Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Keywords
Bronchitis, Chronic, Emphysema, Smokers or ex-Smokers
Brief summary
The study seeks to determine the optimal dose of the Aclidinium/Formoterol combination for investigation in Phase III clinical trials
Detailed description
Dose-finding clinical trial, to assess the efficacy, safety and pharmacokinetics of three different doses of formoterol combined with the inhaled anticholinergic aclidinium bromide, aclidinium bromide monotherapy and formoterol monotherapy
Interventions
DRUGAclidinium bromide and formoterol
once daily
DRUGAclidinium bromide and formoterol placebo
once daily
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Adult males or non-pregnant, non-lactating females aged between 40 and 80 years old, both inclusive. Women of childbearing potential were allowed to enter the trial only if they used two medically approved contraceptive measures (ie, mechanical and pharmacological). (A female was considered to be of childbearing potential unless she had a hysterectomy, was at least one year post-menopause or had undergone tubal ligation. All women of childbearing potential were to have a negative serum pregnancy test at the Screening Visit). 2. Patients with a clinical diagnosis of stable moderate to severe COPD (stages II and III) according to the GOLD 2006 classification (http://www.goldcopd.com). 3. Current or ex-cigarette smoker with a smoking history of at least 10 pack-years. Pack-years were calculated by dividing the number of cigarettes smoked per day by 20 (the number of cigarettes in a pack) and multiplying this figure by the number of years a person had smoked. For example, a person who smoked 40 cigarettes a day and had smoked for 10 years would have had a 20 pack-year smoking history (40 cigarettes per day ÷ 20 cigarettes per pack = 2; 2 x 10 years of smoking = 20 pack-year history). Patients smoking other tobacco types were not allowed, unless they met the cigarette criterion as well. 4. Patients whose Forced Expiratory Volume in 1 second (FEV1) at the Screening Visit measured between 30-45 minutes post inhalation of 400 μg of salbutamol was 30% ≤FEV1 \<80% of the predicted normal value (ie, 100 x Post-salbutamol FEV1/Predicted FEV1 \<80% and ≥30%). (Predicted normal values used for calculation purposes were to be based on European Community for Steel and Coal predicted values) 5. Patients whose FEV1/Forced Vital Capacity (FVC) at the Screening Visit measured between 30- 45 minutes post inhalation of 400 μg of salbutamol was \<70% (ie, 100 x Post-salbutamol FEV1/FVC \<70%). 6. Patients whose COPD symptoms and FEV1 values at the time of randomisation were stable compared to the Screening Visit, according to the Investigator's medical judgment. 7. Patients who were eligible and able to participate in the trial and who consented to do so in writing after the purpose and nature of the investigation had been explained.
Exclusion criteria
1. History or current diagnosis of asthma, allergic rhinitis or atopy, or exercise-induced bronchospasm. 2. Eosinophil count ≥600 cells/mm3. 3. Clinically significant respiratory conditions at the time of Screening Visit defined as: * Use of long-term oxygen therapy \>5 h/day, * Known active tuberculosis, * History of interstitial lung or pulmonary thromboembolic disease, * Pulmonary resection during the past 12 months, * History of life-threatening COPD, * History of bronchiectasis secondary to respiratory diseases others than COPD (eg, cystic fibrosis, Kartagener's syndrome, etc), * Patients who in the Investigator's opinion may have needed to stop or start pulmonary rehabilitation or undergo a thoracotomy during the trial, 4. Hospitalisation due to COPD exacerbation, up to the 3 months prior to the Screening Visit. 5. Signs of a COPD exacerbation or respiratory infection (including the upper respiratory tract), up to the 6 weeks prior to the Screening Visit. 6. Clinically significant cardiovascular conditions at the time of Screening Visit defined as: * Myocardial infarction within the previous 6 months, * Unstable arrhythmia which has required changes in the pharmacological therapy or other intervention within the previous 12 months, or newly diagnosed arrhythmia within the previous 3 months. * Hospitalisation within the previous 12 months for heart failure functional classes III (marked limitation of activity and only comfortable at rest) and IV (need of complete rest, confinement to bed or chair, discomfort at any physical activity and presence of symptoms at rest) as per the New York Heart Association classification (www.americanheart.org) * Thoracic surgery within the previous 24 months 7. Presence of symptomatic prostatic hypertrophy and/or bladder neck obstruction. (However, patients who had a diagnosis of these conditions but without symptoms due to stable concomitant medication for its treatment were allowed to enter trial). 8. Presence of narrow-angle glaucoma. 9. History of untoward reactions or known hypersensitivity to inhaled anticholinergics (including aclidinium bromide), β2 adrenergic agonists or inhaled medication or any component thereof (including report of paradoxical bronchospasm). 10. Life expectancy of less than 1 year. 11. Prolonged QT interval corrected using Bazett's formula (QTcB) interval (\>470 msec) in any of the ECGs performed before randomisation, and/or the use of drugs which may have induced its prolongation. 12. Clinically relevant abnormalities in laboratory results, ECG parameters (other than QTcB), or physical examination if the abnormality defines a disease state listed as an exclusion criterion, except for those related to COPD. 13. Clinically significant diseases other than COPD, which, in the opinion of the Investigator, may have put the patient at risk because of the participation in the trial; or diseases which may have influenced the results of the study or the patient's ability to take part in it. 14. Patients who did not maintain regular day/night, waking/sleeping cycles (eg, night shift workers were to be excluded). 15. Patients who intended to use any concomitant medication not permitted by the protocol or who had not undergone the required wash-out period for a particular prohibited medication. 16. Patients who were unable or unlikely to be cooperative with the study requirements of taking the medication, completion of the Patient Diary and attending the clinic for study visits. 17. Patients who were unable to properly use a dry powder or pressurised metered-dose inhalers (pMDI) inhaler device and/or to perform acceptable and reproducible spirometry measurements as per the ATS/ERS standards (Standardisation of lung function test, 2005 20). 18. History of drug and/or alcohol abuse or addiction during the previous 2 years. 19. Previous participation in another clinical trial with any investigational medicinal product 6 weeks prior to the Screening Visit. (Patients who had participated in a previous clinical trial with aclidinium bromide (Almirall product code LAS34273) were to be allowed to participate in this study provided that the above criterion was fulfilled. This circumstance was to be specifically recorded on the eCRF).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-12 hr | Baseline and treatment Week 4 |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) | Baseline and treatment Week 4 |
| Change From Baseline in Peak Forced Expiratory Volume in One Second (FEV1) | Baseline and treatment Week 4 |
| Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-3 hr | Baseline and treatment Week 4 |
| Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-6 hr | Baseline and treatment Week 4 |
Countries
Australia, Czechia, Poland, Russia
Participant flow
Recruitment details
The study was conducted in a total of 81 sites: 21 in Russia, 13 in Poland, 8 in India, 8 in Romania, 6 in Australia, 5 in Taiwan, 5 in the Czech Republic, 5 in New Zealand, 4 in Hungary, 3 in Malaysia and 3 in Slovakia The first patient was screened in February 2008 and the last patient visit was in November 2008
Pre-assignment details
A total of 808 patients were screened and 566 were randomized into the study Among 242 patients who failed to be randomized, the main reason for screen failure was non-fulfillment of one or more study entry criteria (156 patients), followed by subject's personal request (32 patients)
Participants by arm
| Arm | Count |
|---|---|
| Aclidinium 200 μg / Formoterol 6 μg Aclidinium bromide 200 μg + formoterol fumarate 6 μg fixed dose combination (FDC) once-daily | 121 |
| Aclidinium 200 μg / Formoterol 12 μg Aclidinium bromide 200 μg + formoterol fumarate 12 μg fixed dose combination (FDC) once-daily | 120 |
| Aclidinium 200 μg / Formoterol 18 μg Aclidinium bromide 200 μg + formoterol fumarate 18 μg fixed dose combination (FDC) once-daily | 125 |
| Aclidinium 200 μg Aclidinium bromide 200 μg once-daily | 76 |
| Formoterol 12 μg Formoterol fumarate 12 μg once-daily | 65 |
| Placebo Placebo once-daily | 59 |
| Total | 566 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 2 | 0 | 1 | 1 |
| Overall Study | COPD exacerbation | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Inconsistent reason reported | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Non-fulfilment of in/exclusion criteria | 1 | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 5 | 5 | 0 | 4 | 1 |
Baseline characteristics
| Characteristic | Aclidinium 200 μg / Formoterol 6 μg | Aclidinium 200 μg / Formoterol 12 μg | Aclidinium 200 μg / Formoterol 18 μg | Aclidinium 200 μg | Formoterol 12 μg | Placebo | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 62.9 Years STANDARD_DEVIATION 9 | 63.6 Years STANDARD_DEVIATION 8.9 | 63.9 Years STANDARD_DEVIATION 8.1 | 63.7 Years STANDARD_DEVIATION 9.3 | 64.0 Years STANDARD_DEVIATION 9.8 | 60.7 Years STANDARD_DEVIATION 7.8 | 63.3 Years STANDARD_DEVIATION 8.8 |
| Sex: Female, Male Female | 30 Participants | 22 Participants | 29 Participants | 16 Participants | 11 Participants | 15 Participants | 123 Participants |
| Sex: Female, Male Male | 91 Participants | 98 Participants | 96 Participants | 60 Participants | 54 Participants | 44 Participants | 443 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 | 2 / 121 | 1 / 120 | 3 / 125 | 4 / 76 | 5 / 65 | 2 / 59 |
| serious Total, serious adverse events | 1 / 121 | 1 / 120 | 3 / 125 | 0 / 76 | 1 / 65 | 0 / 59 |
Outcome results
Primary
Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-12 hr
Time frame: Baseline and treatment Week 4
Population: ITT Population defined as all randomised patients who took at least one dose of investigational medicinal product and had at least the baseline and one post-baseline efficacy assessments
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Aclidinium 200 μg / Formoterol 6 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-12 hr | 0.170 Liters |
| Aclidinium 200 μg / Formoterol 12 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-12 hr | 0.219 Liters |
| Aclidinium 200 μg / Formoterol 18 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-12 hr | 0.230 Liters |
| Aclidinium 200 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-12 hr | 0.075 Liters |
| Formoterol 12 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-12 hr | 0.099 Liters |
| Placebo | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-12 hr | -0.036 Liters |
p-value: <0.000195% CI: [0.191, 0.34]ANCOVA
p-value: <0.000195% CI: [0.131, 0.28]ANCOVA
p-value: <0.000195% CI: [0.18, 0.329]ANCOVA
Secondary
Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-3 hr
Time frame: Baseline and treatment Week 4
Population: ITT Population defined as all randomised patients who took at least one dose of investigational medicinal product and had at least the baseline and one post-baseline efficacy assessments
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Aclidinium 200 μg / Formoterol 6 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-3 hr | 0.197 Liters |
| Aclidinium 200 μg / Formoterol 12 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-3 hr | 0.256 Liters |
| Aclidinium 200 μg / Formoterol 18 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-3 hr | 0.250 Liters |
| Aclidinium 200 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-3 hr | 0.088 Liters |
| Formoterol 12 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-3 hr | 0.134 Liters |
| Placebo | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-3 hr | -0.033 Liters |
Secondary
Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-6 hr
Time frame: Baseline and treatment Week 4
Population: ITT Population defined as all randomised patients who took at least one dose of investigational medicinal product and had at least the baseline and one post-baseline efficacy assessments
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Aclidinium 200 μg / Formoterol 6 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-6 hr | 0.206 Liters |
| Aclidinium 200 μg / Formoterol 12 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-6 hr | 0.266 Liters |
| Aclidinium 200 μg / Formoterol 18 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-6 hr | 0.272 Liters |
| Aclidinium 200 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-6 hr | 0.094 Liters |
| Formoterol 12 μg | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-6 hr | 0.137 Liters |
| Placebo | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) for 0-6 hr | -0.033 Liters |
Secondary
Change From Baseline in Peak Forced Expiratory Volume in One Second (FEV1)
Time frame: Baseline and treatment Week 4
Population: ITT Population defined as all randomised patients who took at least one dose of investigational medicinal product and had at least the baseline and one post-baseline efficacy assessments
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Aclidinium 200 μg / Formoterol 6 μg | Change From Baseline in Peak Forced Expiratory Volume in One Second (FEV1) | 0.294 Liters |
| Aclidinium 200 μg / Formoterol 12 μg | Change From Baseline in Peak Forced Expiratory Volume in One Second (FEV1) | 0.357 Liters |
| Aclidinium 200 μg / Formoterol 18 μg | Change From Baseline in Peak Forced Expiratory Volume in One Second (FEV1) | 0.349 Liters |
| Aclidinium 200 μg | Change From Baseline in Peak Forced Expiratory Volume in One Second (FEV1) | 0.184 Liters |
| Formoterol 12 μg | Change From Baseline in Peak Forced Expiratory Volume in One Second (FEV1) | 0.216 Liters |
| Placebo | Change From Baseline in Peak Forced Expiratory Volume in One Second (FEV1) | 0.044 Liters |
Secondary
Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1)
Time frame: Baseline and treatment Week 4
Population: ITT Population defined as all randomised patients who took at least one dose of investigational medicinal product and had at least the baseline and one post-baseline efficacy assessments
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Aclidinium 200 μg / Formoterol 6 μg | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) | 0.042 Liters |
| Aclidinium 200 μg / Formoterol 12 μg | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) | 0.085 Liters |
| Aclidinium 200 μg / Formoterol 18 μg | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) | 0.044 Liters |
| Aclidinium 200 μg | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) | -0.017 Liters |
| Formoterol 12 μg | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) | 0.014 Liters |
| Placebo | Change From Baseline in Trough Forced Expiratory Volume in One Second (FEV1) | -0.031 Liters |