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| Name | Class |
|---|---|
| GlaxoSmithKline | INDUSTRY |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| LAMA alone, then LAMA/LABA combination | Experimental | 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 | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| LAMA/LABA | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 4 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Exercise Endurance Time | Duration of constant work rate cycle exercise at 75% of maximum | 4 weeks |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Denis E O'Donnell, MD, FRCPC | Queen's University and Kingston General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Respiratory Investigation Unit at Kingston General Hospital | Kingston | Ontario | K7L 2V7 | Canada |
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 were enrolled between March 2012 and June 2014.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Randomized Subjects | All 17 randomized subjects. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Of the 17 randomized subjects, 3 subjects were withdrawn (2 AEs, 1 withdrawn consent ) leaving 14 completed subjects for analysis. | Posted | Mean | Standard Deviation | units on a scale | 4 weeks |
|
Over the duration of the study (approximately 12 weeks).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | LAMA Arm | The 4-week treatment period with once daily inhaled umeclidinium (125 mcg). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| COPD exacerbation | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment | An exacerbation of COPD requiring treatment (oral steroids and/or antibiotic). |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Kathy Webb | Queen's University | 613-549-6666 | 4950 | kw2@queensu.ca |
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| ID | Term |
|---|---|
| D029424 | Pulmonary Disease, Chronic Obstructive |
| D009043 | Motor Activity |
| D004417 | Dyspnea |
| ID | Term |
|---|---|
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D002908 | Chronic Disease |
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| ID | Term |
|---|---|
| C573971 | GSK573719 |
| C550468 | vilanterol |
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|
| LAMA | Drug | GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks |
|
|
| 4 weeks |
| 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. | 4 weeks |
| 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. | 4 weeks |
| 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. | 4 weeks |
| 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. | 4 weeks |
| 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. | 4 weeks |
| 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. | 4 weeks |
| 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. | 4 weeks |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| FEV1 %predicted | Post-bronchodilator measurement | Mean | Standard Deviation | % of predicted normal |
|
| FEV1/FVC % ratio | Post-bronchodilator measurement | Mean | Standard Deviation | % |
|
| Smoking history | Mean | Standard Deviation | pack-years |
|
| Baseline Dyspnea Index score | Scoring range for activity-related dyspnea is 0 (most severe) to 12 (none). | Mean | Standard Deviation | units on a scale |
|
| OG001 |
| LABA/LAMA Combination |
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. |
|
|
|
| Secondary | Exercise Endurance Time | Duration of constant work rate cycle exercise at 75% of maximum | Posted | Mean | Standard Deviation | minutes | 4 weeks |
|
|
|
|
| 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. | 14 subjects completed both treatments for comparison. | Posted | Mean | Standard Deviation | L | 4 weeks |
|
|
|
|
| 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. | 14 subjects completed both treatment arms for comparison. | Posted | Mean | Standard Deviation | L/min | 4 weeks |
|
|
|
|
| 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. | Of the 17 randomized subjects, 3 subjects were withdrawn (2 AEs, 1 withdrawn consent ) leaving 14 completed subjects for analysis. | Posted | Mean | Standard Deviation | units on a scale | 4 weeks |
|
|
|
|
| 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. | 14 subjects completed both treatment arms for comparison. | Posted | Mean | Standard Deviation | L | 4 weeks |
|
|
|
|
| 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. | Although 14 subjects completed both treatment arms, only 9 subjects had complete measurements of EMGdi and respiratory pressures. | Posted | Mean | Standard Deviation | percentage of maximum EMGdi | 4 weeks |
|
|
|
|
| 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. | Although 14 subjects completed both treatment arms for comparison, only 9 subjects also had complete measurements of EMGdi and respiratory pressures. | Posted | Mean | Standard Deviation | percentage of maximum Pes | 4 weeks |
|
|
|
|
| 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. | 14 subjects completed both treatment arms for comparison. | Posted | Mean | Standard Deviation | L/s | 4 weeks |
|
|
|
|
| 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. | 14 subjects completed both treatments for comparison. | Posted | Mean | Standard Deviation | L | 4 weeks |
|
|
|
| 0 |
| 17 |
| 1 |
| 17 |
| EG001 | LABA/LAMA Arm | The 4-week treatment period with once daily inhaled fixed-dose combination of umeclidinium (125 mcg) and vilanterol (25 mcg). | 0 | 17 | 0 | 17 |
| EG002 | Washout Period | There was a 2 week washout period between the two treatment arms. | 0 | 17 | 1 | 17 |
|
| Pancreatitis | Endocrine disorders | Non-systematic Assessment |
|
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| D020969 |
| Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D001519 | Behavior |
| D012120 | Respiration Disorders |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |