Trial Outcomes & Findings for Effect of a New Combination Bronchodilator on Exercise in GOLD Stage II Moderate COPD (NCT NCT01491802)

Results Overview

Intensity of dyspnea (defined as breathing discomfort) at a standardized time (isotime) during constant work rate exercise tests as measured by the modified 10-point Borg scale. A rating of 0 represents no dyspnea up to a maximum of 10: a smaller rating is therefore an improvement. Isotime was defined as the highest exercise time in minutes completed in both post-treatment tests.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

17 participants

Primary outcome timeframe

4 weeks

Results posted on

2017-08-15

Participant Flow

Participants were enrolled between March 2012 and June 2014.

There was run-in period of approximately 2 weeks for determination of eligibility and familiarization with all tests to be performed during subsequent treatment visits. There was a 2-week washout period between each 4-week treatment period of this crossover study.

Participant milestones

Participant milestones
Measure	LAMA, Then LAMA/LABA Participants first received LAMA alone (umeclidinium 125 mcg) once daily for 4 weeks. After a 2 week washout period, they received the LAMA/LABA combination product (umeclidinium 125 mcg plus vilanterol 25 mcg) once daily for 4 weeks.	LAMA/LABA, the LAMA Participants first received the LAMA/LABA combination product (umeclidinium 125 mcg plus vilanterol 25 mcg) once daily for 4 weeks. After a 2 week washout period, they received LAMA alone (umeclidinium 125 mcg) once daily for 4 weeks.
Overall Study STARTED	9	8
Overall Study COMPLETED	8	6
Overall Study NOT COMPLETED	1	2

Reasons for withdrawal

Reasons for withdrawal
Measure	LAMA, Then LAMA/LABA Participants first received LAMA alone (umeclidinium 125 mcg) once daily for 4 weeks. After a 2 week washout period, they received the LAMA/LABA combination product (umeclidinium 125 mcg plus vilanterol 25 mcg) once daily for 4 weeks.	LAMA/LABA, the LAMA Participants first received the LAMA/LABA combination product (umeclidinium 125 mcg plus vilanterol 25 mcg) once daily for 4 weeks. After a 2 week washout period, they received LAMA alone (umeclidinium 125 mcg) once daily for 4 weeks.
Overall Study Adverse Event	1	1
Overall Study Withdrawal by Subject	0	1

Baseline Characteristics

Effect of a New Combination Bronchodilator on Exercise in GOLD Stage II Moderate COPD

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Randomized Subjects n=17 Participants All 17 randomized subjects.
Age, Continuous	66 years STANDARD_DEVIATION 10 • n=5 Participants
Sex: Female, Male Female	9 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	17 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment Canada	17 participants n=5 Participants
FEV1 %predicted	70.9 % of predicted normal STANDARD_DEVIATION 69.4 • n=5 Participants
FEV1/FVC % ratio	55.6 % STANDARD_DEVIATION 7.7 • n=5 Participants
Smoking history	49 pack-years STANDARD_DEVIATION 20 • n=5 Participants
Baseline Dyspnea Index score	7.9 units on a scale STANDARD_DEVIATION 1.7 • n=5 Participants

PRIMARY outcome

Timeframe: 4 weeks

Population: Of the 17 randomized subjects, 3 subjects were withdrawn (2 AEs, 1 withdrawn consent ) leaving 14 completed subjects for analysis.

Intensity of dyspnea (defined as breathing discomfort) at a standardized time (isotime) during constant work rate exercise tests as measured by the modified 10-point Borg scale. A rating of 0 represents no dyspnea up to a maximum of 10: a smaller rating is therefore an improvement. Isotime was defined as the highest exercise time in minutes completed in both post-treatment tests.

Outcome measures

Outcome measures
Measure	LAMA n=14 Participants GSK573719 is a long-acting muscarinic antagonist GSK573719: GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks	LABA/LAMA Combination n=14 Participants GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy. GSK573719/GW642444: GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy will be taken once daily for 4 weeks.
Exertional Dyspnea Intensity at Isotime Exercise.	3.9 units on a scale Standard Deviation 2.4	3.4 units on a scale Standard Deviation 2.3

SECONDARY outcome

Timeframe: 4 weeks

Duration of constant work rate cycle exercise at 75% of maximum

Outcome measures

Outcome measures
Measure	LAMA n=14 Participants GSK573719 is a long-acting muscarinic antagonist GSK573719: GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks	LABA/LAMA Combination n=14 Participants GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy. GSK573719/GW642444: GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy will be taken once daily for 4 weeks.
Exercise Endurance Time	7.82 minutes Standard Deviation 6.15	7.49 minutes Standard Deviation 4.99

SECONDARY outcome

Timeframe: 4 weeks

Population: 14 subjects completed both treatments for comparison.

Measurements of pulmonary function included spirometry and body plethysmography. The resting inspiratory capacity (IC) values reported here are 90 minutes post-dose after 4 weeks of treatment.

Outcome measures

Outcome measures
Measure	LAMA n=14 Participants GSK573719 is a long-acting muscarinic antagonist GSK573719: GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks	LABA/LAMA Combination n=14 Participants GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy. GSK573719/GW642444: GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy will be taken once daily for 4 weeks.
Inspiratory Capacity at Rest	2.27 L Standard Deviation 0.40	2.36 L Standard Deviation 0.86

SECONDARY outcome

Timeframe: 4 weeks

Population: 14 subjects completed both treatment arms for comparison.

Ventilation was measured during constant work rate exercise tests. Isotime was defined as the highest exercise time in minutes common to both post-treatment tests.

Outcome measures

Outcome measures
Measure	LAMA n=14 Participants GSK573719 is a long-acting muscarinic antagonist GSK573719: GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks	LABA/LAMA Combination n=14 Participants GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy. GSK573719/GW642444: GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy will be taken once daily for 4 weeks.
Ventilation at Isotime Exercise	44.9 L/min Standard Deviation 16.3	47.5 L/min Standard Deviation 18.4

SECONDARY outcome

Timeframe: 4 weeks

Population: Of the 17 randomized subjects, 3 subjects were withdrawn (2 AEs, 1 withdrawn consent ) leaving 14 completed subjects for analysis.

Intensity rating (modified 10-point Borg scale) measured at a standardized time (isotime) during constant work rate exercise tests. A rating of 0 represents no "unpleasantness of breathing" up to a maximum of 10. An improvement would be noted as a decrease in the Borg scale rating. Isotime was defined as the highest exercise time in minutes common to both post-treatment tests.

Outcome measures

Outcome measures
Measure	LAMA n=14 Participants GSK573719 is a long-acting muscarinic antagonist GSK573719: GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks	LABA/LAMA Combination n=14 Participants GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy. GSK573719/GW642444: GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy will be taken once daily for 4 weeks.
Intensity of "Unpleasantness of Breathing" at Isotime Exercise	4.0 units on a scale Standard Deviation 2.5	3.3 units on a scale Standard Deviation 2.3

SECONDARY outcome

Timeframe: 4 weeks

Population: 14 subjects completed both treatment arms for comparison.

Measurements of inspiratory capacity (IC) were conducted during constant work rate exercise tests. Isotime was defined as the highest time in minutes completed in both post-treatment tests.

Outcome measures

Outcome measures
Measure	LAMA n=14 Participants GSK573719 is a long-acting muscarinic antagonist GSK573719: GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks	LABA/LAMA Combination n=14 Participants GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy. GSK573719/GW642444: GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy will be taken once daily for 4 weeks.
Inspiratory Capacity at Isotime Exercise	1.99 L Standard Deviation 0.56	2.02 L Standard Deviation 0.59

SECONDARY outcome

Timeframe: 4 weeks

Population: Although 14 subjects completed both treatment arms, only 9 subjects had complete measurements of EMGdi and respiratory pressures.

EMGdi was measured during constant work rate exercise tests via a multipair-electrode esophageal catheter. EMGdi expressed as a percentage of its maximum is used as an index of inspiratory neural drive. Isotime was defined as the highest exercise time in minutes common to both post-treatment tests.

Outcome measures

Outcome measures
Measure	LAMA n=9 Participants GSK573719 is a long-acting muscarinic antagonist GSK573719: GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks	LABA/LAMA Combination n=9 Participants GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy. GSK573719/GW642444: GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy will be taken once daily for 4 weeks.
Diaphragm Electromyogram (EMGdi) at Isotime Exercise	53.4 percentage of maximum EMGdi Standard Deviation 17.4	53.5 percentage of maximum EMGdi Standard Deviation 13.5

SECONDARY outcome

Timeframe: 4 weeks

Population: Although 14 subjects completed both treatment arms for comparison, only 9 subjects also had complete measurements of EMGdi and respiratory pressures.

Tidal esophageal pressure (Pes) swings were measured via an esophageal balloon catheter during constant work rate exercise tests. Tidal Pes expressed relative to maximum is an index of respiratory effort. Isotime was defined as the highest exercise time in minutes common to both post-treatment tests.

Outcome measures

Outcome measures
Measure	LAMA n=9 Participants GSK573719 is a long-acting muscarinic antagonist GSK573719: GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks	LABA/LAMA Combination n=9 Participants GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy. GSK573719/GW642444: GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy will be taken once daily for 4 weeks.
Tidal Esophageal Pressure (Pes) Swings at Isotime Exercise	28 percentage of maximum Pes Standard Deviation 17	28 percentage of maximum Pes Standard Deviation 20

SECONDARY outcome

Timeframe: 4 weeks

Population: 14 subjects completed both treatment arms for comparison.

Mean expiratory flow was measured during constant work rate exercise tests. Isotime was defined as the highest exercise time in minutes common to both post-treatment tests.

Outcome measures

Outcome measures
Measure	LAMA n=14 Participants GSK573719 is a long-acting muscarinic antagonist GSK573719: GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks	LABA/LAMA Combination n=14 Participants GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy. GSK573719/GW642444: GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy will be taken once daily for 4 weeks.
Mean Expiratory Flow at Isotime Exercise	2.19 L/s Standard Deviation 0.80	2.34 L/s Standard Deviation 0.92

SECONDARY outcome

Timeframe: 4 weeks

Population: 14 subjects completed both treatments for comparison.

Measurements of pulmonary function included spirometry and body plethysmography. Values reported are 90 minutes post-dose after 4 weeks of treatment.

Outcome measures

Outcome measures
Measure	LAMA n=14 Participants GSK573719 is a long-acting muscarinic antagonist GSK573719: GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks	LABA/LAMA Combination n=14 Participants GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy. GSK573719/GW642444: GSK573719/GW642444 inhalation powder used in the Novel Dry Powder Inhaler (DPI): a long-acting beta2-agonist (GSK642444, 25mcg) with a long-acting muscarinic antagonist (GSK573719, 125mcg) combination therapy will be taken once daily for 4 weeks.
Forced Expiratory Volume in 1 Second (FEV1)	1.56 L Standard Deviation 0.40	1.72 L Standard Deviation 0.46

Adverse Events

LAMA Arm

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

LABA/LAMA Arm

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Washout Period

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	LAMA Arm n=17 participants at risk The 4-week treatment period with once daily inhaled umeclidinium (125 mcg).	LABA/LAMA Arm n=17 participants at risk The 4-week treatment period with once daily inhaled fixed-dose combination of umeclidinium (125 mcg) and vilanterol (25 mcg).	Washout Period n=17 participants at risk There was a 2 week washout period between the two treatment arms.
Respiratory, thoracic and mediastinal disorders COPD exacerbation	0.00% 0/17 • Over the duration of the study (approximately 12 weeks).	0.00% 0/17 • Over the duration of the study (approximately 12 weeks).	5.9% 1/17 • Number of events 1 • Over the duration of the study (approximately 12 weeks).
Endocrine disorders Pancreatitis	5.9% 1/17 • Number of events 1 • Over the duration of the study (approximately 12 weeks).	0.00% 0/17 • Over the duration of the study (approximately 12 weeks).	0.00% 0/17 • Over the duration of the study (approximately 12 weeks).

Additional Information

Kathy Webb

Queen's University

Phone: 613-549-6666

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place