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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00676052
• Collaborator: (none)
• Enrollment: 576
• Locations: 88
• Arms: 6
• Actual Duration (Months): 7.2
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of GSK233705B compared with placebo in subjects with COPD.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: GSK233705 12.5mcg; Drug: GSK233705 25mcg; Drug: GSK233705 50mcg; Drug: GSK233705 100mcg; Drug: GSK233705 200mcg; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 576 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Multicentre Dose Ranging Study for Once Daily GSK233705 in COPD
• Actual Study Start Date: May 16, 2008
• Actual Primary Completion Date: Dec 22, 2008
• Actual Study Completion Date: Dec 22, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 GSK233705 12.5mcg	Drug: GSK233705 12.5mcg; Once daily via dry powder inhaler
Experimental: Arm 2 GSK233705 25mcg	Drug: GSK233705 25mcg; once daily via dry powder inhaler
Experimental: Arm 3 GSK233705 50mcg	Drug: GSK233705 50mcg; Once daily via dry powder inhaler
Experimental: Arm 4 GSK233705 100mcg	Drug: GSK233705 100mcg; Once daily via dry powder inhaler
Experimental: Arm 5 GSK233705 200mcg	Drug: GSK233705 200mcg; Once daily via dry powder inhaler
Placebo Comparator: Arm 6 Placebo	Drug: Placebo; Once daily via dry powder imhaler

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 29 [Baseline (pre-dose Day 1) and 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.

Secondary Outcome Measures

1. Change From Baseline in Weighted Mean for 0 to 24 Hours Serial FEV1 on Day 1 to 2 and 28 to 29 [Baseline (pre-dose Day 1) and Days 1 to 2, Days 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.

2. Change From Baseline in Weighted Mean for 0 to 24 Hours Forced Vital Capacity (FVC) on Day 1 to 2 and 28 to 29 [Baseline (pre-dose Day 1) and Days 1 to 2, Days 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.

3. Change From Baseline in Clinic Visit Trough FVC on Day 29 [Baseline (pre-dose Day 1) and 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Jasper	Alabama	United States	35501
2	GSK Investigational Site	Glendale	Arizona	United States	85306
3	GSK Investigational Site	Fountain Valley	California	United States	92708
4	GSK Investigational Site	Fullerton	California	United States	92835
5	GSK Investigational Site	Los Angeles	California	United States	90048
6	GSK Investigational Site	Los Angeles	California	United States	90095
7	GSK Investigational Site	Riverside	California	United States	92506
8	GSK Investigational Site	Roseville	California	United States	95661
9	GSK Investigational Site	San Diego	California	United States	92103-8415
10	GSK Investigational Site	Brandon	Florida	United States	33511
11	GSK Investigational Site	Panama City	Florida	United States	32405
12	GSK Investigational Site	South Miami	Florida	United States	33143
13	GSK Investigational Site	Coeur d'Alene	Idaho	United States	83814
14	GSK Investigational Site	Madisonville	Kentucky	United States	42431
15	GSK Investigational Site	Lafayette	Louisiana	United States	70503
16	GSK Investigational Site	Sunset	Louisiana	United States	70584
17	GSK Investigational Site	Saint Charles	Missouri	United States	63301
18	GSK Investigational Site	Charlotte	North Carolina	United States	28207
19	GSK Investigational Site	Charleston	South Carolina	United States	29406-7108
20	GSK Investigational Site	Greenville	South Carolina	United States	29615
21	GSK Investigational Site	Spartanburg	South Carolina	United States	29303
22	GSK Investigational Site	Union	South Carolina	United States	29379
23	GSK Investigational Site	Houston	Texas	United States	77030
24	GSK Investigational Site	Abingdon	Virginia	United States	24210
25	GSK Investigational Site	Richmond	Virginia	United States	23229
26	GSK Investigational Site	La Plata	Buenos Aires	Argentina	CP1900
27	GSK Investigational Site	Mar del Plata	Buenos Aires	Argentina	7600
28	GSK Investigational Site	Mar del Plata	Buenos Aires	Argentina	B7600FZN
29	GSK Investigational Site	Pergamino	Buenos Aires	Argentina	2700
30	GSK Investigational Site	Tucuman		Argentina	4000
31	GSK Investigational Site	Dimitrovgrad		Bulgaria	6400
32	GSK Investigational Site	Ruse		Bulgaria	7000
33	GSK Investigational Site	Sofia		Bulgaria	1431
34	GSK Investigational Site	Sofia		Bulgaria
35	GSK Investigational Site	Calgary	Alberta	Canada	T2N 4N1
36	GSK Investigational Site	Bay Roberts	Newfoundland and Labrador	Canada	A0A 1G0
37	GSK Investigational Site	Mississauga	Ontario	Canada	L5A 3V4
38	GSK Investigational Site	Ottawa	Ontario	Canada	K1H 8L6
39	GSK Investigational Site	Toronto	Ontario	Canada	M5G 1N8
40	GSK Investigational Site	Saint Romuald	Quebec	Canada	G6W 5M6
41	GSK Investigational Site	Sainte Jerome	Quebec	Canada	J7Z 5T3
42	GSK Investigational Site	Sainte-Foy	Quebec	Canada	G1V 4G5
43	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7500551
44	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7500691
45	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile
46	GSK Investigational Site	Valparaiso	Valparaíso	Chile	2341131
47	GSK Investigational Site	Santiago		Chile	8380453
48	GSK Investigational Site	Wiesloch	Baden-Wuerttemberg	Germany	69168
49	GSK Investigational Site	Gelnhausen	Hessen	Germany	63571
50	GSK Investigational Site	Hannover	Niedersachsen	Germany	30159
51	GSK Investigational Site	Hannover	Niedersachsen	Germany	30167
52	GSK Investigational Site	Magdeburg	Sachsen-Anhalt	Germany	39112
53	GSK Investigational Site	Dresden	Sachsen	Germany	01307
54	GSK Investigational Site	Luebeck	Schleswig-Holstein	Germany	23552
55	GSK Investigational Site	Schmoelln	Thueringen	Germany	04626
56	GSK Investigational Site	Berlin		Germany	10117
57	GSK Investigational Site	Berlin		Germany	10559
58	GSK Investigational Site	Berlin		Germany	10717
59	GSK Investigational Site	Berlin		Germany	10787
60	GSK Investigational Site	Berlin		Germany	14057
61	GSK Investigational Site	Balassagyarmat		Hungary	2660
62	GSK Investigational Site	Budapest		Hungary	1095
63	GSK Investigational Site	Budapest		Hungary	H-1529
64	GSK Investigational Site	Mátraháza		Hungary	3233
65	GSK Investigational Site	Seoul		Korea, Republic of	133--792
66	GSK Investigational Site	Seoul		Korea, Republic of	152-703
67	GSK Investigational Site	Almelo		Netherlands	7609 PP
68	GSK Investigational Site	Eindhoven		Netherlands	5623 EJ
69	GSK Investigational Site	Hoofddorp		Netherlands	2134 TM
70	GSK Investigational Site	Hoorn		Netherlands	1624 NP
71	GSK Investigational Site	Cavite		Philippines	4114
72	GSK Investigational Site	Quezon City		Philippines	1100
73	GSK Investigational Site	Quezon City		Philippines	1109
74	GSK Investigational Site	Brasov		Romania	500112
75	GSK Investigational Site	Bucharest		Romania	020125
76	GSK Investigational Site	Iasi		Romania	700115
77	GSK Investigational Site	Cape Town	Gauteng	South Africa	7505
78	GSK Investigational Site	Mueckelneck	Gauteng	South Africa	0001
79	GSK Investigational Site	Parktown	Gauteng	South Africa	2193
80	GSK Investigational Site	Bellville		South Africa	7531
81	GSK Investigational Site	Mowbray		South Africa	7700
82	GSK Investigational Site	Bangkok		Thailand	10700
83	GSK Investigational Site	Chiangmai		Thailand	50200
84	GSK Investigational Site	Khon Kaen		Thailand	40002
85	GSK Investigational Site	Songkla		Thailand	90110
86	GSK Investigational Site	Brighton	Sussex East	United Kingdom	BN2 5BE
87	GSK Investigational Site	London		United Kingdom	SE5 9PJ
88	GSK Investigational Site	Norwich		United Kingdom	NR4 7UY

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00676052
• Other Study ID Numbers: AC2110664
• First Posted: May 12, 2008
• Last Update Posted: Oct 9, 2017
• Last Verified: Aug 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: COPD; Multicenter; GSK233705B; double-blind; Chronic Obstructive Pulmonary Disease (COPD); randomized
• Additional relevant MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive

Study Results

Participant Flow

Recruitment Details	This study was conducted across 79 centers: 30 in North America, 28 in Europe and 21 in International regions. The first participant first visit was on 16 May 2008 and last participant last visit was on 22 December 2008.
Pre-assignment Detail	Out of the 963 participants screened for this study, 303 participants were screen failures and 79 participants were run-in failures. Therefore, a total of 581 participants were randomized out of which 5 participants did not receive any study medication, thus 576 participants were included in the intent-to-treat (ITT) Population.

Arm/Group Title	Placebo	GSK233705B 12.5 mcg	GSK233705B 25 mcg	GSK233705B 50 mcg	GSK233705B 100 mcg	GSK233705B 200 mcg
Arm/Group Description	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive placebo administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 12.5 micrograms (mcg) administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 25 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 50 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 100 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 200 mcg administered once daily via a novel dry powder inhaler.
Period Title: Overall Study
STARTED	96	95	96	97	95	97
COMPLETED	87	88	90	92	89	91
NOT COMPLETED	9	7	6	5	6	6

Baseline Characteristics

Arm/Group Title	Placebo	GSK233705B 12.5 mcg	GSK233705B 25 mcg	GSK233705B 50 mcg	GSK233705B 100 mcg	GSK233705B 200 mcg	Total
Arm/Group Description	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive placebo administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 12.5 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 25 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 50 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 100 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 200 mcg administered once daily via a novel dry powder inhaler.	Total of all reporting groups
Overall Participants	96	95	96	97	95	97	576
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.4 (8.73)	62.2 (9.75)	62.2 (8.70)	62.8 (6.99)	61.7 (8.77)	64.1 (8.30)	62.4 (8.58)
Sex: Female, Male (Count of Participants)
Female	46 47.9%	34 35.8%	43 44.8%	45 46.4%	33 34.7%	34 35.1%	235 40.8%
Male	50 52.1%	61 64.2%	53 55.2%	52 53.6%	62 65.3%	63 64.9%	341 59.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1%	1 1.1%	0 0%	0 0%	0 0%	1 1%	3 0.5%
Asian	8 8.3%	7 7.4%	4 4.2%	7 7.2%	8 8.4%	9 9.3%	43 7.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	3 3.1%	1 1.1%	5 5.2%	2 2.1%	3 3.2%	2 2.1%	16 2.8%
White	84 87.5%	86 90.5%	86 89.6%	88 90.7%	83 87.4%	85 87.6%	512 88.9%
More than one race	0 0%	0 0%	1 1%	0 0%	1 1.1%	0 0%	2 0.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at Day 29
Description	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.
Time Frame	Baseline (pre-dose Day 1) and Day 29

Outcome Measure Data

Analysis Population Description

ITT Population. Last observation carried forward (LOCF) data has been presented.

Arm/Group Title	GSK233705B 12.5 mcg	GSK233705B 25 mcg	GSK233705B 50 mcg	GSK233705B 100 mcg	GSK233705B 200 mcg	Placebo
Arm/Group Description	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 12.5 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 25 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 50 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 100 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 200 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive placebo administered once daily via a novel dry powder inhaler.
Measure Participants	94	94	97	94	96	94
Least Squares Mean (Standard Error) [Liter]	0.058 (0.0180)	0.088 (0.0180)	0.060 (0.0178)	0.073 (0.0181)	0.128 (0.0179)	-0.009 (0.0181)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 12.5 mcg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	Analysis performed using ANCOVA with covariates of Baseline, sex, age, smoking status, responsiveness stratum and treatment. Missing trough FEV1 data at Day 29 was imputed using LOCF.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.067
	Confidence Interval	(2-Sided) 95%; 0.017 to 0.117
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 25 mcg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using ANCOVA with covariates of Baseline, sex, age, smoking status, responsiveness stratum and treatment. Missing trough FEV1 data at Day 29 was imputed using LOCF.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.097
	Confidence Interval	(2-Sided) 95%; 0.047 to 0.147
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 50 mcg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	Analysis performed using ANCOVA with covariates of Baseline, sex, age, smoking status, responsiveness stratum and treatment. Missing trough FEV1 data at Day 29 was imputed using LOCF.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.069
	Confidence Interval	(2-Sided) 95%; 0.019 to 0.118
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 100 mcg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	Analysis performed using ANCOVA with covariates of Baseline, sex, age, smoking status, responsiveness stratum and treatment. Missing trough FEV1 data at Day 29 was imputed using LOCF.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.082
	Confidence Interval	(2-Sided) 95%; 0.032 to 0.132
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 200 mcg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using ANCOVA with covariates of Baseline, sex, age, smoking status, responsiveness stratum and treatment. Missing trough FEV1 data at Day 29 was imputed using LOCF.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.137
	Confidence Interval	(2-Sided) 95%; 0.086 to 0.187
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Weighted Mean for 0 to 24 Hours Serial FEV1 on Day 1 to 2 and 28 to 29
Description	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.
Time Frame	Baseline (pre-dose Day 1) and Days 1 to 2, Days 28 to 29

Outcome Measure Data

Analysis Population Description

ITT Population. Participants with analyzable data on the indicated time point have been presented.

Arm/Group Title	GSK233705B 12.5 mcg	GSK233705B 25 mcg	GSK233705B 50 mcg	GSK233705B 100 mcg	GSK233705B 200 mcg	Placebo
Arm/Group Description	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 12.5 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 25 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 50 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 100 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 200 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive placebo administered once daily via a novel dry powder inhaler.
Measure Participants	94	95	97	94	97	94
FEV1, Day 1	0.085 (0.0146)	0.086 (0.0146)	0.102 (0.0143)	0.132 (0.0146)	0.155 (0.0144)	-0.021 (0.0146)
FEV1, Day 28	0.087 (0.0180)	0.122 (0.0179)	0.105 (0.0178)	0.122 (0.0180)	0.150 (0.0178)	-0.020 (0.0182)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 12.5 mcg, Placebo
	Comments	FEV1, Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.106
	Confidence Interval	(2-Sided) 95%; 0.065 to 0.146
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 25 mcg, Placebo
	Comments	FEV1, Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.107
	Confidence Interval	(2-Sided) 95%; 0.067 to 0.147
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 50 mcg, Placebo
	Comments	FEV1, Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.123
	Confidence Interval	(2-Sided) 95%; 0.083 to 0.163
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 100 mcg, Placebo
	Comments	FEV1, Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.152
	Confidence Interval	(2-Sided) 95%; 0.112 to 0.193
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 200 mcg, Placebo
	Comments	FEV1, Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.176
	Confidence Interval	(2-Sided) 95%; 0.135 to 0.216
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 12.5 mcg, Placebo
	Comments	FEV1, Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.106
	Confidence Interval	(2-Sided) 95%; 0.056 to 0.157
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 25 mcg, Placebo
	Comments	FEV, Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.142
	Confidence Interval	(2-Sided) 95%; 0.092 to 0.192
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 50 mcg, Placebo
	Comments	FEV1, Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.124
	Confidence Interval	(2-Sided) 95%; 0.074 to 0.174
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 100 mcg, Placebo
	Comments	FEV1, Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.142
	Confidence Interval	(2-Sided) 95%; 0.092 to 0.193
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 200 mcg, Placebo
	Comments	FEV1, Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.170
	Confidence Interval	(2-Sided) 95%; 0.120 to 0.220
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Weighted Mean for 0 to 24 Hours Forced Vital Capacity (FVC) on Day 1 to 2 and 28 to 29
Description	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.
Time Frame	Baseline (pre-dose Day 1) and Days 1 to 2, Days 28 to 29

Outcome Measure Data

Analysis Population Description

ITT Population. Participants with analyzable data on the indicated time point have been presented.

Arm/Group Title	GSK233705B 12.5 mcg	GSK233705B 25 mcg	GSK233705B 50 mcg	GSK233705B 100 mcg	GSK233705B 200 mcg	Placebo
Arm/Group Description	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 12.5 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 25 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 50 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 100 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 200 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive placebo administered once daily via a novel dry powder inhaler.
Measure Participants	94	95	97	94	97	94
Day 1	0.129 (0.0257)	0.149 (0.0257)	0.160 (0.0253)	0.207 (0.0257)	0.263 (0.0257)	-0.037 (0.0257)
Day 28	0.137 (0.0287)	0.178 (0.0285)	0.150 (0.0283)	0.191 (0.0287)	0.253 (0.0283)	-0.041 (0.0289)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 12.5 mcg, Placebo
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.166
	Confidence Interval	(2-Sided) 95%; 0.094 to 0.237
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 25 mcg, Placebo
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.186
	Confidence Interval	(2-Sided) 95%; 0.115 to 0.258
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 50 mcg, Placebo
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.198
	Confidence Interval	(2-Sided) 95%; 0.127 to 0.268
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 100 mcg, Placebo
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.244
	Confidence Interval	(2-Sided) 95%; 0.172 to 0.315
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 200 mcg, Placebo
	Comments	Day 1
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.301
	Confidence Interval	(2-Sided) 95%; 0.229 to 0.372
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 12.5 mcg, Placebo
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.178
	Confidence Interval	(2-Sided) 95%; 0.098 to 0.258
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 25 mcg, Placebo
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.219
	Confidence Interval	(2-Sided) 95%; 0.139 to 0.298
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 50 mcg, Placebo
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.191
	Confidence Interval	(2-Sided) 95%; 0.111 to 0.270
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 100 mcg, Placebo
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.232
	Confidence Interval	(2-Sided) 95%; 0.152 to 0.312
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 200 mcg, Placebo
	Comments	Day 28
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.294
	Confidence Interval	(2-Sided) 95%; 0.214 to 0.373
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Clinic Visit Trough FVC on Day 29
Description	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.
Time Frame	Baseline (pre-dose Day 1) and Day 29

Outcome Measure Data

Analysis Population Description

ITT Population. Participants with analyzable data on the indicated time point have been presented.

Arm/Group Title	GSK233705B 12.5 mcg	GSK233705B 25 mcg	GSK233705B 50 mcg	GSK233705B 100 mcg	GSK233705B 200 mcg	Placebo
Arm/Group Description	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 12.5 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 25 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 50 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 100 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 200 mcg administered once daily via a novel dry powder inhaler.	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive placebo administered once daily via a novel dry powder inhaler.
Measure Participants	88	90	91	89	91	87
Least Squares Mean (Standard Error) [Liter]	0.088 (0.0301)	0.139 (0.0298)	0.083 (0.0295)	0.152 (0.0300)	0.224 (0.0297)	-0.011 (0.0301)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 12.5 mcg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.099
	Confidence Interval	(2-Sided) 95%; 0.015 to 0.182
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 25 mcg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.150
	Confidence Interval	(2-Sided) 95%; 0.067 to 0.233
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 50 mcg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.094
	Confidence Interval	(2-Sided) 95%; 0.011 to 0.177
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 100 mcg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.163
	Confidence Interval	(2-Sided) 95%; 0.080 to 0.247
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	GSK233705B 200 mcg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Analysis performed using repeated measures with covariates of Baseline, sex, age, smoking status, responsiveness stratum, Day (nominal), treatment and Day by treatment and Day by Baseline interactions.
	Method	Repeated Measures Model
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.235
	Confidence Interval	(2-Sided) 95%; 0.152 to 0.319
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events (AEs) were collected up to follow visit (7 to 9 days post visit 8 or premature discontinuation).
Adverse Event Reporting Description	ITT Population was used in the analysis of safety data.
Arm/Group Title	Placebo		GSK233705B 12.5 mcg		GSK233705B 25 mcg		GSK233705B 50 mcg		GSK233705B 100 mcg		GSK233705B 200 mcg
Arm/Group Description	Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive placebo administered once daily via a novel dry powder inhaler.		Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 12.5 mcg administered once daily via a novel dry powder inhaler.		Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 25 mcg administered once daily via a novel dry powder inhaler.		Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 50 mcg administered once daily via a novel dry powder inhaler.		Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 100 mcg administered once daily via a novel dry powder inhaler.		Eligible participants completed a two week run-in period during which they received placebo once daily via the novel dry powder inhaler. After run-in period, participants were randomized to receive GSK233705B 200 mcg administered once daily via a novel dry powder inhaler.
All Cause Mortality
	Placebo		GSK233705B 12.5 mcg		GSK233705B 25 mcg		GSK233705B 50 mcg		GSK233705B 100 mcg		GSK233705B 200 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/96 (0%)		0/95 (0%)		0/96 (0%)		0/97 (0%)		0/95 (0%)		1/97 (1%)
Serious Adverse Events
	Placebo		GSK233705B 12.5 mcg		GSK233705B 25 mcg		GSK233705B 50 mcg		GSK233705B 100 mcg		GSK233705B 200 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/96 (0%)		0/95 (0%)		2/96 (2.1%)		1/97 (1%)		1/95 (1.1%)		1/97 (1%)
Gastrointestinal disorders
Colitis	0/96 (0%)		0/95 (0%)		1/96 (1%)		0/97 (0%)		0/95 (0%)		0/97 (0%)
Pancreatitis	0/96 (0%)		0/95 (0%)		0/96 (0%)		0/97 (0%)		1/95 (1.1%)		0/97 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma	0/96 (0%)		0/95 (0%)		1/96 (1%)		0/97 (0%)		0/95 (0%)		0/97 (0%)
Renal and urinary disorders
Renal failure acute	0/96 (0%)		0/95 (0%)		0/96 (0%)		0/97 (0%)		0/95 (0%)		1/97 (1%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/96 (0%)		0/95 (0%)		0/96 (0%)		1/97 (1%)		0/95 (0%)		0/97 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		GSK233705B 12.5 mcg		GSK233705B 25 mcg		GSK233705B 50 mcg		GSK233705B 100 mcg		GSK233705B 200 mcg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/96 (7.3%)		4/95 (4.2%)		6/96 (6.3%)		9/97 (9.3%)		5/95 (5.3%)		3/97 (3.1%)
Nervous system disorders
Headache	7/96 (7.3%)	9	4/95 (4.2%)	4	6/96 (6.3%)	6	9/97 (9.3%)	14	5/95 (5.3%)	7	3/97 (3.1%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.