Official Title: “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”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: August 2005

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).

Intervention(s) in this Clinical Trial

• Drug: beclomethasone dipropionate plus formoterol fumarate combination
  • 100mcg beclomethasone diproprionate plus 6 mcg formoterol
• Drug: budesonide plus formoterol combination
  • 200mcg budesonide plus 6 mcg formoterol

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • chf1535
• Active Comparator: 2
  • Symbicort

Primary Measures

• Morning Peak Expiratory Flow (PEF) daily measured by patients.
  • Time Frame: morning approximately 8:00
    Safety Issue?: No

Secondary Measures

• Evening PEF measured by patients daily.
  • Time Frame: evening approximately 20:00
    Safety Issue?: No
• FEV1 measured by patients daily.
  • Time Frame: morning and evening
    Safety Issue?: No
• Standard pulmonary function tests measured at clinics at 2, 4, 8 and 12 weeks.
  • Time Frame: morning before drug intake
    Safety Issue?: No
• Change in FEV1 and PEF from pre-dose to 5, 15, 30 and 60 minutes after study drug intake at week 0 and 12.
  • Time Frame: morning post drug intake
    Safety Issue?: No
• Symptoms scores measured by patients daily.
  • Time Frame: morning and evening
    Safety Issue?: No
• symptoms'free days measured by patients daily.
  • Time Frame: daily
    Safety Issue?: No
• Use of relief salbutamol measured by patients daily.
  • Time Frame: daily
    Safety Issue?: No
• Frequency of asthma exacerbations evaluated at 2, 4, 8 and 12 weeks.
  • Time Frame: morning of the visits retrospective assessment
    Safety Issue?: No
• Adverse event and adverse drug reaction daily.
  • Time Frame: morning of visits retrospective assesment
    Safety Issue?: Yes
• ECG (with QTc interval)at 0 and 12 weeks.
  • Time Frame: morning of start and end of treatment visits
    Safety Issue?: Yes
• Vital signs (heart rate and blood pressure) at 2, 4, 8 and 12 weeks
  • Time Frame: morning of visits
    Safety Issue?: Yes
• Use of relief salbutamol.
  • Time Frame: daily
    Safety Issue?: No
• Frequency of asthma exacerbations.
  • Time Frame: at visits
    Safety Issue?: No

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.

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 Resipiratory Diseases - University of Modena and Reggio Emilia, Modena, Italy  

Information obtained from ClinicalTrials.gov on October 07, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00413387

Study ID Number: MC/PR/033011/002/03

ClinicalTrials.gov Identifier: NCT00413387

Health Authority: Poland: Ministry of Health