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

Study Overview
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Brief Summary
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This short-term study aims to prove the potential cardio-protective physiological effect of inhaled aclidinium bromide/formoterol fumarate on inspiratory pleural pressures. Smoking is associated with gas-trapping (hyperinflation), even in the absence of chronic obstructive pulmonary disease. Breathing in the presence of gas-trapping requires large negative inspiratory pleural pressures, which are transmitted to the surface of the heart and increase cardiac wall stress. Inhaled aclidinium bromide and formoterol fumarate has been shown to reduce gas-trapping, but the impact on inspiratory pleural pressures and biomarkers of cardiac stress in smokers is unknown.

Official Title
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The Effects of Inhaled Aclidinium Bromide/Formoterol Fumarate on Inspiratory Pleural Pressures in Smokers: a Randomized, Double-blind, Placebo-controlled, Cross-over Trial

Conditions
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Smoking

Intervention / Treatment
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* Drug: Aclidinium bromide/formoterol fumarate dihydrate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active arm<br>Aclidinium bromide/formoterol fumarate dihydrate 400 mcg/12 mcg Twice daily (once in the morning, once in the evening) 7-days | Drug: Aclidinium bromide/formoterol fumarate dihydrate<br>* Cross-over design with washout interval. Randomized order of active and placebo arm<br>* Other names: DUAKLIR™ GENUAIR®;|
| Placebo Comparator: Placebo arm<br>Placebo Twice daily (once in the morning, once in the evening) 7-days | Drug: Placebo<br>* Placebo and delivery device matched to active intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inspiratory pleural pressures at rest and throughout incremental exercise (cmH2O) | Mean difference in inspiratory pleural pressure measured by esophageal manometry at rest and throughout incremental exercise | After 7-days of active or placebo drug | 

Secondary Outcome Measures

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