The Effects of Inhaled Aclidinium Bromide/Formoterol Fumarate on Inspiratory Pleural Pressures in Smokers

• Aclidinium bromide/formoterol fumarate dihydrate (Drug), also known as DUAKLIR™ GENUAIR®: Cross-over design with washout interval. Randomized order of active and placebo arm
• Placebo (Drug): Placebo and delivery device matched to active intervention

Primary outcomes

• Inspiratory pleural pressures at rest and throughout incremental exercise (cmH2O) [After 7-days of active or placebo drug]: Mean difference in inspiratory pleural pressure measured by esophageal manometry at rest and throughout incremental exercise

Secondary outcomes

• Resting and exercise-induced changes in plasma natriuretic peptide concentrations (plasma concentration) [After 7-days of active or placebo drug]: Mean difference in atrial natriuretic peptide (exercise induced-changes) and n-terminal pro-B-type natriuretic peptide (resting).
• Resting and dynamic lung volumes (end-inspiratory/end-expiratory lung volume) [After 7-days of active or placebo drug]: Static and operating lung volumes
• Effect modification by gender (self-reported). [After 7-days of active or placebo drug]: Interaction term added to regression model for gender.
• Effect modification by smoking status (self-reported). [After 7-days of active or placebo drug]: Interaction term added to regression model for smoking status.
• Effect modification by hypertension status (Joint National Committee criteria). [After 7-days of active or placebo drug]: Interaction term added to regression model for hypertension status.
• Effect modification by hyperinflation severity (Residual lung volume). [After 7-days of active or placebo drug]: Interaction term added to regression model for hyperinflation severity.
• Effect modification by spirometric chronic obstructive pulmonary disease (COPD) status (forced expired volume in 1 second-to-forced vital capacity ratio below 0.7). [After 7-days of active or placebo drug]: Interaction term added to regression model for spirometric COPD status.

Sex: All, ages: 45 Years to 75 Years

Inclusion Criteria:

* Current and former smokers with ≥20 pack-years of smoking history
* Gas-trapping (residual volume >110% predicted)

Exclusion Criteria:

Physician-diagnosis of chronic obstructive pulmonary disease in the past 1 year and regular use of long-acting antimuscarinic (LAMA) and/or long-acting beta-agonist (LABA) (i.e., at least 30 consecutive days)

* Physician-diagnosis of asthma in the past 5 years
* Regular inhaled corticosteroid (ICS) use in the past 5 years (i.e., at least 30 consecutive days)
* Physician-diagnosis of other lung diseases (sarcoidosis, tuberculosis, cystic fibrosis, pulmonary fibrosis, lung cancer), or long-term oxygen therapy
* Respiratory tract infection within 4-weeks
* Physician-diagnosis of arrhythmia, or significant valvular disease.
* Physician-diagnosis of myocardial infarction, unstable angina or heart failure requiring unscheduled outpatient or emergency department visit within 6-months.
* Arrhythmia or prolonged corrected QT (QTc) on electrocardiogram.
* Inability to use study inhaler
* Glaucoma
* Benign prostatic hypertrophy
* Pregnancy
* Allergy to the study treatment, salbutamol, lidocaine, or severe milk protein allergy (note: lactose intolerance is not an exclusion criteria)
* Contraindications to anti-cholinergic, beta-agonist, or cardiopulmonary exercise testing with manometry
* Inability to provide written informed consent

• B M Smith, MD, Principal investigator, McGill University Health Centre/Research Institute of the McGill University Health Centre