Efficacy and Tolerability of Beclomethasone Dipropionate 100 µg + Formoterol 6 µg pMDI Via HFA-134a Vs. Budesonide 160 µg + Formoterol 4,5 µg Dry Powder Via Turbuhaler®. (Symbicort®)
Efficacy and Tolerability of Beclomethasone Dipropionate 100 µg + Formoterol 6 µg pMDI Via HFA-134a Vs. Budesonide 160 µg + Formoterol 4,5 µg Dry Powder Via Turbuhaler®. (Symbicort®)
The aim of this study was to compare the efficacy and tolerability of the fixed combination
 beclomethasone/formoterol pMDI with that of budesonide/formoterol dry powder via Turbuhaler.
Asthma is a chronic disease that is estimated to affect over 25 million people both in the
 U.S. and in Europe (i.e. approximately 10% of the total population). Pharmacological therapy
 is used to treat reversible airway obstruction, inflammation and hyper-reactivity.
 Medications include preventive treatments in forms of antinflammatory/antiallergic agents
 (i.e. glucocorticosteroids, leukotriene antagonists, cromolyn sodium) and reliever
 treatments, in forms of bronchodilators (i.e. β-adrenergic agonists, anticholinergics). In
 patients treated with inhaled glucocorticosteroids whose asthma is not fully controlled,
 national and international guidelines recommend a stepwise approach. Recent evidence-based
 clinical trials show that the addition of a LABA to inhaled glucocorticosteroids is more
 beneficial in terms of asthma control than increasing the dose of corticosteroids alone.

 COMPARISONS: CHF 1535 (BECLOMETHASONE DIPROPIONATE 100 µg+ FORMOTEROL 6 µg) pMDI via HFA-134a
 compared to SYMBICORT (BUDESONIDE 160 µg + FORMOTEROL 4,5 µg).
Inclusion Criteria:

 -  Clinical diagnosis of moderate to severe persistent asthma for at least 6 months,
 according to GINA revised version 2002 guidelines:

 -  Forced expiratory volume (FEV1) or peak expiratory flow rate (PEFR) > 50% and <
 80% of the predicted normal;

 -  Asthma not adequately controlled with the current therapies, defined as presence
 of daily asthma symptoms > once a week and night-time asthma symptoms > twice a
 month, and daily use of short-acting β2-agonists. These findings are to be based
 on recent medical history and are to be confirmed in the 2-week run-in period.

 -  Treatment with inhaled corticosteroids at a daily dose ≤ 1000 μg of BDP or
 equivalent. The daily dose of inhaled corticosteroids taken at visit 1 will
 be assessed taking into account the following ratios between the doses of
 the different steroids: fluticasone propionate : BDP CFC = 1 : 2; budesonide
 : BDP CFC = 4 : 5; flunisolide : BDP CFC = 1 : 1. The ratios between inhaled
 steroids are irrespective of the formulations (i.e. spray aerosol or powder)
 used. When BDP is given in the new extra-fine HFA-134a formulation (as
 QVAR®, 3M Healthcare), the ratio with BDP CFC is set as 2 : 5. Therefore,
 the maximum allowed daily dose of inhaled corticosteroids at study entry
 will be: budesonide 800 μg, fluticasone propionate 500 μg, flunisolide 1000
 μg, BDP 1000 mcg, BDP HFA extra-fine 400 μg.

 -  Positive response to the reversibility test in the screening visit, defined
 as an increase of at least 12% (or, alternatively, of 200mL) from baseline
 value in the measurement of FEV1 30 minutes following 2 puffs (2 x 100 µg)
 of inhaled salbutamol administered via pMDI. The reversibility test can be
 avoided in patients having a documented positive response in the previous 6
 months.

 -  A co-operative attitude and ability to be trained to correctly use the
 metered dose inhalers and to complete the diary cards.

 -  Written informed consent obtained.

 -  At the end of the 2-week run-in period, the presence of daily asthma
 symptoms (of at least mild intensity) and nighttime asthma symptom (of at
 least mild intensity) > once a week, as well as of daily use of relief
 salbutamol is to be confirmed by reviewing the diary cards for run-in

 Exclusion Criteria:

 -  Inability to carry out pulmonary function testing;

 -  Diagnosis of Chronic Obstructive Pulmonary Disease (COPD) as defined by the
 National Heart Lung and Blood Institute/World Health Organisation (NHLBI/WHO)
 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (30);

 -  History of near fatal asthma;

 -  Evidence of severe asthma exacerbation or symptomatic infection of the airways in
 the previous 8 weeks;

 -  Three or more courses of oral corticosteroids or hospitalisation due to asthma
 during the previous 6 months;

 -  Patients treated with long-acting β2-agonists, anticholinergics and
 antihistamines during the previous 2 weeks, with topical or intranasal
 corticosteroids and leukotriene antagonists during the previous 4 weeks;

 -  Patients who have changed their dose of inhaled corticosteroids during the
 previous 4 weeks, or treatment with inhaled corticosteroids at a daily dose >
 1000 μg of BDP or equivalent (except for extra-fine formulations, see inclusion
 criteria);

 -  Current smokers or recent (less than one year) ex-smokers, defined as smoking at
 least 10 cigarettes/day;

 -  History or current evidence of heart failure, coronary artery disease, myocardial
 infarction, severe hypertension, cardiac arrhythmias;

 -  Diabetes mellitus;

 -  Percutaneous transluminal coronary angioplasty (PTCA) or coronary artery by-pass
 graft (CABG) during the previous six months;

 -  Patients with an abnormal QTc interval value in the ECG test, defined as > 450
 msec in males or > 470 msec in females;

 -  Other haemodynamic relevant rhythm disturbances (including atrial flutter or
 atrial fibrillation with ventricular response, bradycardia (≤ 55 bpm), evidence
 of atrial-ventricular (AV) block on ECG of more than 1st degree;

 -  Clinically significant or unstable concurrent diseases: uncontrolled
 hyperthyroidism, significant hepatic impairment, poorly controlled pulmonary
 (tuberculosis, active mycotic infection of the lung), gastrointestinal (e.g.
 active peptic ulcer), neurological or haematological autoimmune diseases;

 -  Cancer or any chronic diseases with prognosis < 2 years;

 -  Pregnant or lactating females or females at risk of pregnancy, i.e. those not
 demonstrating adequate contraception (i.e. barrier methods, intrauterine devices,
 hormonal treatment or sterilization). A pregnancy test is to be carried out in
 women of a fertile age.

 -  History of alcohol or drug abuse;

 -  Patients treated with monoamine oxidase inhibitors, tricyclic antidepressants or
 beta-blockers as regular use;

 -  Allergy, sensitivity or intolerance to study drugs and/or study drug formulation
 ingredients;

 -  Patients unlikely to comply with the protocol or unable to understand the nature,
 scope and possible consequences of the study;

 -  Patients who received any investigational new drug within the last 12 weeks;

 -  Patients who have been previously enrolled in this study;

 -  At the end of the run-in period, patients will not be admitted to the treatment
 period in the case of an increase of PEFR (L/sec) measured at the clinics at the
 end of the run-in period > 15% in respect of values measured at the start of the
 run-in period;

 -  Patients with asthma exacerbations during the run-in period will also be excluded
 from the study.