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

Study Overview
=================
Brief Summary
-----------------
The aim of the study is to assess and compare efficacy and safety of BI 54903 at 3 doses twice daily (b.i.d.), fluticasone propionate hydrofluoroalkane metered dose inhaler (HFA MDI) at a dose of 220 mcg b.i.d. and placebo b.i.d. over an 8-week treatment period in asthmatic patients aged 12 to 65 years inadequately controlled on low dose Inhaled corticosteroid (ICS) as demonstrated by a decrease in forced expiratory volume in one second (FEV1 (range 10-25%) and an asthma control questionnaire (ACQ-6) greater or equal 1.5 at time of randomisation

Official Title
-----------------
A Randomised, Double-blind, Double-dummy, Placebo-controlled, Parallel-group Study to Assess and Compare Efficacy and Safety of an 8-week Treatment With BI 54903 at Doses of 45.5, 90.9 and 181.8 mcg b.i.d. Administered Via Respimat® Inhaler and Fluticasone Propionate HFA 220 mcg b.i.d. in Patients With Asthma Inadequately Controlled on Low Dose ICS Therapy

Conditions
-----------------
Asthma

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: BI 54903
* Drug: Fluticasone propionate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Must be willing and able to give informed consent Male and female patients aged at least 12 to 65 years 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 All patients must be on a maintenance treatment with either medium-dose inhaled corticosteroid (ICS) plus long acting beta agonist (LABA) or high-dose inhaled corticosteroid (ICS) without long acting beta agonist (LABA), stable for at least six weeks prior to Visit 1 All patients must have a pre-bronchodilator forced expiratory volume in one second (FEV1) of not less than 60 to 90% of predicted normal and an asthma control questionnaire (ACQ-6) mean score of less than 1.5 at the pre-screening Visit 1 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 hydrofluoroalkane metered dose inhaler (HFA MDI) 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 Patients must be able to use Respimat® inhaler and metered dose inhaler (MDI) correctly 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 (at randomisation visit): 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: Patients with significant pulmonary disease other than asthma or other significant medical conditions (as determined by medical history, examination and clinical investigations at screening) Patients with a clinically relevant, abnormal screening haematology and/or blood chemistry finding Patients with a history of upper or lower respiratory tract infection in the past four weeks prior to the pre-screening Visit 1, and during pre-screening and run-in periods Patients with any exacerbation of their underlying asthma during the eight weeks prior to the pre-screening Visit 1 Patients with active allergic rhinitis requiring treatment with systemic corticosteroids Any of the following criteria are met during the pre-screening / run-in period (Visits 1 - 6): in clinic pre-bronchodilator forced expiratory volume in one second (FEV1 %) predicted less than 40%, more than 12 puffs rescue salbutamol/albuterol hydrofluoroalkane metered dose inhaler (HFA MDI) per day for > 2 consecutive days, exacerbation of asthma. Patients with a history of pneumonectomy or who are planning to undergo thoracotomy for any reason 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 Patients with two or more hospitalizations for asthma within the previous twelve months Patients with a recent history of myocardial infarction during the last twelve months or known coronary heart disease that requires treatment Patients with a history of hospitalisation due to heart failure in the past twelve months 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 Patients with significant alcohol or drug abuse in the opinion of the investigator within the past two years Patients with rheumatoid arthritis or other systemic diseases that require immune system modulating treatment Patients suffering from narrow angle glaucoma with a history of glaucoma, increased intraocular pressure, and/or cataracts Pregnant or nursing women Women of childbearing potential not using a highly effective method of birth control. Patients who have been treated with anti-Immunoglobin-E-antibodies (e.g. omalizumab, Xolair®) or other immune system modulating antibodies such as tumor necrosis factor-alpha blockers within six months prior to Visit 1 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 beta-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. Patients who have been treated with leukotriene modifiers, chromones or theophylline within two weeks prior to Visit 1 Patients who have been treated with tiotropium within 3 weeks prior to Visit 1

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 54903 - low dose<br>Respimat inhaler containing low dose BI 54903 plus placebo matching hydrofluoralkane (HFA) metered dose inhaler (MDI) | Drug: Placebo<br>* Placebo matching fluticasone propionate HFA MDI<br>Drug: BI 54903<br>* BI 54903<br>|
| Experimental: BI 54903 - medium dose<br>Respimat inhaler containing medium dose BI 54903 plus placebo matching HFA MDI | Drug: Placebo<br>* Placebo matching fluticasone propionate HFA MDI<br>Drug: BI 54903<br>* BI 54903<br>|
| Experimental: BI 54903 - high dose<br>Respimat inhaler containing high dose BI 54903 plus placebo matching HFA MDI | Drug: Placebo<br>* Placebo matching fluticasone propionate HFA MDI<br>Drug: BI 54903<br>* BI 54903<br>|
| Active Comparator: Fluticasone propionate<br>Fluticasone HFA MDI containing ICS plus placebo matching Respimat inhaler | Drug: Fluticasone propionate<br>* Fluticasone propionate<br>|
| Placebo Comparator: Placebo<br>Placebo matching Respimat inhaler plus placebo matching HFA MDI | Drug: Placebo<br>* Placebo matching fluticasone propionate HFA MDI<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Randomisation Baseline to the End of the 8-week Treatment Period in Trough (Pre-dose and Pre-rescue Bronchodilator) Forced Expiratory Volume in One Second (FEV1) | Mean change from randomisation baseline to the end of the 8-week treatment period in trough (pre-dose and pre-rescue bronchodilator) forced expiratory volume in one second (FEV1). | At baseline and at week 8. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Changes From Randomisation Baseline in Trough (Pre-dose and Pre-rescue Bronchodilator) Forced Vital Capacity (FVC) After 2, 4 and 8-week Treatment Periods | Mean changes from randomisation baseline in trough (pre-dose and pre-rescue bronchodilator) forced vital capacity (FVC) after 2, 4 and 8-week treatment periods. | At baseline and at week 2, 4 and 8. | 
| Mean Changes From Randomisation Baseline in Trough (Pre-dose and Pre-rescue Bronchodilator) Forced Expiratory Volume in One Second (FEV1) After 2 and 4-week Treatment Periods | Mean changes from randomisation baseline in trough (pre-dose and pre-rescue bronchodilator) forced expiratory volume in one second (FEV1) after 2 and 4-week treatment periods. | At baseline and at week 2 and 4. | 
| Mean Changes From Randomisation Baseline in Trough (Morning Pre-dose and Pre-rescue Bronchodilator) FEF25-75 After 2, 4 and 8-week Treatment Periods | Mean change from randomization baseline in through (morning pre-dose and pre-rescue bronchodilator) Forced expiratory flow between 25% and 75% of vital capacity (FEF 25-75) after 2, 4 and 8-week treatment periods. | At baseline and at week 2, 4 and 8. | 
| Mean Pre-dose (and Pre-rescue) Peak Expiratory Flow (PEF) as Assessed Via Asthma Monitor (AM2+) in the Morning and Evening, of the Last Week of the 8-week Treatment Period | Mean pre-dose (and pre-rescue) peak expiratory flow (PEF) as assessed via Asthma monitor (AM2+) in the morning and evening, of the last week of the 8-week treatment period. | 8 weeks | 
| Mean Rescue Medication Use (Daytime and Night-time) as Assessed Via Asthma Monitor (AM2+) in the Morning and Evening, of the Last Week of the 8-week Treatment Period | Mean rescue medication use (daytime and night-time) as assessed via asthma monitor (AM2+) in the morning and evening, of the last week of the 8-week treatment period. | At week 8. | 
| Mean Change From Randomisation Baseline in Asthma Control Questionnaire (ACQ-6) Scores at Subsequent Study Visits | The Asthma Control Questionnaire (ACQ) consists of 6 patient self-evaluated questions with each question in 7-point scale. The items are equally weighted and the ACQ score is the mean of 6 items and ranges between 0 (well controlled) and 6 (extremely poorly controlled). Mean scores of less than or equal to 0.75 indicate well-controlled asthma, scores between 0.76 and less than 1.5 indicate partly controlled asthma, and a score greater than or equal to 1.5 indicates uncontrolled asthma. | At baseline and at week 2, 4 and 8. | 
| Mean Change From Randomisation Baseline in Asthma Quality of Life Questionnaire (AQLQ(S)+12) Scores at Subsequent Study Visits | AQLQ(S)+12 are well established and validated questionnaires to measure control of asthma symptoms and quality of life, which is a patient-reported self-administered outcome questionnaire containing 32 items. Each item is scored on a 7-point scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire are averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life. | At baseline and at week 2, 4 and 8. | 
| Time to Withdrawal Due to First Asthma Exacerbation | Time to withdrawal due to first Asthma exacerbation. | At week 8. |