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 Safety and Efficacy of Tiotropium Inhalation Solution Delivered Via Respimat Inhaler (2.5 and 5 µg Once Daily) Compared With Placebo Over 52 Weeks in Patients With Moderate to Severe Persistent Asthma
Brief Summary: The aim of this trial is to evaluate the safety and efficacy of 2.5 and 5 µg tiotropium over a 52-week treatment period as compared to placebo. Tiotropium inhalation solution delivered by the Respimat inhaler will be examined on top of maintenance treatment with inhaled corticosteroid controller medication in patients with moderate to severe persistent asthma. Efficacy and safety will be assessed by measuring effects on lung function, effects on asthma exacerbations, effects on asthma control, and number of adverse events.


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:

* Physician-diagnosed asthma
* At least one of the following lung function criteria must be documented in the year prior to study entry:

  1. Bronchial hyperresponsiveness confirmed by 12% or greater improvement in amount of air expired in first second during a forced expiratory maneuver (FEV1) post-bronchodilator, or
  2. Methacholine post-diluent baseline (PC20) less than 16 mg/ml, or
  3. Exercise bronchoprovocation test with at least a 20% decrease in FEV1
* Currently on stable dose of daily inhaled corticosteroid for asthma control (i.e., inhaled corticosteroid equivalent to 2 puffs of 44 ug twice per day \[176 ug\] of fluticasone or greater for 8 weeks or longer prior to study entry)
* Poor asthma control as defined by any one of the following criteria:

  1. Use of beta-agonist for asthma symptoms twice a week or more on average in the month prior to study entry
  2. Nocturnal awakening with asthma symptoms more than once per week on average in the month prior to study entry
  3. Two or more emergency department visits, unscheduled physician visits, prednisone courses, or hospitalizations for asthma in the 12 months prior to study entry
  4. Juniper Asthma Control Score (ACS) of 1.25 or greater at the first screening visit
* Absence of GERD symptoms at the time of study entry

Exclusion Criteria:

* Previous anti-reflux or peptic ulcer surgery
* Previous tracheoesophageal fistula repair
* FEV1 less than 60% of predicted normal value at screening visit and as measured immediately before methacholine bronchoprovocation; methacholine bronchoprovocation will be limited to participants with a FEV1 greater than or equal to 70% of predicted value in accordance with American Thoracic Society (ATS) guidelines
* History of a premature birth of less than 33 weeks gestation or any neonate requiring a significant level of respiratory care, including mechanical ventilation
* Any major chronic illness, including but not limited to non-skin cancer, cystic fibrosis, bronchiectasis, myelomeningocele, sickle cell anemia, endocrine disease, congenital heart disease, congestive heart failure, stroke, severe hypertension, insulin-dependent diabetes mellitus, kidney failure, liver disorder, immunodeficiency state, significant neuro-developmental delay or behavioral disorder (excluding mild attention deficit hyperactivity disorder), or other condition that would interfere with participation in the study
* History of phenylketonuria
* Medications for treatment of GI symptoms (e.g., proton pump inhibitors, H2 blockers, bethanechol, metoclopramide) in the month prior to study entry (intermittent anti-acids are allowed)
* Use of theophylline preparations, azoles, anti-coagulants, insulin for Type I diabetes, digitalis, or oral iron supplements when administered for iron deficiency in the month prior to study entry
* Use of any investigative drug in the 2 months prior to study entry
* Previous adverse effects from lansoprazole, other proton pump inhibitors, or sensitivity to aspartame
* Inability or unwillingness of the legal guardian to provide consent
* Inability or unwillingness of the child to provide assent
* Inability to take study medication
* Inability to perform baseline measurements
* Less than 80% completion of screening period diaries
* Inability to contact by telephone
* Planning to move out of the area in the 6 months following study entry
* Pregnancy
C: Inclusion Criteria:

* The general goal of patient selection is to enroll patients for whom asthma physicians might prescribe GERD treatment, but where there is uncertainty whether it might be effective.
* Age 18 or older
* Physician diagnosed asthma
* If amount of air expired in the first second during a forced expiratory maneuver (FEV1) is greater than or equal to 70% predicted normal pre-bronchodilator: demonstrate methacholine 20% from post-diluent baseline (PC20). PC20 less than 16 mg/ml during Visit 1
* If FEV1 less than 70% and greater than or equal to 50% predicted normal pre-bronchodilator: demonstrate 12% reversibility during Visit 1 or within past 12 months
* Currently on stable dose of daily inhaled steroids for asthma control, i.e., inhaled corticosteroid equivalent to 400 ug/day of fluticasone44 or greater for 8 weeks or longer
* Poor asthma control: Either of the following; a score of 1.5 or greater on the Juniper Asthma Control Questionnaire; two or more episodes of asthma symptoms in the past 12 months with each episode requiring at least one of the following: an emergency department visit, unscheduled physician visit, prednisone course, hospitalization
* Non-smoker for 6 months or longer
* Less than 10 pack/year smoking history

Exclusion Criteria:

* Surgery: Previous anti-reflux or peptic ulcer surgery
* Pulmonary function: FEV1 less than 50% predicted normal pre-bronchodilator
* GERD Symptoms: Severe reflux constituting a clinical indication for treatment with a PPI or H2 blocker, typically two or more episodes per week of heartburn requiring antacids
* Other major chronic illnesses; conditions which in the judgment of the Study Physician would interfere with participation in the study, e.g., non-skin cancer, endocrine disease, coronary artery disease, congestive heart failure, stroke, severe hypertension, Type 1 insulin dependent diabetes mellitus, renal failure, liver disorders, immunodeficiency states, major neuropsychiatric disorder
* Medication use: Anti-reflux medication (proton pump inhibitors or H2 blockers) within 1 month Theophylline, azoles, iron, anti-coagulants, insulin (for Type I diabetes), digitalis, any investigative drugs within 1 month
* Drug allergy: Previous adverse effects from proton pump inhibitors or methacholine challenge
* Females of childbearing potential: Pregnant or lactating, unwilling to practice an adequate birth control method (abstinence, combination barrier and spermicide, or hormonal)
* Inability or unwillingness to provide consent
* Inability to perform baseline measurements
* Completion of less than 10 of the last 14 days of screening period diary entry
* Inability to be contacted by telephone
* Intention to move out of the area within 6 months
D: Inclusion Criteria:

* Adults with diagnosis of asthma since at least 6 months.
* Symptoms of asthma during run-in.
* At least 3 months history and present symptoms of 1 or more of the following: burning feeling behind breastbone, pain behind breastbone, acid taste in the mouth.

Exclusion Criteria:

* Patients with clinically relevant abnormalities.
* Patients with a smoking history of ≥10 pack-year.
* Patients who have had previous surgery on the esophagus or the stomach.

Answer: A