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

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

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.

Study Overview

• Status: Completed
• Conditions: Smoking
• Intervention / Treatment: Drug: Aclidinium bromide/formoterol fumarate dihydrate; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University Health Centre Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Active arm; 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; Cross-over design with washout interval. Randomized order of active and placebo arm; Other Names: DUAKLIR™ GENUAIR®
PLACEBO_COMPARATOR: Placebo arm; Placebo Twice daily (once in the morning, once in the evening) 7-days	Drug: Placebo; Placebo and delivery device matched to active intervention

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Investigators: Principal Investigator: B M Smith, MD, McGill University Health Centre/Research Institute of the McGill University Health Centre

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2017
• Primary Completion (ACTUAL): December 1, 2018
• Study Completion (ACTUAL): February 1, 2019

Study Registration Dates

• First Submitted: March 29, 2017
• First Submitted That Met QC Criteria: April 3, 2017
• First Posted (ACTUAL): April 7, 2017

Study Record Updates

• Last Update Posted (ACTUAL): April 8, 2019
• Last Update Submitted That Met QC Criteria: April 4, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Respiratory Aspiration; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Anticonvulsants; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Bromides; Formoterol Fumarate
• Other Study ID Numbers: 2017-2748

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No