| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients with stable moderate to severe chronic obstructive pulmonary disease (COPD) will be included. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 11.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009033 |
| E.1.2 | Term | <Manually entered code. Term in E.1.1> |
|
| 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 evaluate the efficacy of inhaled aclidinium bromide 400 μg BID in moderate to severe COPD patients.
• To assess the safety and tolerability of multiple doses of inhaled aclidinium bromide 400 μg BID in the same target population. |
|
| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males and non-pregnant, non-lactating females aged ≥ 40. Women of childbearing potential are allowed to enter the trial ONLY if they use one medically approved (i.e., mechanical or pharmacological) contraceptive measure. A female is considered to be of childbearing potential unless she has had a hysterectomy, is at least one year post-menopausal or has undergone tubal ligation. All women of childbearing potential must have a negative pregnancy test at the screening
visit. For those females of childbearing potential who are unwilling to use contraceptive measures, they must provide a signed statement ensuring that they will not get pregnant throughout the study.
2. Patients with a clinical diagnosis of COPD, according to the GOLD guidelines:
(http://www.goldcopd.com) and stable airway obstruction.
3. Patients with a post-salbutamol FEV1 equal to or greater than 30% of the predicted value and less than 80% of the predicted value (i.e., 30% ≤ 100xobserved post-salbutamol FEV1/ predicted FEV1 <80%) FEV1 at screening visit will be measured between 10-15 min post inhalation of 400 μg of salbutamol. Predicted normal values to be used for calculation purposes are to be based on
European Community for Steel and Coal predicted values.
4. Post-salbutamol FEV1/FVC < 70% at screening visit (i.e,. 100xpost-salbutamol FEV1/FVC < 70%).
5. Current, or ex-cigarette smokers 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-years history).
Patients smoking other tobacco types will not be allowed, unless they meet the cigarette criterion as well.
6. Patients 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. Patients who are 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 to them.
|
|
| E.4 | Principal exclusion criteria |
1. History or current diagnosis of asthma.
2. A respiratory tract infection (including the upper respiratory tract) or COPD exacerbation in the six weeks prior to the screening visit. Patients who develop a respiratory tract infection or exacerbation during the screening period will be discontinued from the trial prior to randomisation.
3. Patients who have been hospitalised for an acute COPD exacerbation in the 3 months prior to
screening visit.
4. Use of long-term oxygen therapy (≥ 15 hours/day).
5. Patients with a body mass index (BMI) ≥ 40 kg/ m2.
6. Patients who have 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 respiratory conditions defined as but not limited to:
• 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 any 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 pulmonary rehabilitation or a thoracotomy during the trial. Patients on a stable pulmonary rehabilitation program prior to entry and anticipated to be stable throughout the study can be enrolled.
• Lung cancer
8. Clinically significant cardiovascular conditions defined as but not limited to:
• Myocardial infarction during the last 6 months.
• Unstable arrhythmia which has required changes in the pharmacological therapy or other intervention during the last 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.
• Thoracic surgery within the previous 24 months.
9. Patients for whom the use of anticholinergic drugs is contraindicated:
- Patients with a known symptomatic prostatic hypertrophy and/or bladder neck obstruction.
Patients with a diagnosis of these conditions but without symptoms due to stable concomitant medication for its treatment are allowed to enter trial.
- Patients with narrow-angle glaucoma.
10. Patients 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.
11. QTc [calculated according to Bazett’s formula (QTc=QT/RR1/2) above 470 milliseconds in the ECGs performed at screening visit.
12. Patients who can not perform repeatable spirometry attempts at the screening visit (as stated in section 11.3.2.1 of the protocol).
13. History of untoward reactions to inhaled anticholinergics, sympathomimetic amines or inhaled medication or any component thereof (including report of paradoxical bronchospasm).
14. Patients unable to properly use a dry powder or pMDI inhaler device or unable to perform acceptable spirometry.
15. Clinically relevant abnormalities laboratory, ECG parameters (other than QTc), or physical examination results at the screening evaluation that in the investigator’s opinion, preclude study participation.
16. Patients who intend to use any concomitant medication not permitted by this protocol or who have not undergone the required washout period for a particular prohibited medication (see section 10.3.2 of the protocol).
17. Patients with a history of drug and/or alcohol abuse or addiction during the previous 2 years that may prevent compliance with trial activities.
18. Treatment 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.
19. Patients who do 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.
20. Patients who have participated in other studies involving aclidinium bromide.
21. Vulnerable subjects (e.g. persons kept in detention).
22. Patients who are unlikely to be co-operative, take their medication, complete their patient diary or attend the clinic at the required times. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary variable:
Change from baseline in normalised FEV1 area under the curve over the 12-h period immediately after morning IMP administration, AUC0-12, at Day 15 on treatment
The secondary efficacy variables will be the following:
1) Change from baseline in normalised FEV1 AUC0-12 at Day 1 on treatment
2) Change from baseline in normalised FVC AUC0-12 at Days 1 and 15 on treatment
3) Change from baseline in normalised FEV1 AUC0-24at Days 1 and 15 on treatment
4) Change from baseline in normalised FVC AUC0-24 at Days 1 and 15 on treatment
5) Change from baseline in normalised FEV1 AUC12-24 at Days 1 and 15 on treatment
6) Change from baseline in normalised FVC AUC12-24 at Days 1 and 15 on treatment
7) Change from baseline in morning pre-dose FEV1 at Days 1 and 15 on treatment
8) Change from baseline in morning pre-dose FVC at Days 1 and 15 on treatment
9) Change from baseline in evening pre-dose FEV1 at Days 1 and 15 on treatment
10) Change from baseline in evening pre-dose FVC at Days 1 and 15 on treatment
11) Change from baseline in FEV1 after 23 and 24 hours of morning dosing at Day 15 on treatment
12) Change from baseline in FVC after 23 and 24 hours of morning dosing at Day 15 on treatment
13) Change from baseline in morning peak FEV1 at Days 1 and 15 on treatment
14) Change from baseline in morning peak FVC at Days 1 and 15 om treatment
15) Change from baseline in evening peak FEV1 at Days 1 and 15 on treatment
16) Change from baseline in evening peak FVC at Days 1 and 15 on treatment
17) Change from baseline in FEV1 at each specific time-point at Days 1 and 15 on treatment
18) Change from baseline in FVC at each specific time-point at Days 1 and 15 on treatment.
19) Change from baseline in day and night use of relieve medication recorded by the patient (number of puffs) at Weeks 1 and 2 on treatment
20) Change from baseline in COPD symptom scores at Weeks 1 and 2 on treatment |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | Yes |
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
|
| The end of the trial is defined as the last visit of the last patient. |
|
| 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 | 5 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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