Trial Outcomes & Findings for 24-week Trial Comparing GSK573719/GW642444 With GW642444 and With Tiotropium in Chronic Obstructive Pulmonary Disease (NCT NCT01316900)

Last Updated: 2018-01-24

Results Overview

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. .

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

846 participants

Primary outcome timeframe

Baseline and Day 169

Results posted on

2018-01-24

Participant Flow

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.

Participant milestones

Participant milestones
Measure	VI 25 µg 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.	UMEC/VI 62.5/25 µg Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	UMEC/VI 125/25 µg Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	TIO 18 µg Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI.
Overall Study STARTED	209	212	214	208
Overall Study COMPLETED	165	181	173	177
Overall Study NOT COMPLETED	44	31	41	31

Reasons for withdrawal

Reasons for withdrawal
Measure	VI 25 µg 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.	UMEC/VI 62.5/25 µg Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	UMEC/VI 125/25 µg Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	TIO 18 µg Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI.
Overall Study Adverse Event	10	10	15	9
Overall Study Lack of Efficacy	17	9	5	7
Overall Study Protocol Violation	7	1	4	0
Overall Study Protocol-defined Stopping Criteria	2	3	10	5
Overall Study Lost to Follow-up	1	0	1	1
Overall Study Withdrawal by Subject	7	8	6	9

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	VI 25 µg n=209 Participants 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.	UMEC/VI 62.5/25 µg n=212 Participants Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	UMEC/VI 125/25 µg n=214 Participants Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	Tiotropium 18 µg n=208 Participants Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI.	Total n=843 Participants Total of all reporting groups
Age, Continuous	63.2 Years STANDARD_DEVIATION 9.10 • n=5 Participants	63.0 Years STANDARD_DEVIATION 8.67 • n=7 Participants	62.9 Years STANDARD_DEVIATION 8.87 • n=5 Participants	62.6 Years STANDARD_DEVIATION 9.39 • n=4 Participants	62.9 Years STANDARD_DEVIATION 9.00 • n=21 Participants
Sex: Female, Male Female	66 Participants n=5 Participants	64 Participants n=7 Participants	63 Participants n=5 Participants	68 Participants n=4 Participants	261 Participants n=21 Participants
Sex: Female, Male Male	143 Participants n=5 Participants	148 Participants n=7 Participants	151 Participants n=5 Participants	140 Participants n=4 Participants	582 Participants n=21 Participants
Race/Ethnicity, Customized African American/African Heritage	3 participants n=5 Participants	7 participants n=7 Participants	9 participants n=5 Participants	6 participants n=4 Participants	25 participants n=21 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	19 participants n=5 Participants	16 participants n=7 Participants	21 participants n=5 Participants	20 participants n=4 Participants	76 participants n=21 Participants
Race/Ethnicity, Customized Asian - Central/South Asian Heritage	0 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
Race/Ethnicity, Customized Asian - Japanese Heritage	0 participants n=5 Participants	3 participants n=7 Participants	0 participants n=5 Participants	2 participants n=4 Participants	5 participants n=21 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	184 participants n=5 Participants	182 participants n=7 Participants	180 participants n=5 Participants	177 participants n=4 Participants	723 participants n=21 Participants
Race/Ethnicity, Customized Mixed Race	3 participants n=5 Participants	4 participants n=7 Participants	3 participants n=5 Participants	3 participants n=4 Participants	13 participants n=21 Participants

PRIMARY outcome

Timeframe: Baseline and Day 169

Population: 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.

Outcome measures

Outcome measures
Measure	VI 25 µg n=162 Participants 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.	UMEC/VI 62.5/25 µg n=177 Participants Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	UMEC/VI 125/25 µg n=167 Participants Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	TIO 18 µg n=173 Participants Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI.
Change From Baseline (BL) in Trough Forced Expiratory Volume in One Second (FEV1) on Day 169 (Week 24)	0.121 Liters Standard Error 0.0189	0.211 Liters Standard Error 0.0183	0.209 Liters Standard Error 0.0187	0.121 Liters Standard Error 0.0186

SECONDARY outcome

Timeframe: Baseline and Day 168

Population: 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.

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.

Outcome measures

Outcome measures
Measure	VI 25 µg n=161 Participants 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.	UMEC/VI 62.5/25 µg n=173 Participants Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	UMEC/VI 125/25 µg n=166 Participants Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	TIO 18 µg n=168 Participants Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI.
Change From Baseline (BL) in Weighted Mean (WM) 0-6 Hour FEV1 Obtained Post-dose at Day 168	0.178 Liters Standard Error 0.0189	0.254 Liters Standard Error 0.0183	0.263 Liters Standard Error 0.0187	0.181 Liters Standard Error 0.0187

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and Week 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	VI 25 µg n=110 Participants 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.	UMEC/VI 62.5/25 µg n=118 Participants Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	UMEC/VI 125/25 µg n=107 Participants Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	TIO 18 µg n=105 Participants Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI.
Change From Baseline (BL) in the Mean Shortness of Breath With Daily Activities (SOBDA) Score for Week 24	-0.16 Scores on a scale Standard Error 0.043	-0.18 Scores on a scale Standard Error 0.042	-0.18 Scores on a scale Standard Error 0.044	-0.18 Scores on a scale Standard Error 0.044

Adverse Events

VI 25 µg

Serious events: 15 serious events

Other events: 44 other events

Deaths: 0 deaths

UMEC/VI 62.5/25 µg

Serious events: 7 serious events

Other events: 54 other events

Deaths: 0 deaths

UMEC/VI 125/25 µg

Serious events: 5 serious events

Other events: 40 other events

Deaths: 0 deaths

TIO 18 µg

Serious events: 13 serious events

Other events: 37 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	VI 25 µg n=209 participants at risk 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.	UMEC/VI 62.5/25 µg n=212 participants at risk Participants received umeclidinium bromide (UMEC)/VI 62.5/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	UMEC/VI 125/25 µg n=214 participants at risk Participants received UMEC/VI 125/25 µg QD via a DPI. All participants also received placebo QD via a HandiHaler.	TIO 18 µg n=208 participants at risk Participants received tiotropium (TIO) 18 µg QD via a HandiHaler. All participants also received placebo QD via a DPI.
Infections and infestations Nasopharyngitis	8.1% 17/209 • 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). 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.	9.9% 21/212 • 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). 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.	6.5% 14/214 • 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). 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.	7.7% 16/208 • 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). 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.
Infections and infestations Upper respiratory tract infection	2.4% 5/209 • 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). 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.	3.8% 8/212 • 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). 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.	3.3% 7/214 • 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). 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.	3.8% 8/208 • 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). 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.
Nervous system disorders Headache	10.0% 21/209 • 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). 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.	9.4% 20/212 • 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). 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.	6.5% 14/214 • 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). 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.	4.3% 9/208 • 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). 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.
Musculoskeletal and connective tissue disorders Back pain	1.4% 3/209 • 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). 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.	4.7% 10/212 • 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). 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.	3.3% 7/214 • 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). 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.	1.9% 4/208 • 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). 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.
Respiratory, thoracic and mediastinal disorders Cough	1.9% 4/209 • 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). 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.	3.3% 7/212 • 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). 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.	3.3% 7/214 • 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). 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.	2.4% 5/208 • 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). 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.

Additional Information

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Results disclosure agreements

Principal investigator is a sponsor employee 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.
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