Official Title: “DOUBLE BLIND, 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. FLUTICASONE 125 µg + SALMETEROL 25 µg pMDI (SERETIDE®) IN THE 12-WEEK TREATMENT OF ADULT PATIENTS WITH MODERATE TO SEVERE PERSISTENT ASTHMA”

The aim of this study was to compare the efficacy and tolerability of the fixed combination beclomethasone/formoterol pMDI with that of fluticasone/salmeterol pMDI in patients with moderate to severe asthma

Study Type: Interventional

Study Design: Treatment, Randomized, Double-Blind, Active Control, Parallel Assignment, Safety/Efficacy Study

Asthma is a chronic disease that is estimated to affect over 25 million people both in the U.S. and 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 form 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 FLUTICASONE 125 µg + SALMETEROL 25 µg pMDI (SERETIDE®)

Intervention(s) in this Clinical Trial

• Drug: beclomethasone dipropionate plus formoterol fumarate combination
• Drug: fluticasone propionate plus salmeterol xinafoate combination

Primary Measures

• morning peak expiratory flow (PEF) daily measured by patients

Secondary Measures

• evening PEF measured by patients daily
• FEV1 measured by patients daily
• standard pulmonary function tests measured at clinics at 2, 4, 8 and 12 weeks
• change in FEV1 and PEF from pre-dose to 5, 15, 30 and 60 minutes after study drug intake at week 0 and 12
• symptoms scores measured by patients daily
• symptoms’ free days measured by patients daily
• use of relief salbutamol measured by patients daily
• frequency of asthma exacerbations evaluated at 2, 4, 8 and 12 weeks
• adverse events and adverse drug reactions daily
• ECG (with QTc interval) at 0 and 12 weeks
• vital signs (heart rate and blood pressure)at 2, 4, 8 and 12 weeks
• 12-hour (overnight)urinary cortisol/creatinine ratio at week 0 and 12

Inclusion Criteria:

• Clinical diagnosis of moderate to severe persistent asthma for at least 6 months, according to GINA revised version 2002 guidelines (11):
• Forced expiratory volume (FEV1) or peak expiratory flow rate (PEFR) ³ 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 mg, 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 ´ 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 ³ 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Chiesi Farmaceutici S.p.A.

Overall Clinical Trial Officials and Contacts

Leonardo M. Fabbri, MD Study Chair Department of Respiartory Diseases - University of Modena and Reggio Emilia, Modena, Italy  

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00394368

Study ID Number: MC/PR/033011/001/03

ClinicalTrials.gov Identifier: NCT00394368

Health Authority: Poland: Ministry of Health