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 Efficacy and Safety of Tiotropium Inhalation Solution Delivered Via Respimat® Inhaler (2.5 ug and 5 ug Once Daily) Compared to Placebo Over 12 Weeks in Mild Persistent Asthma
Brief Summary: The aim of this trial is to evaluate the efficacy and safety of 2.5 and 5 mcg tiotropium compared to placebo over 12 week treatment period. Tiotropium inhalation solution will be delivered via Respimat inhaler and will be examined on top of maintenance inhaled corticosteroid treatment in patients with mild persistent asthma. Efficacy and safety will be assessed by measuring the effects on lung functions, effects on lung exacerbations, effects on asthma control and numbers of adverse events.


Options:
A: Inclusion Criteria:

* Outpatient at least 12 years of age
* Both genders; females of childbearing potential must be willing to use birth control method
* Pre-bronchodilator FEV1 of 40-90% predicted
* Reversibility FEV1 of at least 12% and 200mls
* Current asthma therapy that includes an inhaled corticosteroid for at least 12 weeks prior to first visit

Exclusion Criteria:

* History of life-threatening asthma
* Respiratory infection or oral candidiasis
* Asthma exacerbation within 12 weeks
* Concurrent respiratory disease or other disease that would confound study participation or affect subject safety
* Allergies to study drugs, study drugs' excipients, medications related to study drugs
* Taking another investigational medication or medication prohibited for use during this study
B: 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.
C: Inclusion Criteria:

* Persistent asthma for at least 1-year
* Must use a daily asthma controller medication for at least 4 weeks prior to randomization, including an inhaled corticosteroid (ICS) with or without a long-acting beta agonist (LABA) or other adjunctive asthma therapy OR be using a leukotriene receptor antagonist (LTRA), xanthine or short acting beta agonist (SABA) as a monotherapy.
* Must be able to discontinue current asthma medication
* Must have a history of at least one asthma exacerbation in previous 4 to 52 weeks

Exclusion Criteria:

* Unstable asthma
* Taking high dose ICS with or without other adjunctive therapy who have an Asthma Control Questionnaire 6 (ACQ6) total score ≥ 1.5
* Taking LTRA, xanthine or SABA monotherapy with an ACQ-6 total score \< 1.5 (controlled)
* Chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), or other significant, non-asthmatic, lung disease
* Clinically significant abnormality, illness or disorder of any body or organ system
* Significant underlying cardiovascular condition which may contraindicate use of a beta-agonist.
* History of smoking greater than 10-pack years
* Had an asthma exacerbation within 4 weeks of the Baseline Visit
* Had more than 4 asthma exacerbations or 2 hospitalizations within 52 weeks of the randomization visit
* Known or suspected hypersensitivity or intolerance to corticosteroids, beta-2 agonists, or any of the (inactive ingredients) excipients present in the medications used in this study
* Require the use of chronic systemic steroids, omalizumab, or other monoclonal or polyclonal antibodies
* Requires the use of beta-blockers
* History of life-threatening asthma, including an asthma episode that required intubation and/or was associated with hypercapnia requiring noninvasive ventilatory support
* Lactating, pregnant, or plans to become pregnant during the course of the trial
D: Inclusion Criteria:

* Informed consent: Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.
* Gender and Age: Male or female subjects aged \>=18 and \<=75years of age at Screening visit.

Female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin \[hCG\] test), not lactating, and at least one of the following conditions applies:

Non-reproductive potential defined as: Pre-menopausal females with one of the following - Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone \[FSH\] and estradiol levels consistent with menopause \[refer to laboratory reference ranges for confirmatory levels\]); Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods 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.

Reproductive potential and agrees to follow one of the options listed below in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days prior to the first dose of study medication and until Week 24.

GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP:

This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long term and persistent basis: Contraceptive subdermal implant that meets the Standard Operating Procedure (SOP) effectiveness criteria including a \<1percent rate of failure per year, as stated in the product label; Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a \<1 percent rate of failure per year, as stated in the product label; Oral Contraceptive, either combined or progestogen alone; Injectable progestogen; Contraceptive vaginal ring; Percutaneous contraceptive patches; Male partner sterilization with documentation of azoospermia prior to the female subject's entry into the study, and this male is the sole partner for that subject; Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository); These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

* Type of subject: Subjects with documented physician's diagnosis of asthma \>=1 year, unsatisfactorily controlled asthma (ACT \<20 at Screening and Randomisation visit) treated by ICS alone and intended to be treated by ICS/LABA maintenance therapy; France Only: A subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a Social Security category.
* Current Asthma Therapy: All subjects must be prescribed maintenance therapy and receiving ICS alone without LABA for at least 4 weeks prior to Randomisation visit; Other background asthma medication such as anti-leukotrienes or theophylline is permitted as an alternative to ICS alone, if initiated at least 4 weeks prior to screening visit.
* Subject questionnaires Subjects must be able to complete the questionnaires themselves.

Exclusion Criteria:

* 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 within the last 6 months before Screening and Randomisation visit.
* Subjects having a severe and unstable asthma, with ACT score \< 15 at Visit 1 and at Visit 2, and/or a history of repeated severe exacerbations (3/year) and/or a severe exacerbation in the previous 6 weeks before Visit 1 and Visit 2.
* Chronic obstructive pulmonary disease (COPD) Respiratory Disease: A subject must not have current evidence or diagnosis of chronic obstructive pulmonary disease at Screening visit.
* Current or former cigarette smokers with a history of cigarette smoking of \>=10 pack-years at screening \[number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)\].
* Other diseases/abnormalities: Subjects with historical or current evidence of uncontrolled or clinically significant disease at Screening and Randomisation visit. 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.
* Subjects with a history of adverse reaction including immediate or delayed hypersensitivity to any intranasal, inhaled, or systemic corticosteroid and LABA therapy and to components of the inhalation powder (e.g., lactose, magnesium stearate) at Screening and Randomisation visit. In addition, subjects with a history of severe milk protein allergy that, in the opinion of the Investigator, contraindicates the subject's participation will also be excluded.
* Investigational Medications: A subject must not have used any investigational drug within 30 days prior to Randomisation visit or within five half-lives (t½) of the prior investigational study (whichever is longer of the two), (if unsure discuss with the medical monitor prior to screening).
* Chronic user of systemic corticosteroids: A subject who, in the opinion of the Investigator, is considered to be a chronic user of systemic corticosteroids for respiratory or other indications (if unsure discuss with the medical monitor prior to screening) at Screening visit.
* Subjects treated by the monoclonal antibody omalizumab or mepolizumab at Visit 1. Treatment with omalizumab or mepolizumab is not allowed during the study.
* Subjects involved in other clinical trials at Screening visit.
* Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study.
* Subjects who plan to move away from the geographical area where the study is being conducted during the study.

Answer: B