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®)

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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Double Blind, Double Dummy, Multinational, Multicentre, Parallel-Group Design Clinical Trial of the Efficacy and Tolerability of CHF 1535 (Beclomethasone Dipropionate 100 µg + Formoterol 6 µg) pMDI Via HFA-134a Vs. Budesonide 160 µg + Formoterol 4,5 µg Dry Powder Via Turbuhaler® (Symbicort®) in the 12-Week Treatment of Adult Patients With Moderate to Severe Persistent Asthma

Conditions
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Bronchial Asthma

Intervention / Treatment
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* Drug: beclomethasone dipropionate plus formoterol fumarate combination
* Drug: budesonide plus formoterol combination


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>chf1535 | Drug: beclomethasone dipropionate plus formoterol fumarate combination<br>* 100mcg beclomethasone diproprionate plus 6 mcg formoterol<br>|
| Active Comparator: 2<br>Symbicort | Drug: budesonide plus formoterol combination<br>* 200mcg budesonide plus 6 mcg formoterol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morning Peak Expiratory Flow (PEF) daily measured by patients. |  | morning approximately 8:00 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evening PEF measured by patients daily. |  | evening approximately 20:00 | 
| FEV1 measured by patients daily. |  | morning and evening | 
| Standard pulmonary function tests measured at clinics at 2, 4, 8 and 12 weeks. |  | morning before drug intake | 
| Change in FEV1 and PEF from pre-dose to 5, 15, 30 and 60 minutes after study drug intake at week 0 and 12. |  | morning post drug intake | 
| Symptoms scores measured by patients daily. |  | morning and evening | 
| symptoms'free days measured by patients daily. |  | daily | 
| Use of relief salbutamol measured by patients daily. |  | daily | 
| Frequency of asthma exacerbations evaluated at 2, 4, 8 and 12 weeks. |  | morning of the visits retrospective assessment | 
| Adverse event and adverse drug reaction daily. |  | morning of visits retrospective assesment | 
| ECG (with QTc interval)at 0 and 12 weeks. |  | morning of start and end of treatment visits | 
| Vital signs (heart rate and blood pressure) at 2, 4, 8 and 12 weeks |  | morning of visits | 
| Use of relief salbutamol. |  | daily | 
| Frequency of asthma exacerbations. |  | at visits | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Combinations, Inhaled therapy, Corticosteroids, Long acting bronchodilators, Beclomethasone, Formoterol, Budesonide