E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
moderate persistent asthma |
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E.1.1.1 | Medical condition in easily understood language |
moderate persistent asthma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003553 |
E.1.2 | Term | Asthma |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 |
This is a confirmatory phase III trial to evaluate efficacy and safety of a 48-week treatment with two doses (2.5 μg and 5 μg) of tiotropium bromide compared to placebo administered via the Respimat® device in adolescent patients (12 to 17 years old) with moderate persistent asthma. |
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E.2.2 | Secondary objectives of the trial |
Secondary efficacy objectives include the evaluation of several additional lung function parameters, asthma control and quality of life (using questionnaires), use of rescue medication and evaluation of asthma exacerbations. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. All patients and their parents (or legally accepted caregiver) must sign and date an informed consent consistent with ICH-GCP guidelines and local legislation prior to participation in the trial.
2. Male or female patients between 12 and 17 years of age.
3. All patients must have at least a 3 months history of asthma at the time of enrolment into the trial.
4.All patients must have been on maintenance treatment with inhaled corticosteroids at a stable medium dose.
5.All patients must be symptomatic (partly controlled) at Visit 1 (screening) and prior to randomisation at Visit 2 as defined by an ACQ mean score of ≥ 1.5.
6. All patients must have a pre-bronchodilator FEV1 ≥60% and ≤ 90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%.
7. All patients must have an increase in FEV1 of ≥ 12% and ≥ 200 mL 15 to 30 minutes after 400 μg salbutamol (albuterol) at Visit 1.
8. All patients should be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment.
9. Patients should be able to use the Respimat® inhaler correctly.
10. Patients must be able to perform all trial related procedures including technically acceptable spirometric manoeuvres, according to ATS/ERS standards and the use of the electronic diary/peak flow meter.
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E.4 | Principal exclusion criteria |
1. Patients with a significant disease other than asthma.
2. Patients with clinically relevant abnormal screening haematology or blood chemistry.
3. Patients with a history of congenital or acquired heart disease, and/or have been hospitalised for cardiac syncope or failure during the past year.
4.Patients with any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year.
5.Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years.
6. Patients with lung diseases other than asthma (e.g. CF). In case of ex-premature infants, a history of significant bronchopulmonary dysplasia will be regarded as exclusion criterion.
7. Patients with known active tuberculosis.
8. Patients with significant alcohol or drug abuse within the past two years.
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 who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1).
11. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution.
12. Pregnant or nursing adolescent female patients
13. Sexually active female patients of child-bearing potential not using a highly effective method of birth control.
14. Patients who have taken an investigational drug within 4 weeks prior to Visit 1.
15. Patients who have been treated with long-acting anticholinergics
16. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation.
17. Patients who have been treated with Anti-IgE treatment within the last 6 months prior to screening.
18. Patients who have been treated with systemic (oral or intravenous) corticosteroids within 4 weeks prior to screening (Visit 1).
19. Patients who have been treated with long-acting theophylline preparations within 2 weeks prior to screening (Visit 1) or during the run-in period
20. Patients who have been treated with other non-approved and according to international guidelines not recommended “experimental” drugs for routine asthma therapy .
21. Patients with any acute asthma exacerbation or respiratory tract infection in the 4 weeks prior to Visit 1.
22. Patients requiring 10 or more puffs of rescue medication (salbutamol/albuterol MDI) per day on more than 2 consecutive days during the run-in period.
23. Patients who have previously been randomised in this trial or are currently participating in another study.
24. Patients who are being treated with oral beta-blocker medication.
25. Patients with a known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated.
26. Patients with renal impairment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is FEV1 peak0-3 response determined at the end of the 24 weeks treatment period. FEV1 peak0-3 is defined as the maximum FEV1 measured within the first three hours post dosing. FEV1 peak0-3 response is defined as the difference of FEV1 peak0-3 and the baseline FEV1 measurement. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Trough FEV1
2. FVC peak0-3 (within 3 hours post dosing) and trough FVC
3. FEV1 (AUC0-3) and FVC (AUC0-3). AUC=area under the curve
4. mean forced expiratory flow between 25% and 75% of the FVC (FEF25-75)
5. Use of PRN rescue medication.
6.Control of asthma as assessed by the Asthma Control Questionnaire (ACQ)
7. Time to first severe asthma exacerbation; time to first asthma exacerbation
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
secondary endpoints 1, 2, 3, 4 and 6: at 12 weeks, 24 weeks and 48 weeks
secondary endpoint 5: weekly means for 48 weeks |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
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.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 |
Chile |
Germany |
Hungary |
Italy |
Korea, Republic of |
Latvia |
Mexico |
Russian Federation |
Slovakia |
Spain |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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Last visit of last patient |
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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 | 1 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |