Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III, Randomised, Double Blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy and Safety Over 48 Weeks of Orally Inhaled Tiotropium Bromide (2.5 and 5 µg Once Daily ) Delivered by the Respimat® Inhaler in Adolescents (12 to 17 Years Old) With Moderate Persistent Asthma.
Brief Summary: The aim of the study is to evaluate efficacy and safety of a 48-week treatment with two doses of tiotropium bromide compared to placebo in adolescent patients with moderate persistent asthma. Efficacy and safety will be assessed by measuring lung function parameters and evaluating the effects on asthma exacerbations, on Quality of life, on health care resource utilisation an on the number of adverse events.


Options:
A: 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.
B: Inclusion criteria:

1. All patients and their parents (or legally accepted caregiver) must sign and date an informed consent consistent with ICH-GCP guidelines and local legislation prior to participation in the trial.
2. Male or female patients between 12 and 17 years of age.
3. 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 test.
4. All patients must have been on maintenance treatment with inhaled corticosteroids at a stable medium dose for at least 4 weeks before Visit 1.
5. All patients must be symptomatic (partly controlled) at Visit 1 (screening) and at randomisation defined by an Asthma Control Questionnaire (ACQ) mean score of more than or equal to 1.5.
6. All patients must have a pre-bronchodilator FEV1 more than or equal to 60% and less than or equal to 90% of predicted normal at Visit 1. Variation of absolute FEV1 values of Visit 1 as compared to Visit 2 must be within ± 30%.
7. All patients must have an increase in FEV1 of equal or above 12% and 200 mL after 400 µg salbutamol (albuterol) at Visit 1. If patients in the lower age range (e.g., 12 to 14 year olds) exhibit a very small total lung volume, positive reversibility testing might be based solely on the relative (12%) post-bronchodilator response.
8. All patients should be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment.
9. Patients should be able to use the Respimat® inhaler correctly.
10. Patients must be able to perform all trial related procedures including technically acceptable spirometric manoeuvres.

Exclusion criteria:

1. Patients with a significant disease other than asthma.
2. Patients with clinically relevant abnormal screening haematology or blood chemistry
3. Patients with a history of congenital or acquired heart disease, and/or have been hospitalised for cardiac syncope or failure during 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.
6. Patients with lung diseases other than asthma (e.g. Cystic Fibrosis). In case of ex-premature infants, a history of significant bronchopulmonary dysplasia will be regarded as exclusion criterion.
7. Patients with known active tuberculosis.
8. Patients with significant alcohol or drug abuse within the past two years.
9. Patients who have undergone thoracotomy with pulmonary resection.
10. 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).
11. Patients with known hypersensitivity to anticholinergic drugs, Benzalkonium chloride (BAC), Ethylenediaminetetraacetic acis (EDTA) or any other components of the tiotropium inhalation solution.
12. Pregnant or nursing adolescent female patients
13. Sexually active female patients of child-bearing 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 long-acting anticholinergics (e.g. tiotropium -Spiriva) within four weeks prior to screening (Visit 1).
16. Patients who are unable to comply with pulmonary medication restrictions prior to randomisation.
17. Patients who have been treated with Anti-IgE treatment (Omalizumab Xolair) within the last 6 months prior to screening.
18. Patients who have been treated with systemic (oral or intravenous) corticosteroids within 4 weeks prior to screening (Visit 1).
19. Patients who have been treated with long-acting theophylline preparations within 2 weeks prior to screening (Visit 1) or during the run-in period
20. Patients who have been treated with other non-approved and according to international guidelines not recommended ¿experimental¿ drugs for routine asthma therapy.
21. Patients with any acute asthma exacerbation or respiratory tract infection in the 4 weeks prior to Visit 1.
22. Patients requiring 10 or more puffs of rescue medication (salbutamol/albuterol) per day on more than 2 consecutive days during the run-in period.
23. Patients who have previously been randomised in this trial or are currently participating in another study.
24. Patients who are being treated with oral beta-blocker medication.
25. Patients with a known narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated.
26. Patients with renal impairment, as defined by a creatinine clearance less than 50 mL/min/1.73 m2 Body Surface Area as calculated by Schwartz formula.
C: Inclusion Criteria:

* Severity of disease: The patient has persistent asthma, with a forced expiratory volume in 1 second (FEV1) 40%-85% of the value predicted for age, height, sex, and race as per the National Health and Nutrition Examination Survey (NHANES III) (Hankinson et al 1999) reference values at screening visit.
* Current asthma therapy: The patient must be on a stable dose of an inhaled corticosteroid (ICS) of at least 440 mcg/day of fluticasone propionate or equivalent for a minimum of 4 weeks before screening visit, or any inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) combination for a minimum of 4 weeks before the prescreening visit.
* Reversibility of disease: The patient has demonstrated at least 12% reversibility of FEV1 and at least 200 mL increase from baseline FEV1 (patients age 18 and older) within 30 minutes after 2-4 inhalations of albuterol/salbutamol hydrofluoroalkane (HFA) MDI (90 mcg ex-actuator) or equivalent at the screening visit
* If female, the patient is currently not pregnant, breast feeding, or attempting to become pregnant. If of childbearing potential, has a negative serum pregnancy test and is willing to commit to using a consistent and acceptable method of birth control.
* Other criteria apply, please contact the investigator for more information

Exclusion Criteria:

* The patient has a history of life-threatening asthma, defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest, or hypoxic seizures.
* The patient is pregnant or lactating, or plans to become pregnant during the study period or for 30 days after the patient's last study-related visit (for eligible patients only, if applicable). Eligible female patients unwilling to employ appropriate contraceptive measures to ensure that pregnancy will not occur during the study will be excluded. Any patient becoming pregnant during the study will be withdrawn from the study.
* The patient has a known hypersensitivity to any corticosteroid or any of the excipients in the study drug or rescue medication formulation.
* The patient currently smokes or has a smoking history of 10 pack-years or more (a pack-year is defined as smoking 1 pack of cigarettes/day for 1 year).
* The patient has had an asthma exacerbation requiring oral corticosteroids within 30 days before the screening visit, or has had any hospitalization for asthma within 2 months before the screening visit.
* The patient has historical or current evidence of a clinically significant disease. Significant disease is defined as any disease that in the medical judgment of the investigator would put the safety of the patient at risk through participation or that could affect the efficacy or safety analysis if the disease/condition worsened during the study.
* Other criteria apply, please contact the investigator for more information
D: Inclusion Criteria:

* Male or Female, Hispanic (self-reported), \> 12 years of age
* Moderate to severe asthma requiring treatment with an inhaled corticosteroid
* Diagnosis of asthma for at least 6 months

Exclusion Criteria:

* Subjects requiring treatment with systemic corticosteroids (e.g., oral, parenteral, ocular)
* Any significant disease or disorder that may jeopardize a subject's safety

Answer: B