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, safety and tolerability of aclidinium bromide doses compared with placebo in the treatment of moderate to severe, stable chronic obstructive pulmonary disease. The study will be 56 weeks in duration; a 2-week run-in period followed by a 12-week double-blind, placebo-controlled treatment period. This will be followed by an open-label 40-week treatment period and a 2-week follow up phone call. All patients will receive the higher Aclidinium Bromide during the 40-week open label treatment period.
Interventions
Aclidinium bromide 200 μg, oral inhalation twice per day 12 weeks of treatment. At week 12, patients who were on Aclidinium bromide 200 μg will receive open label 400µg aclidinium bromide for 40 weeks of treatment.
DRUGPlacebo
Dose-matched placebo, oral inhalation twice per day for 12 weeks. At week 12, patients who were on placebo will receive open label 400 µg aclidinium bromide for 40 weeks of treatment
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A diagnosis of stable moderate to severe COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, 2008; postbronchodilator FEV1/FVC \< 70%, and postbronchodilator FEV1 ≥ 30% and \< 80% predicted * Current or former cigarette smokers
Exclusion criteria
* Patients who have been hospitalized for an acute COPD exacerbation within 3 months before the first visit * Respiratory tract infection or COPD exacerbation in the 6 weeks before Visit 1 * Patient with any clinically significant respiratory conditions other than COPD, cardiovascular conditions or mental illness * History or presence of asthma verified from medical records * Chronic use of oxygen therapy greater than or equal to 15 hours per day * Patient with uncontrolled infection due to HIV and/or active hepatitis * Patients with a history of hypersensitivity reaction to inhaled anticholinergics * Patients with clinically significant cardiovascular conditions, including myocardial infarction during the previous 6 months, newly diagnosed arrhythmia within the previous 3 months, unstable angina, unstable arrhythmia that had required changes in pharmacological therapy or other intervention.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Morning Predose (Trough) Forced Expiratory Volume in 1 Second (FEV1) | Change from baseline (Week 0) to Week 12 | Change from baseline in Trough forced expiratory volume in 1 second before the morning dose of aclidinium bromide, Last Observation Carried Forward (LOCF) |
| Part B: Morning Predose (Trough) FEV1 | Change from baseline (Week 0) to 52 Weeks | Change from Baseline in Morning Pre-dose (trough) Forced Expiratory Volume in 1 Second (FEV1) at Week 52, Lost Observation Carried Forward (LOCF) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Peak Forced Expiratory Volume in 1 Second (FEV1) | Change from baseline (Week 0) to Week 12 | Change from baseline in peak FEV1 at week 12, Last Observation Carried Forward (LOCF) |
| Part B: Peak FEV1 | Change from baseline (Week 0) to 52 Weeks | Change from Baseline in Peak FEV1 (L) at Week 52, Last Observation Carried Forward (LOCF) |
Countries
Canada, United States
Participant flow
Recruitment details
Patient recruitment occurred from December of 2009 to June of 2010 at 112 study sites (110 in the United States and 2 additional sites in Canada).
Pre-assignment details
A total of 544 patients were randomized, with 542 in the Part A Safety population. Of the 454 patients who completed Part A, 448 patients continued into Part B, receiving at least 1 dose of open-label treatment, were included in the Part B Safety Population. Of these patients, 405 had a baseline and postbaseline assessment for the ITT Population.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Part A / Placebo to Aclidinium Bromide 400μg Part B Dose-matched placebo, twice per day, oral inhalation for 12 weeks of double-blind treatment in Part A of the Trial.
After week 12 (conclusion of Part A), patients who were on placebo received open-label Aclidinium Bromide, 400 microgram dose, for an additional 40 weeks. | 182 |
| Aclidinium Bromide(AB) 200μg Part A / AB 200μg to 400μg Part B Aclidinium bromide 200 microgram dose, oral inhalation, twice per day for 12 weeks of double-blind treatment in Part A of the Trial.
After week 12 (conclusion of Part A), patients who were on a double-blind, 200 microgram Aclidinium Bromide dose, were switched to open-label Aclidinium Bromide at a 400 microgram dose for an additional 40 weeks. | 183 |
| Aclidinium Bromide(AB) 400μg Part A / AB 400μg to 400μg Part B Aclidinium bromide, 400 microgram dose, oral inhalation twice per day for 12 weeks of double-blind treatment in Part A of the Trial.
After week 12 (conclusion of Part A), patients who were on a double-blind, 400 microgram Aclidinium Bromide dose, were switched to open-label Aclidinium Bromide at the same 400 microgram dose for an additional 40 weeks. | 177 |
| Total | 542 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part A - 12 Weeks Double Blind Treatment | Adverse Event | 4 | 3 | 8 |
| Part A - 12 Weeks Double Blind Treatment | COPD Exacerbation | 4 | 1 | 6 |
| Part A - 12 Weeks Double Blind Treatment | Lack of Efficacy | 6 | 3 | 2 |
| Part A - 12 Weeks Double Blind Treatment | Lost to Follow-up | 3 | 3 | 2 |
| Part A - 12 Weeks Double Blind Treatment | Other Reason | 3 | 3 | 3 |
| Part A - 12 Weeks Double Blind Treatment | Protocol Violation | 3 | 4 | 3 |
| Part A - 12 Weeks Double Blind Treatment | Withdrawal by Subject | 8 | 12 | 6 |
| Part B - 40 Additional Weeks Open Label | Adverse Event | 10 | 10 | 7 |
| Part B - 40 Additional Weeks Open Label | COPD Exacerbation | 1 | 5 | 1 |
| Part B - 40 Additional Weeks Open Label | Lack of Efficacy | 3 | 5 | 5 |
| Part B - 40 Additional Weeks Open Label | Lost to Follow-up | 5 | 1 | 6 |
| Part B - 40 Additional Weeks Open Label | Other Reason | 4 | 2 | 1 |
| Part B - 40 Additional Weeks Open Label | Protocol Violation | 3 | 6 | 3 |
| Part B - 40 Additional Weeks Open Label | Withdrawal by Subject | 10 | 7 | 9 |
Baseline characteristics
| Characteristic | Aclidinium Bromide(AB) 200μg Part A / AB 200μg to 400μg Part B | Aclidinium Bromide(AB) 400μg Part A / AB 400μg to 400μg Part B | Total | Placebo Part A / Placebo to Aclidinium Bromide 400μg Part B |
|---|---|---|---|---|
| Age, Continuous Part A | 63.4 years STANDARD_DEVIATION 8.5 | 63.2 years STANDARD_DEVIATION 9 | 62.8 years STANDARD_DEVIATION 8.9 | 61.7 years STANDARD_DEVIATION 9.3 |
| Age, Continuous Part B | 63.8 years STANDARD_DEVIATION 8.2 | 63.1 years STANDARD_DEVIATION 8.6 | 62.8 years STANDARD_DEVIATION 8.7 | 61.3 years STANDARD_DEVIATION 9.1 |
| Age, Customized ≥ 40 to < 60 years - Part A | 57 participants | 57 participants | 186 participants | 72 participants |
| Age, Customized ≥ 40 to < 60 years - Part B | 46 participants | 46 participants | 152 participants | 60 participants |
| Age, Customized ≥ 60 to < 70 years - Part A | 79 participants | 77 participants | 228 participants | 72 participants |
| Age, Customized ≥ 60 to < 70 years - Part B | 67 participants | 67 participants | 192 participants | 58 participants |
| Age, Customized ≥ 70 years - Part A | 47 participants | 43 participants | 128 participants | 38 participants |
| Age, Customized ≥ 70 years - Part B | 41 participants | 34 participants | 104 participants | 29 participants |
| Gender Female | 84 Participants | 88 Participants | 254 Participants | 82 Participants |
| Gender Male | 99 Participants | 89 Participants | 288 Participants | 100 Participants |
| Region of Enrollment Canada | 2 participants | 2 participants | 6 participants | 2 participants |
| Region of Enrollment United States | 152 participants | 145 participants | 442 participants | 180 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 182 | 20 / 183 | 28 / 177 | 37 / 147 | 50 / 154 | 52 / 147 |
| serious Total, serious adverse events | 12 / 182 | 11 / 183 | 8 / 177 | 15 / 147 | 20 / 154 | 14 / 147 |
Outcome results
Primary
Part A: Morning Predose (Trough) Forced Expiratory Volume in 1 Second (FEV1)
Change from baseline in Trough forced expiratory volume in 1 second before the morning dose of aclidinium bromide, Last Observation Carried Forward (LOCF)
Time frame: Change from baseline (Week 0) to Week 12
Population: Of 544 patients randomized, 542 patients received at least 1 dose of double-blind treatment and were included in the Safety Population. Of these patients, 541 had a baseline and at least 1 postbaseline FEV1 assessment and qualified for the Intent to Treat (ITT) Population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Part A: Morning Predose (Trough) Forced Expiratory Volume in 1 Second (FEV1) | -0.008 L | Standard Error 0.015 |
| Aclidinium Bromide 200 μg | Part A: Morning Predose (Trough) Forced Expiratory Volume in 1 Second (FEV1) | 0.043 L | Standard Error 0.015 |
| Aclidinium Bromide 400 μg | Part A: Morning Predose (Trough) Forced Expiratory Volume in 1 Second (FEV1) | 0.064 L | Standard Error 0.016 |
p-value: 0.01995% CI: [0.01, 0.09]ANCOVA
p-value: 0.001295% CI: [0.03, 0.12]ANCOVA
Primary
Part B: Morning Predose (Trough) FEV1
Change from Baseline in Morning Pre-dose (trough) Forced Expiratory Volume in 1 Second (FEV1) at Week 52, Lost Observation Carried Forward (LOCF)
Time frame: Change from baseline (Week 0) to 52 Weeks
Population: A total of 544 patients were randomized, with 542 in the Part A Safety population. Of the 454 patients who completed Part A, 448 patients continued into Part B, receiving at least 1 dose of open-label treatment, were included in the Part B Safety Population. Of these patients, 405 had a baseline and postbaseline assessment for the ITT Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Part B: Morning Predose (Trough) FEV1 | 0.045 L | Standard Deviation 0.021 |
| Aclidinium Bromide 200 μg | Part B: Morning Predose (Trough) FEV1 | 0.029 L | Standard Deviation 0.02 |
| Aclidinium Bromide 400 μg | Part B: Morning Predose (Trough) FEV1 | 0.048 L | Standard Deviation 0.021 |
p-value: 0.019295% CI: [0.01, 0.09]ANCOVA
p-value: 0.001295% CI: [0.03, 0.12]ANCOVA
Secondary
Part A: Peak Forced Expiratory Volume in 1 Second (FEV1)
Change from baseline in peak FEV1 at week 12, Last Observation Carried Forward (LOCF)
Time frame: Change from baseline (Week 0) to Week 12
Population: Of 544 patients randomized, 542 patients received at least 1 dose of double-blind treatment and were included in the Safety Population. Of these patients, 541 had a baseline and at least 1 postbaseline FEV1 assessment and qualified for the Intent to Treat (ITT) Population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Part A: Peak Forced Expiratory Volume in 1 Second (FEV1) | 0.087 L | Standard Error 0.018 |
| Aclidinium Bromide 200 μg | Part A: Peak Forced Expiratory Volume in 1 Second (FEV1) | 0.202 L | Standard Error 0.018 |
| Aclidinium Bromide 400 μg | Part A: Peak Forced Expiratory Volume in 1 Second (FEV1) | 0.212 L | Standard Error 0.018 |
Secondary
Part B: Peak FEV1
Change from Baseline in Peak FEV1 (L) at Week 52, Last Observation Carried Forward (LOCF)
Time frame: Change from baseline (Week 0) to 52 Weeks
Population: A total of 544 patients were randomized, with 542 in the Part A Safety population. Of the 454 patients who completed Part A, 448 patients continued into Part B, receiving at least 1 dose of open-label treatment, were included in the Part B Safety Population. Of these patients, 405 had a baseline and postbaseline assessment for the ITT Population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Part B: Peak FEV1 | 0.185 L | Standard Error 0.023 |
| Aclidinium Bromide 200 μg | Part B: Peak FEV1 | 0.176 L | Standard Error 0.023 |
| Aclidinium Bromide 400 μg | Part B: Peak FEV1 | 0.172 L | Standard Error 0.023 |