Please select the eligibility criteria that correspond to the clinical trial below.
Title: A 16-week Randomised, Placebo-controlled, Double-blind, Double-dummy, Parallel-group Study Comparing the Efficacy and Safety of Tiotropium Inhalation Solution Delivered by the Respimat Inhaler (2 Actuations of 2.5 Mcg Once Daily) With That of Salmeterol From the Hydrofluoroalkane Metered Dose Inhaler (2 Actuations of 25 Mcg Twice Daily) in Moderate Persistent Asthma Patients With the B16-Arg/Arg Genotype
Brief Summary: This is a 16 week multicentre, multinational, randomised, double-blind, double-dummy, placebo-controlled, parallel group study to evaluate the long-term efficacy and safety of tiotropium compared to salmeterol in moderate persistent asthmatic (GINA step 3) patients homozygous for arginine at the 16th amino acid position of the beta-adrenergic receptor (ADRB2). Following an initial 4-week run-in period on salmeterol MDI patients will be randomised into the 16 week double-blind treatment period in which they receive either tiotropium once daily administered from the Respimat inhaler or salmeterol twice daily administered from the hydrofluoro-alkane Metered Dose Inhaler (MDI), or placebo twice daily. After the 16 week treatment period all patients will receive salmeterol MDI twice daily for four weeks.

The patients perform daily morning and evening peak flow (PEF) and Forced Expiratory Volume in the First Second (FEV1) measurements with an electronic peak flow meter throughout the study. Daily data on asthma control and use of rescue medication are recorded using an electronic diary included in the electronic peak flow meter. On study visits the Mini-Asthma Quality of Life Questionnaire (Elizabeth Juniper) is administered, pulse and blood pressure and pre-dose pulmonary function testing (FEV1 and Forced Vital Capacity) are performed.


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. 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: Ages eligible for study: 12 years and above; genders eligible for study: both; prior steroid use: steroid-requiring or steroid-free.

Inclusion Criteria:

* History of asthma for at least 12 months.
* For steroid-requiring patients, documented use of inhaled corticosteroid for at least 4 weeks prior to Screening Visit
* For steroid-free patients, no history of inhaled steroid asthma medication for at least 12 weeks prior to Screening Visit.
* Demonstrate FEV-1 of 60-85% of predicted normal values at Screening and Baseline Visit.
* Documented reversibility of 15% within 12 months of Screening or at Screening Visit (15% increase from pre-FEV-1 levels following albuterol inhalation or nebulized albuterol administration).
* Symptoms of Asthma during Run-in
* Females of childbearing potential must have a negative urine pregnancy test at Screening and Baseline Visits. Females are eligible only if they are not pregnant or lactating, and are either sterile, or using acceptable methods of contraception.
* Must otherwise be healthy.
* Provide written informed consent. Wishes of minors must be respected.

Exclusion Criteria:

* Life-threatening asthma within past year or during Run-In Period.
* History of systemic corticosteroid medication within 3 months before Screening Visit.
* History of omalizumab use within past 6 months.
* History of leukotriene receptor antagonist use, e.g. montelukast, within past week.
* Current evidence or history of any clinically significant disease or abnormality including uncontrolled hypertension, uncontrolled coronary artery disease, congestive heart failure, myocardial infarction, or cardiac dysrhythmia.
* Upper or lower respiratory infection within 4 weeks prior to Screening Visit or during Run-In Period.
* Significant, non-reversible, pulmonary disease (e.g., chronic obstructive pulmonary disease \[COPD\], cystic fibrosis, bronchiectasis).
* Known Human Immunodeficiency Virus (HIV)-positive status.
* Smoking history equivalent to "10 pack years".
* Current smoking history within 12 months prior to Screening Visit.
* Current evidence or history of alcohol and/or substance abuse within 12 months prior to Screening Visit.
* Patients who are confined in institution
D: Inclusion Criteria:

* Clinical diagnosis of moderate to severe persistent asthma for at least 6 months, according to GINA revised version 2002 guidelines (11):

  * Forced expiratory volume (FEV1) or peak expiratory flow rate (PEFR) ³ 50% and £ 80% of the predicted normal;
  * Asthma not adequately controlled with the current therapies, defined as presence of daily asthma symptoms \> once a week and night-time asthma symptoms \> twice a month, and daily use of short-acting β2-agonists. These findings are to be based on recent medical history and are to be confirmed in the 2-week run-in period.
* Treatment with inhaled corticosteroids at a daily dose ≤ 1000 μg of BDP or equivalent. The daily dose of inhaled corticosteroids taken at visit 1 will be assessed taking into account the following ratios between the doses of the different steroids: fluticasone propionate : BDP CFC = 1 : 2; budesonide : BDP CFC = 4 : 5; flunisolide : BDP CFC = 1 : 1. The ratios between inhaled steroids are irrespective of the formulations (i.e. spray aerosol or powder) used. When BDP is given in the new extra-fine HFA-134a formulation (as QVAR®, 3M Healthcare), the ratio with BDP CFC is set as 2 : 5. Therefore, the maximum allowed daily dose of inhaled corticosteroids at study entry will be: budesonide 800 μg, fluticasone propionate 500 μg, flunisolide 1000 μg, BDP 1000 mg, BDP HFA extra-fine 400 μg.
* Positive response to the reversibility test in the screening visit, defined as an increase of at least 12% (or, alternatively, of 200mL) from baseline value in the measurement of FEV1 30 minutes following 2 puffs (2 ´ 100 µg) of inhaled salbutamol administered via pMDI. The reversibility test can be avoided in patients having a documented positive response in the previous 6 months.
* A co-operative attitude and ability to be trained to correctly use the metered dose inhalers and to complete the diary cards.
* Written informed consent obtained.
* At the end of the 2-week run-in period, the presence of daily asthma symptoms (of at least mild intensity) and nighttime asthma symptom (of at least mild intensity) \> once a week, as well as of daily use of relief salbutamol is to be confirmed by reviewing the diary cards for run-in.

Exclusion Criteria:

* Inability to carry out pulmonary function testing;
* Diagnosis of Chronic Obstructive Pulmonary Disease (COPD) as defined by the National Heart Lung and Blood Institute/World Health Organisation (NHLBI/WHO) Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (30);
* History of near fatal asthma;
* Evidence of severe asthma exacerbation or symptomatic infection of the airways in the previous 8 weeks;
* Three or more courses of oral corticosteroids or hospitalisation due to asthma during the previous 6 months;
* Patients treated with long-acting β2-agonists, anticholinergics and antihistamines during the previous 2 weeks, with topical or intranasal corticosteroids and leukotriene antagonists during the previous 4 weeks;
* Patients who have changed their dose of inhaled corticosteroids during the previous 4 weeks, or treatment with inhaled corticosteroids at a daily dose \> 1000 μg of BDP or equivalent (except for extra-fine formulations, see inclusion criteria);
* Current smokers or recent (less than one year) ex-smokers, defined as smoking at least 10 cigarettes/day;
* History or current evidence of heart failure, coronary artery disease, myocardial infarction, severe hypertension, cardiac arrhythmias;
* Diabetes mellitus;
* Percutaneous transluminal coronary angioplasty (PTCA) or coronary artery by-pass graft (CABG) during the previous six months;
* Patients with an abnormal QTc interval value in the ECG test, defined as \> 450 msec in males or \> 470 msec in females;
* Other haemodynamic relevant rhythm disturbances (including atrial flutter or atrial fibrillation with ventricular response, bradycardia (≤ 55 bpm), evidence of atrial-ventricular (AV) block on ECG of more than 1st degree;
* Clinically significant or unstable concurrent diseases: uncontrolled hyperthyroidism, significant hepatic impairment, poorly controlled pulmonary (tuberculosis, active mycotic infection of the lung), gastrointestinal (e.g. active peptic ulcer), neurological or haematological autoimmune diseases;
* Cancer or any chronic diseases with prognosis \< 2 years;
* Pregnant or lactating females or females at risk of pregnancy, i.e. those not demonstrating adequate contraception (i.e. barrier methods, intrauterine devices, hormonal treatment or sterilization). A pregnancy test is to be carried out in women of a fertile age.
* History of alcohol or drug abuse;
* Patients treated with monoamine oxidase inhibitors, tricyclic antidepressants or beta-blockers as regular use;
* Allergy, sensitivity or intolerance to study drugs and/or study drug formulation ingredients;
* Patients unlikely to comply with the protocol or unable to understand the nature, scope and possible consequences of the study;
* Patients who received any investigational new drug within the last 12 weeks;
* Patients who have been previously enrolled in this study;
* At the end of the run-in period, patients will not be admitted to the treatment period in the case of an increase of PEFR (L/sec) measured at the clinics at the end of the run-in period ³ 15% in respect of values measured at the start of the run-in period;
* Patients with asthma exacerbations during the run-in period will also be excluded from the study.

Answer: B