Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III, Randomized, Double-blind, Active Controlled, Parallel Group Study, Comparing the Efficacy, Safety and Tolerability of the Fixed Dose Combination FF/UMEC/VI With the Fixed Dose Dual Combination of FF/VI, Administered Once-daily Via a Dry Powder Inhaler in Subjects With Inadequately Controlled Asthma
Brief Summary: A once-daily 'closed' triple FDC therapy of FF/UMEC/VI via a single ELLIPTA® dry powder inhaler (DPI) is being developed by GlaxoSmithKline (GSK) with the aim of providing a new treatment option for the management of asthma by improving lung function, health-related quality of life (HRQoL) and symptom control over established combination therapies. This is a phase III, multi-center, active-controlled, double-blind, parallel-group study to compare the efficacy, safety and tolerability of the FDC of FF/UMEC/VI with the FDC of FF/VI. This study has 5 phases: Pre-Screening (Visit 0), Screening/Run-in, Enrolment/Stabilization, Randomization/Treatment, and Follow up. At Visit 1 (Screening), subjects meeting all protocol defined inclusion/exclusion criteria will enter a 3-week run-in period and will receive fixed dose inhaled corticosteroid/long-acting beta agonist (ICS/LABA) (fluticasone/salmeterol, 250/50 micrograms (mcg), via the DISKUS® DPI) one inhalation twice a day. At Visit 2 (Enrolment), eligible subjects will be enrolled into the 2-week stabilization period to receive FF/VI (100/25 mcg via the ELLIPTA DPI once a day, in the morning). At the conclusion of the stabilization period (Visit 3), all subjects who meet the pre-defined randomization criteria will be randomized 1:1:1:1:1:1 during the treatment period to receive either FF/UMEC/VI (100/62.5/25 mcg; 200/62.5/25 mcg; 100/31.25/25 mcg; 200/31.25/25 mcg) or FF/VI (100/25 mcg; 200/25 mcg) via the ELLIPTA DPI once daily in the morning. The duration of the treatment period is variable but will be a minimum of 24 weeks and a maximum of 52 weeks. Subjects will have up to 6 on-treatment clinic visits scheduled at Visits 3, 4, 5, 6, 7 and 8/End of Study (EOS) (Weeks 0, 4, 12, 24, 36 and 52, respectively). A follow-up visit will be conducted approximately 7 days after the end of treatment period or, if applicable, after the early withdrawal visit. Subjects will be provided with short acting albuterol/salbutamol to be used on an as-needed basis (rescue medication) throughout the study. Approximately 2250 subjects will be randomized, with approximately 375 subjects randomized to each of the 6 double-blind treatment arms to ensure approximately 337 evaluable subjects per treatment arm. DISKUS and ELLIPTA are registered trademarks of GSK groups of companies.


Options:
A: Inclusion Criteria for Screening

* Age: 18 years of age or older at the time of signing the informed consent.
* Diagnosis: Subjects with a diagnosis of asthma as defined by the National Institutes of Health at least one year prior to Visit 0.
* Symptomatic: Subjects with inadequately controlled asthma (ACQ-6 score \>=1.5) despite ICS/LABA maintenance therapy at Visit 1.
* Asthma Control: In the 1 year prior to Visit 1

  * A documented healthcare contact for acute asthma symptoms or
  * A documented temporary change in asthma therapy for acute asthma symptoms, according to a pre-specified asthma action plan (or equivalent)
* Current Asthma Maintenance Therapy: Subjects are eligible if they have required daily ICS/LABA for at least 12 weeks prior to Visit 0 with no changes to maintenance asthma medications during the 6 weeks immediately prior to Visit 0 (including no changes to a stable total dose of ICS of \>250 mcg/day fluticasone proprionate \[FP, or equivalent\]).
* Spirometry: A best pre-bronchodilator morning (ante meridian \[AM\]) FEV1 \>=30% and \<85% of the predicted normal value at Visit 1. Predicted values will be based upon the European Respiratory Society (ERS) Global Lung Function Initiative.
* Reversibility of Disease: airway reversibility defined as \>=12% and \>=200 milliliter (mL) increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1.
* If the subject does not meet the above reversibility criteria at Visit 1 then the reversibility assessment may be repeated once within 7 days of Visit 1 if either criteria a) or b) are met: a) \>=9% increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol at Visit 1. b) Documented evidence of a reversibility assessment within 1 year prior to Visit 1 which demonstrated a post-bronchodilator increase in FEV1 of \>=12% and \>=200 mL.

Should the subject successfully demonstrate airway reversibility (defined as \>=12% and \>=200 mL increase in FEV1 between 20 and 60 minutes following 4 inhalations of albuterol/salbutamol aerosol) at the second attempt then, provided that all other eligibility criteria assessed at Visit 1 are met, the subject may enter the 3-week run-in period.

* Short-Acting beta2 Agonists (SABAs): All subjects must be able to replace their current SABA inhaler with albuterol/salbutamol aerosol inhaler at Visit 1 as needed for the duration of the study. Subjects must be judged capable of withholding albuterol/salbutamol for at least 6 hours prior to study visits.
* Male or eligible Female, defined as having documentation of non-reproductive potential or reproductive potential as follows:

A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test), not lactating, is not planning on becoming pregnant during the study and at least one of the following conditions applies: Non-reproductive potential defined as pre-menopausal females with documented tubal ligation or documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion or hysterectomy or documented bilateral oophorectomy; Postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate clinical profile (e.g., age appropriate, \>45 years, in the absence of hormone replacement therapy). In questionable cases for women \<60 years of age, a blood sample with simultaneous follicle stimulating hormone and estradiol falling into the central laboratory's postmenopausal reference range is confirmatory. Females under 60 years of age, who are on hormone replacement therapy (HRT) and whose menopausal status is in doubt, are required to use a highly effective method to avoid pregnancy if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, subjects can resume use of HRT during the study without use of a highly effective method to avoid pregnancy; Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from the screening visit until after the last dose of study medication and completion of the follow-up visit. The Investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

* Informed Consent: Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form and in this protocol. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials.

Exclusion Criteria for Screening

* Pneumonia: Chest X-ray documented pneumonia in the 6 weeks prior to Visit 1.
* Asthma Exacerbation: Any asthma exacerbation requiring a change in maintenance asthma therapy in the 6 weeks prior to Visit 1. Note: Subjects requiring a temporary change in asthma therapy (e.g., oral corticosteroids or increased dose of ICS) to treat an exacerbation in the 6 weeks prior to Visit 1 are not explicitly excluded at Visit 1 provided that, at the Investigator's discretion, the subject's condition is stable after they have resumed their pre-exacerbation maintenance asthma therapy (without modification) and they are considered appropriate for enrolment into this study of up to 12 month's duration.
* Chronic Obstructive Pulmonary Disease: Subjects with the diagnosis of chronic obstructive pulmonary disease, as per Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, including history of exposure to risk factors (i.e., especially tobacco smoke, occupational dusts and chemicals, smoke from home cooking and heating fuels) and a post-albuterol/salbutamol FEV1/Forced Vital Capacity (FVC) ratio of \<0.70 and a post-albuterol/salbutamol FEV1 of =\<70% of predicted normal values and onset of disease \>=40 years of age.
* Concurrent respiratory disorders: Subjects with current evidence of pneumonia, active tuberculosis, lung cancer, significant bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases or abnormalities other than asthma.
* Risk Factors for Pneumonia: Immune suppression (e.g., human immunodeficiency virus, Lupus) or other risk factors for pneumonia (e.g., neurological disorders affecting control of the upper airway, such as Parkinson's Disease, Myasthenia Gravis).
* Patients at potentially high risk (e.g., very low body mass index (BMI), severely malnourished, or very low FEV1) will only be included at the discretion of the Investigator.
* Other diseases/abnormalities: Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled. 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.
* Unstable liver disease as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices or persistent jaundice, cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Note: Chronic stable hepatitis B and C are acceptable if the subject otherwise meets entry criteria.
* Clinically significant Electrocardiogram abnormality: Evidence of a clinically significant abnormality in the 12-lead ECG performed during screening. The Investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject's medical history and exclude subjects who would be at undue risk by participating in the trial. An abnormal and clinically significant finding is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: Atrial fibrillation (AF) with rapid ventricular rate \>120 Beats Per Minute (BPM); sustained or non-sustained ventricular tachycardia (VT); Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted); QT interval corrected for heart rate by Fridericia's formula (QTcF) \>=500 milliseconds (msec) in subjects with QRS \<120 msec and QTcF \>=530 msec in subjects with QRS \>=120 msec.
* Unstable or life threatening cardiac disease: Subjects with any of the following at Screening (Visit 1) would be excluded: Myocardial infarction or unstable angina in the last 6 months; Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months; New York Heart Association (NYHA) Class IV Heart failure.
* Antimuscarinic effects: Subjects with a medical condition such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy or bladder neck obstruction should only be included if in the opinion of the Investigator the benefit outweighs the risk and that the condition would not contraindicate study participation.
* Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded based on the 5 year waiting period if the subject has been considered cured by treatment.
* Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study.
* Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol for the 6-hour period required prior to spirometry testing at each study visit.
* Tobacco Use: Subjects who are: Current smokers (defined as subjects who have used inhaled tobacco products within the 12 months prior to Visit 1 \[i.e., cigarettes, e-cigarettes/vaping, cigars or pipe tobacco\]) or former smokers with a smoking history of \>=10 pack years (e.g., \>=20 cigarettes/day for 10 years).
* Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years.
* Allergy or Hypersensitivity: A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or magnesium stearate.
* Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits.
* Affiliation with Investigator site: Study Investigators, sub-Investigators, study coordinators, employees of a participating Investigator or study site, or immediate family members of the aforementioned that is involved with this study.
* Inability to read: In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete study related materials.

Inclusion Criteria for Enrolment

* Inadequately controlled asthma: Subjects with inadequately controlled asthma (ACQ-6 score \>=1.5) at Visit 2.
* Percent-predicted FEV1: A best pre-bronchodilator morning (AM) FEV1 \>=30% and \<90% of the predicted normal value at Visit 2. Predicted values will be based upon the ERS Global Lung Function Initiative
* Liver function tests at Visit 1: alanine aminotransferase (ALT) \<2 x upper limit of normal (ULN); alkaline phosphatase \<=1.5xULN; bilirubin \<=1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%)
* Compliance with completion of the Daily eDiary reporting defined as completion of all questions/assessments on \>=4 of the last 7 days during the run-in period.

Exclusion Criteria for Enrolment

* Respiratory Infection: 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 subject's asthma status or the subject's ability to participate in the study.
* Severe asthma exacerbation: Evidence of a severe exacerbation during screening or the run-in period, defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids.
* Asthma medication: Changes in asthma medication (excluding run-in medication and albuterol/salbutamol inhalation aerosol provided at Visit 1).
* Laboratory test abnormalities: Evidence of clinically significant abnormal laboratory tests during screening or run-in 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.

Inclusion Criteria for Randomization

* Compliance with completion of the Daily eDiary reporting defined as completion of all questions/assessments on \>=4 of the last 7 days during the stabilization period.

Exclusion Criteria for Randomization

* Respiratory Infection: Occurrence of a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear during the stabilization period that led to a change in asthma management or, in the opinion of the Investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study.
* Severe asthma exacerbation: Evidence of a severe exacerbation during enrolment or the stabilization period, defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroids.
* Asthma medication: Changes in asthma medication (excluding stabilization period medication provided at Visit 2 and albuterol/salbutamol inhalation aerosol provided at Visit 1).
B: Inclusion Criteria:

* Patients with a diagnosis of asthma, (GINA 2015) for a period of at least 1 year prior to Visit 1 (Screening).
* Patients who have used medium or high dose of ICS/LABA combinations for asthma for at least 3 months and at stable medium or high doses of ICS/LABA for at least 1 month prior to Visit 1.
* Patients must be symptomatic at screening despite treatment with mid or high stable doses of ICS/LABA. Patients with ACQ-7 score ≥ 1.5 at Visit 101 and at Visit 102 (before randomization).
* Patients with documented history of at least one asthma exacerbation which required medical care from a physician, ER visit (or local equivalent structure) or hospitalization in the 12 months prior to Visit 1, and required systemic corticosteroid treatment.
* Pre-bronchodilator FEV1 of \< 80 % of the predicted normal value for the patient according to ATS/ERS guidelines after withholding bronchodilators at both visits 101 and 102.
* Withholding period of bronchodilators prior to spirometry: SABA for ≥ 6 hrs, Twice daily LABA (or FDC of ICS/LABA) for ≥ 12 hrs, Once daily LABA (or FDC of ICS/LABA) for ≥ 24 hrs, SAMA for ≥ 8 hrs, Short acting xanthines for 12 hrs, Long acting xanthines for 24 hrs, .
* Washout period of each drug should be kept as close as possible as above and should not be longer. If longer washout period is needed due to scheduling issues, please contact Novartis Medical monitor.
* A one-time repeat of percentage predicated FEV1 (Pre-bronchodilator) at Visit 101 and/or Visit 102 is allowed in an ad-hoc visit. Repeat of Visit 101 spirometry should be done in an ad-hoc visit to be scheduled on a date that would provide sufficient time to receive confirmation from the spirometry data central reviewer of the validity of the assessment before randomization. Run-in medication should be dispensed once spirometry assessment met inclusion criteria (ATS/ERS quality criteria, FEV1 % predicted normal value, and reversibility) as per equipment
* A one-time rescreen is allowed in case the patient fails to meet the criteria at the repeat, provided the patient returned to the required treatment as per inclusion criteria 4
* Patients who demonstrate an increase in FEV1 of 12% and 200 mL within 30 minutes after administration of 400 µg salbutamol/360 µg albuterol (or equivalent dose) at Visit 101.All patients must perform a reversibility test at Visit 101. If reversibility is not demonstrated at Visit 101 then one of the following criteria need to be met.
* Reversibility should be repeated once.
* Patients may be permitted to enter the study with historical evidence of reversibility that was performed according to ATS/ERS guidelines within 2 years prior to Visit 1.
* Alternatively, patients may be permitted to enter the study with a historical positive bronchoprovocation test that was performed within 2 years prior to Visit 1. If reversibility is not demonstrated at Visit 101 (or after repeated assessment in an ad-hoc visit) and historical evidence of reversibility/bronchoprovocation is not available (or was not performed according to the ATS/ERS guidelines patients must be screen failed
* Spacer devices are permitted during reversibility testing only. The Investigator or delegate may decide whether or not to use a spacer for the reversibility testing

Exclusion Criteria:

* Patients who have had an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit within 6 weeks of Visit 1 (Screening). If patients experience an asthma attack/exacerbation requiring systemic steroids or hospitalization or emergency room visit between Visit 1 and Visit 102 they may be re-screened 6 weeks after recovery from the exacerbation.
* Patients who have ever required intubation for a severe asthma attack/exacerbation.
* Patients who have a clinical condition which is likely to be worsened by ICS administration (e.g. glaucoma, cataract and fragility fractures) who are according to investigator's medical judgment at risk participating in the study.
* Patients treated with a LAMA for asthma within 3 months prior Visit 1 (Screening).
* Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia (BPH) or bladder-neck obstruction or severe renal impairment or urinary retention. BPH patients who are stable on treatment can be considered).
* Patients who have had a respiratory tract infection or asthma worsening as determined by investigator within 4 weeks prior to Visit 1 (Screening) or between Visit 1 and Visit 102. Patients may be re-screened 4 weeks after recovery from their respiratory tract infection or asthma worsening.
* Patients with evidence upon visual inspection (laboratory culture is not required) of clinically significant (in the opinion of investigator) oropharyngeal candidiasis at Visit 102 or earlier, with or without treatment. Patients may be re-screened once their candidiasis has been treated and has resolved.
* Patients with any chronic conditions affecting the upper respiratory tract (e.g. chronic sinusitis) which in the opinion of the investigator may interfere with the study evaluation or optimal participation in the study.
* Patients with a history of chronic lung diseases other than asthma, including (but not limited to) chronic obstructive pulmonary disease, sarcoidosis, interstitial lung disease, cystic fibrosis, clinically significant bronchiectasis and active tuberculosis.
* Patients with Type I diabetes or uncontrolled Type II diabetes.
* Patients who, either in the judgment of the investigator or the responsible Novartis personnel, have a clinically significant condition such as (but not limited to) unstable ischemic heart disease, New York Heart Association (NYHA) Class III/IV left ventricular failure arrhythmia, uncontrolled hypertension, cerebrovascular disease, psychiatric disease, neurodegenerative diseases, or other neurological disease, uncontrolled hypo- and hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or ophthalmologic disorder or patients with a medical condition that might compromise patient safety or compliance, interfere with evaluation, or preclude completion of the study.
* Patients with paroxysmal (e.g., intermittent) atrial fibrillation are excluded. Patients with persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months and controlled with a rate control strategy (i.e., selective beta blockers, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be considered for inclusion. In such patients, atrial fibrillation must be present at the run-in visit (Visit 101) with a resting ventricular rate \< 100/min. At Visit 101 the atrial fibrillation must be confirmed by central reading.
* Patients with a history of myocardial infarction (this should be confirmed clinically by the investigator) within the previous 12 months.
* Concomitant use of agents known to prolong the QT interval unless it can be permanently discontinued for the duration of study
* Patients with a history of long QT syndrome or whose QTc measured at Visit 101 (Fridericia method) is prolonged (\> 450 msec for males and \> 460 msec for females) and confirmed by a central assessor (these patients should not be rescreened).
* Patients with a history of hypersensitivity to lactose, any of the study drugs or to similar drugs within the class including untoward reactions to sympathomimetic amines or inhaled medication or any component thereof.
* Patients who have not achieved an acceptable spirometry result at Visit 101 in accordance with ATS/ERS criteria for acceptability and repeatability. A one-time repeat spirometry is allowed in an ad-hoc visit scheduled as close as possible from the first attempt (but not on the same day) if the spirometry did not qualify due to ATS/ERS criteria at Visit 101 and/or Visit 102. If the patient fails the repeat assessment, the patient may be rescreened once, provided the patient returns to the required treatment as per inclusion criteria 4.
* Patients unable to use the Concept1 dry powder inhaler, Accuhaler or a metered dose inhaler. Spacer devices are not permitted.
* History of alcohol or other substance abuse.
* Patients with a known history of non-compliance to medication or who were unable or unwilling to complete a patient diary or who are unable or unwilling to use Electronic Peak Flow with e-diary device.
* Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift workers).
C: 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 at least 18 years but not more than 75 years.
3. All patients must have at least a 3 month history of asthma at the time of enrolment 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 minutes after 400 mcg salbutamol (albuterol)) resulting in a Forced Expiratory Volume in one second (FEV1) increase of at least 12% and at least 200mL.
6. All patients must have been on maintenance treatment with a medium, stable dose of inhaled corticosteroids for at least for 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. Variation of absolute FEV1 values of Visit 1 (pre-bronchodilator) as compared to Visit 2 (pre-dose) must be within ± 30%.
10. Patients must be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment (Visit 0) and who have a smoking history of less than 10 pack years.
11. Patients must be able to use the Respimat® inhaler and metered dose inhaler correctly.
12. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of electronic diary/peak flow meter.

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 1.
3. Patients with a recent history (i.e. six months or less) of myocardial infarction.
4. Patients who have been hospitalised for cardiac failure during the past year.
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.
6. Patients with lung diseases other than asthma (e.g. Chronic Obstructive Pulmonary Disease (COPD)).
7. Patients with known active tuberculosis.
8. 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.
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 within the past two years.
11. 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).
12. Patients with known hypersensitivity to anticholinergic drugs, benzalkonium chloride (BAC), ethylenediamineteraacetic acid (EDTA), salmeterol xinafoate or any other components of the study medication delivery systems.
13. Pregnant or nursing woman.
14. Women of childbearing potential not using a highly effective method of birth control.
15. Patients who have taken an investigational drug within four weeks prior to Visit 1.
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 the 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 oral or patch beta-adrenergics within four weeks prior to Visit 1 and/or during the Screening period.
19. Patients who have been treated with oral corticosteroids within four weeks prior to Visit 1 and/or during the screening period.
20. 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.
21. Patients who have been treated with cromone within two weeks prior to Visit 1 and/or during the screening period.
22. Patients who have been treated with methylxanthines or phosphodiesterase 4 inhibitors within two weeks prior to Visit 1 and/or during the screening period.
23. 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.
24. Patients with any asthma exacerbation or any respiratory tract infection iin the four weeks prior to Visit 1 and/or during the screening period.
25. Patients who have previously been randomised in this trial or in the respective twin trial (205.419) or are currently participating in another trial.
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: A