Clinical trial NCT00413387: 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®)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Bronchial Asthma
Keywords: Asthma
Combinations
Inhaled therapy
Corticosteroids
Long acting bronchodilators
Beclomethasone
Formoterol
Budesonide
Lead sponsor: Chiesi Farmaceutici S.p.A.
Sponsor class: INDUSTRY
First posted: 2006-12-19
Enrollment: 219
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Morning Peak Expiratory Flow (PEF) daily measured by patients.
timeFrame: morning approximately 8:00
Secondary outcomes:
measure: Evening PEF measured by patients daily.
timeFrame: evening approximately 20:00
measure: FEV1 measured by patients daily.
timeFrame: morning and evening
measure: Standard pulmonary function tests measured at clinics at 2, 4, 8 and 12 weeks.
timeFrame: morning before drug intake
measure: Change in FEV1 and PEF from pre-dose to 5, 15, 30 and 60 minutes after study drug intake at week 0 and 12.
timeFrame: morning post drug intake
measure: Symptoms scores measured by patients daily.
timeFrame: morning and evening
measure: symptoms'free days measured by patients daily.
timeFrame: daily
measure: Use of relief salbutamol measured by patients daily.
timeFrame: daily
measure: Frequency of asthma exacerbations evaluated at 2, 4, 8 and 12 weeks.
timeFrame: morning of the visits retrospective assessment
measure: Adverse event and adverse drug reaction daily.
timeFrame: morning of visits retrospective assesment
measure: ECG (with QTc interval)at 0 and 12 weeks.
timeFrame: morning of start and end of treatment visits
measure: Vital signs (heart rate and blood pressure) at 2, 4, 8 and 12 weeks
timeFrame: morning of visits
measure: Use of relief salbutamol.
timeFrame: daily
measure: Frequency of asthma exacerbations.
timeFrame: at visits
Other outcomes:
Locations:
city: Wien
country: Austria
facility: Ambulance For Paediatric and Pulmonology
city: Bielsko-Biala
country: Poland
facility: Nzoz "Medex"Poradnia Alergologiczna
city: Krakow
country: Poland
facility: Centrum Uslug Medycznych
city: Lodz
country: Poland
facility: Centrum Alergologii
city: Lodz
country: Poland
facility: Prywatny Gabinet Lekarski
city: Lodz
country: Poland
facility: Uniwersytet Medyczny
city: Wroclaw
country: Poland
facility: Nzoz Lekarze Specjalisci
city: Dniepropetrovsk
country: Ukraine
facility: Internal Medicine Department, Dniepropetrovsk State Medical Academy. City Clinical Hospital no. 4
city: Kharkiv
country: Ukraine
facility: Institute of Therapy, Ukranian Academy of Medical Science. Pulmonological Departement
city: Kharkov
country: Ukraine
facility: Kharkov Regional Clinical Hospital. Pulmonological and Allergological Department
city: Kiev
country: Ukraine
facility: Institute of Phthisiology and Pulmonology Academy of Medical Science of the Ukraine, Pulmonology Departement
city: Kiev
country: Ukraine
facility: Institute of Phthisiology and Pulmonology Academy of Medical Science of the Ukraine. Department of Diagnostic, Therapy and Clinical Pharmacology of Lung Diseases
city: Kiev
country: Ukraine
facility: Kiev Medical Academy of Postdiploma Education. Department of Medical Genetics, Clinical Immunology and Allergology
Study officials:
affiliation: Department of Resipiratory Diseases - University of Modena and Reggio Emilia, Modena, Italy
name: Leonardo M. Fabbri, MD
role: STUDY_CHAIR
affiliation: Institute of Lung Pathophysiology, National Research Council, Palermo, Italy
name: Maurizio A. Vignola, MD
role: STUDY_CHAIR
References:
citation: 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.