Chronic Obstructive Pulmonary Disease
Conditions
Keywords
Bronchitis, Chronic, Emphysema
Brief summary
The purpose of this multicenter, dose-ranging study is to compare two Fixed-Dose Combinations of aclidinium bromide and formoterol fumarate with placebo, aclidinium bromide and formoterol fumarate, all administered BID in patients with stable, moderate to severe COPD. Every treatment period is 14-days long and there is a 7-days wash-out period in between them. The trial starts with a run in phase of 10 to 17-days duration and it ends up with a follow up contact 14-days after last treatment dose.
Interventions
DRUGAclidinium 200 μg / formoterol 12 μg
Aclidinium bromide 200 μg + formoterol fumarate 12 μg fixed dose combination (FDC) twice daily
DRUGPlacebo
Placebo control twice daily
DRUGFormoterol 12 μg
Formoterol fumarate 12 μg twice daily
DRUGAclidinium 200 μg
Aclidinium bromide 200 μg twice daily
DRUGAclidinium 200 μg / Formoterol 6 μg
Aclidinium bromide 200 μg + formoterol fumarate 6 μg fixed dose combination (FDC) twice daily
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Adult male or non-pregnant, non-lactating female aged between 40 and 80 years old, both inclusive. 2. Patient with a clinical diagnosis of stable moderate to severe COPD according to the GOLD classification 3. Current, or ex-cigarette smoker with a smoking history of at least 10 pack-years. 4. Patient whose FEV1 at the Screening Visit measured between 10-15 minutes post inhalation of 400 mcg of salbutamol is 30% FEV1 \<80% of the predicted normal value (i.e., 100 x Post-salbutamol \< FEV1/ Predicted FEV1 must be \< 80% and ≥ 30%). 5. Patient whose FEV1/FVC at the Screening Visit measured between 10-15 minutes post inhalation of 400 mcg of salbutamol is \< 70% (i.e., 100 x Post-salbutamol FEV1 /FVC \< 70%). 6. Patient who is eligible and able to participate in the trial and who consent to do so in writing after the purpose and nature of the investigation have been explained. 7. Patient whose COPD symptoms and FEV1 values at the time of randomisation are stable compared to the Screening Visit, according to the investigator's medical judgment
Exclusion criteria
1. History or current diagnosis of asthma or exercise-induced bronchospasm. 2. Clinically significant respiratory conditions at the time of Inform Consent signature 3. Hospitalisation due to COPD exacerbation within the previous 3 months. 4. Signs of a COPD exacerbation or respiratory infection (including the upper respiratory tract) within the previous 6 weeks. 5. Patient who has a resting systolic blood pressure ≥ 200 mmHg, a resting diastolic blood pressure ≥ 120 mmHg or a resting heart rate ≥ 105 bpm at screening visit. 6. Clinically significant cardiovascular conditions 7. Presence of symptomatic prostatic hypertrophy and/or bladder neck obstruction. 8. Presence of narrow-angle glaucoma. 9. QTc \[calculated according to Bazett's formulae (QTc=QT/RR1/2) above 470 milliseconds in the ECG performed at Screening Visit, 10. Patient who does not maintain regular day/night, waking/sleeping cycles
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12h) After Morning Study Drug Administration at Day 14 | 0 and 30 minutes and 1, 2, 3, 4, 6, 8, 10 and 12 hours post-morning dose at Day 14 | FEV1 was measured via spirometry: 2 sets of tests prior to morning dose separated by 30 minutes, and then 1 set at 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-morning dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Morning Pre-dose FEV1 at Day 14 | Day 14 | FEV1 was measured via spirometry: 2 sets of tests prior to morning dose separated by 30 minutes |
| Change From Baseline in Morning Peak FEV1 at Day 14 | 0 and 30 minutes and 1, 2, 3, 4, 6, 8, 10 and 12 hours post-morning dose at Day 14 | FEV1 was measured via spirometry: 2 sets of tests prior to morning dose separated by 30 minutes, and then 1 set at 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-morning dose |
Countries
Czechia, Romania
Participant flow
Recruitment details
This study was conducted at a total of 28 sites (4 sites in Czech Republic, 5 sites in Germany, 3 sites in Hungary, 4 sites in Poland and 12 sites in Romania) The first patient was screened in February 2010 and the last patient visit was in September 2010
Pre-assignment details
A total of 176 patients were screened of whom 135 were assessed as eligible and were randomized into the study There were 41 screen failures, the main reason being non-fulfilment of inclusion/exclusion criteria
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Population All patients randomized into the study | 135 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 | FG018 | FG019 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 1 | Adverse Event | 1 | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 1 | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 1 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Treatment Period 2 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 3 | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 4 | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 4 | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Overall Study Population |
|---|---|
| Age, Continuous | 60.4 Years STANDARD_DEVIATION 7.93 |
| Gender Female | 40 Participants |
| Gender Male | 95 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 / 101 | 0 / 101 | 0 / 102 | 0 / 100 | 0 / 101 |
| serious Total, serious adverse events | 0 / 101 | 2 / 101 | 0 / 102 | 0 / 100 | 1 / 101 |
Outcome results
Primary
Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12h) After Morning Study Drug Administration at Day 14
FEV1 was measured via spirometry: 2 sets of tests prior to morning dose separated by 30 minutes, and then 1 set at 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-morning dose
Time frame: 0 and 30 minutes and 1, 2, 3, 4, 6, 8, 10 and 12 hours post-morning dose at Day 14
Population: Intent to treat (ITT) population: all randomized patients who took at least 1 dose of study drug and had at least 1 baseline and 1 post-baseline assessment of value of FEV1
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12h) After Morning Study Drug Administration at Day 14 | -0.041 Liters | Standard Error 0.021 |
| Aclidinium 200 μg / Formoterol 12 μg | Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12h) After Morning Study Drug Administration at Day 14 | 0.180 Liters | Standard Error 0.021 |
| Aclidinium 200 μg / Formoterol 6 μg | Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12h) After Morning Study Drug Administration at Day 14 | 0.193 Liters | Standard Error 0.021 |
| Aclidinium 200 μg | Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12h) After Morning Study Drug Administration at Day 14 | 0.139 Liters | Standard Error 0.021 |
| Formoterol 12 μg | Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve Over 12 Hours (AUC0-12h) After Morning Study Drug Administration at Day 14 | 0.100 Liters | Standard Error 0.021 |
p-value: <0.000195% CI: [0.174, 0.268]Mixed Models Analysis
p-value: <0.000195% CI: [0.186, 0.281]Mixed Models Analysis
Secondary
Change From Baseline in Morning Peak FEV1 at Day 14
FEV1 was measured via spirometry: 2 sets of tests prior to morning dose separated by 30 minutes, and then 1 set at 30 minutes, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-morning dose
Time frame: 0 and 30 minutes and 1, 2, 3, 4, 6, 8, 10 and 12 hours post-morning dose at Day 14
Population: Intent to treat (ITT) population: all randomized patients who took at least 1 dose of study drug and had at least 1 baseline and 1 post-baseline assessment of value of FEV1
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Morning Peak FEV1 at Day 14 | 0.052 Liters | Standard Error 0.023 |
| Aclidinium 200 μg / Formoterol 12 μg | Change From Baseline in Morning Peak FEV1 at Day 14 | 0.335 Liters | Standard Error 0.023 |
| Aclidinium 200 μg / Formoterol 6 μg | Change From Baseline in Morning Peak FEV1 at Day 14 | 0.347 Liters | Standard Error 0.023 |
| Aclidinium 200 μg | Change From Baseline in Morning Peak FEV1 at Day 14 | 0.255 Liters | Standard Error 0.023 |
| Formoterol 12 μg | Change From Baseline in Morning Peak FEV1 at Day 14 | 0.255 Liters | Standard Error 0.023 |
Secondary
Change From Baseline in Morning Pre-dose FEV1 at Day 14
FEV1 was measured via spirometry: 2 sets of tests prior to morning dose separated by 30 minutes
Time frame: Day 14
Population: Intent to treat (ITT) population: all randomized patients who took at least 1 dose of study drug and had at least 1 baseline and 1 post-baseline assessment of value of FEV1
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Morning Pre-dose FEV1 at Day 14 | -0.059 Liters | Standard Error 0.02 |
| Aclidinium 200 μg / Formoterol 12 μg | Change From Baseline in Morning Pre-dose FEV1 at Day 14 | 0.042 Liters | Standard Error 0.02 |
| Aclidinium 200 μg / Formoterol 6 μg | Change From Baseline in Morning Pre-dose FEV1 at Day 14 | 0.067 Liters | Standard Error 0.02 |
| Aclidinium 200 μg | Change From Baseline in Morning Pre-dose FEV1 at Day 14 | 0.072 Liters | Standard Error 0.02 |
| Formoterol 12 μg | Change From Baseline in Morning Pre-dose FEV1 at Day 14 | 0.027 Liters | Standard Error 0.02 |