28 Days of Use in Each Treatment Phase (Primary Estimand: Hypothetical)</title>
        <description>The occurrence of each type of error for each inhaler (ELLIPTA, DISKUS or HANDIHALER) were evaluated based on the information collected in Correct Use Checklists. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence &amp; did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups &amp; experienced no intercurrent events were included. The number of error is reported as NA for the type of error which was not applicable to the particular inhaler type</description>
        <time_frame>Up to Day 56</time_frame>
        <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>ELLIPTA</title>
            <description>Participants were randomized to use placebo via ELLIPTA in either period 1 or 2.</description>
          </group>
          <group group_id="O2">
            <title>DISKUS</title>
            <description>Participants were randomized to use placebo via DISKUS + HANDIHALER in period 1 or 2.</description>
          </group>
          <group group_id="O3">
            <title>HandiHaler</title>
            <description>Participants were randomized to use placebo via DISKUS + HANDIHALER in period 1 or 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Errors by Type for Each Inhaler After 28 Days of Use in Each Treatment Phase (Primary Estimand: Hypothetical)</title>
          <description>The occurrence of each type of error for each inhaler (ELLIPTA, DISKUS or HANDIHALER) were evaluated based on the information collected in Correct Use Checklists. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence &amp; did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups &amp; experienced no intercurrent events were included. The number of error is reported as NA for the type of error which was not applicable to the particular inhaler type</description>
          <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
          <units>Errors</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="217"/>
                <count group_id="O2" value="217"/>
                <count group_id="O3" value="217"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Par exhales while holding inhaler away from mouth</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="9"/>
                    <measurement group_id="O3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par takes long steady deep breath in through mouth</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par breathes out slowly and gently</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par opened cover</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par slid lever away from mouthpiece</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par didn't tilt/shake device post dose preparation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par took a quick deep breath through the Diskus</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par removed Diskus from mouth,held breath for long</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par breathed out slowly</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par closed the cover of the inhaler</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par did not exhale into the mouthpiece</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par opened mouthpiece &amp; center chamber is showing</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par opened only 1 capsule from the blister card</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par placed capsule in center chamber of inhaler</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par pressed green piercing button&amp;released button</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par exhaled fully</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par closed lips tightly around mouthpiece</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par didn't block air intake vents with fingers</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par breathed in deeply</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par heard or felt the capsule vibrate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par held breath for few seconds &amp; removed inhaler</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par resumed normal breathing</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Par didn't pierce use capsule for 2nd inhalation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O2" value="NA">NA indicates error not applicable for that particular inhaler</measurement>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Participants With Atleast One Error After 28 Days of Inhaler Use in Each Treatment Phase (Primary Estimand: Hypothetical)</title>
        <description>Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included</description>
        <time_frame>Up to Day 56</time_frame>
        <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>All Study Participants</title>
            <description>Participants received placebo via ELLIPTA dry powder inhaler (DPI) or DISKUS DPI in combination with HandiHaler DPI based on the following treatment sequences: Treatment Sequence A (ELLIPTA in period 1 and DISKUS + HandiHaler in period 2, followed by PQ 1.); Treatment Sequence B (ELLIPTA in period 1 and DISKUS + HandiHaler in period 2, followed by PQ2); Treatment Sequence C (DISKUS + HandiHaler in period 1 and ELLIPTA in period 2, followed by PQ1); or Treatment Sequence D (DISKUS + HandiHaler in period 1 and ELLIPTA in period 2, followed by PQ2). Participants continued to take their own prescribed COPD medication and rescue medications for the entire 56-day study period. All participants on study received placebo only and participant flow reflects this as the only treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Atleast One Error After 28 Days of Inhaler Use in Each Treatment Phase (Primary Estimand: Hypothetical)</title>
          <description>Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included</description>
          <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="217"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Atleast 1 error-ELLIPTA&amp;0 errors-DISKUS+HandiHaler</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Atleast 1error-DISKUS+HandiHaler&amp;0errors-ELLIPTA</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23"/>
                  </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</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <method_desc>Sensitivity Analyses (Primary Estimand: Hypothetical)</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Errors Per Participant for Each Treatment Group After 28 Days of Use (Primary Estimand: Hypothetical)</title>
        <description>Participants were provided with PIL explaining correct use of inhaler. Overall error includes both critical and non-critical errors. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
        <time_frame>Up to Day 56</time_frame>
        <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>ELLIPTA</title>
            <description>Participants were randomized to use placebo via ELLIPTA in either period 1 or 2.</description>
          </group>
          <group group_id="O2">
            <title>DISKUS + HandiHaler</title>
            <description>Participants were randomized to use placebo via DISKUS + HANDIHALER in period 1 or 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Errors Per Participant for Each Treatment Group After 28 Days of Use (Primary Estimand: Hypothetical)</title>
          <description>Participants were provided with PIL explaining correct use of inhaler. Overall error includes both critical and non-critical errors. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
          <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
          <units>Errors per participant</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="217"/>
                <count group_id="O2" value="217"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="0" upper_limit="1"/>
                    <measurement group_id="O2" value="0.6" lower_limit="0" upper_limit="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Errors Per Participant for Each Treatment Group After 28 Days of Use</title>
        <description>Assessment of errors was conducted by HCP trained in the correct inhaler use of the three inhalers based on the checklist of errors. The median number of overall errors made by per participant was assessed for ELLIPTA and DISKUS + HandiHaler both on Day 1 and Day 28 for each treatment group. The difference was calculated by subtracting values of Day 28 from Day1 for each treatment regimen. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
        <time_frame>Day 1 and Day 28 of each treatment group</time_frame>
        <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>ELLIPTA</title>
            <description>Participants were randomized to use placebo via ELLIPTA in either period 1 or 2.</description>
          </group>
          <group group_id="O2">
            <title>DISKUS + HandiHaler</title>
            <description>Participants were randomized to use placebo via DISKUS + HANDIHALER in period 1 or 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Errors Per Participant for Each Treatment Group After 28 Days of Use</title>
          <description>Assessment of errors was conducted by HCP trained in the correct inhaler use of the three inhalers based on the checklist of errors. The median number of overall errors made by per participant was assessed for ELLIPTA and DISKUS + HandiHaler both on Day 1 and Day 28 for each treatment group. The difference was calculated by subtracting values of Day 28 from Day1 for each treatment regimen. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
          <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
          <units>Errors per participant</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="217"/>
                <count group_id="O2" value="217"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0" lower_limit="-3" upper_limit="1"/>
                    <measurement group_id="O2" value="0.0" lower_limit="-10" upper_limit="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Errors for Each Treatment Group in Participants With One or More Errors After 28 Days of Use (Primary Estimand: Hypothetical)</title>
        <description>Participants were provided with the PIL, explaining correct use of the inhaler. Overall error includes both critical and non-critical errors. Assessment of errors was conducted by HCP trained in the correct inhaler use of the three inhalers based on the checklist of errors. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
        <time_frame>Up to Day 56</time_frame>
        <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>ELLIPTA</title>
            <description>Participants were randomized to use placebo via ELLIPTA in either period 1 or 2.</description>
          </group>
          <group group_id="O2">
            <title>DISKUS + HandiHaler</title>
            <description>Participants were randomized to use placebo via DISKUS + HANDIHALER in period 1 or 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Errors for Each Treatment Group in Participants With One or More Errors After 28 Days of Use (Primary Estimand: Hypothetical)</title>
          <description>Participants were provided with the PIL, explaining correct use of the inhaler. Overall error includes both critical and non-critical errors. Assessment of errors was conducted by HCP trained in the correct inhaler use of the three inhalers based on the checklist of errors. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
          <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
          <units>Errors per participant</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="217"/>
                <count group_id="O2" value="217"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.0" lower_limit="1" upper_limit="1"/>
                    <measurement group_id="O2" value="4.4" lower_limit="1" upper_limit="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Errors for Each Treatment Group in Participants With One or More Errors After 28 Days of Use</title>
        <description>Assessment of errors was conducted by health care professionals trained in the correct inhaler use of the three inhalers based on the checklist of errors. The median of overall errors made by each participant was assessed for ELLIPTA and DISKUS + HandiHaler both on Day 1 and Day 28. The difference was calculated by subtracting values of Day 28 from Day1 for each treatment regimen. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
        <time_frame>Day 1 and Day 28 of each treatment group</time_frame>
        <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>ELLIPTA</title>
            <description>Participants were randomized to use placebo via ELLIPTA in either period 1 or 2.</description>
          </group>
          <group group_id="O2">
            <title>DISKUS + HandiHaler</title>
            <description>Participants were randomized to use placebo via DISKUS + HANDIHALER in period 1 or 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Errors for Each Treatment Group in Participants With One or More Errors After 28 Days of Use</title>
          <description>Assessment of errors was conducted by health care professionals trained in the correct inhaler use of the three inhalers based on the checklist of errors. The median of overall errors made by each participant was assessed for ELLIPTA and DISKUS + HandiHaler both on Day 1 and Day 28. The difference was calculated by subtracting values of Day 28 from Day1 for each treatment regimen. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
          <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
          <units>Errors per participant</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="217"/>
                <count group_id="O2" value="217"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.7" lower_limit="-1" upper_limit="1"/>
                    <measurement group_id="O2" value="2.6" lower_limit="-4" upper_limit="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Zero Critical Errors After 28 Days of Each Treatment Group Use (Primary Estimand: Hypothetical)</title>
        <description>A checklist for correct use of each inhaler was developed based on the steps identified in the PIL. A critical error was defined as an error that was most likely to result in no, or a significantly reduced amount, of medication being inhaled by the participant. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
        <time_frame>Up to Day 56</time_frame>
        <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>ELLIPTA</title>
            <description>Participants were randomized to use placebo via ELLIPTA in either period 1 or 2.</description>
          </group>
          <group group_id="O2">
            <title>DISKUS + HandiHaler</title>
            <description>Participants were randomized to use placebo via DISKUS + HANDIHALER in period 1 or 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Zero Critical Errors After 28 Days of Each Treatment Group Use (Primary Estimand: Hypothetical)</title>
          <description>A checklist for correct use of each inhaler was developed based on the steps identified in the PIL. A critical error was defined as an error that was most likely to result in no, or a significantly reduced amount, of medication being inhaled by the participant. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
          <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="217"/>
                <count group_id="O2" value="217"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="215"/>
                    <measurement group_id="O2" value="193"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>stratified exact logistic model</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>8.85</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>3.45</ci_lower_limit>
            <ci_upper_limit_na_comment>The upper bound of the 95% CI could not be calculated due to the low number of events and is therefore displayed as NA.</ci_upper_limit_na_comment>
            <estimate_desc>Participants included in the model as fixed strata, treatment option was included in the exact statement and period included as fixed effects.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Participants With Atleast One Error After 28 Days of Inhaler Use in Each Treatment Phase (Supplementary Estimand: Composite)</title>
        <description>Supplementary estimand estimated the composite effect of initial randomized treatment. A sensitivity analysis using the Cochran-Mantel-Haenszel test was performed on participants with discordant results. Participants who withdrew during period 2 were included in the analysis using early withdrawal data where available or imputation otherwise. Participants who experienced an intercurrent event in Period 1 were excluded from the analysis.</description>
        <time_frame>Up to Day 56</time_frame>
        <group_list>
          <group group_id="O1">
            <title>All Study Participants</title>
            <description>Participants received placebo via ELLIPTA dry powder inhaler (DPI) or DISKUS DPI in combination with HandiHaler DPI based on the following treatment sequences: Treatment Sequence A (ELLIPTA in period 1 and DISKUS + HandiHaler in period 2, followed by PQ 1.); Treatment Sequence B (ELLIPTA in period 1 and DISKUS + HandiHaler in period 2, followed by PQ2); Treatment Sequence C (DISKUS + HandiHaler in period 1 and ELLIPTA in period 2, followed by PQ1); or Treatment Sequence D (DISKUS + HandiHaler in period 1 and ELLIPTA in period 2, followed by PQ2). Participants continued to take their own prescribed COPD medication and rescue medications for the entire 56-day study period. All participants on study received placebo only and participant flow reflects this as the only treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Atleast One Error After 28 Days of Inhaler Use in Each Treatment Phase (Supplementary Estimand: Composite)</title>
          <description>Supplementary estimand estimated the composite effect of initial randomized treatment. A sensitivity analysis using the Cochran-Mantel-Haenszel test was performed on participants with discordant results. Participants who withdrew during period 2 were included in the analysis using early withdrawal data where available or imputation otherwise. Participants who experienced an intercurrent event in Period 1 were excluded from the analysis.</description>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="224"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Atleast 1 error-ELLIPTA&amp;0 errors-DISKUS+HandiHaler</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Atleast 1error-DISKUS+HandiHaler&amp;0errors-ELLIPTA</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27"/>
                  </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</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <method_desc>Sensitivity Analyses (Supplementary Estimand: Composite)</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Atleast One Critical Error After 28 Days of Each Treatment Group Use (Primary Estimand: Hypothetical)</title>
        <description>A critical error was defined as an error that was most likely to result in no, or a significantly reduced amount, of medication being inhaled by the participant. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
        <time_frame>Up to Day 56</time_frame>
        <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>All Study Participants</title>
            <description>Participants received placebo via ELLIPTA dry powder inhaler (DPI) or DISKUS DPI in combination with HandiHaler DPI based on the following treatment sequences: Treatment Sequence A (ELLIPTA in period 1 and DISKUS + HandiHaler in period 2, followed by PQ 1.); Treatment Sequence B (ELLIPTA in period 1 and DISKUS + HandiHaler in period 2, followed by PQ2); Treatment Sequence C (DISKUS + HandiHaler in period 1 and ELLIPTA in period 2, followed by PQ1); or Treatment Sequence D (DISKUS + HandiHaler in period 1 and ELLIPTA in period 2, followed by PQ2). Participants continued to take their own prescribed COPD medication and rescue medications for the entire 56-day study period. All participants on study received placebo only and participant flow reflects this as the only treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Atleast One Critical Error After 28 Days of Each Treatment Group Use (Primary Estimand: Hypothetical)</title>
          <description>A critical error was defined as an error that was most likely to result in no, or a significantly reduced amount, of medication being inhaled by the participant. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.</description>
          <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
          <units>Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="217"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Atleast 1 critical error with ELLIPTA</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Atleast 1 critical error with DISKUS+HandiHaler</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23"/>
                  </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</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <method_desc>Sensitivity Analyses (Primary Estimand: Hypothetical)</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Atleast One Critical Error After 28 Days of Each Treatment Group Use (Supplementary Estimand: Composite)</title>
        <description>Supplementary estimand estimated the composite effect of initial randomized treatment. A sensitivity analysis using the Cochran-Mantel-Haenszel test was performed on participants with discordant results. Participants who withdrew during period 2 were included in the analysis using early withdrawal data where available or imputation otherwise. Participants who experienced an intercurrent event in Period 1 were excluded from the analysis.</description>
        <time_frame>Up to Day 56</time_frame>
        <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>All Study Participants</title>
            <description>Participants received placebo via ELLIPTA dry powder inhaler (DPI) or DISKUS DPI in combination with HandiHaler DPI based on the following treatment sequences: Treatment Sequence A (ELLIPTA in period 1 and DISKUS + HandiHaler in period 2, followed by PQ 1.); Treatment Sequence B (ELLIPTA in period 1 and DISKUS + HandiHaler in period 2, followed by PQ2); Treatment Sequence C (DISKUS + HandiHaler in period 1 and ELLIPTA in period 2, followed by PQ1); or Treatment Sequence D (DISKUS + HandiHaler in period 1 and ELLIPTA in period 2, followed by PQ2). Participants continued to take their own prescribed COPD medication and rescue medications for the entire 56-day study period. All participants on study received placebo only and participant flow reflects this as the only treatment.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Atleast One Critical Error After 28 Days of Each Treatment Group Use (Supplementary Estimand: Composite)</title>
          <description>Supplementary estimand estimated the composite effect of initial randomized treatment. A sensitivity analysis using the Cochran-Mantel-Haenszel test was performed on participants with discordant results. Participants who withdrew during period 2 were included in the analysis using early withdrawal data where available or imputation otherwise. Participants who experienced an intercurrent event in Period 1 were excluded from the analysis.</description>
          <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="217"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Atleast 1 error-ELLIPTA&amp;0 errors-DISKUS+HandiHaler</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Atleast 1error-DISKUS+HandiHaler&amp;0errors-ELLIPTA</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27"/>
                  </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</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>Cochran-Mantel-Haenszel</method>
            <method_desc>Sensitivity Analyses (Supplementary Composite Estimand)</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Participants With Zero Errors After 28 Days of Inhaler Use in Each Treatment Phase(Supplementary Estimand: Composite)</title>
        <description>Supplementary estimand estimated the composite effect of initial randomized treatment. The analysis was performed using stratified exact logistic model. Participants were included in the model as fixed strata, treatment option was included in the exact statement and period included as fixed effects. Participants who withdrew during period 2 were included in the analysis using early withdrawal data where available or imputation otherwise. Participants who experienced an intercurrent event in Period 1 were excluded from the analysis.</description>
        <time_frame>Up to Day 56</time_frame>
        <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>ELLIPTA</title>
            <description>Participants were randomized to use placebo via ELLIPTA in either period 1 or 2.</description>
          </group>
          <group group_id="O2">
            <title>DISKUS + HandiHaler</title>
            <description>Participants were randomized to use placebo via DISKUS + HANDIHALER in period 1 or 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Zero Errors After 28 Days of Inhaler Use in Each Treatment Phase(Supplementary Estimand: Composite)</title>
          <description>Supplementary estimand estimated the composite effect of initial randomized treatment. The analysis was performed using stratified exact logistic model. Participants were included in the model as fixed strata, treatment option was included in the exact statement and period included as fixed effects. Participants who withdrew during period 2 were included in the analysis using early withdrawal data where available or imputation otherwise. Participants who experienced an intercurrent event in Period 1 were excluded from the analysis.</description>
          <population>ITT Population. Only those participants with data available at specified time point were analyzed.</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="224"/>
                <count group_id="O2" value="224"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="95"/>
                    <measurement group_id="O2" value="85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>stratified exact logistic model</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>6.06</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>2.08</ci_lower_limit>
            <ci_upper_limit>24.55</ci_upper_limit>
            <estimate_desc>Participants included in the model as fixed strata, treatment option was included in the exact statement and period included as fixed effects.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to Day 56</time_frame>
      <desc>Intent-to-Treat Population was used to collect Adverse Events. Since all participants received placebo as treatment, data has been clubbed for all the arms. The non-serious AEs are reported using a frequency threshold of &gt;5%</desc>
      <group_list>
        <group group_id="E1">
          <title>All Study Participants</title>
          <description>Participants received placebo via ELLIPTA dry powder inhaler (DPI) or DISKUS DPI in combination with HandiHaler DPI based on the following treatment sequences: Treatment Sequence A (ELLIPTA in period 1 and DISKUS + HandiHaler in period 2, followed by PQ 1.); Treatment Sequence B (ELLIPTA in period 1 and DISKUS + HandiHaler in period 2, followed by PQ2); Treatment Sequence C (DISKUS + HandiHaler in period 1 and ELLIPTA in period 2, followed by PQ1); or Treatment Sequence D (DISKUS + HandiHaler in period 1 and ELLIPTA in period 2, followed by PQ2). Participants continued to take their own prescribed COPD medication and rescue medications for the entire 56-day study period.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 20.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="239"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="239"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="239"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="239"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="239"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="239"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="239"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysarthria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="239"/>
              </event>
              <event>
                <sub_title>Hemiparesis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="239"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="239"/>
              </event>
              <event>
                <sub_title>Acute respiratory failure</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="239"/>
              </event>
              <event>
                <sub_title>Pneumonia aspiration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="239"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="239"/>
              </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>
      <email>GSKClinicalSupportHD@gsk.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03227445
org study id: 206901
nct id: NCT03227445
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: Yes
This randomized, cross over study aims to find out the benefits of delivering triple therapy
      using a single ELLIPTA® DPI (fixed-dose combination triple therapy) versus delivering triple
      therapy using two different types of inhalers (open triple therapy) including DISKUS® with
      HandiHaler® to subjects with COPD. Correct inhaler use, critical errors and performance
      attributes will also be assessed. Approximately 240 subjects with COPD will be randomized in
      the study. The study will be conducted in 3 visits and will be completed in approximately 56
      days. At Visit 1 (Day 1) and Visit 2 (Day 28) subjects will be randomized to receive a
      placebo ELLIPTA inhaler once daily (QD) or a placebo DISKUS twice daily (BID) with placebo
      HandiHaler QD inhaler in 1:1 ratio in a cross-over manner for the study period (28 days for
      each period). At Visit 3 (Day 56), subjects will be asked to complete preference
      questionnaire 1 or 2. There will be no active treatment and subjects will continue to take
      their own prescribed COPD maintenance and rescue medication during the entire study period.
      ELLIPTA and DISKUS are the registered trademarks of GlaxoSmithKline group of companies.
      HandiHaler is the registered trademark of Boehringer Ingelheim group of companies.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Subjects will be randomized to receive a placebo ELLIPTA inhaler QD or a placebo DISKUS BID with placebo HandiHaler QD inhaler at Visit 1 and Visit 2 in a cross-over manner followed by Preference Questionnaire 1 or 2
primary purpose: Treatment
masking: None (Open Label)
masking description: This will an open-label study and blinding will not be performed.
measure: Percentage of Participants With Zero Errors After 28 Days of Inhaler Use in Each Treatment Phase (Primary Estimand: Hypothetical)
time frame: Up to Day 56
description: A checklist for correct use of each inhaler was developed in Patient Instruction Leaflets (PIL's). Participants were guided by trained health care provider (HCP) to demonstrate correct use of inhaler. Baseline assessment was conducted when participant initially dispensed the inhaler. Second assessment was conducted after each 28day dosing period. Correct Use Check list was completed by HCP at each visit. Primary hypothetical estimand is the estimate of treatment effect of all participants who stayed on their randomized study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. Participants could attend visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. Participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included
measure: Percentage of Participants With Atleast One Error After 28 Days of Inhaler Use in Each Treatment Phase (Primary Estimand: Hypothetical)
time frame: Up to Day 56
description: Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included
measure: Percentage of Participants With Atleast One Error After 28 Days of Inhaler Use in Each Treatment Phase (Supplementary Estimand: Composite)
time frame: Up to Day 56
description: Supplementary estimand estimated the composite effect of initial randomized treatment. A sensitivity analysis using the Cochran-Mantel-Haenszel test was performed on participants with discordant results. Participants who withdrew during period 2 were included in the analysis using early withdrawal data where available or imputation otherwise. Participants who experienced an intercurrent event in Period 1 were excluded from the analysis.
measure: Percentage of Participants With Zero Errors After 28 Days of Inhaler Use in Each Treatment Phase(Supplementary Estimand: Composite)
time frame: Up to Day 56
description: Supplementary estimand estimated the composite effect of initial randomized treatment. The analysis was performed using stratified exact logistic model. Participants were included in the model as fixed strata, treatment option was included in the exact statement and period included as fixed effects. Participants who withdrew during period 2 were included in the analysis using early withdrawal data where available or imputation otherwise. Participants who experienced an intercurrent event in Period 1 were excluded from the analysis.
measure: Number of Errors by Type for Each Inhaler After 28 Days of Use in Each Treatment Phase (Primary Estimand: Hypothetical)
time frame: Up to Day 56
description: The occurrence of each type of error for each inhaler (ELLIPTA, DISKUS or HANDIHALER) were evaluated based on the information collected in Correct Use Checklists. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence & did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups & experienced no intercurrent events were included. The number of error is reported as NA for the type of error which was not applicable to the particular inhaler type
measure: Number of Errors Per Participant for Each Treatment Group After 28 Days of Use (Primary Estimand: Hypothetical)
time frame: Up to Day 56
description: Participants were provided with PIL explaining correct use of inhaler. Overall error includes both critical and non-critical errors. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.
measure: Change in Errors Per Participant for Each Treatment Group After 28 Days of Use
time frame: Day 1 and Day 28 of each treatment group
description: Assessment of errors was conducted by HCP trained in the correct inhaler use of the three inhalers based on the checklist of errors. The median number of overall errors made by per participant was assessed for ELLIPTA and DISKUS + HandiHaler both on Day 1 and Day 28 for each treatment group. The difference was calculated by subtracting values of Day 28 from Day1 for each treatment regimen. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.
measure: Number of Errors for Each Treatment Group in Participants With One or More Errors After 28 Days of Use (Primary Estimand: Hypothetical)
time frame: Up to Day 56
description: Participants were provided with the PIL, explaining correct use of the inhaler. Overall error includes both critical and non-critical errors. Assessment of errors was conducted by HCP trained in the correct inhaler use of the three inhalers based on the checklist of errors. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.
measure: Change in Errors for Each Treatment Group in Participants With One or More Errors After 28 Days of Use
time frame: Day 1 and Day 28 of each treatment group
description: Assessment of errors was conducted by health care professionals trained in the correct inhaler use of the three inhalers based on the checklist of errors. The median of overall errors made by each participant was assessed for ELLIPTA and DISKUS + HandiHaler both on Day 1 and Day 28. The difference was calculated by subtracting values of Day 28 from Day1 for each treatment regimen. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.
measure: Number of Participants With Zero Critical Errors After 28 Days of Each Treatment Group Use (Primary Estimand: Hypothetical)
time frame: Up to Day 56
description: A checklist for correct use of each inhaler was developed based on the steps identified in the PIL. A critical error was defined as an error that was most likely to result in no, or a significantly reduced amount, of medication being inhaled by the participant. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.
measure: Number of Participants With Atleast One Critical Error After 28 Days of Each Treatment Group Use (Primary Estimand: Hypothetical)
time frame: Up to Day 56
description: A critical error was defined as an error that was most likely to result in no, or a significantly reduced amount, of medication being inhaled by the participant. Primary estimand is the treatment effect estimated in participants who stayed on their randomised study device sequence and did not change their standard COPD maintenance medication device to one delivered via ELLIPTA, DISKUS or HANDIHALER, throughout both 28 day treatment periods. The participant could attend the visit without the device/s they were randomised to, in which case correct use cannot be assessed as described in the protocol. For primary estimand, a sensitivity analysis using Cochran-Mantel-Haenszel test was performed on participants with discordant results. Only those participants who completed error assessments for both randomized treatment groups and experienced no intercurrent events were included.
measure: Number of Participants With Atleast One Critical Error After 28 Days of Each Treatment Group Use (Supplementary Estimand: Composite)
time frame: Up to Day 56
description: Supplementary estimand estimated the composite effect of initial randomized treatment. A sensitivity analysis using the Cochran-Mantel-Haenszel test was performed on participants with discordant results. Participants who withdrew during period 2 were included in the analysis using early withdrawal data where available or imputation otherwise. Participants who experienced an intercurrent event in Period 1 were excluded from the analysis.
arm group label: Treatment sequence A
arm group type: Experimental
description: Eligible subjects will use ELLIPTA DPI QD for 28 days in Period 1 followed by DISKUS BID with HandiHaler QD use for 28 days in Period 2. These subjects will then be asked to complete preference questionnaire 1 at Visit 3 (Day 56).
arm group label: Treatment sequence B
arm group type: Experimental
description: Eligible subjects will use ELLIPTA DPI QD for 28 days in Period 1 followed by DISKUS BID with HandiHaler QD use for 28 days in Period 2. These subjects will then be asked to complete preference questionnaire 2 at Visit 3 (Day 56).
arm group label: Treatment sequence C
arm group type: Experimental
description: Eligible subjects will use DISKUS BID with HandiHaler QD for 28 days in Period 1 followed by ELLIPTA DPI QD use for 28 days in Period 2. These subjects will then be asked to complete preference questionnaire 1 at Visit 3 (Day 56).
arm group label: Treatment sequence D
arm group type: Experimental
description: Eligible subjects will use DISKUS BID with HandiHaler QD for 28 days in Period 1 followed by ELLIPTA DPI QD use for 28 days in Period 2. These subjects will then be asked to complete preference questionnaire 2 at Visit 3 (Day 56).
intervention type: Device
intervention name: ELLIPTA placebo DPI
description: ELLIPTA is a dry powder inhaler used via oral route. It will be a placebo DPI with two strips with 30 blisters per strip. First strip will contain lactose monohydrate and the second strip will contain lactose monohydrate blended with magnesium stearate.
arm group label: Treatment sequence A
arm group label: Treatment sequence B
arm group label: Treatment sequence C
arm group label: Treatment sequence D
intervention type: Device
intervention name: DISKUS placebo DPI
description: DISKUS is a dry powder inhaler used via oral route. It will be a placebo DPI with one blister strip that will contain lactose monohydrate.
arm group label: Treatment sequence A
arm group label: Treatment sequence B
arm group label: Treatment sequence C
arm group label: Treatment sequence D
intervention type: Device
intervention name: HandiHaler placebo DPI
description: HandiHaler is a dry powder inhaler used via oral route. It will be a DPI with placebo capsules that will contain lactose monohydrate.
arm group label: Treatment sequence A
arm group label: Treatment sequence B
arm group label: Treatment sequence C
arm group label: Treatment sequence D
intervention type: Other
intervention name: Inhaler preference questionnaires
description: Preference questionnaires will be given to subjects to understand the inhaler preference. There will be 2 types of questionnaire, preference questionnaires 1 and 2, which will be randomized at visit 3 (Day 56).
arm group label: Treatment sequence A
arm group label: Treatment sequence B
arm group label: Treatment sequence C
arm group label: Treatment sequence D
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
last name: GSK Clinical Trials
role: Study Director
affiliation: GlaxoSmithKline
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country: United States
citation: Kerwin EM, Spangenthal S, Zvarich M, Millar V, Jain R, Collison K, Sharma R. ELLIPTA Versus DISKUS plus HandiHaler in COPD: A Randomized, Open-Label, Crossover Study in a Clinical Trial Setting. Chronic Obstr Pulm Dis. 2020 Apr;7(2):118-129. doi: 10.15326/jcopdf.7.2.2019.0153.
PMID: 32324983
responsible party type: Sponsor
mesh term: Lung Diseases
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
sharing ipd: Yes
ipd description: IPD for this study will be made available via the Clinical Study Data Request site.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
ipd access criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
ipd url: https://clinicalstudydatarequest.com/Posting.aspx?ID=20372
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