28-day Repeat Dose Study of GSK573719

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01030965
• Collaborator: (none)
• Enrollment: 285
• Locations: 20
• Arms: 4
• Actual Duration (Months): 6.6
• Patients Per Site: 14.3
• Patients Per Site Per Month: 2.2

Study Details

Study Description

Brief Summary

The study will evaluate the efficacy, safety, and pharmacokinetics of GSK573719 compared with placebo in subjects with COPD

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: GSK573719 125mcg; Drug: GSK573719 250mcg; Drug: GSK573719 500mcg; Drug: Placebo	Phase 2

Detailed Description

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate 3 doses of GSK573719 administered once-daily over 28 days in subjects with COPD.

Study Design

• Study Type: Interventional
• Actual Enrollment: 285 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy and Safety of GSK573719 Delivered Once-daily Over 28 Days in Subjects With COPD
• Actual Study Start Date: Dec 15, 2009
• Actual Primary Completion Date: Jul 4, 2010
• Actual Study Completion Date: Jul 4, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GSK573719 125mcg 125mcg once-daily via novel dry powder inhaler	Drug: GSK573719 125mcg; 125mcg once-daily
Experimental: GSK573719 250mcg 250mcg once-daily via novel dry powder inhaler	Drug: GSK573719 250mcg; 250mcg once-daily
Experimental: GSK573719 500mcg 500mcg once-daily via novel dry powder inhaler	Drug: GSK573719 500mcg; 500mcg once-daily
Placebo Comparator: Placebo once-daily via novel dry powder inhaler	Drug: Placebo; once-daily

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Day 29 [Baseline and Day 29]

   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 29 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after dosing on Day 28. Baseline is defined as the mean of the FEV1 values obtained at 30 minutes and immediately pre-dose on Day 1. Change from Baseline is defined as the difference between trough on Day 29 and Baseline. Analysis was performed using a repeated measures model with covariates of Baseline (BL), country, sex, age, treatment, smoking status, day, day by Baseline interaction, and day by treatment interaction.

Secondary Outcome Measures

1. Change From Baseline in Weighted Mean 0-6 Hour FEV1 Obtained Post-dose at Day 1 and Day 28 [Baseline, Day 1, and Day 28]

   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), and then dividing the value by the time interval over which the AUC was calculated. The weighted mean was calculated using the 0-6 hour post-dose measurements at Days 1 and 28, which included pre-dose (30 minutes prior to dosing on Day 1, or 24 hours after the previous day's dose on Day 28), and post-dose at 15 minutes, 30 minutes, 1 hour, 3 hours, and 6 hours. Baseline is defined as the mean of the FEV1 values obtained at 30 minutes and immediately pre-dose on Day 1. Change from Baseline is defined as the difference between weighted mean at Days 1 and 28 and Baseline. Analysis was performed using a repeated measures model with covariates of Baseline, country, sex, age, treatment, smoking status, day, day by Baseline interaction, and day by treatment interaction.

2. Change From Baseline in Serial FEV1 Over 24 Hours After Dosing at Day 1 and Day 28 [Baseline, Day 1, and Day 28]

   Serial spirometry assessments were conducted on Day 1 and Day 28 over the course of 24 hours and were obtained 0 (Day 28 only), 1, 3, 6, 23, and 24 hours after dosing. Baseline is defined as the mean of the FEV1 values obtained at 30 minutes and immediately pre-dose on Day 1. Change from Baseline is defined as the difference between FEV1 on Days 1 and 28 and Baseline.

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

• 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 25 to 70% of predicted normal

Exclusion Criteria:

• Asthma

• Other significant respiratory disorders besides COPD, including alpha-1 deficiency

• Previous lung resection surgery

• Chest X-ray or CP scan showing clinically significant abnormalities not due to COPD

• 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 or clinical lab finding (including Hepatitis B or C)

• Cancer

• Allergy or hypersensitivity to anticholinergics or inhaler excipients

• Diseases that would contraindicate 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

• Participation in acute phase of pulmonary rehabilitation program

• History of alcohol or drug abuse within 2 years prior to screening

• History of psychiatric disease limiting validity of consent

• Affiliation with the investigative site

• Previous use of GSK573719

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Madisonville	Kentucky	United States	42431
2	GSK Investigational Site	Charlotte	North Carolina	United States	28207
3	GSK Investigational Site	Spartanburg	South Carolina	United States	29303
4	GSK Investigational Site	Union	South Carolina	United States	29379
5	GSK Investigational Site	Tallinn		Estonia	10138
6	GSK Investigational Site	Tallinn		Estonia	13419
7	GSK Investigational Site	Tallinn		Estonia	13619
8	GSK Investigational Site	Tartu		Estonia	51014
9	GSK Investigational Site	Wiesbaden	Hessen	Germany	65187
10	GSK Investigational Site	Schwerin	Mecklenburg-Vorpommern	Germany	19055
11	GSK Investigational Site	Grosshansdorf	Schleswig-Holstein	Germany	22927
12	GSK Investigational Site	Berlin		Germany	10787
13	GSK Investigational Site	Berlin		Germany	13125
14	GSK Investigational Site	Berlin		Germany	14057
15	GSK Investigational Site	Hamburg		Germany	20253
16	GSK Investigational Site	Bialystok		Poland	15-027
17	GSK Investigational Site	Bialystok		Poland
18	GSK Investigational Site	Gidle		Poland	97-540
19	GSK Investigational Site	Krakow		Poland	31-023
20	GSK Investigational Site	Lublin		Poland	20-637

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

• Decramer M, Maltais F, Feldman G, Brooks J, Harris S, Mehta R, Crater G. Bronchodilation of umeclidinium, a new long-acting muscarinic antagonist, in COPD patients. Respir Physiol Neurobiol. 2013 Jan 15;185(2):393-9. doi: 10.1016/j.resp.2012.08.022. Epub 2012 Sep 28.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01030965
• Other Study ID Numbers: 113589
• First Posted: Dec 14, 2009
• Last Update Posted: Mar 9, 2018
• Last Verified: Feb 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: Chronic Bronchitis; Anticholinergic; Emphysema; Long-acting muscarinic antagonist; COPD
• Additional relevant MeSH terms: Pulmonary Disease, Chronic Obstructive

Study Results

Participant Flow

Pre-assignment Detail	The study consisted of a Run-in Period of 5 to 8 days, followed by a 28-day Treatment Period. A total of 421 participants were screened; of these, 125 were screen failures, 10 were Run-in failures, 288 were randomized, and 285 received at least one dose of study drug (three participants were randomized but did not receive study drug).

Arm/Group Title	Placebo	UMEC 125 µg	UMEC 250 µg	UMEC 500 µg
Arm/Group Description	Participants received matching placebo once daily (QD) in the morning via a dry powder inhaler (DPI) for 28 days.	Participants received umeclidinium bromide (UMEC) 125 micrograms (µg) QD in the morning via a DPI for 28 days.	Participants received UMEC 250 µg QD in the morning via a DPI for 28 days.	Participants received UMEC 500 µg QD in the morning via a DPI for 28 days.
Period Title: Overall Study
STARTED	71	71	72	71
COMPLETED	67	65	68	64
NOT COMPLETED	4	6	4	7

Baseline Characteristics

Arm/Group Title	Placebo	UMEC 125 µg	UMEC 250 µg	UMEC 500 µg	Total
Arm/Group Description	Participants received matching placebo once daily (QD) in the morning via a dry powder inhaler (DPI) for 28 days.	Participants received umeclidinium bromide (UMEC) 125 micrograms (µg) QD in the morning via a DPI for 28 days.	Participants received UMEC 250 µg QD in the morning via a DPI for 28 days.	Participants received UMEC 500 µg QD in the morning via a DPI for 28 days.	Total of all reporting groups
Overall Participants	71	71	72	71	285
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.3 (6.80)	60.1 (8.75)	60.3 (8.45)	62.6 (9.30)	61.4 (8.41)
Sex: Female, Male (Count of Participants)
Female	24 33.8%	35 49.3%	30 41.7%	34 47.9%	123 43.2%
Male	47 66.2%	36 50.7%	42 58.3%	37 52.1%	162 56.8%
Race/Ethnicity, Customized (Number) [Number]
African American/African Heritage	1 1.4%	4 5.6%	3 4.2%	1 1.4%	9 3.2%
White	70 98.6%	67 94.4%	69 95.8%	69 97.2%	275 96.5%
African American/African Heritage & White	0 0%	0 0%	0 0%	1 1.4%	1 0.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) at Day 29
Description	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 29 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after dosing on Day 28. Baseline is defined as the mean of the FEV1 values obtained at 30 minutes and immediately pre-dose on Day 1. Change from Baseline is defined as the difference between trough on Day 29 and Baseline. Analysis was performed using a repeated measures model with covariates of Baseline (BL), country, sex, age, treatment, smoking status, day, day by Baseline interaction, and day by treatment interaction.
Time Frame	Baseline and Day 29

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all participants randomized to treatment who received >=1 dose of randomized study medication in the treatment period. All participants with >=1 post-BL assessment and non-missing covariate data are included in the analysis. The number of participants represents participants who provided data at Day 29.

Arm/Group Title	Placebo	UMEC 125 µg	UMEC 250 µg	UMEC 500 µg
Arm/Group Description	Participants received matching placebo once daily (QD) in the morning via a dry powder inhaler (DPI) for 28 days.	Participants received umeclidinium bromide (UMEC) 125 micrograms (µg) QD in the morning via a DPI for 28 days.	Participants received UMEC 250 µg QD in the morning via a DPI for 28 days.	Participants received UMEC 500 µg QD in the morning via a DPI for 28 days.
Measure Participants	67	64	68	64
Least Squares Mean (Standard Error) [Liters]	0.013 (0.025)	0.171 (0.025)	0.181 (0.025)	0.163 (0.025)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, UMEC 125 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Repeated Measures Analysis of Covariance
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.159
	Confidence Interval	(2-Sided) 95%; 0.088 to 0.229
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, UMEC 250 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Repeated Measures Analysis of Covariance
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.168
	Confidence Interval	(2-Sided) 95%; 0.099 to 0.238
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, UMEC 500 µg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Repeated Measures Analysis of Covariance
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.150
	Confidence Interval	(2-Sided) 95%; 0.080 to 0.220
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Weighted Mean 0-6 Hour FEV1 Obtained Post-dose at Day 1 and Day 28
Description	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), and then dividing the value by the time interval over which the AUC was calculated. The weighted mean was calculated using the 0-6 hour post-dose measurements at Days 1 and 28, which included pre-dose (30 minutes prior to dosing on Day 1, or 24 hours after the previous day's dose on Day 28), and post-dose at 15 minutes, 30 minutes, 1 hour, 3 hours, and 6 hours. Baseline is defined as the mean of the FEV1 values obtained at 30 minutes and immediately pre-dose on Day 1. Change from Baseline is defined as the difference between weighted mean at Days 1 and 28 and Baseline. Analysis was performed using a repeated measures model with covariates of Baseline, country, sex, age, treatment, smoking status, day, day by Baseline interaction, and day by treatment interaction.
Time Frame	Baseline, Day 1, and Day 28

Outcome Measure Data

Analysis Population Description

ITT Population. Participants (par.) with >=1 post-BL assessment and non-missing covariate data are included in the analysis. Different par. may have been analyzed at different time points (n=X, X, X, X in the category titles), so the overall number of par. analyzed reflects everyone in the ITT Population with data avaialable at >=1 time point.

Arm/Group Title	Placebo	UMEC 125 µg	UMEC 250 µg	UMEC 500 µg
Arm/Group Description	Participants received matching placebo once daily (QD) in the morning via a dry powder inhaler (DPI) for 28 days.	Participants received umeclidinium bromide (UMEC) 125 micrograms (µg) QD in the morning via a DPI for 28 days.	Participants received UMEC 250 µg QD in the morning via a DPI for 28 days.	Participants received UMEC 500 µg QD in the morning via a DPI for 28 days.
Measure Participants	70	71	72	70
Day 1, n=70, 70, 71, 70	0.005 (0.015)	0.211 (0.015)	0.224 (0.014)	0.173 (0.015)
Day 28, n=65, 64, 68, 64	0.009 (0.024)	0.220 (0.024)	0.204 (0.023)	0.122 (0.024)

3. Secondary Outcome

Title	Change From Baseline in Serial FEV1 Over 24 Hours After Dosing at Day 1 and Day 28
Description	Serial spirometry assessments were conducted on Day 1 and Day 28 over the course of 24 hours and were obtained 0 (Day 28 only), 1, 3, 6, 23, and 24 hours after dosing. Baseline is defined as the mean of the FEV1 values obtained at 30 minutes and immediately pre-dose on Day 1. Change from Baseline is defined as the difference between FEV1 on Days 1 and 28 and Baseline.
Time Frame	Baseline, Day 1, and Day 28

Outcome Measure Data

Analysis Population Description

ITT Population. All participants with >=1 post-BL assessment and non-missing covariate data are included in the analysis. Different participants may have been analyzed at different time points (represented by n=X, X, X, X in the category titles), so the overall number of participants analyzed reflects everyone in the ITT Population.

Arm/Group Title	Placebo	UMEC 125 µg	UMEC 250 µg	UMEC 500 µg
Arm/Group Description	Participants received matching placebo once daily (QD) in the morning via a dry powder inhaler (DPI) for 28 days.	Participants received umeclidinium bromide (UMEC) 125 micrograms (µg) QD in the morning via a DPI for 28 days.	Participants received UMEC 250 µg QD in the morning via a DPI for 28 days.	Participants received UMEC 500 µg QD in the morning via a DPI for 28 days.
Measure Participants	71	71	72	71
Day 1, 1 hour, n=70, 71, 72, 71	0.013 (0.015)	0.196 (0.015)	0.212 (0.015)	0.145 (0.015)
Day 1, 3 hours, n=70, 71, 72, 71	0.008 (0.018)	0.255 (0.018)	0.274 (0.018)	0.227 (0.018)
Day 1, 6 hours, n=70, 71, 72, 70	-0.004 (0.019)	0.232 (0.019)	0.221 (0.019)	0.186 (0.019)
Day 1, 23 hours, n=70, 70, 72, 70	-0.036 (0.019)	0.171 (0.019)	0.186 (0.019)	0.107 (0.019)
Day 1, 24 hours, n=69, 71, 72, 70	-0.002 (0.019)	0.211 (0.018)	0.216 (0.018)	0.153 (0.018)
Day 28, 0 hours, n=67, 64, 69, 65	-0.017 (0.024)	0.165 (0.024)	0.203 (0.024)	0.140 (0.024)
Day 28, 1 hour, n=67, 64, 68, 65	-0.008 (0.025)	0.207 (0.026)	0.182 (0.025)	0.067 (0.026)
Day 28, 3 hours, n=67, 65, 67, 64	0.008 (0.026)	0.267 (0.026)	0.204 (0.026)	0.168 (0.026)
Day 28, 6 hours, n=65, 65, 68, 64	-0.005 (0.028)	0.206 (0.028)	0.181 (0.027)	0.141 (0.028)
Day 28, 23 hours, n=67, 64, 68, 64	-0.013 (0.026)	0.144 (0.027)	0.161 (0.026)	0.157 (0.027)
Day 28, 24 hours, n=67, 64, 68, 64	0.024 (0.025)	0.204 (0.026)	0.192 (0.025)	0.170 (0.026)

Adverse Events

Time Frame	On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication up to 4 weeks.
Adverse Event Reporting Description	On-treatment serious adverse events (SAEs) and non-serious AEs are reported for members of the Intent-to-Treat (ITT) Population, comprised of all participants randomized to treatment who received at least one dose of randomized study medication in the treatment period.
Arm/Group Title	Placebo		UMEC 125 µg		UMEC 250 µg		UMEC 500 µg
Arm/Group Description	Participants received matching placebo once daily (QD) in the morning via a dry powder inhaler (DPI) for 28 days.		Participants received umeclidinium bromide (UMEC) 125 micrograms (µg) QD in the morning via a DPI for 28 days.		Participants received UMEC 250 µg QD in the morning via a DPI for 28 days.		Participants received UMEC 500 µg QD in the morning via a DPI for 28 days.
All Cause Mortality
	Placebo		UMEC 125 µg		UMEC 250 µg		UMEC 500 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		UMEC 125 µg		UMEC 250 µg		UMEC 500 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/71 (0%)		1/71 (1.4%)		1/72 (1.4%)		1/71 (1.4%)
Eye disorders
Retinal detachment	0/71 (0%)		1/71 (1.4%)		0/72 (0%)		0/71 (0%)
Infections and infestations
Gastroenteritis viral	0/71 (0%)		0/71 (0%)		0/72 (0%)		1/71 (1.4%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/71 (0%)		0/71 (0%)		1/72 (1.4%)		0/71 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		UMEC 125 µg		UMEC 250 µg		UMEC 500 µg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/71 (8.5%)		5/71 (7%)		9/72 (12.5%)		13/71 (18.3%)
Infections and infestations
Nasopharyngitis	3/71 (4.2%)		2/71 (2.8%)		1/72 (1.4%)		2/71 (2.8%)
Nervous system disorders
Headache	3/71 (4.2%)		3/71 (4.2%)		4/72 (5.6%)		6/71 (8.5%)
Respiratory, thoracic and mediastinal disorders
Cough	2/71 (2.8%)		0/71 (0%)		6/72 (8.3%)		8/71 (11.3%)

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.