Comparison of Two Daily Dose Regimens of Tiotropium 5 µg Once Daily and Tiotropium 2.5 µg Twice Daily for 4 Weeks on Top of Maintenance Therapy With Inhaled Corticosteroid Controller Medication

A Randomised, Double- Blind, 2 Way Cross-over Study to Determine 24-hour FEV1-time Profile of Inhaled Tiotropium, Delivered Via the Respimat Inhaler, After 4 Weeks of Once Daily [5 mcg in the Evening (2 Actuations of 2.5 mcg)] or Twice Daily [2.5 mcg in the Morning and Evening (2 Actuations of 1.25 mcg)] Administration in Patients With Moderate Persistent Asthma.

Determine the 24-hour FEV1-profile of tiotropium solution for inhalation after 4 weeks treatment periods of 5 mcg tiotropium administered once daily in the evening and 2.5 mcg tiotropium administered twice daily (morning and evening). In addition compare the 24 hours pharmacokinetic profile of 5 mcg tiotropium administered once daily and 2.5mcg tiotropium administered twice daily in pharmacokinetic sub-investigation.

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.
2. Male or female patients aged at least 18 years at Visit 0 but not more than 75 years at Visit 0.
3. All patients must have at least a 3 months history of asthma at the time of enrolment (signing ICF) into the trial. The initial diagnosis of asthma must have been made before the patient's age of 40.
4. All patients must have a pre-bronchodilator FEV1 = 60% predicted and = 90% of predicted normal at Visit 1.Variation of absolute pre-bronchodilator FEV1 values at Visit 1 and Visit 2 must be within ± 30%.
5. Patient's diagnosis of asthma has to be confirmed at Visit 1 with bronchodilator reversibility (ie 10 minutes prior to and 15-30 minutes after inhalation of 400 µg salbutamol) defined as an FEV1 increase of = 12% and = 200 mL.
6. All patients must have a diagnosis of moderate persistent asthma and must be symptomatic despite their current maintenance treatment with medium doses of ICS.
7. All patients must be symptomatic at Visit 1and Visit 2 as defined by an ACQ mean score of = 1.5.
8. All patients must have maintenance treatment with stable medium daily dose of ICS for at least 4 weeks prior to Visit 1.
9. 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 at Visit 0.
10. Patients must be able to use the Respimat inhaler correctly.
11. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the AM3 (e-diary) compliance of at least 80% is required.
12. Patients taking a chronic pulmonary medication allowed by the study protocol must be willing to continue this therapy for the entire duration of the study (exception: times of acute disease deterioration).

Exclusion criteria:

1. 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 at Visit 1 if the abnormality defines a significant disease as defined in exclusion criterion no. 1.

3. Patients requiring more than 12 puffs of rescue medication (salbutamol MDI) per 24 hours for more than 2 consecutive days between Visit 1 and Visit 2 (screening period).

4. Patients with a recent history (ie six months or less) of Acute Coronary Syndrome (STEMI, non-STEMI, Unstable Angina Pectoris) prior to Visit 1 (screening).

5. Patients who have been hospitalised for cardiac failure during the past year prior to Visit 1 (screening).

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 prior to Visit 1 (screening).

7. Patients with lung diseases other than asthma (eg 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 prior to Visit 1 (screening). 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 on Investigator's assessment within the past two years prior to Visit 1 (screening).

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 anticholinergic drugs, BAC, EDTA or any other components of the study medication delivery systems.

14. Pregnant or nursing women, including female patients with positive ß-HCG test at Visit 1.

15. Female patients of child-bearing potential not using highly effective method of birth control. As defined in ICH (M3) [R09-1400], note 3, highly effective methods of birth control are defined as those, alone or in combination, that result in a low failure rate (ie less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised partner. Barrier contraceptives (eg male condom or diaphragm) are acceptable if used in combination with spermicides (eg 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.

16. Patients who have been treated with restricted medication prior to Visit 1 and/or during the screening period.

17. 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. Refer to Section 6.1 for information on re-scheduling of visits.

18. Patients who are currently participating in another trial or who have been participating in another trial within one month prior to Visit 0, and patients who have previously been randomised in this trial.