| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| 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 establish the olodaterol dose in the DFDC EIS with BI 54903 which is equivalent in bronchodilator efficacy and systemic exposure to the reference dose in AIS (5μg) in free combination with BI 54903 EIS. |
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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 |
Optional pharmacokinetic sub-study :
Blood and urine samples of approximately 42 patients (to receive PK data from at least 36 patients) will be collected and PK parameters of olodaterol evaluated.
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| E.3 | Principal inclusion criteria |
1. All patients must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and local legislation prior to trial related procedures, which includes medication washout and restrictions.
2. Male or female patients aged at least 18 to 75 years.
3. All patients must have a diagnosis of asthma by a physician at least three months prior to screening Visit 1. The diagnosis of asthma must be according to the 2009 Global Initiative for Asthma (GINA) Guidelines (P10-03196 ). The initial diagnosis of asthma must have been made before the age of 40 years.
4. All patients must have been on maintenance treatment with a low or medium dose ICS with or without LABA, stable dose of inhaled corticosteroids (see Appendix 10.4) (alone or in a fixed combination with a LABA) for at least for 6 weeks prior to Visit 1.
5. All patients must have at Visit 1 (screening) an ACQ-6 (see Appendix 10.5) mean score of < 1.5.
6. All patients must meet the following spirometric guidelines before randomisation:
a. Pre-bronchodilator clinic measured FEV1 ≥50% and ≤90% of predicted normal prior to randomisation (measured ≥6 hours of the last use of short acting bronchodilator) at the end of the run in period (Visit 2). Predicted normal values will be calculated according to ECSC [R94-1408] (see Appendix 10.4). The spirometer used to assess lung function (MasterScope® CT) will be programmed with the equation to calculate the predicted normal values. Visit 2 may be rescheduled twice within 7 days if FEV1 is not within the range ≥50% predicted and ≤90% predicted.
b. FEV1 reversibility: Improvement in FEV1 ≥12% above baseline and an absolute change of at least 200 ml within 15-30 minutes after administration of 400 μg salbutamol HFA MDI. Reversibility testing must occur at the end of run-in period at Visit 2 (see Appendix 10.4). If post-bronchodilator FEV1 at Visit 2 is not greater than 12% and 200 ml of prebronchodilator FEV1, Visit 2 can be re-scheduled twice within 7 days.
7. Patients must be never-smokers or ex-smokers with a smoking history of less than 10 pack-years (see Appendix 10.4 for calculation) and smoking cessation at least one year prior to screening (Visit 1).
8. Patients must be able to use the Respimat® inhaler (Appendix 10.1) and metered dose inhaler (Appendix 10.2) correctly in the opinion of the investigator.
9. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of paper diary. |
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| E.4 | Principal exclusion criteria |
1. Patients with a significant disease other than asthma.
2. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patient's ability to participate in the trial.
3. Patients with a clinically relevant abnormal screening (Visit 1) haematology or blood chemistry if the abnormality defines a significant disease as defined in exclusion criterion 1.
4. Patients with a recent history (i.e. six months or less) of myocardial infarction.
5. Patients who have been hospitalised for cardiac failure during the past year.
6. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
7. Patients with lung diseases other than asthma (e.g. COPD).
8. Patients with known active tuberculosis.
9. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed.
10. Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion no. 1.
11. Patients with significant alcohol or drug abuse in the opinion of the investigator within the past two years.
12. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening).
13. Patients with known hypersensitivity to LABA drugs, ciclesonide, BAC, EDTA, salmeterol or any other components of the study medication delivery systems.
14. Pregnant or nursing woman.
15. Women of childbearing potential not using a highly effective method of birth control.
Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence or vasectomised partner. Barrier methods of contraception are accepted if condom or occlusive cap are used together with spermicides (e.g. foam, gel). Female patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years.
16. Patients who have taken an investigational drug within four weeks prior to Visit 1.
17. Patients who have been treated with beta-blocker medication
- within four weeks prior to Visit 1 and/or
- during the run-in period (period between Visit 1 and Visit 2).
18. Topical cardio-selective beta-blocker eye medications for non-narrow angle glaucoma
are allowed.
19. Patients who have been treated with short or long-acting anticholinergic
- within four weeks prior to Visit 1 and/or
- during the run-in period (period between Visit 1 and Visit 2).
20. Patients who have been treated with oral or patch beta-adrenergics
- within four weeks prior to Visit 1 and/or
- during the run-in period (period between Visit 1 and Visit 2)
21. Patients who have been treated with oral corticosteroids
- within four weeks prior to Visit 1 and/or
- during the run-in period (period between Visit 1 and Visit 2).
22. Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®
- within 6 months prior to Visit 1 and/or
- during the run-in period (period between Visit 1 and Visit 2).
23. Patients who have been treated with cromones
- within two weeks prior to Visit 1 and/or
- during the run-in period (period between Visit 1 and Visit 2).
24. Patients who have been treated with methylxanthines or phosphodiesterase 4
inhibitors
- within two weeks prior to Visit 1 and/or
- during the run-in period (period between Visit 1 and Visit 2).
25. Patients who have been treated with other non-approved and according to
international guidelines not recommended ’experimental’ drugs for routine asthma
therapy (e.g. TNF-alpha blockers, methotrexate, cyclosporin)
- within four weeks prior to Visit 1 and/or
- during the run-in period (period between Visit 1 and Visit 2).
26. Patients with any asthma exacerbation or any respiratory tract infection
- in the four weeks prior to Visit 1 and/or
- during the run-in period (period between Visit 1 to Visit 2).
27. Patients who have previously been randomised in this trial or are currently participating in another trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is FEV1 (AUC0-12h). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 0:05, 0:15, 01:00, 02:00, 03:00, 04:00, 06:00, 08:00, 10:00, 12:00 hours after administration of study medication. |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoint are the following:
- FEV1 (AUC0-24h), FEV1 (AUC12-24h) and peak FEV1. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
0:05, 0:15, 01:00, 02:00, 03:00, 04:00, 06:00, 08:00, 10:00, 12:00,
14:00, 22:00, 23:00, 24:00 hours after administration of study medication and 12:00, 14:00, 22:00, 23:00, 24:00 hours after
administration of study medication, respectively. |
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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 | Yes |
| 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 | 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 |
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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.8.2.4 | Number of treatment arms in the trial | 7 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 | No |
| 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 |
| Canada |
| Croatia |
| Russian Federation |
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| 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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| End of trial : last visit last subject (last visit 8) |
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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 | 15 |
| 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 | 15 |
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