COPD
Conditions
Keywords
COPD, Combination therapy, Anticholinergic, Beta2-agonist, Exercise, Dyspnea, Respiratory mechanics
Brief summary
Preliminary information from our laboratory indicated that even patients with milder chronic obstructive pulmonary disease (COPD) can have significant physiological derangements which become more pronounced during exercise, leading to intolerable dyspnea at lower levels of ventilation than in health. This study will explore pathophysiological mechanisms of dyspnea and activity limitation in GOLD stage II COPD and will determine if there is a sound physiological rationale for the use of dual long-acting beta2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) therapy (GSK573719/ GW642444 Inhalation Powder) versus LAMA alone (GSK573719) as treatment for dyspnea and exercise intolerance in this subpopulation. Objectives of this study are to determine if: 1) neuromechanical uncoupling of the respiratory system contributes to exertional dyspnea in milder COPD, and 2) treatment with LABA/LAMA improves dyspnea and exercise endurance compared with LAMA by improving neuromechanical coupling. The investigators hypothesize that: 1) dyspnea is related to excessive dynamic lung hyperinflation, tidal volume restriction and increased ratio of central respiratory neural drive to tidal volume displacement, a measure of neuromechanical uncoupling of the respiratory system, and 2) LABA/LAMA will improve dyspnea and exercise endurance, which will be explained by partial reversal of the above mechanical abnormalities. The investigators will conduct a randomized, double-blind crossover study and compare the effects of once-daily LABA/LAMA over 4-weeks with LAMA on dyspnea, exercise endurance and ventilatory mechanics in GOLD stage II COPD.
Interventions
DRUGLAMA/LABA
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.
DRUGLAMA
GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks
Sponsors
GlaxoSmithKline
Queen's University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Stable moderate COPD * Post-bronchodilator FEV1/FVC\<0.7 and 50%≤FEV1\<80% predicted * Baseline Dyspnea Index ≤ 9 and MRC dyspnea scale \>2 * Cigarette smoking history at least 20 pack-years
Exclusion criteria
* Presence of a significant disease other than COPD that could contribute to dyspnea and exercise limitation * Important contraindications to clinical exercise testing * Use of daytime oxygen * History of asthma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Exertional Dyspnea Intensity at Isotime Exercise. | 4 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Inspiratory Capacity at Rest | 4 weeks | 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. |
| Ventilation at Isotime Exercise | 4 weeks | 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. |
| Intensity of Unpleasantness of Breathing at Isotime Exercise | 4 weeks | 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. |
| Inspiratory Capacity at Isotime Exercise | 4 weeks | 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. |
| Exercise Endurance Time | 4 weeks | Duration of constant work rate cycle exercise at 75% of maximum |
| Tidal Esophageal Pressure (Pes) Swings at Isotime Exercise | 4 weeks | 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. |
| Mean Expiratory Flow at Isotime Exercise | 4 weeks | 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. |
| Forced Expiratory Volume in 1 Second (FEV1) | 4 weeks | Measurements of pulmonary function included spirometry and body plethysmography. Values reported are 90 minutes post-dose after 4 weeks of treatment. |
| Diaphragm Electromyogram (EMGdi) at Isotime Exercise | 4 weeks | 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. |
Countries
Canada
Participant flow
Recruitment details
Participants were enrolled between March 2012 and June 2014.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Randomized Subjects All 17 randomized subjects. | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Randomized Subjects |
|---|---|
| Age, Continuous | 66 years STANDARD_DEVIATION 10 |
| Baseline Dyspnea Index score | 7.9 units on a scale STANDARD_DEVIATION 1.7 |
| FEV1/FVC % ratio | 55.6 % STANDARD_DEVIATION 7.7 |
| FEV1 %predicted | 70.9 % of predicted normal STANDARD_DEVIATION 69.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment Canada | 17 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 8 Participants |
| Smoking history | 49 pack-years STANDARD_DEVIATION 20 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 17 | 0 / 17 | 1 / 17 |
| serious Total, serious adverse events | 0 / 17 | 0 / 17 | 0 / 17 |
Outcome results
Primary
Exertional Dyspnea Intensity at Isotime Exercise.
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.
Time frame: 4 weeks
Population: Of the 17 randomized subjects, 3 subjects were withdrawn (2 AEs, 1 withdrawn consent ) leaving 14 completed subjects for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAMA | Exertional Dyspnea Intensity at Isotime Exercise. | 3.9 units on a scale | Standard Deviation 2.4 |
| LABA/LAMA Combination | Exertional Dyspnea Intensity at Isotime Exercise. | 3.4 units on a scale | Standard Deviation 2.3 |
Comparison: A paired t-test using a 2-sided test of significance was used to compare values after LAMA versus LABA/LAMA treatment.p-value: 0.09t-test, 2 sided
Secondary
Diaphragm Electromyogram (EMGdi) at Isotime Exercise
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.
Time frame: 4 weeks
Population: Although 14 subjects completed both treatment arms, only 9 subjects had complete measurements of EMGdi and respiratory pressures.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAMA | Diaphragm Electromyogram (EMGdi) at Isotime Exercise | 53.4 percentage of maximum EMGdi | Standard Deviation 17.4 |
| LABA/LAMA Combination | Diaphragm Electromyogram (EMGdi) at Isotime Exercise | 53.5 percentage of maximum EMGdi | Standard Deviation 13.5 |
Comparison: A paired t-test using a 2-sided test of significance was used to compare values after LAMA versus LABA/LAMA treatment.p-value: 0.96t-test, 2 sided
Secondary
Exercise Endurance Time
Duration of constant work rate cycle exercise at 75% of maximum
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAMA | Exercise Endurance Time | 7.82 minutes | Standard Deviation 6.15 |
| LABA/LAMA Combination | Exercise Endurance Time | 7.49 minutes | Standard Deviation 4.99 |
Comparison: A paired t-test using a 2-sided test of significance was used to compare values after LAMA versus LABA/LAMA treatment.p-value: 0.68t-test, 2 sided
Secondary
Forced Expiratory Volume in 1 Second (FEV1)
Measurements of pulmonary function included spirometry and body plethysmography. Values reported are 90 minutes post-dose after 4 weeks of treatment.
Time frame: 4 weeks
Population: 14 subjects completed both treatments for comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAMA | Forced Expiratory Volume in 1 Second (FEV1) | 1.56 L | Standard Deviation 0.4 |
| LABA/LAMA Combination | Forced Expiratory Volume in 1 Second (FEV1) | 1.72 L | Standard Deviation 0.46 |
Secondary
Inspiratory Capacity at Isotime Exercise
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.
Time frame: 4 weeks
Population: 14 subjects completed both treatment arms for comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAMA | Inspiratory Capacity at Isotime Exercise | 1.99 L | Standard Deviation 0.56 |
| LABA/LAMA Combination | Inspiratory Capacity at Isotime Exercise | 2.02 L | Standard Deviation 0.59 |
Comparison: A paired t-test using a 2-sided test of significance was used to compare values after LAMA versus LABA/LAMA treatment.p-value: 0.573t-test, 2 sided
Secondary
Inspiratory Capacity at Rest
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.
Time frame: 4 weeks
Population: 14 subjects completed both treatments for comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAMA | Inspiratory Capacity at Rest | 2.27 L | Standard Deviation 0.4 |
| LABA/LAMA Combination | Inspiratory Capacity at Rest | 2.36 L | Standard Deviation 0.86 |
Comparison: A paired t-test using a 2-sided test of significance was used to compare values after LAMA versus LABA/LAMA treatment.p-value: 0.197t-test, 2 sided
Secondary
Intensity of Unpleasantness of Breathing at Isotime Exercise
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.
Time frame: 4 weeks
Population: Of the 17 randomized subjects, 3 subjects were withdrawn (2 AEs, 1 withdrawn consent ) leaving 14 completed subjects for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAMA | Intensity of Unpleasantness of Breathing at Isotime Exercise | 4.0 units on a scale | Standard Deviation 2.5 |
| LABA/LAMA Combination | Intensity of Unpleasantness of Breathing at Isotime Exercise | 3.3 units on a scale | Standard Deviation 2.3 |
Comparison: A paired t-test using a 2-sided test of significance was used to compare values after LAMA versus LABA/LAMA treatment.p-value: 0.044t-test, 2 sided
Secondary
Mean Expiratory Flow at Isotime Exercise
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.
Time frame: 4 weeks
Population: 14 subjects completed both treatment arms for comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAMA | Mean Expiratory Flow at Isotime Exercise | 2.19 L/s | Standard Deviation 0.8 |
| LABA/LAMA Combination | Mean Expiratory Flow at Isotime Exercise | 2.34 L/s | Standard Deviation 0.92 |
Comparison: A paired t-test using a 2-sided test of significance was used to compare values after LAMA versus LABA/LAMA treatment.p-value: 0.028t-test, 2 sided
Secondary
Tidal Esophageal Pressure (Pes) Swings at Isotime Exercise
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.
Time frame: 4 weeks
Population: Although 14 subjects completed both treatment arms for comparison, only 9 subjects also had complete measurements of EMGdi and respiratory pressures.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAMA | Tidal Esophageal Pressure (Pes) Swings at Isotime Exercise | 28 percentage of maximum Pes | Standard Deviation 17 |
| LABA/LAMA Combination | Tidal Esophageal Pressure (Pes) Swings at Isotime Exercise | 28 percentage of maximum Pes | Standard Deviation 20 |
Comparison: A paired t-test using a 2-sided test of significance was used to compare values after LAMA versus LABA/LAMA treatment.p-value: 0.944t-test, 2 sided
Secondary
Ventilation at Isotime Exercise
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.
Time frame: 4 weeks
Population: 14 subjects completed both treatment arms for comparison.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LAMA | Ventilation at Isotime Exercise | 44.9 L/min | Standard Deviation 16.3 |
| LABA/LAMA Combination | Ventilation at Isotime Exercise | 47.5 L/min | Standard Deviation 18.4 |
Comparison: A paired t-test using a 2-sided test of significance was used to compare values after LAMA versus LABA/LAMA treatment.p-value: 0.006t-test, 2 sided