Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III, Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (2.5 ug and 5 ug Once Daily) Compared to Placebo Over 12 Weeks in Mild Persistent Asthma
Brief Summary: The aim of this trial is to evaluate the efficacy and safety of 2.5 and 5 mcg tiotropium compared to placebo over 12 week treatment period. Tiotropium inhalation solution will be delivered via Respimat inhaler and will be examined on top of maintenance inhaled corticosteroid treatment in patients with mild persistent asthma. Efficacy and safety will be assessed by measuring the effects on lung functions, effects on lung exacerbations, effects on asthma control and numbers of adverse events.


Options:
A: Inclusion Criteria:

* men and women aged 18 or older
* stable mild-to-moderate asthma
* baseline methacholine PC20 less than or equal to 8mg/mL and FEV1 greater than or equal to 65% of predicted (asthmatic participants)
* baseline methacholine PC20 greater than 16mg/mL (healthy participants)

Exclusion Criteria:

* use of long-acting bronchodilators or long-acting muscarinic antagonists within 30 days of Visit 1
* pregnant or lactating
* cardiovascular, prostate, kidney or urinary retention problems
* respiratory illness within 4 weeks of Visit 1
* allergen-induced asthma exacerbating within 4 weeks of Visit 1
* hypokalemia
* diabetes
* glaucoma
* smokers and exsmokers with greater than 10 pack years
B: 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.
C: Inclusion Criteria:

1. Consent to participate in the study
2. Age 4-11 years old
3. Male or eligible female - Female subjects should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation
4. Asthma diagnosis for at least 6 months
5. Ability to answer questions regarding asthma control and use a metered dose inhaler and DISKUS
6. A history of clinical varicella infection or recipient of a varicella vaccine in countries where the product label includes a warning regarding more serious chickenpox infections in patients using corticosteroids.
7. History of at least once occurrence of asthma exacerbation within the prior 12 months
8. Currently being treated for asthma and no change in asthma therapy for the last 4 weeks (Eligible subjects include: subjects with use of short-acting beta-agonist, leukotriene receptor antagonist, theophylline, or cromolyn whose asthma is not well-controlled; subjects on low-dose ICS monotherapy whose asthma is not well-controlled; subjects on low-dose ICS and one or more adjunctive therapy whose asthma is either controlled or not well-controlled asthma; subjects on medium-dose ICS monotherapy whose asthma is either controlled or not well-controlled; and subjects on medium-dose ICS and one or more adjunctive therapy whose asthma is well-controlled)

Exclusion Criteria:

1. History of life-threatening asthma
2. Unstable asthma
3. Current use of high-dose ICS or ICS/LABA therapy to treat asthma symptoms
4. Concurrent respiratory disease: Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, cystic fibrosis, bronchopulmonary dysplasia, or other severe respiratory abnormalities other than asthma.
5. Respiratory infection
6. Subjects with only exercise-induced asthma
7. An asthma exacerbation within the last 4 weeks or more than 4 separate exacerbations in the last 12 months
8. Hospitalization for asthma within 4 weeks or more than 2 hospitalizations within the last 12 months
9. Other current evidence of clinically significant uncontrolled disease/conditions of any body or organ system
10. Neurological or psychiatric disease or history of drug or alcohol abuse of a subject or his/her guardian which in the opinion of the investigator could interfere with the subject's proper completion of the protocol requirements
11. Participation in an interventional study or used any investigational drug for any disease state within the last 30 days
12. Any adverse reaction including immediate or delayed hypersensitivity to any beta-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy, or vehicle contained within these medication
13. Severe hypersensitivity to cow's milk proteins
14. Administration of prescription or over the counter medications that would significantly affect the course of asthma, or interact with sympathomimetic amines such as: anti-IgE (omalizumab), anticonvulsants (barbiturates, hydantoins, carbamazepine); polycyclic antidepressants, beta-adrenergic blockers; phenothiazines, monoamine oxidase inhibitors, or diuretics
15. Potent cytochrome P450 3A4 (CYP3A4) inhibitors within the last 4 weeks (e.g., ritonavir, ketoconazole, itraconzole)
16. Affiliation with investigator's site, including a immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.
17. A Child in Care (CiC) is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation.
D: 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 18 years or more at Visit 0 and 75 years or less at Visit 0.

   All patients must have
3. at least a 3 months history of asthma at the time of enrolment into the trial. The initial diagnosis of asthma must have been made before the patient's age of 40;
4. a pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1)= 60% predicted and = 90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%.
5. Patient's diagnosis of asthma has to be confirmed at Visit 1 with a bronchodilator reversibility (within 10 minutes pre and 15-30 minutes after 400 µg salbutamol/albuterol) resulting in a FEV1 increase of = 12% and = 200mL. If this is not achieved the reversibility test may be repeated once within two weeks.
6. All patients must be symptomatic despite their current maintenance treatment with low doses of inhaled corticosteroids.
7. All patients must be symptomatic at Visit 1 (screening) and Visit 2 as defined by an Asthma Control Questionnaire (ACQ) mean score of = 1.5.
8. All patients must have been on maintenance treatment with a low, stable dose of inhaled corticosteroids 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 and who have a smoking history of less than 10 pack years ((see Appendix 10.3 for calculation).
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 e-Diary/peak flow meter (e-Diary-compliance of at least 80% is required; refer to Section 6.2.1 for instructions).
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) 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 number 1.
3. Patients requiring more than 10 puffs of rescue medication (salbutamol/albuterol MDI) per 24 hours on 2 consecutive days during the screening period.
4. Patients with a recent history (i.e. six months or less) of Acute Coronary Syndrome (STEMI, Non-STEMI and Unstable Angina Pectoris).
5. Patients who have been hospitalised for cardiac failure during the past year.
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.
7. Patients with lung diseases other than asthma (e.g. 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. 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.
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 tiotropium inhalation solution.
14. Pregnant or nursing woman, including female patients with positive beta-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).
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 oral or patch beta-adrenergics, systemic, i.e. oral or intravenous corticosteroids, 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 depot corticosteroids within six months prior to Visit 1 and/or during the screening period.
19. Patients who have ever been treated with anti-IgE antibodies.
20. Patients who have been treated with leukotriene modifiers, systemic anticholinergics, cromolyn sodium or nedocromil sodium and methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period.
21. Patients who have been treated with inhaled long acting beta adrenergics and long acting beta adrenergics combination products within four weeks prior to Visit 0 and/or during the screening period.
22. Patients who have taken an investigational drug within four weeks or six half lives whichever is greater 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 and/or during the screening period (period between Visit 1 and Visit 2).
24. Patients with any asthma exacerbation or any respiratory tract infection in the four weeks prior to Visit 1 and/or during the screening period (period between Visit 1 and Visit 2).
25. Current participation in another trial.

Answer: D