A 52-Week, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Evaluate the Safety and Tolerability of GSK573719/GW642444 and GSK573719 in Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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The purpose of this 52-week study is to evaluate the long-term safety (in terms of adverse events, COPD exacerbations, laboratory, ECG, and Holter findings, vital signs, use of rescue medication and lung function) of GSK573719/GW642444 Inhalation Powder 125/25mcg in subjects with COPD. The long-term safety of GSK573719 Inhalation Powder 125mcg will also be evaluated. A placebo arm is included to evaluate these products compared to an inactive control.

Detailed Description
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Several studies have demonstrated the efficacy and safety of combining an individual LABA compound plus an individual LAMA compound in COPD. These studies have shown the combination of these two products to be superior to either agent alone on a variety of outcomes in COPD. The beneficial effects of this combination regimen are likely due to the different mechanisms of action of the two bronchodilators (smooth bronchial muscle relaxation from activation of beta2 receptors from the LABA product and inhibition of acetylcholine-mediated smooth bronchial muscle contraction via blockade of muscarinic receptors from the LAMA product). The availability of a LABA/LAMA combination in one product instead of two individual products is a technical and therapeutic advancement in the pharmacological armamentarium for COPD and may lead to increased patient compliance due to once-daily administration. The purpose of this 52-week study is to evaluate the long-term safety (in terms of adverse events, COPD exacerbations, laboratory, ECG, and Holter findings, vital signs, use of rescue medication, and lung function) of GSK573719/GW642444 Inhalation Powder 125/25mcg in subjects with COPD. The long-term safety of GSK573719 Inhalation Powder 125mcg will also be evaluated. A placebo arm is included to evaluate these products compared to an inactive control. All treatments will be delivered once-daily via the nDPI. This study will establish the long-term safety profile of GSK573719/GW642444 Inhalation Powder 125/25mcg once-daily in subjects with COPD. The safety profile of GSK573719 Inhalation Powder125mcg once-daily will also be evaluated.

Official Title
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A 52 Week Study to Evaluate the Safety and Tolerability of GSK573719/GW642444 125mcg Once-daily Alone and in Combination With GW642444 25mcg Once-daily Via Novel Dry Powder Inhaler (nDPI) in Subjects With Chronic Obstructive Pulmonary Disease

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: 125/25 mcg once-daily GSK573719/GW642444
* Drug: 125mcg once-daily GSK573719
* Drug: Placebo once-daily


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: outpatient signed and dated written informed consent 40 years of age or older male and female subjects COPD diagnosis at least 10 pack-year smoking history post-albuterol/salbutamol FEV1/FVC ratio of <0.70 and post-albuterol/salbutamol FEV1 greater than or equal to 35% and less than or equal to 80% of predicted normal Exclusion Criteria: Pregant or lactating women or women planning to become pregnant during the study current diagnosis of asthma other respiratory disorders other than COPD other diseases/abnormalities that are uncontrolled including cancer not in remission for at least 5 years chest x-ray or CT scan with clinically significant abnormalities not believed to be due to COPD hypersensitivity to anticholinergics, beta-agonists, lactose/milk protein or magnesium stearate or medical conditions associated with inhaled anticholinergics hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1 lung volume reduction surgery within 12 months prior to Visit 1 abnormal and clinically significant ECG at Visit 1 abnormal and clinically significant Holter monitor finding at Visit 1 significantly abnormal finding from laboratory tests at Visit 1 unable to withhold albuterol/salbutamol and/or ipratropium bromide at least 4 hours prior to spirometry at each visit use of depot corticosteroids within 12 weeks of Visit 1 use of oral or parenteral corticosteroids within 6 weeks of Visit 1 use of anitbiotics for lower respiratory tract infection within 6 weeks of Visit 1 use of cytochrome P450 3A4 inhibitors within 6 weeks of Visit 1 us of long-acting beta-agonist (LABA)/inhaled corticosteroid (ICS) products if LABA/ICS therapy is discontinued completely within 30 days of Visit 1 use of ICS at a dose of >10000mcg/day of fluticasone propionate or equivalent within 30 days of Visit 1 initiation or discontinuation of ICS within 30 days of Visit 1 use of tiotropium within 14 days of Visit 1 use of roflumilast within 14 days of Visit 1 use of theophyllines within 48 hours of Visit 1 use of oral leukotriene inhibitors within 48 hours prior to Visit 1 use of long-acting oral beta-agonists within 48 hours of Visit 1 use of short-acting oral beta-agonists within 12 hours of Visit 1 use of inhaled long-acting beta-agonists within 48 hours prior to Visit 1 use of LABA/ICS combination products only if discontinuing LABA therapy and switching to ICS monotherapy within 48 hours of Visit 1 for the LABA component use of sodium cromoglycate or nedocromil sodium within 24 hours of Visit 1 use of inhaled short acting beta-agonists within 4 hours of Visit 1 use of inhaled short-acting anticholinergics within 4 hours of Visit 1 use of inhaled short-acting anticholinergic/short-acting beta2-agonist combination products within 4 hours of Visit 1 use of any other investigational medication within 30 days or 5 drug half-lives (whichever is longer) of Visit 1 long-term oxygen therapy prescribed for >12 hours per day regular use of short-acting bronchodilators use of CPAP or NIPPV participation in the maintenance phase of a pulmonary rehabilitation program known or suspected history of alcohol or drug abluse with 2 years prior to Visit 1 anyone affiliated with the investigator site (e.g., investigator, study coordinator, etc.) previous use of GSK573719, GW642444 , GSK573719/GW642444 combination, GSK233705/GW642444 combination, or Fluticasone Furoate/GW642444 combination

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 120 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK573719/GW642444<br>125/25 mcg once-daily | Drug: 125/25 mcg once-daily GSK573719/GW642444<br>* GSK573719/GW642444<br>|
| Experimental: GSK573719<br>125 mcg once-daily | Drug: 125mcg once-daily GSK573719<br>* GSK573719<br>|
| Placebo Comparator: Placebo<br>inactive | Drug: Placebo once-daily<br>* inactive<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any On-treatment Adverse Event (AE) or Any Serious Adverse Event (SAE) | An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury with hyperbilirubinaemia. Medical or scientific judgment was to have been exercised in other important medical events. AEs with an onset on or after the date of the first dose of study drug and up to 1 day after the date of the last recorded dose of study drug were considered to be on-treatment AEs, Refer to the general AE/SAE module for a complete list of AEs and SAEs. | From the start of study drug up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With at Least One Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Over the Course of the 52-week Treatment Period | A COPD exacerbation is defined as worsening symptoms of COPD requiring a systemic corticosteroid, an antibiotic, and/or hospitalization. | From the start of study drug up to 52 weeks | 
| Time to the First On-treatment COPD Exacerbation | An on-treatment COPD exacerbation is defined as worsening symptoms of COPD requiring a systemic corticosteroid, an antibiotic, and/or hospitalization at any time during the 52-week Treatment Period. The time to the first on-treatment exacerbation was calculated as the exacerbation onset date of the first on-treatment exacerbation minus the date of the start of treatment + 1. The median time to the first on-treatment exacerbation was derived from the Kaplan-Meier analysis. A participant who did not experience an exacerbation prior to completing the study or withdrawal is considered censored; a time to first COPD exacerbation cannot be calculated for these participants. | From the start of study drug up to 52 weeks | 
| Change From Baseline in Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), Creatine Kinase (CK), and Gamma Glutamyl Transferase (GGT) at Months 3, 6, 9, and 12 | Blood samples were collected for the measurement of ALT, ALP, AST, CK, and GGT at Baseline and Months 3, 6, 9, and 12. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The value defined as the Baseline value is the most recent value collected prior to the start of treatment. For most participants, the Baseline value is the value collected at the Screening visit; however, for some participants, the Baseline value may have been collected at an unscheduled visit. | Baseline; Months 3, 6, 9, and 12 | 
| Change From Baseline in Albumin, Total Protein, and Hemoglobin at Months 3, 6, 9, and 12 | Blood samples were collected for the measurement of albumin, total protein, and hemoglobin at Baseline and Months 3, 6, 9, and 12. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The value defined as the Baseline value is the most recent value collected prior to the start of treatment. For most participants, the Baseline value is the value collected at the Screening visit; however, for some participants, the Baseline value may have been collected at an unscheduled visit. | Baseline; Months 3, 6, 9, and 12 | 
| Change From Baseline in Calcium, Carbon Dioxide (CO2) Content/Bicarbonate, Chloride, Glucose, Inorganic Phosphorus (IP), Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) at Months 3, 6, 9, and 12 | Blood samples were collected for the measurement of calcium, CO2 content/bicarbonate, chloride, glucose, IP, potassium, sodium, and urea/BUN at Baseline and Months 3, 6, 9, and 12. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The value defined as the Baseline value is the most recent value collected prior to the start of treatment. For most participants, the Baseline value is the value collected at the Screening visit; however, for some participants, the Baseline value may have been collected at an unscheduled visit. | Baseline; Months 3, 6, 9, and 12 | 
| Change From Baseline in Creatinine, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, and Uric Acid at Months 3, 6, 9, and 12 | Blood samples were collected for the measurement of creatinine, direct bilirubin, indirect bilirubin, total bilirubin, and uric acid at Baseline and Months 3, 6, 9, and 12. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The value defined as the Baseline value is the most recent value collected prior to the start of treatment. For most participants, the Baseline value is the value collected at the Screening visit; however, for some participants, the Baseline value may have been collected at an unscheduled visit. | Baseline; Months 3, 6, 9, and 12 | 
| Change From Baseline in the Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Segmented Neutrophils in Blood at Months 3, 6, 9, and 12 | Blood samples were collected for the measurement of the percentage of basophils, eosinophils, lymphocytes, monocytes, and segmented neutrophils at Baseline and Months 3, 6, 9, and 12. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The value defined as the Baseline value is the most recent value collected prior to the start of treatment. For most participants, the Baseline value is the value collected at the Screening visit; however, for some participants, the Baseline value may have been collected at an unscheduled visit. | Baseline; Months 3, 6, 9, and 12 | 
| Change From Baseline in Eosinophil Count, Platelet Count, and White Blood Cell (WBC) Count at Months 3, 6, 9, and 12 | Blood samples were collected for the measurement of eosinophils, platelets, and WBC count at Baseline and Months 3, 6, 9, and 12. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The value defined as the Baseline value is the most recent value collected prior to the start of treatment. For most participants, the Baseline value is the value collected at the Screening visit; however, for some participants, the Baseline value may have been collected at an unscheduled visit. | Baseline; Months 3, 6, 9, and 12 | 
| Change From Baseline in Hematocrit at Months 3, 6, 9, and 12 | Blood samples were collected for the measurement of hematocrit at Baseline and Months 3, 6, 9, and 12. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. The value defined as the Baseline value is the most recent value collected prior to the start of treatment. For most participants, the Baseline value is the value collected at the Screening visit; however, for some participants, the Baseline value may have been collected at an unscheduled visit. | Baseline; Months 3, 6, 9, and 12 | 
| Change From Baseline to Maximum Systolic Blood Pressure (SBP) and Change From Baseline to Minimum Diastolic Blood Pressure (DBP) Over the Course of the 52-week Treatment Period | Baseline is defined as the most recent recorded value before dosing on Day 1. The maximum post-Baseline value for SBP and the minimum post-Basline value for DBP were derived using any scheduled, unscheduled, or early withdrawal visit made after the start of study treatment. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; from the start of study drug up to 52 weeks | 
| Maximum Change From Baseline in Pulse Rate Over the Course of the 52-week Treatment Period | Baseline is defined as the most recent recorded value before dosing on Day 1. The maximum post-Baseline value for pulse rate was derived using any scheduled, unscheduled, or early withdrawal visit made after the start of study treatment. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; from the start of study drug up to 52 weeks | 
| Maximum Change From Baseline in the Electrocardiogram (ECG) Parameters of QT Interval Corrected for Heart Rate by Bazett's Formula (QTcB), QT Interval Corrected for Heart Rate by Fridericia's Formula (QTcF), and PR Interval Over the Course of the 52-week | 12-lead ECG measurements were obtained. Baseline is defined as the most recent recorded value before dosing on Day 1. The maximum post-Baseline values for QTcF, QTcB, and PR interval were derived using any scheduled, unscheduled, or early withdrawal visit made after the start of study treatment. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; from the start of study drug up to 52 weeks | 
| Maximum Change From Baseline in the ECG Parameter of Heart Rate Over the Course of the 52-week Treatment Period | 12-lead ECG measurements were obtained. Baseline is defined as the most recent recorded value before dosing on Day 1. The maximum post-Baseline value for heart rate was derived using any scheduled, unscheduled, or early withdrawal visit made after the start of study treatment. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline; from the start of study drug up to 52 weeks | 
| Number of Participants With the Indicated ECG Result Interpretations at Any Time Post-Baseline | Post-Baseline visits include scheduled, unscheduled, and Early Withdrawal visits. Only the worst-case interpretation was counted for each participant. Clinical significance and abnormal/normal findings are based on the assessment of the independent cardiologists. | From the start of study drug up to 52 weeks | 
| Number of Participants With the Indicated Change From Screening to Any Time Post-Baseline in Holter ECG Interpretation | Twenty-four hour Holter monitor (12-lead) evaluations were obtained. Holter Baseline values were those recorded at Screening. An any time post-Baseline Holter evaluation was derived as the worst evaluation recorded at any scheduled, unscheduled, or early withdrawal visit made after the start of study treatment. Change from Screening was calculated as the post-Screening value minus the Screening value. The order of severity for change from Screening Holter evaluation from worst to best is: clinically significant change: unfavorable; no change or insignificant change; clinically significant change: favorable, unable to compare, based on the assessment of the independent cardiologists. | Screening; from the start of study drug up to 52 weeks | 
| Change From Baseline in the Mean Number of Puffs of Rescue Medication (Salbutamol and/or Ipratropium Bromide) Per Day Over the Course of the 52-week Treatment Period | Participants recorded the number of puffs and/or the number of nebules of rescue albuterol/salbutamol and/or ipratropium bromide used in the past 24 hours for the relief of COPD symptoms in the daily diary. The total puffs of rescue medication for each day was calculated as follows: (number of salbutamol puffs + number of ipratropium puffs + [2 * number of salbutamol nebules] + [2 * number of ipratropium nebules]). Baseline is the mean during the week prior to Day 1. Change from Baseline was calculated as the mean number of puffs/day over Weeks 1-52 minus the mean number of puffs/day at Baseline. Analysis was performed using an Analysis of Covariance (ANCOVA) model with covariates of treatment, Baseline (mean during the week prior to Day 1), smoking status, and center group. | Baseline; from the start of study drug up to 52 weeks | 
| Change From Baseline in the Percentage of Rescue-free Days Over the Course of the 52-week Treatment Period | Rescue-free days are defined as days on which albuterol/salbutamol and/or ipratropium bromide was not used. Baseline is the percentage during the week prior to Day 1. Change from Baseline was calculated as the mean percentage of rescue-free days over Weeks 1-52 minus the mean percentage of rescue-free days at Baseline. | From the start of study drug up to 52 weeks | 
| Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at Months 1, 3, 6, 9, and 12 | FEV1 and FVC are measures of lung function. FEV1 is defined as the maximal amount of air that can be forcefully exhaled in one second. FVC is defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. Trough FEV1 and FVC were the values obtained approximately 24 hours after the previous morning's dose of study medication. Baseline is the value recorded pre-dose on Day 1. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using a repeated measures model with covariates of treatment, Baseline (assessment made immediately pre-dose on Day 1), smoking status, center group, month, and month by Baseline and month by treatment interactions. | Baseline; Months 1, 3, 6, 9, and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Obstructive Pulmonary Disease, COPD, nDPI, long-acting beta agonist, long-acting muscarinic antagonist, tolerability, safety