Efficacy and Safety Study Comparing Respimat ® Budesonide With Turbohaler ® Budesonide in Symptomatic Adult Moderate to Severe Asthmatics Requiring Inhaled Corticosteroids and Bronchodilator Therapy

A Twelve-week, Efficacy and Safety Study Comparing Respimat ® Budesonide (100 and 200 mcg, 2 Puffs Bid) With Turbohaler ® Budesonide (200 mcg, 2 Puffs Bid) in Symptomatic Adult Moderate to Severe Asthmatic Requiring Inhaled Corticosteroids and Bronchodilator Therapy.

To establish that at least one of the two doses of Budesonide, as an ethanolic solution inhaled from the Respimat ® inhaler (100 and 200 mcg, 2 puffs bid) for a 12-week study period in symptomatic moderate to severe asthmatic patients, gives a therapeutic response, which is not inferior to that obtained from the dose of Budesonide inhaled from the Turbohaler ® (200 mcg, 2 puffs bid) and that the safety profile is at least as good

Inclusion Criteria:

• Patients of either sex aged 18 - 65 years (inclusive)

• Non-smokers or ex smokers. HAVING stopped smoking >= 1 year prior to screening and with a smoking history of <= 10 pack years

• Diagnosis of MODERATE to SEVERE bronchial asthma with a duration of at least 6 months with the inclusion criteria 4 plus 5 and a diagnosis of asthma according to the WHO guidelines for at least one year

• Increase of asthma symptoms (wheeze, cough, shortness of breath, chest tightness) when exposure to any of the following stimuli: cold, dry air, dust, smoke, exercise and allergens

• Patients on a stable dosage of either

  • 800 mcg <= BDP (beclomethasone dipropionate) <= 1600 mcg daily or other inhaled steroid with or without inhaled long acting β2-agonists or oral xanthines at screening visit 1 for the past 4 weeks and short acting β2-agonists prn for the past 6 weeks or
  • 400 mcg <= BDP < 800 mcg daily or other inhaled steroid and inhaled long-acting β2-agonists (or oral xanthines), at screening visit 1 for the past 4 weeks and short acting β2-agonists prn for the past 6 weeks

• FEV1 >= 60% but <= 90 % predicted normal at visit 1 after withholding respiratory drugs as per section 4.2.1. Predicted normal values are based on the guidelines for standardized function testing of the European Community for Coal and Steel (ECCS)

  • Males: FEV1 pred. (L) = 4.30 x Height (m) - 0.029 x Age (yrs) - 2.49
  • Females: FEV1 pred. (L) = 3.95 x Height (m) - 0025 x Age (yrs) - 2.60

• Patient must demonstrate an improvement in FEV 1 >= 12% above baseline and an absolute change of at least 200 ml within 30 minutes after administration of two puffs of salbutamol MDI (metered dose inhaler) (100 mcg per puff). Historical data within the previous 6 months are acceptable

• Patients must be able to be trained in the proper use of MDI, Turbohaler® and Respimat® and to perform technically satisfactory pulmonary function tests

• Patients must be willing and be able to give informed written consent prior to participation in the trial i.e. prior to pre-study wash-out of their usual pulmonary medications and are willing and able to complete the entire study as described in the protocol

Exclusion Criteria:

• Patients with a history of seasonal exacerbation of asthma suggesting seasonal asthma which would not be controlled by medication allowed in the protocol (see 4.2.2) and likely to occur during the time period that the patients will be in the study

• History of cardiovascular, renal, neurologic, liver, immunologic or endocrine dysfunction if they are clinically significant. A clinically significant disease is defined as one which in the opinion of the investigator may either put the patient at risk because of participation in the study or a disease which may influence the results of the study or the patient's ability to participate in the study

• Patients with a recent history (<= 1 year) of myocardial infarction and/or (<= 3 years) of heart failure or patients with any cardiac arrhythmia requiring drug therapy

• History of cancer within the past 5 years excluding treated basal cell carcinoma

• Patients with current psychiatric disorders which would interfere with the conduct of the trial

• Patients with history or presence of glaucoma and/or posterior subcapsular cataracts

• Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criteria

• Patients with active tuberculosis with indication for treatment

• Patients with a history of cystic fibrosis, bronchiectasis, chronic bronchitis or emphysema

• Patients with active rhinitis requiring treatment with intranasal steroids and/or ketotifen

• Patients with upper respiratory tract infection in the past 6 weeks prior to screening visit 1 resulting in exacerbation of asthma symptoms

• Patients with unstable asthma as defined by any of the following: having required hospitalization for asthma exacerbation in the past 6 months, or a history of life-threatening asthma exacerbation resulted in respiratory failure and requiring intubation or ICU admission of longer than 24 hours in the past 5 years

• Patients with clinically signification abnormal baseline haematology, blood chemistry or urinalysis (if the abnormality defines a disease listed as an exclusion criterion)

• Patients with any of the abnormal laboratory values below:

  • SGOT (serum glutamate oxaloacetate transaminase) > 200% of the upper limit of the normal range
  • SGPT (serum glutamate pyruvate transaminase) > 200% of the upper limit of the normal range
  • Creatinine > 125% of the upper limit of the normal range
  • Bilirubin > 150% of the upper limit of the normal range, with the exception of Gilbert's disease will be excluded regardless of the clinical condition

• Patients with known intolerance hypersensitivity to one of the aerosolized products including inhaled steroids (budesonide and beclomethasone dipropionate), salbutamol, ethylenediaminetetraacetic acid, ethanol, citric or oleic acid

• Patients using oral or other systemic (intramuscular or intravenous) corticosteroids in the past 8 weeks or other potent immunosuppressant (i.e. methotrexate) medication in the past 3 months

• Patients using beta blocker therapy, ACE inhibitors (an exception was provided if the ACE inhibitor have been at a stable dose for six months with no reported incidence of cough) monoamine oxidase inhibitors, tricyclic antidepressants, cromolyn or nedocromil sodium, ketotifen, astemizole or any other antihistamine drug, or a combination of an inhaled long acting β2-agonist plus oral xanthine or having received an influenza vaccine within 1 week of Screening Visit 1

• Patients on nebulised β2-agonists, anticholinergics or steroids in the 4 weeks before screening visit 1

• If a patient is on allergen desensitization therapy, this should have been as a maintenance dose for the previous 3 months and continued throughout the treatment period

• Unstable respiratory medication dosage in the last 4 weeks prior to screening visit 1

• Patients with a significant history and/or active alcohol or drug abuse. Significant is defined as that which in the opinion of the investigator may either put the patient at risk because of participation in the study or may influence the results of the study or the patient's ability to participate in the study

• Patients who have taken any investigational drug, one month or six half-lives (whichever is greater) prior to the Screening Visit

• Pregnant or nursing women and sexually active women with childbearing potential not using a medically approved method of contraception (i.e. oral contraceptives, intrauterine devices, diaphragm, Norplant® or double-barrier)

• Previous participation in the randomised period of this study