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24-week Trial Comparing GSK573719/GW642444 With GW642444 and With Tiotropium in Chronic Obstructive Pulmonary Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01316900
Recruitment Status : Completed
First Posted : March 16, 2011
Results First Posted : February 10, 2014
Last Update Posted : January 24, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Pulmonary Disease, Chronic Obstructive
Interventions Drug: GSK573719/GW642444 125/25
Drug: GSK573719/GW642444 62.5/25
Drug: GW642444
Drug: tiotropium bromide
Enrollment 846
Recruitment Details  
Pre-assignment Details Participants (par.) who met eligibility criteria at Screening (Visit 1) completed a 7- to10-day run-in period and were then randomized to a 24-week treatment period. A total of 1141 par. were screened; 846 par. were randomized (3 par. were randomized [2 in error] and received no study drug) and 843 par. received at least one dose of study drug.
Arm/Group Title VI 25 µg UMEC/VI 62.5/25 µg UMEC/VI 125/25 µg TIO 18 µg
Hide Arm/Group Description Participants received vilanterol (VI) 25 micrograms (µg) once daily (QD) via a dry powder inhaler (DPI). All participants also received placebo QD via a HandiHaler. Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler. Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler. Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI.
Period Title: Overall Study
Started 209 212 214 208
Completed 165 181 173 177
Not Completed 44 31 41 31
Reason Not Completed
Adverse Event             10             10             15             9
Lack of Efficacy             17             9             5             7
Protocol Violation             7             1             4             0
Protocol-defined Stopping Criteria             2             3             10             5
Lost to Follow-up             1             0             1             1
Withdrawal by Subject             7             8             6             9
Arm/Group Title VI 25 µg UMEC/VI 62.5/25 µg UMEC/VI 125/25 µg Tiotropium 18 µg Total
Hide Arm/Group Description Participants received vilanterol (VI) 25 micrograms (µg) once daily (QD) via a dry powder inhaler (DPI). All participants also received placebo QD via a HandiHaler. Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler. Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler. Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI. Total of all reporting groups
Overall Number of Baseline Participants 209 212 214 208 843
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 209 participants 212 participants 214 participants 208 participants 843 participants
63.2  (9.10) 63.0  (8.67) 62.9  (8.87) 62.6  (9.39) 62.9  (9.00)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 209 participants 212 participants 214 participants 208 participants 843 participants
Female
66
  31.6%
64
  30.2%
63
  29.4%
68
  32.7%
261
  31.0%
Male
143
  68.4%
148
  69.8%
151
  70.6%
140
  67.3%
582
  69.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 209 participants 212 participants 214 participants 208 participants 843 participants
African American/African Heritage 3 7 9 6 25
American Indian or Alaska Native 19 16 21 20 76
Asian - Central/South Asian Heritage 0 0 1 0 1
Asian - Japanese Heritage 0 3 0 2 5
White - White/Caucasian/European Heritage 184 182 180 177 723
Mixed Race 3 4 3 3 13
1.Primary Outcome
Title Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24)
Hide 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 measurements were taken electronically by spirometry on Days 2, 28, 56, 84, 112, 168, and 169. Baseline is defined as the mean of the assessments made 30 minutes pre-dose and 5 minutes pre-dose on Treatment Day 1. Trough FEV1 is defined as the mean of the FEV1 values obtained at 23 and 24 hours after the previous morning's dosing (ie., trough FEV1 on Day 169 is the mean of the FEV1 values obtained 23 and 24 hours after the morning dosing on Day 168). Change from Baseline at a particular visit was calculated as the trough FEV1 at that visit minus Baseline. Analysis was performed using a repeated measures model with covariates of treatment, Baseline , smoking status, center group, day, and day by Baseline and day by treatment interactions. ITT=Intent-to-Treat; par.=participants. .
Time Frame Baseline and Day 169
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population excluding par. from Investigator 040688: all randomized par. who received >=1 dose of study drug, except for those from Investigator 040688. Par. analyzed are those with data available at the presented time point; but, all par. without missing covariate information and with >=1 post-BL measurement were included in the analysis.
Arm/Group Title VI 25 µg UMEC/VI 62.5/25 µg UMEC/VI 125/25 µg TIO 18 µg
Hide Arm/Group Description:
Participants received vilanterol (VI) 25 micrograms (µg) once daily (QD) via a dry powder inhaler (DPI). All participants also received placebo QD via a HandiHaler.
Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.
Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.
Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI.
Overall Number of Participants Analyzed 162 177 167 173
Least Squares Mean (Standard Error)
Unit of Measure: Liters
0.121  (0.0189) 0.211  (0.0183) 0.209  (0.0187) 0.121  (0.0186)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection VI 25 µg, UMEC/VI 62.5/25 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value 0.090
Confidence Interval (2-Sided) 95%
0.039 to 0.142
Estimation Comments Least squares mean difference=UMEC/VI 62.5/25 µg minus VI 25 µg.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection UMEC/VI 62.5/25 µg, TIO 18 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments nominal p-value
Method Mixed Models Analysis
Comments Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value 0.090
Confidence Interval (2-Sided) 95%
0.039 to 0.141
Estimation Comments Least squares mean difference=UMEC/VI 62.5/25 µg minus Tio 18 µg.
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection VI 25 µg, UMEC/VI 125/25 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value 0.088
Confidence Interval (2-Sided) 95%
0.036 to 0.140
Estimation Comments Least squares mean difference=UMEC/VI 125/25 µg minus VI 25 µg.
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection UMEC/VI 125/25 µg, TIO 18 µg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Mixed Models Analysis
Comments Restricted maximum likelihood (REML)-based repeated measures approach (MMRM).
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value 0.088
Confidence Interval (2-Sided) 95%
0.036 to 0.140
Estimation Comments Least squares mean difference=UMEC/VI 125/25 µg minus TIO 18 µg.
2.Secondary Outcome
Title Change From Baseline (BL) in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168
Hide 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 WM 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 WM was calculated at Days 1, 84, and Day 168 using the 0-6-hour post-dose FEV1 measurements collected on that day, which included pre-dose (Day 1: 30 minutes [min] and 5 min prior to dosing; other serial visits: 23 and 24 hours after the previous morning dose) and post-dose at 15 minutes, 30 minutes, 1 hour, 3 hours, and 6 hours. Change from BL at a particular visit was calculated as WM at that visit minus BL. Analysis was performed using a repeated measures model with covariates of treatment, BL (mean of the two assessments made 30 minutes and 5 minutes pre-dose on Day 1), smoking status, center group, day, and day by BL and day by treatment interactions.
Time Frame Baseline and Day 168
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population excluding participants from Investigator 040688. Par. analyzed are those with data available at the presented time point; but, all par. without missing covariate information and with >=1 post-Baseline measurement were included in the analysis.
Arm/Group Title VI 25 µg UMEC/VI 62.5/25 µg UMEC/VI 125/25 µg TIO 18 µg
Hide Arm/Group Description:
Participants received vilanterol (VI) 25 micrograms (µg) once daily (QD) via a dry powder inhaler (DPI). All participants also received placebo QD via a HandiHaler.
Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.
Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.
Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI.
Overall Number of Participants Analyzed 161 173 166 168
Least Squares Mean (Standard Error)
Unit of Measure: Liters
0.178  (0.0189) 0.254  (0.0183) 0.263  (0.0187) 0.181  (0.0187)
3.Other Pre-specified Outcome
Title Change From Baseline (BL) in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24
Hide Description The newly developed SOBDA questionnaire assesses dyspnea or shortness of breath (SOB) with daily activities. The SOBDA questionnaire is made up of 13 items completed by the participant (par.) each evening prior to bedtime, when the par. is instructed to reflect on the current day's activities. The daily score is computed as the mean of the scores on the 13 items (>=7 items must have non-missing responses for this to be calculated). The par. is assigned a weekly mean SOBDA score ranging from 1 to 4 (greater scores indicate more severe breathlessness with daily activities) based on the mean of 7 days of data (>=4 of 7 days must be completed for a weekly mean to be calculated). Change from BL is the mean weekly SOBDA score minus BL. Analysis was performed using MMRM with covariates of treatment, BL (mean score in the week prior to treatment), smoking status, center group, week, week by BL and week by treatment interactions. This MMRM analysis only included Weeks 4, 8, 12, and 24.
Time Frame Baseline and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population excluding participants from Investigator 040688. Participants analyzed are those with data available at the presented time point; but, all participants without missing covariate information and with >=1 post-Baseline measurement were included in the analysis.
Arm/Group Title VI 25 µg UMEC/VI 62.5/25 µg UMEC/VI 125/25 µg TIO 18 µg
Hide Arm/Group Description:
Participants received vilanterol (VI) 25 micrograms (µg) once daily (QD) via a dry powder inhaler (DPI). All participants also received placebo QD via a HandiHaler.
Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.
Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.
Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI.
Overall Number of Participants Analyzed 110 118 107 105
Least Squares Mean (Standard Error)
Unit of Measure: Scores on a scale
-0.16  (0.043) -0.18  (0.042) -0.18  (0.044) -0.18  (0.044)
Time Frame On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the end of treatment (up to 24 weeks).
Adverse Event Reporting Description On-treatment SAEs and non-serious AEs were reported for members of the Intent-to-Treat (ITT) Population, comprised of all participants randomized to treatment who received at least one dose of trial medication during the treatment period.
 
Arm/Group Title VI 25 µg UMEC/VI 62.5/25 µg UMEC/VI 125/25 µg TIO 18 µg
Hide Arm/Group Description Participants received vilanterol (VI) 25 micrograms (µg) once daily (QD) via a dry powder inhaler (DPI). All participants also received placebo QD via a HandiHaler. Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler. Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler. Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI.
All-Cause Mortality
VI 25 µg UMEC/VI 62.5/25 µg UMEC/VI 125/25 µg TIO 18 µg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Hide Serious Adverse Events
VI 25 µg UMEC/VI 62.5/25 µg UMEC/VI 125/25 µg TIO 18 µg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   15/209 (7.18%)   7/212 (3.30%)   5/214 (2.34%)   13/208 (6.25%) 
Cardiac disorders         
Acute myocardial infarction  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Angina pectoris  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Cardiac failure acute  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Cardiac failure congestive  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Supraventricular extrasystoles  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Gastrointestinal disorders         
Abdominal pain  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Abdominal pain upper  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Gastrointestinal haemorrhage  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Mallory-Weiss syndrome  1  0/209 (0.00%)  0/212 (0.00%)  0/214 (0.00%)  1/208 (0.48%) 
General disorders         
Non-cardiac chest pain  1  0/209 (0.00%)  0/212 (0.00%)  0/214 (0.00%)  2/208 (0.96%) 
Infections and infestations         
Pneumonia  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  2/208 (0.96%) 
Appendicitis  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Gastroenteritis  1  0/209 (0.00%)  0/212 (0.00%)  0/214 (0.00%)  1/208 (0.48%) 
Infective exacerbation of chronic obstructive airways diseas  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Osteomyelitis  1  0/209 (0.00%)  0/212 (0.00%)  0/214 (0.00%)  1/208 (0.48%) 
Urinary tract infection  1  0/209 (0.00%)  0/212 (0.00%)  0/214 (0.00%)  1/208 (0.48%) 
Injury, poisoning and procedural complications         
Craniocerebral injury  1  0/209 (0.00%)  0/212 (0.00%)  0/214 (0.00%)  1/208 (0.48%) 
Foot fracture  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Lower limb fracture  1  0/209 (0.00%)  0/212 (0.00%)  1/214 (0.47%)  0/208 (0.00%) 
Lumbar vertebral fracture  1  0/209 (0.00%)  0/212 (0.00%)  0/214 (0.00%)  1/208 (0.48%) 
Meniscus lesion  1  0/209 (0.00%)  1/212 (0.47%)  0/214 (0.00%)  0/208 (0.00%) 
Vascular graft occlusion  1  0/209 (0.00%)  0/212 (0.00%)  0/214 (0.00%)  1/208 (0.48%) 
Wound  1  0/209 (0.00%)  0/212 (0.00%)  0/214 (0.00%)  1/208 (0.48%) 
Metabolism and nutrition disorders         
Hyperglycaemia  1  0/209 (0.00%)  0/212 (0.00%)  0/214 (0.00%)  1/208 (0.48%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Adenoma benign  1  0/209 (0.00%)  0/212 (0.00%)  0/214 (0.00%)  1/208 (0.48%) 
Bladder cancer stage III  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Hepatic neoplasm malignant  1  0/209 (0.00%)  1/212 (0.47%)  0/214 (0.00%)  0/208 (0.00%) 
Lung neoplasm  1  0/209 (0.00%)  0/212 (0.00%)  0/214 (0.00%)  1/208 (0.48%) 
Nervous system disorders         
Syncope  1  1/209 (0.48%)  0/212 (0.00%)  1/214 (0.47%)  0/208 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Chronic obstructive pulmonary disease  1  2/209 (0.96%)  5/212 (2.36%)  3/214 (1.40%)  3/208 (1.44%) 
Acute respiratory failure  1  0/209 (0.00%)  1/212 (0.47%)  0/214 (0.00%)  0/208 (0.00%) 
Pleurisy  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Vascular disorders         
Hypertension  1  1/209 (0.48%)  0/212 (0.00%)  0/214 (0.00%)  0/208 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
VI 25 µg UMEC/VI 62.5/25 µg UMEC/VI 125/25 µg TIO 18 µg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   44/209 (21.05%)   54/212 (25.47%)   40/214 (18.69%)   37/208 (17.79%) 
Infections and infestations         
Nasopharyngitis  1  17/209 (8.13%)  21/212 (9.91%)  14/214 (6.54%)  16/208 (7.69%) 
Upper respiratory tract infection  1  5/209 (2.39%)  8/212 (3.77%)  7/214 (3.27%)  8/208 (3.85%) 
Musculoskeletal and connective tissue disorders         
Back pain  1  3/209 (1.44%)  10/212 (4.72%)  7/214 (3.27%)  4/208 (1.92%) 
Nervous system disorders         
Headache  1  21/209 (10.05%)  20/212 (9.43%)  14/214 (6.54%)  9/208 (4.33%) 
Respiratory, thoracic and mediastinal disorders         
Cough  1  4/209 (1.91%)  7/212 (3.30%)  7/214 (3.27%)  5/208 (2.40%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: GSK Response Center
Organization: GlaxoSmithKline
Phone: 866-435-7343
Layout table for additonal information
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01316900    
Other Study ID Numbers: 113360
First Submitted: March 15, 2011
First Posted: March 16, 2011
Results First Submitted: December 19, 2013
Results First Posted: February 10, 2014
Last Update Posted: January 24, 2018