Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo and Salmeterol HydroFluoroAlkane (HFA) Metered Dose Inhaler (MDI) (50 mcg Twice Daily) in Patient With Moderate Persistent Asthma I

• Peak FEV1 Within 3 Hours Post-dose Response [ Time Frame: 24 weeks ]
  Peak forced expiratory volume in one second (FEV1) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
• Trough FEV1 Response [ Time Frame: 24 weeks ]
  Trough FEV1 response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
• The Responder Rate as Assessed by the ACQ From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808) [ Time Frame: 24 weeks ]

  The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period (on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)). A patient was considered to be a responder if he or she was reported with an improvement (decrease) in the ACQ total score of at least 0.5 points.

  The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment).

• Peak forced expiratory volume in one second (FEV1) response (within 3 hours post dosing) [ Time Frame: 24 weeks ]
• Trough FEV1 response [ Time Frame: 24 weeks ]
• The responder as assessed by the Asthma Control Questionnaire (ACQ) (on combined data from the two twin trials 205.418 and 205.419) [ Time Frame: 24 weeks ]

• Peak FVC Within 3 Hours Post-dose Response [ Time Frame: 24 weeks ]
  Peak forced vital capacity (FVC) response within 3 hours post-dose determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
• Trough FVC Response [ Time Frame: 24 weeks ]
  Trough FVC response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
• FEV1 Area Under Curve 0-3 Hours (AUC0-3h) Response [ Time Frame: 24 weeks ]
  Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24-week treatment. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week. FEV1 AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
• FVC Area Under Curve 0-3 Hours (AUC0-3h) Response [ Time Frame: 24 weeks ]
  Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2) determined at the end of the 24-week treatment. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. FVC AUC 0-3h was calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time (3h) to report in litres.
• Trough PEF Response [ Time Frame: 24 weeks ]
  Trough peak expiratory flow (PEF) response determined at the end of the 24-week treatment. Response was defined as change from baseline (10 minutes before the first dose of trial medication at visit 2). Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
• Total Asthma Quality of Life Questionnaire (AQLQs)) Score [ Time Frame: 24 weeks ]
  Total score from the Standardised Asthma Quality of Life Questionnaire (AQLQ(s)) determined at the end of 24-week treatment. The AQLQ(s) contains 32 questions, each question has a 7 point scale from 1 (highest intensity) till 7 (no symptoms). Total score was defined as the sum of all items divided by the number of items. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
• Total Asthma Control Questionnaire (ACQ) Score at the End of the 24-week Treatment Period [ Time Frame: 24 weeks ]
  Control of asthma as assessed by the ACQ determined at the end of 24-week treatment. The ACQ contains 7 questions, each question has a 7 point scale from 0 (no symptoms) till 6 (highest intensity). Total score was defined as the sum of all items divided by the number of items. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
• The Responder Rate as Assessed by the ACQ [ Time Frame: 24 weeks ]
  The responder rate as assessed by the Asthma Control Questionnaire (ACQ) determined at the end of the 24-week treatment period. A patient was considered to be a responder if he or she was reported with an improvement (decrease) in ACQ total score of at least 0.5 points. The ACQ total score was calculated as the mean of the responses to 7 questions and was analysed as an absolute value. The score ranges from 0 (no impairment) to 6 (maximum impairment).
• Mean Pre-dose Morning PEF (PEF a.m.) Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]
  Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
• Mean Pre-dose Evening PEF (PEF p.m.) Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]
  Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
• PEF Variability [ Time Frame: Last 7 days before week 24 visit ]
  PEF daily variability was assesed by patients at home using the AM3 device. PEF variability is the absolute difference between morning and evening PEF value divided by their mean, based on the weekly mean response at week 24. Means are adjusted for treatment, centre, week, baseline, treatment by week, and baseline by week.
• Mean Pre-dose Morning FEV1 (FEV1 a.m.) Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]
  Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
• Mean Pre-dose Evening FEV1 (FEV1 p.m.) Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]
  Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
• Mean Number of Puffs of Rescue Medication During the Entire 24-h Day Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]
  Daily use of salbutamol (albuterol) rescue medication as needed during the entire study period. Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week.
• Asthma Symptom-free Days Based on the Weekly Mean Response at Week 24 [ Time Frame: Baseline and last 7 days before week 24 visit ]
  Weekly means obtained during the last 7 days before week 24 measured by patients at home using the AM3 device. Response was defined as change from baseline. Means are adjusted for treatment, country, week, baseline, treatment by week, and baseline by week. An asthma symptom-free day was defined as a day with no reported symptoms and no use of rescue medication.
• Time to First Severe Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808) [ Time Frame: 24 weeks ]
  Time to first severe asthma exacerbation during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821).
• Time to First Asthma Exacerbation From the Two Twin Trials 205.419 (NCT01172821) and the Present 205.418 (NCT01172808) [ Time Frame: 24 weeks ]
  Time to first asthma exacerbation (including severe, non-severe; symptomatic, asymptomatic; i.e. any exacerbation) during the 24-week treatment period on combined data from the two twin trials 205.418 (NCT01172808) and 205.419 (NCT01172821)

• Peak (within 3 hours post dosing) and trough forced vital capacity (FVC) [ Time Frame: 24 weeks ]
• FEV1 (Area Under the Curve; AUC0-3h) and FVC (AUC0-3h) [ Time Frame: 24 weeks ]
• Individual in-clinic FEV1, Forced Vital Capacity (FVC) and Peak Expiratory Flow (PEF) measurements at all time-points including peak, trough and AUC0-3h [ Time Frame: 0, 4, 8, 16 and 24 weeks ]
• Quality of Life as assessed by standardised Asthma Quality of Life Questionnaire (AQLQ (S)) [ Time Frame: 4, 8, 16 and 24 weeks ]
• PEF am/pm: change from baseline in mean weekly pre-dose morning and evening PEF measured by patients at home [ Time Frame: last week of 24 week treatment period ]
• Use of PRN salbutamol (albuterol) rescue medication [ Time Frame: weekly means of 24 week treatment period ]
• Asthma symptoms as assessed by the patient's electronic diary [ Time Frame: all days during 24 weeks of treatment ]
• Asthma symptom free days [ Time Frame: all days during 24 weeks of treatment ]
• The responder as assessed by the ACQ questionnaire for each twin trial separately [ Time Frame: 24 weeks ]
• Time to first severe asthma exacerbation (on combined data from the two twin trials 205.418 and 205.419) [ Time Frame: during 24 weeks of treatment ]
• Time to first asthma exacerbation (on combined data from the two twin trials 205.418 and 205.419) [ Time Frame: during 24 weeks of treatment ]
• The ACQ value (on combined data from the two twin trials 205.418 and 205.419) [ Time Frame: 4, 8, 16 and 24 weeks ]
• All adverse events [ Time Frame: Day 0 until end of follow up (31 weeks) ]
• Vital signs until 3 hours post-dose [ Time Frame: 0, 4, 8, 16 and 24 weeks ]
• Vital status information (dead or alive) of prematurely discontinued patients [ Time Frame: Planned date follow up visit (31 weeks) ]
• FEV1 (Area Under the Curve; AUC0-12h), FEV1 (AUC12-24h), FEV1 (AUC0-24h), FVC (AUC0-12h), FVC (AUC12-24h) and FVC (AUC0-24h) [ Time Frame: 24 weeks ]
• Maximum concentration of tiotropium in plasma (Cmax) [ Time Frame: Day 1 ]
• Time from dosing to maximum tiotropium plasma concentration (tmax) [ Time Frame: Day 1 ]
• area under the concentration-time curve of tiotropium in plasma over the time interval from 0 to the last quantifiable data point within the first dosing interval [ Time Frame: Day 1 ]
• amount of tiotropium that is eliminated unchanged in urine from the time point t1 to time point t2 [ Time Frame: Day 1 ]
• fraction of tiotropium dose excreted in urine from time point t1 to t2 [ Time Frame: Day 1 ]
• area under the concentration-time curve of tiotropium in plasma over the time interval t1 to t2 [ Time Frame: Day 1 ]
• area under the concentration-time curve of tiotropium in plasma over the time interval from 0 extrapolated to infinity [ Time Frame: Day 1 ]
• the percentage of the AUC0-infinity that is obtained by extrapolation [ Time Frame: Day 1 ]
• terminal rate constant of tiotropium in plasma [ Time Frame: Day 1 ]
• terminal half-life of tiotropium in plasma [ Time Frame: Day 1 ]
• mean residence time of tiotropium in the body after inhalation [ Time Frame: Day 1 ]
• apparent clearance of tiotropium in the plasma after extravascular administration [ Time Frame: Day 1 ]
• apparent volume of distribution of tiotropium during the terminal phase following an extravascular dose [ Time Frame: Day 1 ]
• renal clearance of tiotropium in plasma from the time point t1 to time point t2 [ Time Frame: Day 1 ]
• pre-dose concentration of tiotropium in plasma [ Time Frame: Day 7, 14 and 21 ]
• tiotropium plasma concentration 5 minutes post-dosing [ Time Frame: Day 7, 14 and 21 ]
• area under the concentration time curve of tiotropium in plasma over the time interval t1 to t2 at steady state [ Time Frame: Day 28 ]
• area under the plasma concentration-time curve at steady state over a uniform dosing interval at steady state [ Time Frame: Day 28 ]
• maximum measured concentration of tiotropium in plasma at steady state [ Time Frame: Day 28 ]
• time from dosing to the maximum concentration of tiotropium in plasma at steady state [ Time Frame: Day 28 ]
• terminal rate constant in plasma at steady state [ Time Frame: Day 28 ]
• terminal half-life of tiotropium in plasma at steady state [ Time Frame: Day 28 ]
• mean residence time of tiotropium in the body after inhalational administration to steady state [ Time Frame: Day 28 ]
• apparent clearance of tiotropium from plasma after extravascular administration to steady state [ Time Frame: Day 28 ]
• apparent volume of distribution of tiotropium during the terminal phase following an extravascular dose [ Time Frame: Day 28 ]
• amount of tiotropium that is eliminated in urine from the time point t1 to time point t2 (Ae0-2, Ae2-6 at steady state) [ Time Frame: Day 28 ]
• fraction of tiotropium eliminated in urine from time point t1 to time point t2 (fe0-2, fe2-6 at steady state) [ Time Frame: Day 28 ]
• renal clearance of tiotropium from the time point t1 until the time point t2) (CLR,0-2, CLR, 2-6 at steady state) [ Time Frame: Day 28 ]
• predose concentration of tiotropium in plasma at steady state [ Time Frame: Day 28 ]
• minimum concentration of tiotropium in plasma at steady state [ Time Frame: Day 28 ]
• Accumulation ratio, maximum concentration of tiotropium in plasma following 28 doses (RA,Cmax,28 based on Cmax) [ Time Frame: Day 28 ]
• RA,AUC based on AUC [ Time Frame: Day 28 ]
• health care resource utilisation (HCRU) [ Time Frame: 4, 8, 16 and 24 weeks ]
• Quality of Life (EQ-5D) [ Time Frame: 4, 8, 16 and 24 weeks ]

• Drug: Placebo
  Placebo that represents comparator
• Drug: tiotropium Respimat® low dose
  IMP
• Drug: tiotropium Respimat® high dose
  IMP
• Drug: 50 mcg salmeterol HFA MDI
  Active comparator
• Drug: Placebo
  Placebo that represents BI drug

• Experimental: tiotropium low dose
  Once daily, delivered with Respimat® inhaler (+ inhalation of placebo HFA MDI twice daily)
  Interventions:

  • Drug: Placebo
  • Drug: tiotropium Respimat® low dose
• Experimental: tiotropium high dose
  Once daily, delivered with Respimat® inhaler (+ inhalation of placebo HFA MDI twice daily)
  Interventions:

  • Drug: Placebo
  • Drug: tiotropium Respimat® high dose
• Active Comparator: 50 mcg salmeterol
  Twice daily, delivered with HFA MDI (+ inhalation of placebo Respimat® inhaler once daily)
  Interventions:

  • Drug: 50 mcg salmeterol HFA MDI
  • Drug: Placebo
• Placebo Comparator: placebo
  Once daily, delivered with Respimat® inhaler + twice daily delivered with HFA MDI
  Interventions:

  • Drug: Placebo
  • Drug: Placebo

Inclusion criteria:

1. All patients must sign and date an Informed Consent Form consistent with International Conference on Harmonisation - Good Clinical Practice (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.
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 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 minutes after 400 mcg salbutamol (albuterol)) resulting in a Forced Expiratory Volume in one second (FEV1) increase of at least 12% and at least 200mL.
6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids for at least for 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 Asthma Control Questionnaire (ACQ) mean score of at least 1.5.
8. All patients must have a pre-bronchodilator FEV1 at least 60% and less than or equal to 90% of predicted normal at Visit 1.
9. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%.
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.
11. Patients must be able to use the Respimat® inhaler and metered dose inhaler 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.

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 (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. Chronic Obstructive Pulmonary Disease (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, benzalkonium chloride (BAC), ethylenediamineteraacetic acid (EDTA), salmeterol xinafoate or any other components of the study medication delivery systems.
13. Pregnant or nursing woman.
14. Women of childbearing potential not using a highly effective method of birth control.
15. Patients who have taken an investigational drug within four weeks prior to Visit 1.
16. Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period. Topical cardio-selective beta-blocker eye medications for non-narrow angle glaucoma are allowed.
17. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®) within four weeks prior to Visit 1 and/or during the screening period.
18. Patients who have been treated with oral or patch beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period.
19. Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 and/or during the screening period.
20. 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.
21. Patients who have been treated with cromone within two weeks prior to Visit 1 and/or during the screening period.
22. Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period.
23. Patients who have been treated with other non-approved and according to international guidelines not recommended "experimental" drugs for routine asthma therapy within four weeks prior to Visit 1 and/or during the screening period.
24. Patients with any asthma exacerbation or any respiratory tract infection iin the four weeks prior to Visit 1 and/or during the screening period.
25. Patients who have previously been randomised in this trial or in the respective twin trial (205.419) or are currently participating in another trial.