A 24-week Study to Compare Umeclidinium/Vilanterol (UMEC/VI), UMEC and Salmeterol in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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COPD is characterized by an airflow limitation, which is not fully reversible, usually progressive and accompanied by chronic cough, sputum production and dyspnea, which can be a major cause of disability and anxiety associated with the disease. In addition, COPD is associated with poor health-related quality of life (HRQoL). Pharmacologic therapy is used to improve lung function, reduce symptoms, reduce the frequency and severity of exacerbations, and also to improve health status and exercise tolerance. This is a multi-center, randomized, double blind, double dummy, 3-arm parallel group study to compare umeclidinium/vilanterol (62.5/25 microgram [mcg], once daily), umeclidinium (62.5 mcg, once daily), and salmeterol (50 mg, twice daily) in male and female subjects with COPD. The primary purpose of this study is to demonstrate improvements in lung function for subjects treated with UMEC/VI compared with UMEC for 24 weeks. Approximately 2424 subjects will be randomized across 3 parallel arms in 1:1:1 ratio. Subjects will be stratified based on long-acting bronchodilator usage during the run-in period (none, one or 2 long-acting bronchodilators per day). Subjects will receive either UMEC/VI inhalation powder (62.5/25 microgram [mcg] once daily) administered via the ELLIPTA® dry powder inhaler (DPI) and placebo twice daily via DISKUS® DPI; or UMEC (62.5 mcg once daily) administered via the ELLIPTA DPI and placebo twice daily via DISKUS DPI or salmeterol (50 mcg twice daily [BID]) administered via the DISKUS DPI and placebo once daily via ELLIPTA DPI. The duration of the study will be 29 to 31 weeks including a pre-screening period of 2 weeks, run-in period of 4 weeks, treatment period of 24 weeks and follow-up period of 1 week. ELLIPTA and DISKUS are trademarks of GSK group of companies.

Official Title
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A 24-week Treatment, Multi-center, Randomized, Double-blind, Double-dummy, Parallel Group Study to Compare Umeclidinium/Vilanterol, Umeclidinium, and Salmeterol in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: UMEC/VI 62.5/25 mcg via ELLIPTA
* Drug: UMEC 62.5 mcg via ELLIPTA
* Drug: Salmeterol 50 mcg via DISKUS
* Drug: Placebo via ELLIPTA
* Drug: Placebo via DISKUS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 40 years or older at date of signing informed consent at Screening Visit 1 Outpatient with a diagnosis of COPD Persistent airflow limitations as indicated by a pre and post-albuterol/salbutamol FEV1/FVC ratio of <0.70 and a post-albuterol/salbutamol FEV1 of >=30% to <=80% predicted normal values at Screening Visit 1. A CAT score of >=10 at Screening Visit 1 Current or former cigarette smokers with a history of cigarette smoking of >=10 pack-years (number of pack years = [number of cigarettes per day / 20] multiplied by number of years smoked [e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years both equal 10 pack-years]). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Pipe and/or cigar use cannot be used to calculate pack-year history. Male and female subjects are eligible to participate in the study. A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin test), not lactating, and at least one of the following conditions applies: non-reproductive potential defined as pre-menopausal females with documented tubal ligation or documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or hysterectomy or documented bilateral oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases, a blood sample with simultaneous follicle stimulating hormone and estradiol levels consistent with menopause must be tested. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. A female subject with reproductive potential is eligible to participate if she is not pregnant and agrees to follow one of the highly effective methods for avoiding pregnancy in females of reproductive potential from 30 days prior to the first dose of study medication and until (at least five terminal half-lives or until any continuing pharmacologic effect has ended, whichever is longer) after the last dose of study medication and completion of the follow-up visit. The investigator is responsible for ensuring that subjects understand how to properly use methods of contraception. Capable of giving signed informed consent prior to study participation. Exclusion criteria A current diagnosis of asthma (Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD, which is the primary cause of their respiratory symptoms). Subjects with known alpha-antitrypsin deficiency as the underlying cause of COPD Subjects with active tuberculosis are excluded. Subjects with other respiratory disorders (e.g., clinically significant: bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases) are excluded if these conditions are the primary cause of their respiratory symptoms. Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease as per investigator assessment); stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis; chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen or positive hepatitis C antibody test result or within 3 months prior to first dose of study treatment) are acceptable if subject otherwise meets entry criteria. Subjects with unstable or life threatening cardiac disease. The investigational product should be used with caution in subjects with severe cardiovascular disease. In the opinion of the investigator, use will only be considered if the benefit is likely to outweigh the risk in conditions such as myocardial infarction or unstable angina in the last 6 months, or unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months, or New York Heart Association Class IV heart failure. The investigator will determine the clinical significance of each abnormal electrocardiogram (ECG) finding in relation to the subject's medical history and exclude subjects who would be at undue risk by participating in the trial. Subjects with the following abnormalities are excluded from participation in the study: atrial fibrillation with rapid ventricular rate >120 beats per minute (bpm), sustained or non-sustained ventricular tachycardia, second degree heart block Mobitz type II or third degree heart block (unless pacemaker or defibrillator had been inserted). Subjects with medical conditions such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction will be excluded unless, in the opinion of the study physician, the benefit outweighs the risk. Any subject who is considered unlikely to survive the duration of the study period or has any rapidly progressing disease or immediate life-threatening illness (e.g., cancer). In addition, any subject who has any other condition (e.g., neurological condition) that is likely to affect respiratory function will not be included in the study. Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1. Pneumonia and/or moderate or severe COPD exacerbation that has not resolved at least 14 days prior to Screening Visit 1and at least 30 days following the last dose of oral/systemic corticosteroids (if applicable). Subjects who had received inhaled corticosteroids (ICS) or ICS/ long-acting beta-agonist for the treatment of COPD in the 6 weeks prior to Screening Visit1. Subjects who had >1 moderate exacerbation in the 12 months prior to Screening Visit 1, or one severe exacerbation requiring hospitalization in the 12 months prior to Screening Visit 1. Other respiratory tract infections that have not resolved at least 7 days prior to Screening Visit 1. Subjects with lung volume reduction surgery (including procedures such as endobronchial valves) within the 12 months prior to Screening Visit 1. Use of long-term oxygen therapy described as resting oxygen therapy >3 Liter (L)/minute (min) at screening required to maintain adequate oxygenation (e.g., oxygen saturation in arterial blood [SaO2] >90%; oxygen use <=3 L/min flow is not exclusionary, and subjects may adjust oxygen levels up or down as needed during the study.) Use of ICS within 6 weeks prior to Screening Visit 1; use of depot corticosteroids within 12 weeks prior to Screening Visit 1; use of systemic, oral or parenteral corticosteroids within 6 weeks prior to Screening Visit 1 (Localized corticosteroid injections [e.g., intra-articular and epidural] are permitted); use of antibiotics (for lower respiratory tract infection) within 6 weeks prior to Screening Visit 1; use of phosphodiesterase 4 (PDE4) inhibitor (e.g., roflumilast) within 14 days prior to Screening Visit 1; use of long-acting beta-agonist/ ICS combination products within 6 weeks prior to Screening Visit 1; use of theophyllines within 48 hours prior to Screening Visit 1; use of oral long-acting beta2-agonists within 48 hours and short-acting beta2-agonists within 12 hours prior to Screening Visit 1; use of inhaled short-acting beta2-agonists within 4 hours prior to Screening Visit 1 (use of study provided albuterol/salbutamol is permitted during the study, except in the 4-hour period prior to spirometry testing); use of inhaled short-acting anticholinergics within 4 hours prior to Screening Visit 1; use of inhaled short-acting anticholinergic/short-acting beta2-agonist combination products within 4 hours prior to Screening Visit 1; use of any other investigational medication within 30 days or within 5 drug half-lives (whichever is longer) prior to Screening Visit 1. Subject unable to withhold albuterol/salbutamol for the 4-hour period required prior to spirometry testing at each study visit. Regular use (prescribed for daily/ regular use, not for as-needed use) of short-acting bronchodilators (e.g., albuterol/salbutamol). A known or suspected history of alcohol or drug abuse within 2 years prior to Screening Visit 1 that in the opinion of the investigator would prevent the subject from completing the study procedures. Any history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, sympathomimetic, lactose/milk protein or magnesium stearate. Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Screening Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded. Subject is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study. In the opinion of the investigator, any subject who is unable to read and/or would not be able to complete questionnaires on the electronic diary.

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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UMEC/VI 62.5/25 mcg via ELLIPTA + placebo via DISKUS<br>Subjects will be instructed to self-administer one dose of UMEC/VI 62.5/25 mcg inhalation powder each morning via ELLIPTA DPI and placebo twice daily (morning and evening) via DISKUS DPI. | Drug: UMEC/VI 62.5/25 mcg via ELLIPTA<br>* ELLIPTA DPI inhaler will contain two individual blister strips with 30 blisters per strip; the first strip contains umeclidinium bromide (62.5 mcg per blister) blended with lactose monohydrate and magnesium stearate and second strip contains vilanterol trifenatae (25 mcg per blister) blended with lactose monohydrate and magnesium stearate.<br>Drug: Placebo via DISKUS<br>* Lactose dry powder will be administered using DISKUS for both treatment periods. The DISKUS inhaler will contain one blister strip, which will have 60 blisters of lactose dry powder. The DISKUS will provide a total of 60 doses (60 blisters) and will deliver, when actuated, the contents of a single blister strip.<br>|
| Experimental: UMEC 62.5 mcg via ELLIPTA + placebo via DISKUS<br>Subjects will be instructed to self-administer one dose of UMEC 62.5 mcg inhalation powder each morning via ELLIPTA DPI and placebo twice daily (morning and evening) via DISKUS DPI. | Drug: UMEC 62.5 mcg via ELLIPTA<br>* The ELLIPTA inhaler will contain one blister strip, which will have 30 blisters of umeclidinium bromide (62.5 mcg).<br>Drug: Placebo via DISKUS<br>* Lactose dry powder will be administered using DISKUS for both treatment periods. The DISKUS inhaler will contain one blister strip, which will have 60 blisters of lactose dry powder. The DISKUS will provide a total of 60 doses (60 blisters) and will deliver, when actuated, the contents of a single blister strip.<br>|
| Experimental: Salmeterol 50 mcg via DISKUS + placebo via ELLIPTA<br>Subjects will be instructed to self-administer one dose of salmeterol 50 mcg twice daily (morning and evening) via DISKUS DPI and placebo once daily morning via ELLIPTA DPI. | Drug: Salmeterol 50 mcg via DISKUS<br>* The DISKUS inhaler will contain one blister strip, which will have 60 blisters of salmeterol xinafoate (50 mcg). The DISKUS will provide a total of 60 doses (60 blisters) and will deliver, when actuated, the contents of a single blister strip.<br>Drug: Placebo via ELLIPTA<br>* Lactose dry powder will be administered using ELLIPTA for both treatment periods. ELLIPTA DPI inhaler will contain two individual blister strips with 30 blisters per strip; containing lactose dry powder.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Week 24 | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 at Week 24 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on the previous day. Baseline trough FEV1 is the mean of the values measured at 30 minutes and 5 minutes pre-dose on Day 1. Change from Baseline was calculated as the trough FEV1 value on Week 24 minus the Baseline value. Analysis was performed using a repeated measures model (MMRM) with covariates of Baseline FEV1, geographical region, stratum (number of bronchodilators per day during run-in), visit, treatment, visit by Baseline and visit by treatment interaction. ITT population comprised of all randomized participants (excluding those who were randomized in error) who received at least one dose of study medication. | Baseline (Pre-dose on Day 1) and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Self Administered Computerized (SAC) Transient Dyspnea Index (TDI) Focal Score at Week 24 | TDI focal score comprises of 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6, lower scores indicates impairment. TDI focal score was calculated as the sum of 3 individual scores (range is -18 to +18). Lower score indicates deterioration of dyspnea. If a score is missing for any of the three scales, then the TDI focal score was set to missing. Analysis was performed using mixed model repeated measures (MMRM) with covariates of SAC BDI focal score, geographical region, stratum (no. of bronchodilators per day during run-in), visit, treatment, visit by SAC BDI and visit by treatment interactions. | Week 24 | 
| Percentage of TDI Responders According to SAC TDI Focal Score | TDI focal score comprises of 3 individual scales (Functional Impairment, Magnitude of Task, Magnitude of Effort). Each of these scales had a possible score ranging from -6 to +6, lower scores indicates impairment. TDI focal score was calculated as the sum of 3 individual scores (range is -18 to +18). Lower score indicates deterioration of dyspnea. If a score is missing for any of the three scales, then TDI focal score was set to missing. A participant was considered as a responder if the on-treatment TDI focal score was at least 1 unit at that visit. Non-response was SAC TDI focal score of less than 1 unit or a missing SAC TDI focal score with no subsequent non-missing on-treatment scores. Analysis was performed using a generalized linear mixed model with treatment as an explanatory variable and visit, SAC BDI focal score, stratum (no. of bronchodilators per day during run-in), geographical region, visit by SAC BDI and visit by treatment interactions included as covariates. | Week 24 | 
| Mean Change From Baseline in Evaluating Respiratory Symptoms (E-RS) Total Score | The E-RS is intended to capture information related to respiratory symptoms. A daily symptom score for E-RS is derived by summing 11 item-scores. The domains include: respiratory symptoms (RS)-breathlessness (RS-BRL comprised of 5 items, score range [0-17]), RS-cough and sputum (RS-CSP comprised of 3 items, score range [0-11]), and RS-chest symptoms (RS-CSY comprised of 3 items, score range [0-12]). Total score ranged between 0-40 and higher values indicates severe respiratory symptoms. The instrument was completed each night prior to going to bed. Baseline E-RS score is the mean within-participant daily score over 7 days prior to randomization. Change from Baseline is the difference at Week 21-Week 24 value and Baseline value. Analysis was performed using MMRM with covariates of Baseline score, geographical region, stratum (no. of bronchodilators per day during run-in), 4-weekly period, treatment, 4-weekly period by Baseline and 4-weekly period by treatment interactions. | Baseline (Pre-dose on Day 1) and Week 21 to Week 24 | 
| Mean Change From Baseline in E-RS Subscale Score | The E-RS is intended to capture information related to respiratory symptoms. A daily symptom score for E-RS is derived by summing 11 item-scores. The domains include: respiratory symptoms (RS)-breathlessness (RS-BRL comprised of 5 items, score range [0-17]), RS-cough and sputum (RS-CSP comprised of 3 items, score range [0-11]), and RS-chest symptoms (RS-CSY comprised of 3 items, score range [0-12]). Total score ranged between 0-40 and higher values indicates severe respiratory symptoms. The instrument was completed each night prior to going to bed. Baseline E-RS score is the mean within-participant daily score over 7 days prior to randomization. Change from Baseline is the difference at Week 21-Week 24 value and Baseline value. Analysis was performed using MMRM with covariates of Baseline score, geographical region, stratum (no. of bronchodilators per day during run-in), 4-weekly period, treatment, 4-weekly period by Baseline and 4-weekly period by treatment interactions. | Baseline (Pre-dose on Day 1) and Week 21 to Week 24 | 
| Percentage of E-RS Responders According to E-RS Total Score | The E-RS is intended to capture information related to respiratory symptoms. A daily symptom score for E-RS is derived by summing 11 item-scores. The domains include: RS-BRL comprised of 5 items, score range (0-17); RS-CSP comprised of 3 items, score range (0-11); and RS-CSY comprised of 4 items, score range (0-12). Total score ranged between 0-40 and higher values indicates severe respiratory symptoms. The instrument was completed each night prior to going to bed. Response is defined as an E-RS total score of at least 2 or 3.35 below Baseline. Participants with a Baseline but all missing post-Baseline data are also considered a non-responder. Analysis was performed using a generalized linear mixed model with treatment as an explanatory variable and four-weekly period, Baseline score, stratum (no. of bronchodilators per day during run-in), geographical region, four-weekly period by baseline and four-weekly period by treatment interactions included as covariates. | Week 21 to Week 24 | 
| Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score | SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on HRQoL of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Baseline is last non-missing score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the value at Week 24. Analysis was performed using mixed model repeated measures (MMRM) with covariates of Baseline SGRQ total score, geographical region, stratum (no. of bronchodilators per day during run-in), visit, treatment, visit by Baseline and visit by treatment interactions. | Baseline (Pre-dose on Day 1) and Week 24 | 
| Percentage of Responders Based on the Saint (St) George Respiratory Questionnaire COPD Specific (SGRQ) Total Score | SGRQ is a disease-specific questionnaire designed to measure impact of respiratory disease and its treatment on HRQoL of participants with COPD. It contains 14 questions with a total of 40 items grouped into domains (Symptoms, Activity and Impacts). SGRQ total score was calculated as 100 multiplied by summed weights from all positive items divided by sum of weights for all items in questionnaire. It ranges from 0 to 100, higher score indicates poor HRQoL. Analysis was performed using a generalized linear mixed model with treatment as an explanatory variable and visit, Baseline SGRQ score, stratum (no. of bronchodilators per day during run-in), geographical region, visit by Baseline and visit by treatment interactions included as covariates. Response was defined as an SGRQ total score of 4 or more units below Baseline. | Week 24 | 
| Change From Baseline in COPD Assessment Test (CAT) | The CAT is a participant-completed instrument designed to provide a simple and reliable measure of health status in COPD for the assessment and long-term follow-up of the individual participant. The CAT consists of eight items, each formatted on a differential scale. Participants rated their experience on a 6-point scale for each question, ranging from 0 (no impact) to 5 (high impact). A total CAT score was calculated by summing the non-missing scores on the eight items ranging from 0 to 40 with higher scores indicating greater disease impact. Baseline is defined as the last non-missing score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the value at Week 24. Analysis was performed using mixed model repeated measures (MMRM) with covariates of Baseline CAT score, geographical region, stratum (no. of bronchodilators per day during run-in), visit, treatment, visit by Baseline and visit by treatment interactions. | Baseline (Pre-dose on Day 1) and Week 24 | 
| Percentage of Responders According to CAT | The CAT is a participant-completed instrument designed to provide a simple and reliable measure of health status in COPD for the assessment and long-term follow-up of the individual participant. The CAT consists of eight items. Participants rated their experience on a 6-point scale for each question, ranging from 0 (no impact) to 5 (high impact). A total CAT score was calculated by summing the non-missing scores on the eight items ranging from 0 to 40 with higher scores indicate greater disease impact. Response was defined as an CAT score of >=2 below Baseline. Non response was defined as CAT score <2 units below Baseline or a missing CAT score with no subsequent on treatment scores. Analysis performed using a generalized linear mixed model with treatment as an explanatory variable and visit, baseline CAT score, stratum (no. of bronchodilators per day during run-in), geographical region, visit by baseline and visit by treatment interactions included as covariates. | Week 24 | 
| Number of Participants With on Treatment Adverse Events (AE) and Serious Adverse Events (SAE) | An AE is any untoward medical occurrence in a participant or clinical investigation participant , temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events associated with liver injury and impaired liver function based on pre-defined criteria were categorized as SAE. | Up to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, Vilanterol, HRQoL, Salmeterol, Umeclidinium