Efficacy and Safety Study of Two Fixed-dose Combinations of Aclidinium Bromide With Formoterol Fumarate Compared With Aclidinium Bromide, Formoterol Fumarate and Placebo

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of this multicenter, randomized, double-blind, placebo-controlled, 4-period, incomplete-block crossover, dose-ranging study comparing 2 fixed dose combinations (FDCs) of aclidinium bromide with formoterol fumarate or with placebo, aclidinium bromide and formoterol fumarate, all administered twice a day (BID) in patients with stable, moderate to severe chronic obstructive pulmonary disease (COPD) beginning with a 2-week run-in period and with a 7-10 day washout each between treatment period.

Official Title
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Efficacy and Safety Study of Two Fixed-Dose Combinations of Aclidinium Bromide With Formoterol Fumarate Compared With Aclidinium Bromide, Formoterol Fumarate, and Placebo All Administered Twice Daily (BID) to Patients With Stable, Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Aclidinium 400 μg / Formoterol 12 μg
* Drug: Aclidinium 400 μg / Formoterol 6 μg
* Drug: Aclidinium 400 μg
* Drug: Formoterol 12 μg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Understand the study procedures and be willing to participate in the study as indicated by signing the ICF and HIPAA form Be male or female aged 40 to 80 years, inclusive Have a diagnosis of stable, moderate to severe COPD (stages II and III) as defined by guidelines of the Global Initiative for Chronic Obstructive Lung Disease (2008) Be a current or former cigarette smoker with a smoking history of at least 10 pack-years Have post-albuterol/salbutamol FEV1 values ≥ 30% and < 80% of the predicted value. FEV1 will be measured at the Screening Visit (Visit 1) between 10 and 15 minutes after inhalation of albuterol/salbutamol. Have post-albuterol/salbutamol FEV1/FVC values < 70% (ie, 100 × post- albuterol/salbutamol FEV1/FVC < 70%). If female, be at least 1 year postmenopausal or surgically sterile (defined as having a hysterectomy or tubal ligation). Women of childbearing potential must have a negative serum β-human chorionic gonadotropin pregnancy test at screening Be in good stable health (as judged by the Investigator) other than the COPD, based on medical history, physical examination, ECG, spirometry, and clinical laboratory data evaluations Have COPD symptoms and FEV1 values at the time of randomization that are stable compared with those at Screening (Visit 1), according to the Investigator's medical judgment Exclusion Criteria: Have been hospitalized for an acute COPD exacerbation within 3 months before screening Have any respiratory tract infection (including the upper respiratory tract) or signs of a COPD exacerbation or respiratory infection in the 6 weeks before Screening (Visit 1). Have any clinically significant respiratory conditions other than COPD Have a history or presence of asthma verified from medical records Have used theophylline (including long-acting theophylline) within the previous 3 months before study entry Have Stage II hypertension, defined as systolic pressure of 160 and above, and diastolic pressure of 100 and above Chronic use of oxygen therapy ≥ 15 hours a day Have a history, current diagnosis, or presence of exercise-induced bronchospasm Have a body mass index ≥ 40 kg/m2 Have participated in an pulmonary rehabilitation program within the previous 3 months Have clinically significant cardiovascular conditions Have uncontrolled infection resulting from human immunodeficiency virus and/or active hepatitis Have symptomatic prostatic hypertrophy and/or bladder neck obstruction. Have narrow-angle glaucoma Have a history of hypersensitivity reaction (including report of paradoxical bronchospasm) to inhaled anticholinergics (including aclidinium bromide), β2 adrenergic agonists, or any other inhaled medication or any component thereof Have a QTcB, as indicated in the centralized reading report, above 470 msec in the resting ECGs performed at Screening (Visit 1) and/or patients who are using medications that may prolong the QT interval Have clinically relevant abnormalities in the results of clinical laboratory tests, in ECG parameters other than QTc, in results of the physical examination, Have any concurrent medical condition that, in the judgment of the Investigator, might interfere with the conduct of the study, confound the interpretation of the study results, or endanger the patient's well-being Do not maintain regular day/night, waking/sleeping cycles (eg, patients with history of sleep apnea syndrome or any disease related with sleep disturbances such as restless legs syndrome or somnambulism)

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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: Aclidinium 400 μg / Formoterol 12 μg<br>Aclidinium bromide 400 μg / formoterol fumarate 12 μg fixed dose combination administered twice-daily (BID) | Drug: Aclidinium 400 μg / Formoterol 12 μg<br>* Aclidinium bromide 400 μg / formoterol fumarate 12 μg fixed dose combination administered twice-daily (BID) for a 14 day period within four different treatment periods.<br>|
| Experimental: Aclidinium 400 μg / formoterol 6 μg<br>Aclidinium bromide 400 μg / formoterol fumarate 6 μg fixed dose combination administered twice-daily (BID) | Drug: Aclidinium 400 μg / Formoterol 6 μg<br>* Aclidinium bromide 400 μg / formoterol fumarate 6 μg fixed dose combination administered twice-daily (BID) for a 14 day period within four different treatment periods.<br>|
| Experimental: Aclidinium 400 μg<br>Aclidinium bromide 400 μg administered twice-daily (BID) | Drug: Aclidinium 400 μg<br>* Aclidinium bromide 400 μg administered twice-daily (BID) for a 14 day period within four different treatment periods.<br>|
| Active Comparator: Formoterol 12 μg<br>Formoterol fumarate 12 μg twice-daily | Drug: Formoterol 12 μg<br>* Formoterol fumarate 12 μg twice-daily for a 14 day period within four different treatment periods.<br>|
| Placebo Comparator: Placebo<br>Placebo twice-daily | Drug: Placebo<br>* Placebo twice-daily delivered by inhalation for a 14 day period within four different treatment periods.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12) |  | 0 to 12 hours post-dose on Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1) |  | Day 14 | 
| Change From Baseline in Morning Peak Forced Expiratory Volume in One Second (FEV1) |  | Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Obstructive Pulmonary Disease, COPD, Chronic Bronchitis, Emphysema, Airflow Obstruction, Chronic, Chronic Airflow Obstruction, Chronic Obstructive Airway Disease, Chronic Obstructive Lung Disease