GSK573719 Dose Ranging Study in Chronic Obstructive Pulmonary Disease

Study Overview
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Brief Summary
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The study will evaluate the dose response, safety, and pharmacokinetics of GSK573719 compared with placebo in subjects with COPD.

Detailed Description
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This is multicenter, randomized, double-blind, double-dummy, placebo-controlled, three-way cross-over, incomplete block design study to evaluation of 5 doses of GSK573719 administered once-daily and 3 doses of GSK573719 administered twice-daily over 14 days in subjects with COPD and will include tiotropium as an open-label active control. The pharmacokinetic profile of GSK573719 will also be evaluated.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, 3-Way Cross-Over Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of GSK573719 Administered Once- and Twice-Daily in Subjects With COPD

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Drug: Tiotropium
* Drug: Placebo
* Drug: GSK573179


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A signed and dated written informed consent prior to study participation Males or females of non-childbearing potential 40 to 80 years of age COPD diagnosis 10 pack-years history or greater of cigarette smoking Post-bronchodilator FEV1/FVC ratio of 0.70 or less Post-bronchodilator FEV1 of 35 to 70% of predicted normal Exclusion Criteria: Asthma Other significant respiratory disorders besides COPD, including alpha-1 deficiency Previous lung resection surgery Use of oral steroids or antibiotics for a COPD exacerbation within 6 weeks of screening Hospitalization for COPD or pneumonia within 3 months of screening Any significant disease that would put subject at risk through study participation BMI greater than 35 Pacemaker Significantly abnormal ECG, Holter, or clinical lab finding (including Hepatitis B or C) Cancer Allergy or hypersensitivity to anticholinergics or inhaler excipients Diseases that would contra-indicate the use of anticholinergics Use of oral corticosteroids within 6 weeks of screening Use of long-acting beta-agonists within 48 hours of screening Use of tiotropium within 14 days of screening Use of theophyllines or anti-leukotrienes within 48 hours of screening Use of short-acting bronchodilators within 4 to 6 hours of screening Use of investigational medicines within 30 days of screening Use of high dose inhaled corticosteroids Use of long-term oxygen therapy, CPAP or NIPPV Previous use of GSK573719

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Inactive/ excipients only<br>|
| Active Comparator: Tiotropium<br>Tiotropium | Drug: Tiotropium<br>* long-acting muscarinic receptor antagonist; 18mcg once-daily<br>|
| Experimental: Arm 1<br>GSK573719 1000mcg once daily | Drug: GSK573179<br>* GSK573179 investigational drug<br>|
| Experimental: Arm 2<br>GSK573719 500mcg once daily | Drug: GSK573179<br>* GSK573179 investigational drug<br>|
| Experimental: Arm 3<br>GSK573719 250mcg once daily | Drug: GSK573179<br>* GSK573179 investigational drug<br>|
| Experimental: Arm 4<br>GSK573719 125mcg once daily | Drug: GSK573179<br>* GSK573179 investigational drug<br>|
| Experimental: Arm 5<br>GSK573719 62.5 mcg once daily | Drug: GSK573179<br>* GSK573179 investigational drug<br>|
| Experimental: Arm 6<br>GSK573719 250mcg twice daily | Drug: GSK573179<br>* GSK573179 investigational drug<br>|
| Experimental: Arm 7<br>GSK573719 125mcg twice daily | Drug: GSK573179<br>* GSK573179 investigational drug<br>|
| Experimental: Arm 8<br>GSK573719 62.5mcg twice daily | Drug: GSK573179<br>* GSK573179 investigational drug<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 Day 15 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 15 is defined as the value obtained 24 hours after the morning dose administered on Day 14. Analysis were 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 participant. Change from Baseline for each treatment period is the trough FEV1 at Day 15 minus the Baseline value for that treatment period. | Baseline and Day 15 of each treatment period (up to Study Day 71) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (BL) in Weighted Mean FEV1 Over 0 to 24 Hours Obtained Post-dose on Day 14 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 (h) post-dose measurements at Day 14 of each treatment period, which included pre-dose and post-dose 1, 3, 6, 9, 12, 13, 15, 18, 21 and 24 hours. Analysis performed using a mixed model with covariates 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 trough FEV1 at Day 15 minus the BL value for that TP. | Baseline and Day 14 of each treatment period (TP; up to Study Day 70) | 
| Change From Baseline (BL) in Serial FEV1 Over 0-28 Hours After the Morning Dose at Day 14 of Each Treatment Period | Serial FEV1 for OQ dosing is recorded at the pre-AM dose (time 0 h) and at 1, 3, 6, 9, 12,13, 15, 18, 21, 24 and 28 hs after the AM dose on D 14. For BID dosing, the 12 h AM dose corresponds to the pre-PM dose, 13 h AM dose corresponds to the 1 h PM dose, 15 h AM dose corresponds to the 3 h PM dose, 18 h AM corresponds to the 6 h PM dose, 21 h AM dose corresponds to 9 h PM dose, 24 h AM dose corresponds to the 12 h PM dose and 28 h AM dose corresponds to the 16 h PM dose in the table. Analysis performed using a mixed model with covariates of mean BL, period BL, trt, period, time, time by period BL interaction, time by mean BL interaction and time by trt interaction as fixed effects and par. as a random effect. BL is the FEV1 value recorded pre-dose on D 1 of each TP; mean BL is the mean of the BLs for each par. and period BL is the difference between the BL and the mean BL in each TP for each par. Change from BL for each TP is the trough FEV1 at Day 15 minus the BL value for that TP. | Baseline and Day (D) 14 of each treatment period (TP; up to Study Day 70) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dose ranging, Chronic Bronchitis, Long-acting muscarinic antagonist, cross-over, COPD, Emphysema, Chronic Obstructive Pulmonary Disease (COPD), anticholinergic