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 | 12.0 |
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, safety and tolerability of the two fixed-dose combinations of aclidinium bromide and formoterol fumarate compared to placebo, all administered twice daily in patients with moderate to severe chronic obstructive pulmonary disease (COPD). |
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E.2.2 | Secondary objectives of the trial |
To determine which of the two combinations provide the greater benefit in terms of efficacy, safety and tolerability. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adult male or non-pregnant, non-lactating female aged between 40 and 80 years old, both inclusive. Female of childbearing potential must have a negative pregnancy test at Screening and be using a medically acceptable method of contraception (either double-barrier contraception or a barrier method plus a spermicidal or hormonal agent). (A female is considered to be of childbearing potential unless she is at least 1 year postmenopausal or surgically sterile (defined as having a hysterectomy or tubal ligation)). 2. Patient with a clinical diagnosis of stable moderate to severe COPD (stages II and III) according to the GOLD 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 10-15 minutes post inhalation of 400 μg of salbutamol is 30% ≤ FEV1 <80% of the predicted normal value (i.e., 100 x Postsalbutamol FEV1/ Predicted FEV1 must be < 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)19). 5. Patient whose FEV1/FVC at the Screening Visit measured between 10-15 minutes post inhalation of 400 μg 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.
In addition, before randomisation: 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. |
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E.4 | Principal 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 defined as: • Use of long-term oxygen therapy > 15h/day, • Known active tuberculosis or history of lung cancer, • History of interstitial lung or pulmonary thromboembolic disease, • Pulmonary resection or surgery during the past 12 months, • 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, 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 on pulmonary rehabilitation program for less the 6 weeks. 6. 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. 7. Clinically significant cardiovascular conditions 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. 8. Presence of symptomatic prostatic hypertrophy and/or bladder neck obstruction. (However, patients with a diagnosis of these conditions but well-controlled, stable and without symptoms due to stable concomitant medication for its treatment are allowed to enter trial). 9. Presence of narrow-angle glaucoma. 10. 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). 11. Life expectancy of less than 1 year. 12. QTc [calculated according to Bazett’s formulae (QTc=QT/RR1/2) above 470 milliseconds in the ECG performed at Screening Visit, as indicated in the centralised reading report. 13. 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. 14. 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. 15. Patient who does not maintain regular day/night, waking/sleeping cycles (e.g., history of sleep apnoea syndrome, any disease related with sleep disturbances such as restless-legs syndrome or somnambulism). Moreover, night shift workers will be excluded. 16. 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. 17. 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. 18. Patient with any other serious or uncontrolled physical or mental dysfunction which at the discretion of the investigator could place the patient at higher risk derived from his/her participation in the study, could confound the results of the trial, or is likely to prevent the patient from complying with the requirements of the trial or completing the trial period. 19. 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 testing, 2005 18). 20. Patient with history of drug and/or alcohol abuse or addiction during the previous 2 years. 21. Patient who has previously participated in another clinical trial with any Investigational Medicinal Product (IMP) within 1 month prior to the screening visit or the equivalent time of 6 half-lives of the IMP, whichever is longer. 22. Patient who has participated in a previous clinical trial with aclidinium bromide (alone or in combination) (Almirall product code LAS34273). 23. Vulnerable subjects (e.g., persons kept in detention). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy variable: Change from baseline in normalised FEV1 area under the curve over the 12h after morning IMP administration (FEV1 AUC0-12) at Day 14. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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 | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
4 period balanced incomplete cross-over |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
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 | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
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 | 10 |
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 |