| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderate persistent asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 14.0 |
| 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 |
|
| 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 |
Demonstrate 24 hour bronchodilator efficacy and safety of tiotropium 5 μg
administered once daily (in the evening) delivered by the Respimat® inhaler for four
weeks in comparison to placebo. Evaluate efficacy and safety of tiotropium 2.5 μg
administered twice daily delivered by the Respimat® inhaler for four weeks in
comparison to placebo and to tiotropium 5 μg administered once daily (in the
evening) delivered by the Respimat® inhaler for four weeks in patients with moderate persistent asthma. |
|
| E.2.2 | Secondary objectives of the trial |
| The effect on asthma control, nighttime awakenings and rescue medication use will be evaluated. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Outpatients with a history of asthma and a current diagnosis of moderate persistent asthma (according to GINA guideline) are eligible for inclusion if they fulfil all the inclusion criteria and none of the exclusion 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 at least 18 years but not more than 75 years.
All patients must have at least a 3 months history of asthma at the time of enrolment into the trial. The diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (15 minutes after 400 μg salbutamol) resulting in a FEV1 increase of ≥ 12% and ≥ 200mL.
4. The initial diagnosis of asthma must have been made before the patient's age of 40.
5. All patients must have a diagnosis of moderate persistent asthma and must be
symptomatic despite their current maintenance treatment with medium doses of inhaled corticosteroids.
6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (alone or in a fixed combination with a
LABA or SABA) for at least 4 weeks prior to Visit 1.
8.All patients must have a pre-bronchodilator FEV1 ≥ 60% predicted and ≤ 90% of
predicted normal at Visit 1.Predicted normal values will be calculated according to ECSC [R94-1408].
9. All patients must have an increase in FEV1 of ≥ 12% and ≥ 200 mL 15 minutes after 400 µg salbutamol at Visit 1. NOTE: If this not achieved the reversibility test may be repeated once within two weeks. |
|
| E.4 | Principal exclusion criteria |
Patients with a significant disease other than asthma.
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.
2. Patients with a clinically relevant abnormal screening hematology or blood chemistry if the abnormalitiy defines a significant disease as defined in exclusion criterion no. 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 significant alcohol or drug abuse within the past two years.
11. 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).
12. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the study medication delivery systems.
13. Pregnant or nursing women.
14. 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 sterilised byhysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two years.
15. Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 or during the screening period. Topical cardio-selective beta-blocker eye medications for non-arrow angle glaucoma are allowed.
16. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) within four weeks prior to Visit 1 or during the screening period.
17. Patients who have been treated with oral beta-adrenergics within four weeks prior to Visit 1 or during the screening period.
18. Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 or during the screening period.
19. Patients who have been treated with anti-IgE antibodies, e.g. omalizumab (Xolair®),within 6 months prior to Visit 1 or during the screening period.
20. Patients who have been treated with cromolyn sodium or nedocromil sodium within two weeks prior to Visit 1 or during the screening period.
21. Patients who have been treated with methylxanthines within two weeks prior to Visit 1 or during the screening period.
22. Patients who have taken an investigational drug within four weeks prior to Visit 1.
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 or during the screening period.
24. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 or during the screening period.
Visit 1 and/or Visit 2 should be postponed in case of an asthma exacerbation or
respiratory tract infection.
25. Patients who have previously been randomised in this trial or are currently participating in another trial.
26. Patients who have been treated with depot corticosteroids within six months prior to Visit 1 or during the screening period.
27. Patients who have been treated with leukotriene modifiers within two weeks prior to Visit 1 or during the screening period. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable will be the forced expiratory volume in one second (FEV1).
The primary endpoint is the FEV1 area under the curve (AUC) 0-24 hours (AUC0-24h) (L) determined at the end of each 4 week treatment period. All measurements will be performed in relation to evening (p.m.) dosing |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| at the end of each 4 week treatment period |
|
| E.5.2 | Secondary end point(s) |
1. Peak expiratory flow (PEF) a.m. / p.m. at the end of each dosing interval (L/min) measured by patients at home using the AM2+® device (weekly means obtained during the last week of each period of randomised treatment will be compared).
2. FEV1 (AUC0-12h) and FEV1 (AUC12-24h) measured following each dosing determined at the end of each 4 week period of randomised treatment.
3. Peak FEV1 (L) (within 24 hours post-dose) measured following the evening trial-drug inhalation at the end of each 4 week period of randomised treatment.
4. Trough FEV1 (L) at the end of each 4 week period of randomised treatment. Trough FEV1 is defined as FEV1 value (performed at 10 minutes prior to the evening trial-drug inhalation) at the end of the dosing interval.
5. Trough forced vital capacity (FVC) (L) at the end of each dosing interval (as defined above for FEV1) determined at the end of each 4 week period of randomised treatment.
6. FVC (AUC0-12h) and FVC (AUC12-24h) and peak FVC (L) (within 24 hours post-dose) measured following each dosing determined at the end of each 4 week treatment period.
7. Individual FEV1, FVC (L) and PEF (L/min) measurements at each timepoint at visits; AUC0-24h of FVC (L) and PEF (L/min)
8. PEF variability: PEF variability (L/min) is the absolute difference between morning and evening PEF value divided by the mean of these two values (weekly means obtained during the last week of each period of randomised treatment will be compared).
9. Use of prn salbutamol rescue medication during the entire study period:
Number of puffs of rescue therapy used per day (i.e. the full 24 hour period, the daytime and the nighttime evaluated separately and together; weekly means obtained during the last week of each period of randomised treatment will be compared).
10. Weekly mean number of nighttime awakenings as assessed by the patient’s electronic diary (e-Diary incorporated in the AM2+® device) obtained during the last week of each period of randomised treatment.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. at the end of each dosing interval
2. following each dosing (at the end of each 4 week period of randomised treatment)
3. following the evening trial-drug inhalation at the end of each 4 week period of randomised treatment.
4. at the end of each 4 week period of randomised treatment.
5. at the end of each dosing interval (at the end of each 4 week period of randomised treatment).
6. following each dosing determined at the end of each 4 week treatment period.
7. measurements at each timepoint at visits;
8. weekly means (last week of each period of randomised treatment)
9. during the entire study period: per day; weekly means (last week of each period of randomised treatment)
10. Weekly mean (last week of each period of randomised treatment)
|
|
| 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 | 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.8.2.4 | 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 | 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| The end of the trial is the last visit of the last patient 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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