E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with severe persistent asthma who are still symptomatic despite being treated with high-dose inhaled corticosteroids and long-acting beta2-agonists. Additional asthma treatments are allowed including systemic corticosteroids at stable doses (5mg/day) and others (like montelukast, omalizumab, etc.). |
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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 | 10049106 |
E.1.2 | Term | Asthma chronic |
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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 |
Evaluate the long term efficacy of the IMP compared to placebo with regard to lung function and patient-reported outcomes, including exacerbations, quality of life and asthma control Combine data with twin trial 205.416 (2008-001413-14) to take advantage of higher sample size |
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E.2.2 | Secondary objectives of the trial |
Evaluate the long term safety of the IMP compared to placebo Evaluate effects on health care resource utilisation (health economic analysis) Evaluate pharmacogenomics and impact on efficacy (B16/B27 of beta2 receptor) (participation voluntarily with a separate consent and independent from trial consent) Evaluate pharmacokinetics in urine and blood in a subset of app. 40 patients at selected sites Evaluate 24h lung function in a subset of patients at selected sites |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. signed and dated Informed Consent Form consistent with ICH-GCP guidelines and local legislation prior to participation in the trial 2. Male or female patients aged at least 18 years but not more than 75 years. 3. At least a 5-year history of asthma (GINA 2007) 4. Diagnosis of asthma before the patient’s age of 40. 5. All patients must have a diagnosis of severe persistent asthma and must be symptomatic despite treatment with high, stable doses of inhaled corticosteroids and a long-acting beta adrenergic agent 6. All patients must have been on treatment with a high, stable dose of inhaled corticosteroids and a long-acting beta2 adrenergic agent for at least 4 weeks before the screening visit. Additional sustained release theophylline and/or leukotriene modifier and/or omalizumab (Xolair®) and/or oral glucocortico-steroids are allowed in stable doses. 7. ACQ mean score of >= 1.5 at screening and randomisation visit 8. History of one or more asthma exacerbation in the past year that required an addition or increased dose of systemic corticosteroids. 9. Post bronchodilator (i.e. 30 minutes after inhalation of 4 puffs of 100 μg salbutamol/albuterol) FEV1 ≤ 80% of predicted normal and FEV1 ≤ 70% of FVC 10. Variation of FEV1 at Visit 1 and Visit 2 must be within +/- 30%. 11. Never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment and who have a smoking history of less than 10 pack years. |
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E.4 | Principal exclusion criteria |
1. Any significant disease other than asthma which 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. Clinically relevant abnormal screening haematology or blood chemistry if the abnormality defines a significant disease 3. Recent history (i.e. six months or less) of myocardial infarction. 4. Hospitalisation for cardiac failure during the past year. 5. Unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year. 7. Lung diseases other than asthma (e.g. COPD). 8. Known active tuberculosis. 9. Alcohol or drug abuse within the past two years. 10. Past thoracotomy with pulmonary resection. 12. Oral corticosteroid medication at stable doses >=5 mg prednisolone 13. Known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution. 14. Pregnant or nursing women. 15. Women of childbearing potential not using a highly effective method of birth control. 16. Patients who have taken an investigational drug within four weeks or six half-lives 17. Patients who have been treated with tiotropium within four weeks 18. Patients who have been treated with beta-blocker medication within four weeks 19. Patients who have been treated with oral beta-adrenergics within four weeks 20. 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 21. Any asthma exacerbation in the four weeks prior 22. Any respiratory tract infection in the four weeks prior 23. Patients who have previously been randomised in this trial or in the respective twin trial or are currently participating in another trial. 24. Known narrow-angle glaucoma 25. People who are serving a custodial sentence, or who are detained under local mental health legislation/regulations. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The two co-primary efficacy variables of this individual trial are the peak FEV1 within 3 hours post-dosing and the trough FEV1.
1. The first co-primary efficacy endpoint is the peak FEV1 response (within 3 hours post dosing) determined after a treatment period of 24 weeks. Peak FEV1 response is defined as the change from baseline in peak FEV1. Baseline is the pre-treatment FEV1 measured at Visit 2 in the morning 10 minutes prior to the morning dose of patient’s usual asthma medication and first dose of trial medication.
2. The second co-primary endpoint will be trough FEV1 response determined after a treatment period of 24 weeks. Trough FEV1 is defined as the FEV1 measured at the -10 minute time point at the end of the dosing interval (24 hours post drug administration). Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline FEV1 will be the pre-treatment FEV1 measured at Visit 2 in the morning 10 minutes prior to the morning dose of patient’s usual asthma medication and first dose of trial medication.
One additional co-primary endpoint, the time to first severe asthma exacerbation after 48 weeks, is considered primary only in the analysis of pooled data from the two twin trials 205.416 and 205.417. The two trials will be combined for these analyses to obtain adequate numbers of patients. 3. Time to first severe asthma exacerbation during the 48-week treatment period. This endpoint will be evaluated on pooled data only. An additional report for the pooled data will be prepared.
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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.8.3 |
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 | 15 |
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 |
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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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Protocol-section 6.2.3 - The Last-Patient-Out date of the overall trial will be determined by the time point when the last patient finished the complete trial including the 48-week treatment period and 30 days follow-up period.
Protocol-section 8.6 provides information on discontinuations of the trial by the sponsor, e.g. Failure to meet expected enrolment goals overall or any efficacy/safety information that could significantly affect continuation of the trial. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |