| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe Chronic Obstructive Pulmonary Disease (COPD). |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009033 |
| E.1.2 | Term | Chronic obstructive pulmonary disease |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess the efficacy and safety of three combinations of aclidinium bromide 200µg with formoterol (6, 12 or 18µg) compared to placebo, monotherapy treatment formoterol 12µg and monotherapy treatment aclidinium bromide 200µg in patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD).
To determine the optimal formoterol dose combined with aclidinium bromide to be investigated in subsequent clinical trials.
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| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Sub-study assessing extended serum glucose and potassium levels and 24-hour Holter ECG of which details are given on page 6 of the protocol. |
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| E.3 | Principal inclusion criteria |
1. Adult male or non-pregnant, non-lactating female aged between 40 and 80 years old, both inclusive. Women of childbearing potential are allowed to enter the trial ONLY if they use TWO medically approved contraceptive measures (i.e., mechanical and pharmacological).
(A female is considered to be of childbearing potential unless she has had a hysterectomy, is at least one year post-menopause or has undergone tubal ligation. All women of childbearing potential must have a negative serum pregnancy test at the Screening Visit).
2. Patient 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 are 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 has smoked. For example, a person who smokes 40 cigarettes a day and has smoked for 10 years would have 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 will not be allowed, unless they meet the cigarette criterion as well.
4. Patient whose FEV1 at the Screening Visit measured between 30-45 minutes post inhalation of 400 mg of salbutamol is 30% ≤ FEV1 <80% of the predicted normal value (i.e., 100 x Post-salbutamol FEV1/ Predicted FEV1 <80% and ≥ 30%).
(Predicted normal values to be used for calculation purposes are to be based on European Community for Steel and Coal predicted values (Quanjer et al. 1993)).
5. Patient whose FEV1/FVC at the Screening Visit measured between 30-45 minutes post inhalation of 400 mg of salbutamol is <70% (i.e., 100 x Post-salbutamol FEV1/FVC <70%).
6. 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.
7. 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.
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| E.4 | Principal exclusion criteria |
Patients allowed to enter the trial must not present any of the following conditions at Screening Visit and/or before randomisation:
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 > 15h/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 (e.g., cystic fibrosis, Kartagener’s syndrome, etc),
· Patients who in the investigator’s opinion may need 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 with a diagnosis of these conditions but without symptoms due to stable concomitant medication for its treatment are 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 QTcB interval (> 470 msec) in any of the ECGs performed before randomisation, and/or the use of drugs which may induce 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 put the patient at risk because of the participation in the trial; or diseases which may influence the results of the study or the patient’s ability to take part in it.
14. Patient who does not maintain regular day/night, waking/sleeping cycles (e.g., night shift workers will be excluded).
15. Patient who intends to use any concomitant medication not permitted by this protocol or who have not undergone the required washout period for a particular prohibited medication.
16. Patient who is 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. Patient who is unable to properly use a dry powder or pMDI inhaler device and/or to perform acceptable and reproducible spirometry measurements as per the ATS/ERS standards (Standardisation of lung function test, 2005 18).
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 having participated in a previous clinical trial with aclidinium bromide (Almirall product code LAS34273) will be allowed to participate in this study provided that the above criterion is fulfilled. This circumstance will be specifically recorded on the eCRF).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Variable:
Change from baseline in the normalised FEV1 area under the curve over 12-hour (AUC 0-12) after 4 weeks of treatment.
Secondary Efficacy Variables:
· Change from baseline in the trough FEV1 after 4 weeks of treatment, where the trough FEV1 is defined as the average of the best technically acceptable FEV1 values measured at 23 and 24hours after the last IMP administration.
· Change from baseline in the peak FEV1 after 4 weeks of treatment, where the peak FEV1 is defined as the maximum of the technically acceptable FEV1 values over the first 3 hours after the last IMP administration.
· Change from baseline in the normalised FEV1 area under the curve over 3-hour (AUC 0-3) and over 6-hour (AUC 0-6) after 4 weeks of treatment.
Additional Efficacy Variables:
FEV1
· Change from baseline in the trough FEV1 after 2 weeks of treatment.
· Change from baseline in the peak FEV1 after 2 weeks of treatment.
· Change from baseline in the normalised FEV1 AUC 0-3 after 2 weeks of treatment.
· Change from baseline in the normalised FEV1 area under the curve over 24-hour (AUC 0-24) and between 12 and 24 hours (AUC 12-24) after 4 weeks of treatment.
· Change from baseline in FEV1 at each time point after 4 weeks of treatment.
· Time to peak FEV1 defined as the time interval between the time of last IMP administration and the time of the observed peak FEV1, after the first IMP administration and after 2 and 4 weeks of treatment.
FVC and IC
· Change from baseline in the normalised FVC and IC AUC 0-12, AUC 0-24 and AUC 12-24 after 4 weeks of treatment.
· Change from baseline in the normalised FVC and IC AUC 0-3 after 2 and 4 weeks of treatment.
· Change from baseline in the trough FVC after 2 and 4 weeks of treatment where the trough FVC is defined as the average of the best technically acceptable FVC values measured at 23 and 24 hours after the IMP administration.
· Change from baseline in the trough IC after 2 and 4 weeks of treatment, where the trough IC is defined as the average of technically acceptable IC values measured at 23 and 24 hours after the IMP administration.
· Change from baseline in the peak FVC and IC after 2 and 4 weeks of treatment, where the peak FVC and IC are defined as the maximum of the technically acceptable FVC and IC values over the first 3 hours after the IMP administration.
Other efficacy variables
· Averages of the day and night use of rescue medication over the last 2 weeks of treatment.
· Change from baseline in the average of daily COPD symptom scores (breathlessness, cough, sputum and nighttime symptoms) over the last 2 weeks of treatment.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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