Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (2.5 mcg and 5 mcg Once Daily) Over 12 Weeks as add-on Controller Therapy on Top of Usual Care in Adolescents (12 to 17 Years Old) With Severe Persistent Asthma
Brief Summary: The overall purpose of the trial is to evaluate efficacy and safety of tiotropium inhalation solution delivered via Respimat® inhaler (2.5 mcg and 5 mcg once daily) over 12 weeks, compared to placebo, as add-on controller therapy on top of usual care in adolescents (12 to 17 years old) with severe persistent asthma.

The primary objective of the trial is to demonstrate superiority of tiotropium (5 mcg and possibly 2.5 mcg once daily in the evening) over placebo with regard to the primary pulmonary function endpoint after 12 weeks of treatment.

Secondary objectives are to evaluate efficacy of tiotropium with regard to other endpoints, and to evaluate the safety of tiotropium, compared to placebo, as add-on controller therapy on top of usual care in this patient population.


Options:
A: Inclusion Criteria:

* Male or female patients at least 18 years or older (females less than one year post-menopausal must have a negative serum or urine pregnancy test recorded within 72 hours prior to the first dose of study medication, be non-lactating, and willing to use adequate and highly effective methods of contraception throughout the study. A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilization, implants, injectables, combined oral contraceptives, some IUDs (Intrauterine Device, hormonal), sexual abstinence or vasectomised partner).
* Known history of mild to moderate-severe reversible asthma for \> 6 months prior to the screening visit.
* Demonstrate a FEV1 of \>40% to \<80% for predicted normal values (EGKS normal values, 1983) during the screening phase following appropriate withholding of asthma medications (if applicable).

  * No beta agonist use on day of screening.
  * No use of combination asthma therapy on day of screening.
  * Inhaled corticosteroids are allowed on day of screening.
* Documented reversibility of \> 15% in FEV1 in the screening phase.
* Demonstrate satisfactory technique in the use of the pressurized MDI.
* Willing and able to enter information in the electronic diary and attend all study visits.
* Willing and able to substitute study medication for their pre study prescribed asthma medication for the duration of the study.
* Written informed consent obtained.

Exclusion Criteria:

* Life-threatening asthma within the past year. This category includes those patients with a history of near-fatal asthma, a hospitalization or an emergency visit for asthma or prior intubation for asthma.
* History of systemic (injectable) corticosteroid medication within 1 month before the Screening Visit.
* History of omalizumab use within the past 6 months.
* History of leukotriene receptor antagonist use, e.g. montelukast, within the past week.
* Current evidence or history of any clinically significant disease or abnormality including uncontrolled coronary artery disease, congestive heart failure, myocardial infarction, or cardiac dysrhythmia. 'Clinically significant' is defined as any disease that, in the opinion of the Investigator, would put the patient at risk through study participation, or which would affect the outcome of the study.
* An upper or lower respiratory infection within 4 weeks prior to the Screening Visit.
* Significant, non-reversible, active pulmonary disease (e.g., chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchiectasis, tuberculosis).
* Known Human Immunodeficiency Virus (HIV)-positive status.
* A smoking history equivalent to "10 pack years" (i.e., at least 1 pack of 20 cigarettes /day for 10 years or 10 packs/day for 1 year, etc)
* Current smoking history within 12 months prior to the Screening Visit.
* Current evidence or history of alcohol and/or substance abuse within 12 months prior to the Screening Visit.
* Patients who have taken beta-blocking agents, tricyclic antidepressants, monoamine oxidase inhibitors, astemizole (Hismanal), quinidine type antiarrhythmics, or potent CYP 3A4 inhibitors such as ketoconazole within the past week.
* Current use of medications that will have an effect on bronchospasm and/or pulmonary function.
* Current evidence or history of hypersensitivity or idiosyncratic reaction to test medications or components.
* Receipt of an investigational drug within 30 days of the Screening Visit (12 weeks if an oral or injectable steroid).
* Current participation in a clinical study.
B: Inclusion Criteria:

* History of asthma ≥ 1 year and diagnosed before 40 years old
* Uncontrolled asthma with double therapy only on medium doses of Inhaled CorticoSteroid (ICS) in combination with Long-acting beta2 Agonist (LABA) with ACQ-7 (Asthma Control Questionnaire) ≥1.5
* Pre-bronchodilator FEV1 \<80% of the predicted normal value
* Positive reversibility test
* At least 1 documented asthma exacerbation in the previous year

Exclusion Criteria:

* Pregnant or lactating women
* Diagnosis of Chronic Obstructive Pulmonary Disease (COPD)
* Patients with any asthma exacerbation or respiratory tract infection in the 4 weeks prior screening
* Current or ex-smokers (\>= 10 packs year)
* Any change in dose, schedule or formulation of ICS + LABA combination in the 4 weeks prior screening
C: INCLUSION CRITERIA:

Subjects eligible for enrolment in the study must meet all of the following criteria:

* Type of Subject: Outpatient
* Age: 12 years of age or older at Visit 1. For sites in the following countries, subjects recruited will be ≥18 years of age: Bulgaria, Czech Republic, Germany, Greece, Lithuania, New Zealand, Russian Federation, Turkey and any other countries where local regulations or the regulatory status of study medication permit enrolment of adults only.
* Gender: Male or Eligible Female
* To be eligible for entry into the study, females of childbearing potential must commit to consistent and correct use of an acceptable method of birth control, as defined by the following:
* Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject
* Implants of levonorgestrel
* Injectable progestogen
* Oral contraceptive (either combined estrogen/progestin or progestin only)
* Any intrauterine device (IUD) with a documented failure rate of less than 1% per year.
* Females of childbearing potential who are not sexually active must commit to complete abstinence from intercourse throughout the clinical trial and for a period after the trial to account for elimination of the drug (minimum of six days).
* Double barrier method - spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a spermicide and female diaphragm).
* NB: For German sites, female subjects must use a method of birth control other than the double barrier method.
* The contraceptive transdermal patch, Ortho Evra (if the subject is less than 198 pounds)
* Female subjects should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation. A serum pregnancy test is required of all females. This test will be performed at the initial screening visit (Visit 1) and Visit 8. In addition, a urine pregnancy test will be performed on the evening of the double-blind treatment visit, prior to randomization (Visit 3) and at Visits 4 through 7.
* Asthma Diagnosis: Asthma as defined by the National Institutes of Health \[National Institutes of Health, 2007\].
* Severity of Disease: A best FEV1 of 40%-90% of the predicted normal value during Visit 1. NHANES III predicted values will be used for subjects aged ≥ 12 years and adjustments to predicted values will be made for African American subjects. \[Hankinson, 1999\].
* Reversibility of Disease: Demonstrated a ≥ 12% and ≥200mL reversibility of FEV1 within approximately 30-minutes following 4 inhalations of albuterol/salbutamol inhalation aerosol (if required, spacers are permitted for reversibility testing only) or one nebulized albuterol/salbutamol solution at the Screening Visit. If a subject fails to demonstrate an increase in FEV1 ≥12% and ≥200mL, then the subject is not eligible for the study and will not be allowed to re-screen.
* Current Anti-Asthma Therapy: Subjects must have been using a inhaled corticosteroid for at least 8 weeks prior to Visit 1 and maintained on a stable dose of inhaled corticosteroids for four weeks prior to Visit 1 at one of the following doses: \[fluticasone propionate MDI CFC/HFA \>220mcg exactuator or ≤250mcg ex valve\]; \[fluticasone propionate DPI ≤200mcg\]; \[beclomethasone dipropionate DPI ≤ 420mcg exactuator or ≤ 500mcg ex-valve\]; \[beclomethasone dipropionate HFA (Qvar) ≤ 160mcg exactuator or ≤ 200mcg ex-valve\]; \[budesonide DPI MDI ≤400mcg\]; \[flunisolide ≤ 1000mcg\]; \[triamcinolone acetonide ≤1000mcg\]; \[mometasone furoate DPI \>200mcg or ≤ 220mcg\]; \[ciclesonide MDI HFA ≤ 160mcg ex-actuator dose / ≤ 200mcg ex-valve dose\].
* Short- Acting Beta2-Agonists: All subjects must be able to replace their current short-acting beta2-agonists with albuterol/salbutamol inhalation aerosol at Visit 1 for use as needed for the duration of the study. The use of spacer devices with metered dose inhaler (MDI) or nebulized albuterol/salbutamol will not be allowed during the study with the exception of their use during reversibility testing at Visit 1. Subjects must be able to withhold all inhaled short-acting beta sympathomimetic bronchodilators for at least 6 hours prior to all study visits.
* Informed Consent: All subjects must be able and willing to give written informed consent to take part in the study.
* Compliance: Subjects must be able to comply with completion of the Daily Diary (includes paper medical conditions diary).
* French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Inclusion Criteria for Randomization

At the end of the run-in period, a subject will be eligible to enter the treatment period of the study if he/she meets the following criteria at Visit 3:

1. Evening pre-dose percent predicted FEV1 of between 40% and 90% of their predicted normal.
2. Any combination of the daily asthma symptom scores (day-time plus night-time) of ≥1 or albuterol/salbutamol use on at least 4 of the last 7 consecutive days of the run-in period (immediately preceding Visit 3).

EXCLUSION CRITERIA:

* History of Life-threatening asthma: Defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures.
* Respiratory Infection: Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of Visit 1 and led to a change in asthma management, or in the opinion of the Investigator is expected to affect the subjects asthma status or the subjects ability to participate in the study.
* Asthma Exacerbation: Any asthma exacerbation requiring oral corticosteroids within 3 months of Visit 1. A subject must not have had any hospitalization for asthma within 6 months prior to Visit 1.
* Concurrent Diseases/Abnormalities: Historical or current evidence of clinically significant uncontrolled disease including, but not limited to: cardiovascular disease, hepatic disease, renal disease, hematological disease, neurological disease, or pulmonary disease (including, but not confined to chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, bronchopulmonary dysplasia, and chronic obstructive pulmonary disease). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study. The list of additional excluded conditions/diseases includes, but is not limited to the following: congestive heart failure, clinically significant coronary artery disease, stroke within 3 months of Visit 1, poorly controlled peptic ulcer, immunologic compromise, tuberculosis (current or untreated), Addison's disease, uncontrolled thyroid disorder, known aortic aneurysm, clinically significant cardiac arrhythmia, uncontrolled hypertension, hematological, hepatic, or renal disease, current malignancy, cushings disease, uncontrolled diabetes mellitus, recent history of drug or alcohol abuse.
* Oropharyngeal Examination: A subject will not be eligible for the run-in if he/she has clinical visual evidence of oral candidiasis at Visit 1.
* Investigational Medications: A subject must not have participated in a study or used any investigational drug within 30 days prior to Visit 1.
* Drug Allergy: Any adverse reaction including immediate or delayed hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the novel dry powder inhaler or DISKUS/ACCUHALER (i.e., lactose or magnesium stearate).
* Milk Protein Allergy: History of severe milk protein allergy.
* Immunosuppressive Medications: A subject must not be using, or require use, of immunosuppressive medications during the study.

NOTE: Immunotherapy for the treatment of allergies is allowed during the study provided that the treatment was initiated prior to Visit 1 and the subject is maintained on a stable regimen throughout the study period.

* Attendance: A subject will not be eligible if he/she or his/her parent or legal guardian has any infirmity, disability, or geographical location which seems likely (in the opinion of the Investigator) to impair compliance with any aspect of this study protocol or scheduled visits to the study center and non-compliant with study medication or procedures (e.g. completion of daily diary). Neurological or psychiatric disease or history of drug or alcohol abuse which in the opinion of the investigator could interfere with the subject's proper completion of the protocol requirements excludes study participation.
* Tobacco Use : Current smoker or a smoking history of 10 pack years or more (e.g. 20 cigarettes/day for 10 years). A subject may not have used tobacco products within the past one year (i.e., cigarettes, cigars, or pipe tobacco).
* Affiliation with Investigator's Site: A subject will not be eligible for this study if he/she is an immediate family member of the participating Investigator, sub-Investigator, study coordinator, or employee of the participating Investigator.
* Corticosteroid Use: Administration of systemic, oral or depot corticosteroids within 12 weeks of Visit 1.
* Potent Cytochrome P450 3A4 (CYP3A4) inhibitors: Patients who are receiving potent CYP3A4 inhibitors within 4 weeks of Visit 1 (e.g., ritonavir, ketoconazole, itraconazole).

Exclusion Criteria for Randomization At the end of the run-in period, a subject will not be eligible to enter the treatment period of the study if they meet any of the following criteria.

1. Clinical Laboratory Abnormalities: Clinically significant abnormal laboratory tests during Visit 1 which are still abnormal upon repeat analysis and are not believed to be due to disease(s) present. Each Investigator will use his/her own discretion in determining the clinical significance of the abnormality. When in doubt, GlaxoSmithKline, or designee, should be notified so that a joint decision can be made.
2. Changes in asthma medication (excluding albuterol/salbutamol inhalation aerosol provided at Visit 1).
3. Occurrence of a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear during the run-in period that led to a change in asthma management, or in the opinion of the Investigator is expected to affect the subjects asthma status or the subjects ability to participate in the study.
4. Asthma exacerbation, defined as any worsening of asthma requiring any treatment other than rescue albuterol/salbutamol or regular inhaled corticosteroid use. This includes requiring the use of systemic corticosteroids and / or emergency room visit or hospitalization or a change in subject's regular inhaled corticosteroid dose.
5. A subject will not be eligible for randomization if he/she has an abnormal visual oropharyngeal exam at the randomization Visit 3 (visual clinical evidence of oral candidiasis).
6. Non-compliance with completion of the Daily Diary, defined as: -Completion of AM and PM symptom scores on less than 4 days out of the last 7 days immediately preceding Visit 3.

   * Completion of AM and PM rescue use on less than 4 days out of the last 7 days immediately preceding Visit 3.
   * Completion of AM and PM PEF measurements on less than 4 days out of the last 7 days immediately preceding Visit 3.
   * Recording run-in asthma medication use on less than 4 days out of the last 7 days immediately preceding Visit 3.
D: Inclusion criteria:

1. All patients and their parent(s) (or legally accepted representative) must sign and date respectively an informed assent and an informed consent consistent with International Conference on Harmonisation - Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) guidelines and local legislation prior to the patient's participation in the trial. A separate informed consent/assent is required for pharmacogenomic sampling.
2. Male or female patients between 12 and 17 years of age (at date of informed consent/assent).
3. All patients must have at least a 3-month history of asthma at the time of enrolment into the trial.
4. All patients must have been on maintenance treatment with an inhaled corticosteroid either at stable high dose in combination with another controller medication, OR at stable medium dose in combination with two other controller medications, for at least 4 weeks before Visit 1.
5. 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.
6. All patients must have a pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1) = 60% and = 90% of predicted normal at Visit 1.
7. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator, considered as 100%) as compared to Visit 2 (pre-dose) must be within ± 30%.
8. All patients must confirm the diagnosis of asthma by bronchodilator reversibility at Visit 1, resulting in an increase in FEV1 of = 12% and = 200 mL 15 to 30 minutes after 400 µg salbutamol (albuterol). If patients in the lower age range (e.g. 12 to 14 year old patients) exhibit a very small total lung volume, positive reversibility testing might be based solely on the relative (=12%) post-bronchodilator response.
9. All patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment.
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 spirometric manoeuvres according to American Thoracic Society/ European Respiratory Society (ATS/ERS) standards and use of the electronic diary/peak flow meter (diary compliance of at least 80% is required).

Exclusion criteria:

1. Significant disease other than asthma.
2. Abnormal haematology or blood chemistry.
3. History of heart disease, and/or hospitalised for cardiac syncope or failure.
4. Any unstable or life-threatening or requiring intervention or cardiac arrhythmia.
5. Malignancy for which the patient has undergone resection, radiation therapy or chemotherapy.
6. Active tuberculosis.
7. Alcohol or drug abuse.
8. Thoracotomy with pulmonary resection.
9. Pulmonary rehabilitation program.
10. Hypersensitivity to anticholinergic drugs, or any components of the study medication delivery system.
11. Pregnant or nursing adolescent female patients.
12. Female patients of child-bearing potential not using a highly effective method of birth control.
13. Investigational drug within four weeks or six half lives prior to Visit 1.
14. Long-acting anticholinergics within four weeks prior to Visit 1.
15. Systemic corticosteroids at a high dose or at a not stable low dose within four weeks prior to Visit 1.
16. Leukotriene modifiers if not stabilised for at least four weeks prior to Visit 1.
17. Long-acting theophylline preparations if not stabilised for at least two weeks prior to Visit 1.
18. Anti Immunoglobulin E (Anti-IgE) treatment if not stabilised for at least six months prior to Visit 1.
19. Cromones if not stabilised within four weeks prior to Visit 1.
20. Oral beta-blocker medication within four weeks prior to Visit 1.
21. Systemic oral or i.v. or s.c. beta-adrenergics within four weeks prior to Visit 1.
22. Other non-approved and according to international guidelines not recommended experimental drugs for routine asthma therapy within four weeks prior to Visit 1.
23. Any acute asthma exacerbation or respiratory tract infection in the four weeks prior to Visit 1and/or in the four weeks prior to Visit 2. In case of an asthma deterioration occurring in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2, the visit must be postponed.
24. Randomised in this trial or currently participating in another trial.
25. Narrow-angle glaucoma, or any other disease where anticholinergic treatment is contraindicated.
26. Moderate to severe renal impairment.
27. Patients requiring 10 or more puffs of rescue medication per day on more than 2 consecutive days in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2. In case of an asthma deterioration occurring in the four weeks prior to Visit 1 and/or in the four weeks prior to Visit 2, the visit must be postponed.

Answer: D