A Randomized, Double Blind, Placebo Controlled, Incomplete Block, Crossover, Dose Ranging Study to Evaluate the Dose Response of GSK573719 Administered Once or Twice Daily Over 7 Days in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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The purpose of this study is to further characterize the dose response of GSK573719 at doses of 15.6 micrograms (mcg) to 125 mcg once daily in patients with chronic obstructive pulmonary disease (COPD). Treatment with doses of GSK573719 dosed twice daily will also be included to further evaluate dosing frequency. Treatment with tiotropium (18 mcg) once daily via the Handihaler will be included as an active control. A placebo treatment will be included in order to evaluate absolute treatment effect of the different doses of GSK573719.

Detailed Description
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Inhaled bronchodilators, such as beta 2 agonists and anticholinergics, and inhaled corticosteroids are the mainstays of therapy in patients diagnosed with COPD. Anticholinergic bronchodilators or long acting muscarinic receptor antagonists function by blocking endogenous airway smooth muscle cholinergic tone. Treatment with anticholinergics has been shown to significantly improve forced expiratory volume in 1 second (FEV1), resting and dynamic lung hyperinflation, symptoms, and exercise capacity in patients with COPD. Currently tiotropium is the only approved long acting muscarinic antagonist available for treatment of COPD. This is a multicenter, randomized, double-blind, placebo controlled, three way crossover, incomplete block study to evaluate 4 doses of GSK573719 inhaled once daily and 2 doses of GSK573719 inhaled twice daily over 7 days in patients with COPD. Tiotropium will be included as an open label active comparator. A placebo treatment will be included to evaluate treatment effect of each GSK573719 dose. Pharmacokinetic profiles of GSK573719 will also be determined. Each eligible subject will receive a sequence of 3 of 8 potential treatments for a total of 3 treatment periods per subject. There will be 7 clinic visits, during three of which 24 hour serial spirometry will be performed. The total duration of subject participation is approximately 9 weeks.

Official Title
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A Randomized, Double Blind, Placebo Controlled, Incomplete Block, Crossover, Dose Ranging Study to Evaluate the Dose Response of GSK573719 Administered Once or Twice Daily Over 7 Days in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: GSK573719
* Drug: GSK573719
* Drug: GSK573719
* Drug: GSK573719
* Drug: GSK573719
* Drug: GSK573719
* Drug: Tiotropium
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outpatient A signed and dated written informed consent prior to study participation. Male or female adults. 40 to 80 years of age at Visit 1 Diagnosis of COPD Current or former cigarette smokers with a history of cigarette smoking of greater than or equal to 10 pack-years Post-albuterol forced expiratory volume in 1 second (FEV1)/ forced vital capacity (FVC)<0.70 and post albuterol FEV1 of greater than or equal to 35% and less than or equal to 70% of predicted normal values Exclusion Criteria: Women who are pregnant or lactating or are planning on becoming pregnant during the study. A current diagnosis of asthma Known alpha-1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer Other significant respiratory conditions in addition to COPD Other diseases that are uncontrolled including cancer in remission for less than 5 years Chest x-ray or CT scan with clinically significant abnormalities not believed to be due to the presence of COPD Hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate A medical condition that contraindicates study participation or use of an inhaled anticholinergic Hospitalization for COPD or pneumonia within 12 weeks of Visit 1 Any previous lung resection surgery A body mass index (BMI) value of >35 kilogram (kg)/meter squared (m2) An abnormal and significant electrocardiogram finding at Visit 1 Significantly abnormal finding from clinical chemistry or haematology tests at Visit 1. A positive Hepatitis B surface antigen or positive Hepatitis C antibody Medically unable to withhold albuterol (salbutamol) for the 6 hour period prior to study visits Use of depot corticosteroids within 12 weeks of Visit 1 Use of oral or parenteral corticosteroids or antibiotics for lower respiratory tract infection within 6 weeks of Visit 1 Use of long-acting beta-agonist (LABA)/inhaled corticosteroid (ICS) product if LABA/ICS therapy is discontinued within 30 days of Visit 1 Use of ICS at a dose of >1000mcg/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 or phosphodiesterase 4 inhibitors within 14 days of Visit 1 Use of theophyllines, oral leukotriene inhibitors, long-acting oral beta-agonists, or inhaled long-acting beta-agonists within 48 hours of Visit 1 Short-acting oral beta-agonists within 12 hours of 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, inhaled short-acting anticholinergics, or inhaled short-acting anticholinergic/short-acting beta-agonist combination products within 6 hours of Visit 1 Use of any other investigational medication within 30 days or 5 drug half-lives (whichever is longer) Oxygen therapy prescribed for greater than 12 hours a day Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators Use of continuous positive airway pressure (CPAP), nocturnal positive pressure or non-invasive positive pressure ventilation (NIPPV), including use for sleep apnea. Acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1 A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1 Anyone affiliated with investigator site Previous use of GSK573719 or GSK53719/GW642444

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tiotropium<br>18 mcg, inhaled long acting muscarinic antagonist | Drug: Tiotropium<br>* 18 mcg once daily<br>|
| Experimental: GSK573719<br>inhaled medication | Drug: GSK573719<br>* 125 mcg once daily<br>Drug: GSK573719<br>* 62.5 mcg once daily<br>Drug: GSK573719<br>* 31.25 mcg once daily<br>Drug: GSK573719<br>* 15.6 mcg once daily<br>Drug: GSK573719<br>* 31.25 mcg twice daily<br>Drug: GSK573719<br>* 15.6 mcg twice daily<br>|
| Placebo Comparator: Placebo<br>inactive/excipients only | Drug: Placebo<br>* once or twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Final Dose-response Model for Trough Forced Expiratory Volume in One Second (FEV1) | The trough FEV1 data for both the once-daily (QD) and twice-daily (BID) UMEC doses were included in a parametric analysis in order to evaluate trough FEV1dose response. The Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed separately and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as a function of dose given the repeated measures for trough FEV1 response within each participant on different days. The fixed-effects parameters of the dose response model include Emax (the maximum predicted FEV1 response), ED50 (potency), and S0 (estimated Baseline FEV1). FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Data for Emax and S0 are reported in this table. mITT=Modified Intent-to-Treat; par.=participants; BL=Baseline. | Day 7 and Day 8 of each treatment period (up to Study Day 50) | 
| Final Dose-response Model for Trough FEV1 for ED50 (Potency) Parameter | The trough FEV1 data for both the once-daily (QD) and twice-daily (BID) UMEC doses were included in a parametric analysis in order to evaluate dose response. Both a Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as a function of dose given the repeated measures for trough FEV1 response within each participant on different days. ED50 is defined as the potency and is the dose that yields 50% of Emax (maximum predicted FEV1 response). FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. | Day 7 and Day 8 of each treatment period (up to Study Day 50) | 
| Final Dose-response Model Parameter β-FEV1MB-S0 for Trough FEV1 | The trough FEV1 data for both the once-daily (QD) and twice-daily (BID) UMEC doses were included in a parametric analysis in order to evaluate dose response. Both a Day 8 dataset and a pooled dataset for Day 7 and Day 8 were analyzed and reported. The rationale for pooling Day 7 and Day 8 (post-hoc analysis) was to ensure informative interpretation of FEV1 response as a function of dose given the repeated measures for trough FEV1 response within each participant on different days. β-FEV1MB-S0 is defined as the covariate (Baseline trough FEV1) effect on the mean Baseline trough FEV1 estimate (S0). FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. | Day 7 and Day 8 of each treatment period (up to Study Day 50) | 
| Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) on Day 8 of Each Treatment Period | 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 on Treatment Day 8 is defined as the value obtained 24 hours after the morning dose administered on Day 7. Analysis was performed using a mixed model with covariates of mean Baseline, period Baseline, treatment, and period as fixed effects and participant as a random effect. Baseline is the FEV1 value recorded pre-dose on Day 1 of each treatment period, mean Baseline is the mean of the Baselines for each participant, and period Baseline is the difference between the Baseline and the mean Baseline in each treatment period for each particiapant. Change from Baseline for each treatment period is the trough FEV1 at Day 8 minus the Baseline value for that treatment period. | Baseline and Day 8 of each treatment period (up to Study Day 50) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (BL) in Serial FEV1 Over Time on Day 7 of Each Treatment Period | Serial FEV1 for once daily dosing is recorded at the pre-AM dose (AMD; time 0 hour [h]) and at 1, 3, 6, 9, 12,13, 15, 23, and 24 hours after the AMD on Day 7. For twice daily dosing, the 12 h AMD corresponds to the pre-PM dose (PMD), the 13 h AMD corresponds to the 1 h PMD, the 15 h AMD corresponds to the 3 h PMD, the 23 h AMD corresponds to the 11 h PMD, and the 24 h AMD corresponds to the 12 h PMD in this table. Analysis was performed using a mixed model with covariates of mean BL, period BL, treatment, period, time, time by period BL interaction, time by mean BL interaction, and time by treatment interaction as fixed effects and participant as a random effect. BL is the value recorded pre-dose on Day 1 of each TP, mean BLis the mean of the BLs for each participant, and period BL is the difference between the BL and the mean BL in each TP for each participant. Change from BL for each timepoint within a TP is the serial FEV1 measure at that timepoint minus the BL value for that TP. | Baseline and Day 7 of each treatment period (TP; up to Study Day 49) | 
| Change From Baseline (BL) in Weighted Mean FEV1 Over 0 to 24 Hours After the Morning Dosing on Day 7 of Each Treatment Period | FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The weighted mean FEV1 was derived by calculating the area under the FEV1/time curve (AUC) using the trapezoidal rule, and then dividing the value by the time interval over which the AUC was calculated. The weighted mean FEV1 was calculated using 0-24 hour post-dose measurements at Day 7 of each treatment period, which included pre-dose and post-dose 1, 3, 6, 9, 12, 13, 15, 23, and 24 hours. Analysis was performed using a mixed model with covariates of mean BL, period BL, treatment, and period as fixed effects and participant as a random effect. BL is the FEV1 value recorded pre-dose on Day 1 of each TP, mean BL is the mean of the BLs for each participant, and period BL is the difference between the BL and the mean BL in each TP for each participant. Change from BL for each TP is the weighted mean FEV1 at Day 7 minus the BL value for that TP. | Baseline and Day 7 of each treatment period (TP; up to Study Day 49) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Long acting muscarinic antagonist, Tiotropium, Chronic Bronchitis, Emphysema, Chronic Obstructive Pulmonary Disease