| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Twenty-four moderate to severe COPD patients will be included in the study. |
|
| 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 | 10010952 |
| E.1.2 | Term | COPD |
|
| 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, in moderate to severe Chronic Obstructive Pulmonary Disease (COPD) patients, the pharmacokinetics of:
a) Formoterol 12 µg delivered by Foradil® via Aerolizer® (AER), once a day (one puff) for one day.
b) Formoterol 12 µg delivered by Foradil® via Aerolizer® (AER), twice a day (one puff twice a day) for one day.
c) Formoterol 12 µg delivered by Almirall Inhaler (ALM), once a day (one puff) for one day.
d) Fixed Dose Combination (FDC) of formoterol 12 µg + aclidinium bromide 200 µg delivered by Almirall Inhaler (ALM), once a day (one puff) for one day.
|
|
| E.2.2 | Secondary objectives of the trial |
| To assess the safety, tolerability and effects on lung function after one single day of therapy (qd or bid) of the above mentioned 4 treatments |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult caucasian male and non-pregnant, non-lactating female patients aged between 40 and 80 years, both inclusive, with stable moderate to severe COPD. Women of childbearing potential are allowed to enter the trial ONLY if they use a medically approved (mechanical or pharmacological) contraceptive measure. A female is considered to be of childbearing potential unless she has had an hysterectomy, is at least one year post-menopausal or has undergone tubal ligation. All women of childbearing potential must have a negative pregnancy test in serum at screening.
2. Clinical diagnosis of moderate to severe COPD (stages II and III according to the 2006 GOLD classification), in stable conditions (no COPD exacerbation within the previous 6 weeks).
3. Screening FEV1 value of 30 =< FEV1 < 80% of the predicted normal value (i.e, 100 x observed post-salbutamol FEV1 / predicted FEV1), measured between 30-45 minutes post-inhalation of 400 mcg of salbutamol.
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).
4. Post-salbutamol FEV1 / FVC < 70% at screening.
5. Presence of COPD symptoms and FEV1 values at the time of randomisation remaining stable compared to Screening Visit, according to the investigators criteria.
6. Current or ex-smokers with a 10 pack-yrs smoking history.
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 cigarretes a day and has smoked for 10 years would have a 20 pack-year smoking history (40 cigarretes per day / 20 cigarretes per pack = 2; 2 x 10 years of smoking = 20 pack-year history).
Patients smoking other tobacco types will be allowed if they meet the cigarette criterion as well.
7. No clinically relevant abnormal physical findings or results of laboratory at screening examination, except those related with COPD.
8. No clinically relevant values in the results of laboratory screening examination, except those related with COPD.
9. No abnormalities in the screening 12-lead ECG, except those considered to be not clinically relevant, as determined by the investigator. QT and QTc [calculated according to Bazett’s formulae (QTc=QT [msec] / RR[sec]1/2), as indicated in the paper tracing generated by the equipment used to record the ECGs] lower than 500 milliseconds for males and females, and lower than or equal to 450 and 470 milliseconds for males and females, respectively, in the ECGs performed at screening and before each IMP administration.
10. Eligibility and ability to participate in the trial and consent to do so in writing after the purpose and nature of the investigation have been explained |
|
| E.4 | Principal exclusion criteria |
1. Presence of clinically significant diseases other than COPD, which may either put the patient at risk because of participation in the trial, or diseases which may influence the results of the study or the patient’s ability to take part in it.
2. Diagnosis of current or recent (less than 2 years) symptoms of asthma, allergic rhinitis or atopy.
3. Presence of exercise-induced bronchospasm, pulmonary diseases or history of thoracic surgery.
4. Presence of a respiratory tract infection (including the upper respiratory tract) or COPD exacerbation in the 6 weeks prior to screening. Patients who develop a respiratory tract infection or exacerbation during the run-in period will be discontinued from the trial prior to randomisation.
5. Hospitalisation for an acute exacerbation in the 3 months prior to screening.
6. Eosinophil count 600 cells / mm3.
7. Evidence of contraindicated use of anticholinergic drugs such as known symptomatic prostatic hypertrophy, bladder neck obstruction or narrow-angle glaucoma.
8. Use of long-term oxygen therapy (≥ 15 hours/day).
9. Presence of any clinically significant respiratory conditions defined as:
・ 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 pulmonary rehabilitation or a thoracotomy during the trial.
10. Presence of any clinically significant cardiovascular conditions defined as:
・ 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.
・ Arterial hypertension not sufficiently controlled by antihypertensive treatment (RR systolic > 170 mmHg; RR diastolic > 95 mmHg).
・ Clinically relevant tachycardia (heart rate>100 bpm) or bradycardia (heart rate < 45 bpm).
11. Recent (less than 12 months) stroke.
12. Unstable diabetes mellitus.
13. History of untoward reactions to inhaled anticholinergics, 2-agonists, sympathomimetic amines or inhaled medication or any component thereof (including report of paradoxical bronchospasm).
14. Intention to use any concomitant medication not permitted by this protocol or insufficient washout period for a particular prohibited medication (see section 10.3).
15. Treatment with β2-antagonists (including eye drops).
16. Treatment with drugs that may modify QT interval (non-potassium sparing diuretics, MAOIs, TCAs, SSRIs, antipsychotic agents, serotonin receptor agonists, macrolide antibiotics, fluoroquinolone antibiotics, anti-protozoal antibiotics and antihypertensive agents).
17. Loss of more than 400 mL of blood within the previous 3 months, or more than 250 mL within the month before entering the trial.
18. Positive test for hepatitis B surface antigen or HBc, HIV or hepatitis C antibodies. Patients vaccinated for Hepatitis B and not infected from the disease can take part in the trial.
19. Inability to properly use a dry powder or pMDI inhaler device or to perform a spirometry.
20. History of drug and/or alcohol abuse during the last 2 years, that may interfere with the trial activities compliance.
21. Inability to communicate adequately with investigators and to comply with protocol requirements.
22. Treatment with any Investigational Medicinal Product (IMP) within 6 weeks prior to screening or the equivalent time to 5 half-lives of the IMP, whichever is longer.
23. Poor venous access.
24. Non maintenance of regular day/night, waking/sleeping cycles (e.g., night shift workers will be excluded).
25. Likelihood of not being co-operative, not taking the medication, not completing the Paper Diary Cards or not attending the clinic at the required times |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Relative bioavailability of formoterol 12 µg delivered by Almirall Inhaler (ALM) qd versus formoterol 12 µg delivered by Aerolizer (AER) qd.
- Relative formoterol bioavailability of 12 µg + aclidinium bromide 200µg ALM qd versus 12 µg ALM qd.
- Relative formoterol bioavailability of 12 µg + aclidinium bromide 200µg ALM qd versus 12 µg AER qd.
- Relative formoterol bioavailability of 12 µg ALM qd versus 12 µg AER bid.
- Relative formoterol bioavailability of 12 µg + aclidinium bromide 200 µg ALM qd versus 12 µg AER bid.
|
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| 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 |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Formoterol Aerolizer and Formoterol Almirall Inhaler |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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
|
| End of the trial is definied as last visit/last patient out. |
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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 | |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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