Comparative Study of ELLIPTA Dry Powder Inhaler (DPI) Versus DISKUS DPI Used With HandiHaler DPI in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Device: ELLIPTA placebo DPI
* Device: DISKUS placebo DPI
* Device: HandiHaler placebo DPI
* Other: Inhaler preference questionnaires


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be capable of giving signed informed consent. Subjects must have a diagnosis of COPD with a documented history of COPD for at least 12 months, in accordance with the definition by the American Thoracic Society/European Respiratory Society. Subjects must be 40 years of age inclusive, at the time of signing the informed consent. Male or female subjects will be included. Females must not be pregnant or planning pregnancy during the study or not lactating. Subjects must have a documented post albuterol forced expiratory volume in one second (FEV1)/ forced vital capacity (FVC) ratio <0.70 and FEV1 <=70% of predicted obtained within two years of Visit 1. Current or former (defined as subjects who have quit smoking for at least 3 months prior to Screening/Visit 1) cigarette smokers with a > 10 pack-year smoking history [Number of pack-years = (number of cigarettes per day/20) x number of years smoked (example, 10 pack-years is equal to 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years]. All subjects should be currently receiving maintenance treatment for COPD for at least 4 weeks prior to Randomization/Visit 1 and evaluated as unlikely to change COPD treatment within 4 weeks of Visit 1. All subjects should be able to stay on their prescribed maintenance COPD inhaler (s) without change throughout the entire treatment period. Subjects must be able to read, comprehend, and record information in English. Exclusion Criteria: Subjects must not have a current diagnosis of asthma. Subjects must not have used the ELLIPTA, DISKUS, or HandiHaler inhalers in the 12 months prior to Visit 1. Subjects must not be receiving their current COPD medications with the ELLIPTA, DISKUS, or HandiHaler inhalers. Subjects must not be receiving only inhaled short-acting beta-adrenergic agonists, i.e., albuterol as their daily COPD therapy (as needed or regularly scheduled). Subjects must not have experienced more than 1 COPD exacerbation which required hospitalization in the 12 months prior to Visit 1. Subjects must not have a known or suspected history of alcohol or drug abuse within the last 2 years. Subjects must not have a history of hypersensitivity to any component of the study inhalers (example, lactose, magnesium stearate). In addition, subjects with a history of severe milk protein allergy that, in the opinion of the study physician, contraindicates participation will also be excluded. Subjects with other respiratory disorders, including active tuberculosis, active lung cancer, sarcoidosis, lung fibrosis, pulmonary hypertension, or pulmonary disease (including but not confined to asthma, bronchiectasis with the need for treatment, cystic fibrosis, and bronchopulmonary dysplasia), interstitial lung diseases or other active pulmonary diseases. Subjects with historical, or current evidence of clinically significant or rapidly progressing or unstable cardiovascular, neurological, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the participant at risk through participation, or which would affect the analysis if the disease/condition exacerbated during the study will be excluded. Subjects with history of psychiatric disease, intellectual impairment, poor motivation or other conditions that will limit the validity of informed consent to participate in the study will be excluded. Subjects at risk of non-compliance, or unable to comply with the study procedures, or unable to continue their current medications. Subjects who have received an investigational drug and/or medical device/inhaler within 30 days of entry into this study (Screening/Visit 1), or within five drug half-lives of the investigational drug, whichever is longer. Subjects will not be eligible for this study if he/she is an immediate family member of the participating investigator, sub investigator, study coordinator, or employee of the participating investigator.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment sequence A<br>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). | Device: ELLIPTA placebo DPI<br>* 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.<br>Device: DISKUS placebo DPI<br>* 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.<br>Device: HandiHaler placebo DPI<br>* HandiHaler is a dry powder inhaler used via oral route. It will be a DPI with placebo capsules that will contain lactose monohydrate.<br>Other: Inhaler preference questionnaires<br>* 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).<br>|
| Experimental: Treatment sequence B<br>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). | Device: ELLIPTA placebo DPI<br>* 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.<br>Device: DISKUS placebo DPI<br>* 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.<br>Device: HandiHaler placebo DPI<br>* HandiHaler is a dry powder inhaler used via oral route. It will be a DPI with placebo capsules that will contain lactose monohydrate.<br>Other: Inhaler preference questionnaires<br>* 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).<br>|
| Experimental: Treatment sequence C<br>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). | Device: ELLIPTA placebo DPI<br>* 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.<br>Device: DISKUS placebo DPI<br>* 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.<br>Device: HandiHaler placebo DPI<br>* HandiHaler is a dry powder inhaler used via oral route. It will be a DPI with placebo capsules that will contain lactose monohydrate.<br>Other: Inhaler preference questionnaires<br>* 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).<br>|
| Experimental: Treatment sequence D<br>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). | Device: ELLIPTA placebo DPI<br>* 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.<br>Device: DISKUS placebo DPI<br>* 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.<br>Device: HandiHaler placebo DPI<br>* HandiHaler is a dry powder inhaler used via oral route. It will be a DPI with placebo capsules that will contain lactose monohydrate.<br>Other: Inhaler preference questionnaires<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Zero Errors After 28 Days of Inhaler Use in Each Treatment Phase (Primary Estimand: Hypothetical) | 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 | Up to Day 56 | 
| Percentage of Participants With Atleast One Error After 28 Days of Inhaler Use in Each Treatment Phase (Primary Estimand: Hypothetical) | 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 | Up to Day 56 | 
| Percentage of Participants With Atleast One Error After 28 Days of Inhaler Use in Each Treatment Phase (Supplementary Estimand: Composite) | 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. | Up to Day 56 | 
| Percentage of Participants With Zero Errors After 28 Days of Inhaler Use in Each Treatment Phase(Supplementary Estimand: Composite) | 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. | Up to Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Errors by Type for Each Inhaler After 28 Days of Use in Each Treatment Phase (Primary Estimand: Hypothetical) | 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 | Up to Day 56 | 
| Number of Errors Per Participant for Each Treatment Group After 28 Days of Use (Primary Estimand: Hypothetical) | 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. | Up to Day 56 | 
| Change in Errors Per Participant for Each Treatment Group After 28 Days of Use | 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. | Day 1 and Day 28 of each treatment group | 
| Number of Errors for Each Treatment Group in Participants With One or More Errors After 28 Days of Use (Primary Estimand: Hypothetical) | 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. | Up to Day 56 | 
| Change in Errors for Each Treatment Group in Participants With One or More Errors After 28 Days of Use | 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. | Day 1 and Day 28 of each treatment group | 
| Number of Participants With Zero Critical Errors After 28 Days of Each Treatment Group Use (Primary Estimand: Hypothetical) | 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. | Up to Day 56 | 
| Number of Participants With Atleast One Critical Error After 28 Days of Each Treatment Group Use (Primary Estimand: Hypothetical) | 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. | Up to Day 56 | 
| Number of Participants With Atleast One Critical Error After 28 Days of Each Treatment Group Use (Supplementary Estimand: Composite) | 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. | Up to Day 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DISKUS, HandiHaler, COPD, Placebo, Cross-over, Dry powder inhaler, ELLIPTA