Chronic Obstructive Pulmonary Disease
Conditions
Keywords
Chronic Obstructive Pulmonary Disease, COPD, Chronic Bronchitis, Emphysema, Airflow Obstruction, Chronic, Chronic Airflow Obstruction, Chronic Obstructive Airway Disease, Chronic Obstructive Lung Disease
Brief summary
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.
Interventions
DRUGAclidinium 400 μg / Formoterol 12 μg
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.
DRUGAclidinium 400 μg / Formoterol 6 μg
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.
DRUGAclidinium 400 μg
Aclidinium bromide 400 μg administered twice-daily (BID) for a 14 day period within four different treatment periods.
DRUGFormoterol 12 μg
Formoterol fumarate 12 μg twice-daily for a 14 day period within four different treatment periods.
DRUGPlacebo
Placebo twice-daily delivered by inhalation for a 14 day period within four different treatment periods.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | 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
| Measure | 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 |
Countries
United States
Participant flow
Recruitment details
The study was conducted in a total of 20 study centers in the United States. The first patient was screened in December 2009 and the last patient visit was in August 2010.
Participants by arm
| Arm | Count |
|---|---|
| Overall Population Safety population defined as all randomized patients who took at least one dose of double-blind investigational product | 128 |
| Total | 128 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 | FG018 | FG019 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 | Adverse Event | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 1 | 0 | 1 | 0 |
| Period 1 | Did not meet inc/exc criteria | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 1 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 2 | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Period 2 | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 2 | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 |
| Period 2 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 |
| Period 4 | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Period 4 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Overall Population |
|---|---|
| Age, Continuous | 61.5 Years STANDARD_DEVIATION 8.8 |
| Gender Female | 73 Participants |
| Gender Male | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 87 | 0 / 91 | 0 / 94 | 0 / 92 | 0 / 92 |
| serious Total, serious adverse events | 2 / 87 | 0 / 91 | 1 / 94 | 1 / 92 | 0 / 92 |
Outcome results
Primary
Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12)
Time frame: 0 to 12 hours post-dose on Day 14
Population: ITT Population defined as randomized patients who took at least one dose of double-blind investigational product and who had at least 1 baseline and 1 post-baseline assessment of FEV1
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium 400 μg / Formoterol 12 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12) | 0.187 Liters | Standard Error 0.019 |
| Aclidinium 400 μg / Formoterol 6 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12) | 0.189 Liters | Standard Error 0.018 |
| Aclidinium 400 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12) | 0.144 Liters | Standard Error 0.018 |
| Formoterol 12 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12) | 0.114 Liters | Standard Error 0.019 |
| Placebo | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12) | -0.013 Liters | Standard Error 0.018 |
p-value: <0.000195% CI: [0.156, 0.245]Mixed Models Analysis
p-value: <0.000195% CI: [0.158, 0.245]Mixed Models Analysis
Secondary
Change From Baseline in Morning Peak Forced Expiratory Volume in One Second (FEV1)
Time frame: Day 14
Population: ITT Population defined as randomized patients who took at least one dose of double-blind investigational product and who had at least 1 baseline and 1 post-baseline assessment of FEV1
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium 400 μg / Formoterol 12 μg | Change From Baseline in Morning Peak Forced Expiratory Volume in One Second (FEV1) | 0.355 Liters | Standard Error 0.022 |
| Aclidinium 400 μg / Formoterol 6 μg | Change From Baseline in Morning Peak Forced Expiratory Volume in One Second (FEV1) | 0.348 Liters | Standard Error 0.021 |
| Aclidinium 400 μg | Change From Baseline in Morning Peak Forced Expiratory Volume in One Second (FEV1) | 0.260 Liters | Standard Error 0.021 |
| Formoterol 12 μg | Change From Baseline in Morning Peak Forced Expiratory Volume in One Second (FEV1) | 0.245 Liters | Standard Error 0.022 |
| Placebo | Change From Baseline in Morning Peak Forced Expiratory Volume in One Second (FEV1) | 0.073 Liters | Standard Error 0.022 |
p-value: <0.000195% CI: [0.23, 0.333]Mixed Models Analysis
p-value: <0.000195% CI: [0.224, 0.325]Mixed Models Analysis
Secondary
Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1)
Time frame: Day 14
Population: ITT Population defined as randomized patients who took at least one dose of double-blind investigational product and who had at least 1 baseline and 1 post-baseline assessment of FEV1
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium 400 μg / Formoterol 12 μg | Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1) | 0.124 Liters | Standard Error 0.018 |
| Aclidinium 400 μg / Formoterol 6 μg | Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1) | 0.129 Liters | Standard Error 0.018 |
| Aclidinium 400 μg | Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1) | 0.080 Liters | Standard Error 0.018 |
| Formoterol 12 μg | Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1) | 0.071 Liters | Standard Error 0.018 |
| Placebo | Change From Baseline in Morning Pre-dose (Trough) Forced Expiratory Volume in One Second (FEV1) | -0.008 Liters | Standard Error 0.018 |
p-value: <0.000195% CI: [0.083, 0.181]Mixed Models Analysis
p-value: <0.000195% CI: [0.088, 0.185]Mixed Models Analysis