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®)

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 Overview

• Status: Completed
• Conditions: Bronchial Asthma
• Intervention / Treatment: Drug: beclomethasone dipropionate plus formoterol fumarate combination; Drug: budesonide plus formoterol combination

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 219
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria
    • Ambulance For Paediatric and Pulmonology
• Poland
  • Bielsko-Biala, Poland
    • Nzoz "Medex"Poradnia Alergologiczna
  • Krakow, Poland
    • Centrum Uslug Medycznych
  • Lodz, Poland
    • Centrum Alergologii
  • Lodz, Poland
    • Prywatny Gabinet Lekarski
  • Lodz, Poland
    • Uniwersytet Medyczny
  • Wroclaw, Poland
    • NZOZ Lekarze Specjalisci
• Ukraine
  • Dniepropetrovsk, Ukraine
    • Internal Medicine Department, Dniepropetrovsk State Medical Academy. City Clinical Hospital no. 4
  • Kharkiv, Ukraine
    • Institute of Therapy, Ukranian Academy of Medical Science. Pulmonological Departement
  • Kharkov, Ukraine
    • Kharkov Regional Clinical Hospital. Pulmonological and Allergological Department
  • Kiev, Ukraine
    • Institute of Phthisiology and Pulmonology Academy of Medical Science of the Ukraine, Pulmonology Departement
  • Kiev, Ukraine
    • Institute of Phthisiology and Pulmonology Academy of Medical Science of the Ukraine. Department of Diagnostic, Therapy and Clinical Pharmacology of Lung Diseases
  • Kiev, Ukraine
    • Kiev Medical Academy of Postdiploma Education. Department of Medical Genetics, Clinical Immunology and Allergology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; chf1535	Drug: beclomethasone dipropionate plus formoterol fumarate combination; 100mcg beclomethasone diproprionate plus 6 mcg formoterol
Active Comparator: 2; Symbicort	Drug: budesonide plus formoterol combination; 200mcg budesonide plus 6 mcg formoterol

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Chiesi Farmaceutici S.p.A.
• Investigators: Study Chair: Leonardo M. Fabbri, MD, Department of Resipiratory Diseases - University of Modena and Reggio Emilia, Modena, Italy; Study Chair: Maurizio A. Vignola, MD, Institute of Lung Pathophysiology, National Research Council, Palermo, Italy

Publications and helpful links

General Publications

• Papi A, Paggiaro PL, Nicolini G, Vignola AM, Fabbri LM; Inhaled Combination Asthma Treatment versus SYmbicort (ICAT SY) Study Group. Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma. Eur Respir J. 2007 Apr;29(4):682-9. doi: 10.1183/09031936.00095906. Epub 2006 Nov 15. Erratum In: Eur Respir J. 2007 Jun;29(6):1286. Eur Respir J. 2008 Sep;32(3):822.

Study record dates

Study Major Dates

• Study Start: September 1, 2004
• Primary Completion (Actual): August 1, 2005
• Study Completion (Actual): October 1, 2005

Study Registration Dates

• First Submitted: December 18, 2006
• First Submitted That Met QC Criteria: December 18, 2006
• First Posted (Estimate): December 19, 2006

Study Record Updates

• Last Update Posted (Actual): August 3, 2020
• Last Update Submitted That Met QC Criteria: July 30, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Asthma; Formoterol; Corticosteroids; Budesonide; Beclomethasone; Inhaled therapy; Combinations; Long acting bronchodilators
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Budesonide; Beclomethasone; Formoterol Fumarate
• Other Study ID Numbers: MC/PR/033011/002/03