| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderate persistent asthma |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003555 |
| E.1.2 | Term | Asthma bronchial |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 and safety of three doses of tiotropium inhalation solution (1.25, 2.5 and 5.0 μg) delivered ex mouthpiece by the Respimat® inhaler in patients with moderate persistent asthma once daily in the evening on top of inhaled corticosteroids. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives, assessed in patient subgroups, are: to evaluate the 24 hour exposure to tiotropium and to demonstrate 24 hour bronchodilator efficacy and safety of tiotropium in patients with moderate persistent asthma when administered 1.25μg, 2.5 μg and 5.0 μg tiotropium inhalation solution ex mouthpiece once daily in the evening. Not performed in Austria. |
|
| E.2.3 | Trial contains a sub-study | No |
| 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 participation in the trial (i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test at Visit 1).
2. Male or female patients aged between 18 and 75 years (at date of informed consent).
3. All patients must have at least a 3 month history of asthma at the time of enrolment into the trial. The diagnosis should be confirmed at Visit 1 by fulfilling inclusion criterion no. 5.
4. The initial diagnosis of asthma must have been made before the patient's age of 40.
5. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (15 to 30 minutes after 4 puffs of 100 μg salbutamol) resulting in a FEV1 increase of ≥ 12% and ≥ 200mL (see Appendix 10.3).
6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (as detailed in Appendix 10.3) (alone or in a fixed combination with a LABA or SABA) for at least 4 weeks prior to Visit 1.
7. All patients must be symptomatic at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an ACQ (see Appendix 10.4) mean score of ≥ 1.5.
NOTE: If the patient is not eligible due to the predefined score at Visit 1, the patient should not be further evaluated. If the patient is not eligible due to the predefined score at Visit 2, the patient’s Visit 2 can be repeated once for further assessment (see section 6.1).
8. All patients must have a pre-bronchodilator FEV1 ≥ 60% and ≤ 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to ECSC [R94-1408] (see Appendix 10.3).
9. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30% (see Appendix 10.3 for calculation).
10. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack years (see Appendix 10.3 for calculation).
11. Patients must be able to use the Respimat® inhaler (Appendix 10.1) correctly.
12. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of electronic diary/peak flow meter (diary compliance of at least 80% is required; refer to section 6.1 for instructions). |
|
| E.4 | Principal exclusion criteria |
1. Patients with a significant disease other than asthma (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.)
2. 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.
3. Patients with a recent history (i.e. six months or less) of myocardial infarction.
4. Patients who have been hospitalised for cardiac failure during the past year.
5. Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
6. Patients with lung diseases other than asthma (e.g. COPD).
7. Patients with known active tuberculosis.
8. 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.
9. 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.
10. Patients with known moderate to severe renal impairment (as judged by the investigator).
11. Patients with known narrow angle glaucoma or any other disease where anticholinergic treatment is contraindicated.
12. Patients with significant symptomatic prostatic hyperplasia or bladder-neck obstruction (to the discretion of the investigator). Patients whose symptoms are controlled on treatment may be included.
13. Patients with significant alcohol or drug abuse within the past two years (to the discretion of the investigator).
14. Patients who are currently in a pulmonary rehabilitation program or have completed pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening) or who will start a rehabilitation program during the study.
15. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the study medication delivery system (Respimat®/ tiotropium inhalation solution).
16. Pregnant or nursing woman.
17. 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 (e.g. condom, diaphragma or occlusive cap) are accepted if used together with spermicides (e.g. foam, gel). Female patients will be considered to be of childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years.
18. Patients who have taken an investigational drug within four weeks prior to Visit 1.
19. Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). Topical cardio-selective beta-blocker eye medications for non-arrow angle glaucoma are allowed.
20. Patients who have been treated within four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2) with:
- the long-acting anticholinergic tiotropium (Spiriva®)
- oral or patch beta-adrenergics
- oral corticosteroids
21. Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®) within 6 months prior to Visit 1 and/or during the screening period.
22. Patients who have been treated within two weeks prior to Visit 1 and/or during the screening period with
- methylxanthines or phosphodiesterase 4 inhibitors
- cromone
23. Patients who have been treated with other non-approved and according to international guidelines not recommended ’experimental’ drugs for routine asthma therapy (e.g. TNFalpha blockers, methotrexate, cyclosporin) within four weeks prior to Visit 1 and/or during the screening period.
27. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 and/or during the screening period. Visit 1 and/or Visit 2 should be postponed in case of an asthma exacerbation or respiratory tract infection.
28. Patients who have previously been randomised in this trial or are currently participating in another trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Peak FEV1 response (within 3 hours post dosing).
Efficacy will be evaluated based on PFT measurements over 3 hours: The primary efficacy variable will be forced expiratory volume in one second (FEV1). The primary efficacy endpoint is FEV1 Peak0-3 response determined at the end of each of the four 4-week treatment periods. FEV1 Peak0-3 is defined as the maximum FEV1 measured within the first 3 h post dosing. FEV1 Peak0-3 response is defined as the difference of FEV1 Peak0-3 and the FEV1 baseline measurement. Baseline is the pre-treatment FEV1 measured at visit 2 in the evening 10 minutes prior to administration of the first dose of study medication. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
|
| 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 trial is the last visit of the last subject undergoing the trial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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