Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase II Randomised, Double-blind, Placebo Controlled, Cross-over Efficacy and Safety Comparison of Three Doses of Tiotropium Inhalation Solution Delivered Via Respimat Inhaler (1.25, 2.5 and 5.0 Mcg Once Daily) Versus Placebo in Patients With Moderate Persistent Asthma.
Brief Summary: Rationale for the current trial is to evaluate the efficacy and safety of three doses (1.25 µg, 2.5 µg and 5.0 µg ex mouthpiece) of tiotropium inhalation solution in patients with moderate persistent asthma who are still symptomatic despite regular maintenance therapy with inhaled corticosteroids (ICS).

The data collected in the present trial will provide useful information to health care providers and patients regarding the efficacy and safety of a once daily inhalation of three different doses of tiotropium solution delivered by the Respimat® inhaler in addition to inhaled corticosteroids in the treatment of not fully controlled moderate asthma in comparison to placebo. The Pharmacokinetics (PK) of tiotropium is well established in COPD patients. However, there is currently no PK data available for the 3 doses of tiotropium being tested in this trial in patients with moderate persistent asthma. Tiotropium is a once daily drug. Hence, the rationale for blood and urine sampling for PK analysis over 24 hours in a subset of patients is to confirm the PK of the 3 doses in moderate asthma patients. Rationale for the 24-hour pulmonary function test sub-investigation is to demonstrate that a once daily dosing of tiotropium inhalation solution is effective and safe in the treatment of moderate persistent asthma.


Options:
A: Inclusion criteria:

1. All patients including the patients under age (under 20 years old) must sign and date an Informed Consent Form consistent with ICH-GCP guidelines and Good Clinical Practice (GCP) prior to participation in the trial \[i.e. prior to any trial procedures, including any pre-trial washout of medications and medication restrictions for pulmonary function test (PFT) at Visit 1\]. Regarding patients under age, a guardian or a legally authorised representative must also sign and date an Informed Consent Form.
2. Male or female outpatients aged at least 18 years but not more than 75 years at Visit 0.
3. All patients must have at least a 12-week history of asthma at the time of enrolment (Visit 0) 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 (15-30 minutes after 400 µg salbutamol) resulting in a Forced Expiratory Volume in one second (FEV1) increase of at least 12% and at least 200 mL .
6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids (ICS) \[alone or in a fixed combination with a Long-acting beta-adrenergic (LABA)\] for at least 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. Patients must be never-smokers or ex-smokers who stopped smoking at least one year (52 weeks) prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack years.
10. Patients must be able to use the Respimat inhaler correctly, which is judged at the discretion of the investigator..
11. Patients must be able to perform all trial related procedures including technically acceptable PFTs and use of electronic diary (eDiary)/peak flow meter, which is judged at the discretion of the investigator.

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 no 1.
3. Patients with a recent history (i.e. 6 months or less) of myocardial infarction prior to Visit 0.
4. Patients who have been hospitalised for cardiac failure during the past year prior to Visit 0.
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 prior to Visit 0.
6. Patients with lung diseases other than asthma (e.g. COPD).
7. Patients with known active tuberculosis.
8. Patients with malignancy and/or patients who have undergone resection, radiation therapy or chemotherapy for malignancy within the last 5 years prior to Visit 0. 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, which is judged at the discretion of the investigator, within the past 2 years prior to Visit 0.
11. Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediaminetetraacetic acid (EDTA), or any other components of the study medication delivery systems.
12. Pregnant or nursing women.
13. Women of childbearing 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 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.
16. 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.
17. Patients who have been treated with oral beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period.
18. Patients who have been treated with systemic corticosteroids within four weeks prior to Visit 1 and/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 and/or during the screening period.
20. 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.
21. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 and/or during the screening period.
22. Patients who are currently participating in another trial.
23. Patients with narrow-angle glaucoma and/or micturition disorder due to prostatic hyperplasia.
24. Patients with below 80% of the eDiary completion compliance on Visit 2 (diary compliance of at least 80% is required).
B: Inclusion criteria:

1. All patients must sign and date an Informed Consent Form consistent with the Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) 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 between 18 and 75 years (at date of informed consent).
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 no. 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 to 30 minutes after 4 puffs of 100 µg salbutamol) resulting in a Forced Expiratory Volume in one second (FEV1) increase of = 12% and = 200mL.
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 long acting or short acting beta agonist \[LABA or SABA\]) for at least 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 = 1.5.
8. All patients must have a pre-bronchodilator FEV1 = 60% and = 90% of predicted normal at Visit 1. Predicted normal values will be calculated according to the European Community for Steel and Coal (ECSC).
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 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 (diary compliance of at least 80% is required).

Exclusion criteria:

1. Patients with a significant disease other than asthma.
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.
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.
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 known moderate to severe renal impairment.
11. Patients with known narrow angle glaucoma or any other disease where anticholinergic treatment is contraindicated.
12. Patients with significant symptomatic prostatic hyperplasia or bladder-neck obstruction. Patients whose symptoms are controlled on treatment may be included.
13. Patients with significant alcohol or drug abuse within the past two years (to the discretion of the investigator).
14. Patients who are currently in a pulmonary rehabilitation program or have completed pulmonary rehabilitation program in the 6 weeks prior to Visit 1 (screening) or who will start a rehabilitation program during the study.
15. Patients with known hypersensitivity to anticholinergic drugs, Benzalkonium chloride (BAC), Ethylenediaminetetraacetate (EDTA) or any other components of the study medication delivery system (Respimat®/ tiotropium inhalation solution).
16. Pregnant or nursing woman.
17. Women of childbearing potential not using a highly effective method of birth control.
18. Patients who have taken an investigational drug within four weeks prior to Visit 1.
19. Patients who have been treated with beta-blocker medication within four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2). Topical cardio-selective beta-blocker eye medications for non-arrow angle glaucoma are allowed.
20. 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 (period between Visit 1 and Visit 2).
21. Patients who have been treated with oral or patch beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period (period between Visit 1 and Visit 2)
22. Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 and/or during the screening period.
23. Patients who have been treated with anti-Immunoglobuline E (anti-IgE) antibodies, e.g. omalizumab, within 6 months prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2).
24. Patients who have been treated with cromone within two weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2).
25. Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2).
26. Patients who have been treated with other non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy (e.g. Tumor Necrosis Factor (TNF)-alpha blockers, methotrexate, cyclosporin) within four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2).
27. Patient with any asthma exacerbation or respiratory tract infection in the 4 weeks prior to visit 1 and/or during the screening period.
C: Inclusion_Criteria:

1. Patients homozygous for arginine at the 16th amino acid position of the beta2 adrenergic receptor (B16 Arg/Arg)
2. All patients must sign and date an Informed Consent Form for the study prior to participation in the trial
3. Male or female outpatients with at least 18 years of age, but not older than 65 years
4. Patients must have a documented history of asthma
5. Patients must be current non-smokers or ex-smokers with a cigarette smoking history of \<10 pack-years
6. Patients must be on a maintenance treatment with inhaled corticosteroids with a total daily dose of 400 - 1000 mcg budesonide or equivalent

Exclusion_Criteria:

1. Patients with a significant disease other than asthma
2. Patients with a recent history (i.e., six months or less) of myocardial infarction
3. Patients who have been hospitalized for heart failure (New York Heart Association class III or IV) within 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. Patients with treated basal cell carcinoma are allowed.
6. Patients with a diagnosis of chronic obstructive pulmonary disease (COPD)
7. Patients with a history of life threatening pulmonary obstruction, or a history of cystic fibrosis or clinically evident bronchiectasis
8. Patients with known active tuberculosis
9. Patients who have undergone thoracotomy with pulmonary resection.
10. Patients who have completed a pulmonary rehabilitation program in the six weeks prior to visit 1 or patients who are currently in a pulmonary rehabilitation program that will not be maintained throughout the duration of the study.
D: 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 (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 5-year history of asthma at the time of enrolment into the trial and the diagnosis of asthma must have been made before the patient´s age of 40.
4. 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
5. All patients must have a history of one or more asthma exacerbation in the past year.
6. Patients must have evidence of treated, severe, persistent asthma in postbronchodilatory pulmonary function tests.
7. Patients should be 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
8. Patients must be able to use the Respimat® inhaler correctly
9. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the 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 clinically relevant abnormal screening haematology or blood chemistry.
3. Patients with a recent history (i.e. six months or less) of myocardial infarction, hospitalisation for cardiac failure during the past year, any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year, known active tuberculosis, malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years (treated basal cell carcinoma allowed), lung diseases other than asthma (e.g. COPD), significant alcohol or drug abuse within the past two years, 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.
4. 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).
5. Patients using oral corticosteroid medication at stable doses exceeding 5 mg prednisolone or prednisolone equivalent every day or 10 mg prednisolone or prednisolone equivalent every second day.
6. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution.
7. Pregnant or nursing women or women of childbearing potential not using a highly effective method of birth control. 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.
8. Patients who have taken an investigational drug within four weeks or six half-lives (whichever is greater) prior to Visit 1.
9. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva®), beta-blocker medication, oral beta-adrenergics, 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 prior to the Screening Visit (Visit 1) or during the screening period.
10. Patients with any asthma exacerbation or respiratory tract infection in the four weeks prior to the trial.
11. Patients who have previously been randomised in this trial or in the respective twin trial (205.416 versus 205.417) or are currently participating in another trial.
12. Patients with a known narrow-angle glaucoma.

Note:

As with other anticholinergic drugs, tiotropium should be used with caution in patients with prostatic hyperplasia or bladder neck obstruction.

As with all predominantly renally excreted drugs, patients with moderate to severe renal impairment (known creatinine clearance of \<= 50 mL/min) treated with tiotropium should be monitored closely.

Answer: B