Dose-Ranging Study Of GSK233705B In Subjects With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of GSK233705B compared with placebo in subjects with COPD.

Official Title
-----------------
Multicentre Dose Ranging Study for Once Daily GSK233705 in COPD

Conditions
-----------------
Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
-----------------
* Drug: GSK233705 12.5mcg
* Drug: GSK233705 25mcg
* Drug: GSK233705 50mcg
* Drug: GSK233705 100mcg
* Drug: GSK233705 200mcg
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A signed and dated written informed consent prior to study participation. Male or female adults. A female is eligible to enter and participate in this study if she is of: non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who is post-menopausal; or child-bearing potential, has a negative pregnancy test at Visit 1/Visit 1A, and agrees to one of the protocol-specified acceptable contraceptive methods used consistently and correctly (i.e. according to the approved product label and the instructions of the physician for the duration of the study - Screening through follow-up contact) 40 to 80 years of age at Visit 1 An established clinical history of COPD Current or previous cigarette smokers with a history of cigarette smoking of ≥ 10 pack-years 1. A post-albuterol/salbutamol FEV1/FVC ratio of ≤0.70 and a post-albuterol/salbutamol FEV1 of ≥35 and ≤70% of predicted normal values Exclusion Criteria: Subjects meeting any of the following criteria must not be enrolled in the study: Women who are pregnant or lactating. A current diagnosis of asthma. Known respiratory disorders other than COPD including but not limited to α-1 antitrypsin deficiency as the underlying cause of COPD, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, and interstitial lung disease. Any previous lung resection surgery (e.g., lung volume reduction surgery or lobectomy) Clinically significant Chest X-ray or computed tomography (CT) scan abnormalities within 6 months prior to Visit 1 that are not believed to be due to COPD. Use of oral corticosteroids or antibiotics for COPD within 6 weeks prior to Visit 1. Hospitalization for COPD or pneumonia within 3 months prior to Visit 1. Use of antibiotics for a lower respiratory tract infection within 30 days prior to Visit 1. Clinically significant and uncontrolled cardiovascular, neurological, psychiatric, renal, gastro-intestinal, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities. An abnormal and clinically significant 12-lead electrocardiogram (ECG) that results in active medical problem. Positive for Hepatitis B or Hepatitis C at Visit 1. A current malignancy or previous history of cancer in remission for <5 years prior to Visit 1 A history of allergy or hypersensitivity to ipratropium, tiotropium, or atropine and any of their derivatives, lactose/milk protein or magnesium stearate. Medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the study investigator would prevent use of an inhaled anticholingeric. Medically unable to withhold albuterol/salbutamol for 6 hours prior to spirometry testing at each study visit or to withhold ipratropium (if applicable) for the 6-hour period prior to the first 3 study visits (ipratropium cannot be used after Visit 3). Additional Medications: Unable to stop using certain medications such as bronchodilators and corticosteroids for the protocol-specified times prior to Visit 1 (the Investigator will discuss the specific medications) Use of inhaled corticosteroids at a dose greater than 1000 mcg/day of fluticasone propionate or equivalent within 30 days prior to Visit 1. Use of long-term oxygen therapy (LTOT) or supplemental oxygen required for greater than 12 hours a day. Oxygen use as needed is not exclusionary. Clinically significant sleep apnea that requires continuous positive airway pressure (CPAP) Use of regular nebulized therapy Use of nocturnal positive pressure or non-invasive positive pressure ventilation (NIPPV) Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. An investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the above who is involved in this study History of psychiatric disease, intellectual deficiency, poor motivation, substance abuse in the two years prior to Visit 1 (including drug and alcohol), or other conditions, which will limit the validity of informed consent to participate in the study. Use of GSK233705B in previous studies.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>GSK233705 12.5mcg | Drug: GSK233705 12.5mcg<br>* Once daily via dry powder inhaler<br>|
| Experimental: Arm 2<br>GSK233705 25mcg | Drug: GSK233705 25mcg<br>* once daily via dry powder inhaler<br>|
| Experimental: Arm 3<br>GSK233705 50mcg | Drug: GSK233705 50mcg<br>* Once daily via dry powder inhaler<br>|
| Experimental: Arm 4<br>GSK233705 100mcg | Drug: GSK233705 100mcg<br>* Once daily via dry powder inhaler<br>|
| Experimental: Arm 5<br>GSK233705 200mcg | Drug: GSK233705 200mcg<br>* Once daily via dry powder inhaler<br>|
| Placebo Comparator: Arm 6<br>Placebo | Drug: Placebo<br>* Once daily via dry powder imhaler<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 29 | The trough FEV1 is defined as the mean of the FEV1 values obtained 23 and 24 hours after dosing on Day 28. The Baseline FEV1 is the mean of the two assessments made 30 minutes pre-dose and immediately pre-dose [time 0] on Day 1. Change from Baseline was calculated by subtracting the post-baseline assessment value from the Baseline value. | Baseline (pre-dose Day 1) and Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Weighted Mean for 0 to 24 Hours Serial FEV1 on Day 1 to 2 and 28 to 29 | Weighted means serial FEV1 was derived by calculating the area under curve (AUC), and then dividing by the time interval over which the AUC was calculated. Baseline was defined at pre-dose Day 1. The weighted mean change from Baseline is the weighted mean minus Baseline. The AUC was calculated using the trapezoidal rule. For all post-dose observations, actual times that the spirometry measurements were conducted was used for the calculation. Pre-dose observations were counted as 0 hr observations - that is they had their time set to the time of dosing. The pre-dose value used for the calculation of the AUC was the mean of the two pre-dose observations (-30 and 0 min for Day 1 or 28). If one of these observations was missing, the remaining single pre-dose observation was used. | Baseline (pre-dose Day 1) and Days 1 to 2, Days 28 to 29 | 
| Change From Baseline in Weighted Mean for 0 to 24 Hours Forced Vital Capacity (FVC) on Day 1 to 2 and 28 to 29 | Weighted means serial FVC was derived by calculating the AUC, and then dividing by the time interval over which the AUC was calculated. Baseline was defined at pre-dose Day 1. The weighted mean change from Baseline is the weighted mean minus Baseline. The AUC was calculated using the trapezoidal rule. For all post-dose observations, actual times that the spirometry measurements were conducted was used for the calculation. Pre-dose observations were counted as 0 hr observations - that is they had their time set to the time of dosing. The pre-dose value used for the calculation of the AUC was the mean of the two pre-dose observations (-30 and 0 min for Day 1 or 28). If one of these observations was missing, the remaining single pre-dose observation was used. | Baseline (pre-dose Day 1) and Days 1 to 2, Days 28 to 29 | 
| Change From Baseline in Clinic Visit Trough FVC on Day 29 | The trough FVC is defined as the mean of the FVC values obtained 23 and 24 hours after dosing on Day 28. The Baseline FVC is the mean of the two assessments made 30 minutes pre-dose and immediately pre-dose [time 0] on Day 1. Change from Baseline was calculated by subtracting the post-baseline assessment value from the Baseline value. | Baseline (pre-dose Day 1) and Day 29 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COPD, Multicenter, GSK233705B, double-blind, Chronic Obstructive Pulmonary Disease (COPD), randomized