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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01491802
First Posted: December 14, 2011
Last Update Posted: August 15, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Dr. Denis O'Donnell, Queen's University
  Purpose
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.

Condition Intervention Phase
COPD Drug: LAMA/LABA Drug: LAMA Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A 4-week Randomized, Double-blind, Crossover Study to Assess the Effect of a New LABA/LAMA Combination Versus LAMA Alone on Exertional Dyspnea, Exercise Endurance and Neuromechanical Coupling in Patients With GOLD Stage II COPD

Resource links provided by NLM:


Further study details as provided by Dr. Denis O'Donnell, Queen's University:

Primary Outcome Measures:
  • Exertional Dyspnea Intensity at Isotime Exercise. [ Time Frame: 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:
  • Exercise Endurance Time [ Time Frame: 4 weeks ]
    Duration of constant work rate cycle exercise at 75% of maximum

  • Inspiratory Capacity at Rest [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 4 weeks ]
    Measurements of pulmonary function included spirometry and body plethysmography. Values reported are 90 minutes post-dose after 4 weeks of treatment.


Enrollment: 17
Study Start Date: January 2012
Study Completion Date: September 2014
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LAMA alone, then LAMA/LABA combination
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.
Drug: LAMA/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.
Other Names:
  • GSK573719+GW642444
  • umeclidinium (GSK573719) / vilanterol (GW642444)
  • Anoro ELLIPTA
Drug: LAMA
GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks
Other Name: umeclidinium
Experimental: LABA/LAMA combination, then LAMA alone
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.
Drug: LAMA/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.
Other Names:
  • GSK573719+GW642444
  • umeclidinium (GSK573719) / vilanterol (GW642444)
  • Anoro ELLIPTA
Drug: LAMA
GSK573719 (125mcg) inhalation powder is a long-acting muscarinic antagonist that will be taken once daily for 4 weeks
Other Name: umeclidinium

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01491802


Locations
Canada, Ontario
Respiratory Investigation Unit at Kingston General Hospital
KIngston, Ontario, Canada, K7L 2V7
Sponsors and Collaborators
Queen's University
GlaxoSmithKline
Investigators
Principal Investigator: Denis E O'Donnell, MD, FRCPC Queen's University and Kingston General Hospital
  More Information

Responsible Party: Dr. Denis O'Donnell, Principal Investigator, Queen's University
ClinicalTrials.gov Identifier: NCT01491802     History of Changes
Other Study ID Numbers: DMED-1426-11
First Submitted: December 12, 2011
First Posted: December 14, 2011
Results First Submitted: December 13, 2016
Results First Posted: August 15, 2017
Last Update Posted: August 15, 2017
Last Verified: May 2017

Keywords provided by Dr. Denis O'Donnell, Queen's University:
COPD
Combination therapy
Anticholinergic
Beta2-agonist
Exercise
Dyspnea
Respiratory mechanics

Additional relevant MeSH terms:
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs