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

Phase 3

Completed

Conditions: COPD

Interventions: Drug: LAMA/LABA
Drug: LAMA

Registration Number: NCT01491802

Lead Sponsor: Queen's University

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 17

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
LAMA alone, then LAMA/LABA combination	LAMA/LABA	Participants will first receive an inhaled long-acting muscarinic antagonist (LAMA) once daily for 4 weeks. After a 2 week washout period, they will then receive the fixed-dose combination product \[LAMA plus long-acting beta2-agonist (LABA)\] once daily for 4 weeks.
LAMA alone, then LAMA/LABA combination	LAMA	Participants will first receive an inhaled long-acting muscarinic antagonist (LAMA) once daily for 4 weeks. After a 2 week washout period, they will then receive the fixed-dose combination product \[LAMA plus long-acting beta2-agonist (LABA)\] once daily for 4 weeks.
LABA/LAMA combination, then LAMA alone	LAMA/LABA	Participants will first receive a long-acting muscarinic antagonist (LAMA) plus long-acting beta2-agonist (LABA) combination product once daily for 4 weeks. After a 2 week washout period, they will then receive the LAMA single product once daily for 4 weeks.
LABA/LAMA combination, then LAMA alone	LAMA	Participants will first receive a long-acting muscarinic antagonist (LAMA) plus long-acting beta2-agonist (LABA) combination product once daily for 4 weeks. After a 2 week washout period, they will then receive the LAMA single product once daily for 4 weeks.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
Exercise Endurance Time	4 weeks	Duration of constant work rate cycle exercise at 75% of maximum
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.
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.
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.