Study on BI 54903 (Inhaled Corticosteroid) Administered Twice Daily Via Respimat Inhaler in Patients With Asthma Inadequately Controlled on Medium Dose Inhaled Corticosteroid (ICS).

A Randomised, Double-blind, Double-dummy, Active-controlled, Parallel-group Study to Assess and Compare Efficacy and Safety of an 8-week Treatment With BI 54903 at Doses of 90.9, 181.8 and 363.6 µg b.i.d. Administered Via Respimat® Inhaler and Fluticasone Propionate HFA MDI 440 µg b.i.d. in Patients With Asthma Inadequately Controlled on Medium Dose ICS Therapy

The aim of the study is to assess and compare efficacy and safety of BI 54903 at three different dosages (b.i.d)., fluticasone propionate hydrofluoroalkane (HFA) metered dose inhaler (MDI) at a dose of 440 mcg b.i.d and low dose fluticasone propionate 88 mcg b.i.d. over an 8-week treatment period in asthmatic patients aged 12 to 65 years inadequately controlled medium dose ICS therapy as demonstrated by a decrease in forced expiratory volume in one second (FEV1) range 10 to 25 % and an asthma control questionnaire-6 (ACQ-6) equal or greater than 1.5 at time of randomisation.

Inclusion criteria:

1. Must be willing and able to give informed consent.

2. Male and female patients aged at least 12 to 65 years.

3. All patients must have a history of asthma diagnosed by a physician for at least three months at the time of enrolment into the trial according to the 2009 Global Initiative for Asthma (GINA) Guidelines. The initial diagnosis of asthma must have been made before the age of 40 years.

4. All patients must be on a maintenance treatment with high-dose ICS with long-acting beta 2-agonist (LABA), stable for at least six weeks prior to Visit 1

5. All patients must have a pre-bronchodilator FEV1 of not less than 60 to 90% of predicted normal and an ACQ-6 mean score of less than 1.5 at the pre-screening Visits 1and 2.

6. Patients must be never-smokers or ex-smokers with a smoking history of less than 10 pack-years and smoking cessation at least one year prior to screening .

7. Patients must be able to use Respimat® inhaler and MDI correctly

8. Patients must be able to perform all trial-related procedures including technically acceptable pulmonary function tests and electronic peak expiratory flow (PEF) measurements, and must be able to maintain records during the study period as required in the protocol.

   To enter treatment period following additional criteria have to be met:

9. All patients must have an improvement in FEV1 not less than 12 % above baseline and an absolute change of at least 200 mL within 15-30 min after administration of 400 mcg salbutamol/albuterol HFA MDI as demonstrated at Visit 1 or during one of the visits during run-in period.

10. During the run-in period (at the same clinic visit) all patients must be both symptomatic (ACQ-6 mean score equal to or greater than 1.5) and have shown a decrease in morning pre-bronchodilator FEV1 not less than 10% and less than or equal to 25% from pre-screening baseline FEV1 at Visit 2.

Exclusion criteria:

1. Patients with significant pulmonary disease other than asthma or other significant medical conditions (as determined by medical history, examination and clinical investigations at screening) that may, in the opinion of the investigator, result in any of the following: (i) put the patient at risk because of participation in this 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 haematology and/or blood chemistry finding, if the abnormality indicates a significant disease as defined in exclusion criterion no. 1.

3. Patients with a history of upper respiratory tract infection (URTI) or lower respiratory tract infection (LRTI) in the past four weeks prior to the pre-screening Visit 1, and during pre-screening and run-in periods.

4. Patients with any exacerbation of their underlying asthma during the eight weeks prior to the pre-screening Visit 1.

5. Patients with active allergic rhinitis requiring treatment with systemic corticosteroids.

6. Any of the following criteria are met during the pre-screening/run-in period (Visits 1 - 6):

   • in clinic pre-bronchodilator FEV1 % predicted less than 40%,
   • more than 12 puffs rescue salbutamol/albuterol HFA MDI per day for > 2 consecutive days,
   • exacerbation of asthma.

7. Patients with a history of pneumonectomy or who are planning to undergo thoracotomy for any reason.

8. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the six weeks prior to the first screening visit 1.

9. Patients with two or more hospitalizations for asthma within the previous 12 months.

10. Patients with a recent history of myocardial infarction during the last twelve months or known coronary heart disease that requires treatment

11. Patients with a history of hospitalisation due to heart failure in the past twelve months

12. Patients with myocarditis or any unstable or life-threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year

13. Patients with significant alcohol or drug abuse in the opinion of the investigator within the past two years

14. Patients with rheumatoid arthritis or other systemic diseases that require immune system modulating treatment

15. Patients suffering from or with a history of glaucoma, increased intraocular pressure, and/or cataracts

16. Pregnant or nursing women

17. Women of childbearing potential not using a highly effective method of birth control.

18. Patients who have been treated with anti-IgE-antibodies (e.g. omalizumab, Xolair®) or other immune system modulating antibodies such as tumor necrosis factor-alpha blockers (TNF-alpha blockers) within six months prior to Visit 1.

19. Patients who have been treated with the following drugs during the past four weeks prior to Visit 1 or are foreseen to need this during the study:

    • Non-selective ß-blockers (topical cardio-selective beta-blocker eye medications for non-narrow angle glaucoma are allowed),
    • Oral or other systemic corticosteroids,
    • Oral beta-agonists,
    • Changes in allergen desensitisation therapy in last 6 months,
    • Immune system modulating agents such as methotrexate or cyclosporine,
    • Inhibitors of cytochrome P450 3A4 such as antifungals (e.g. ketoconazole, itraconazole), antibiotics (e.g. erythromycin) or antiretroviral drugs.

20. Patients who have been treated with leukotriene modifiers, chromones or theophylline within two weeks prior to Visit 1.

21. Patients who have been treated with tiotropium within 3 weeks prior to Visit 1.