Clinical trial NCT00394368: EFFICACY AND TOLERABILITY OF BECLOMETHASONE DIPROPIONATE 100 µg + FORMOTEROL 6 µg pMDI VIA HFA-134a vs. FLUTICASONE 125 µg + SALMETEROL 25 µg pMDI
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Bronchial Asthma
Keywords: asthma
combinations
inhaled therapy
corticosteroids
long acting bronchodilators
salmeterol
beclomethasone
formoterol
fluticasone
Lead sponsor: Chiesi Farmaceutici S.p.A.
Sponsor class: INDUSTRY
First posted: 2006-11-01
Enrollment: 180
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 fluticasone/salmeterol pMDI in patients with moderate to severe asthma

Detailed description: 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®)

Eligibility criteria: 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.

Primary outcomes:
measure: morning peak expiratory flow (PEF) daily measured by patients
Secondary outcomes:
measure: evening PEF measured by patients daily
measure: FEV1 measured by patients daily
measure: standard pulmonary function tests measured at clinics at 2, 4, 8 and 12 weeks
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
measure: symptoms scores measured by patients daily
measure: symptoms' free days measured by patients daily
measure: use of relief salbutamol measured by patients daily
measure: frequency of asthma exacerbations evaluated at 2, 4, 8 and 12 weeks
measure: adverse events and adverse drug reactions daily
measure: ECG (with QTc interval) at 0 and 12 weeks
measure: vital signs (heart rate and blood pressure)at 2, 4, 8 and 12 weeks
measure: 12-hour (overnight)urinary cortisol/creatinine ratio at week 0 and 12
Other outcomes:
Locations:
city: Gdansk
country: Poland
facility: Nzoz "Non nocere"
city: Gdansk
country: Poland
facility: Outpatients Department of Allergology "Medcare"
city: Krakow
country: Poland
facility: Nzoz "Krakow Poludnie" Pulmonologic Policlinic
city: Krakow
country: Poland
facility: Specialist Allergy Center All-Med
city: Warszawa
country: Poland
facility: Private Institute of Health and Beauty
city: Wroclaw
country: Poland
facility: Dolnoslaski Centre of Medical Diagnostic "Dolmed"
city: Kharkiv
country: Ukraine
facility: Kharkiv City Clinical Hospital 13 Pulmonological Department
city: Kiev
country: Ukraine
facility: Institute of Phthisiology and Pulmonology, Academy of Medical Science of Ukraine, Depatment of Diagnostic, Therapy and Clinical Pharmacology of Lung Disease
city: Kiev
country: Ukraine
facility: Republican Clinical Hospital Institute of Phthisiology and Pulmonology Academy of Medical Science of Ukraine, Clinical Functional Department
city: Kiev
country: Ukraine
facility: Republican Clinical Hospital, Institute of Phthisiology and Pulmonology, Academy of Medical Science of Ukraine, Pulmonology Department
city: Lugansk
country: Ukraine
facility: Department of Hospital Therapy of Lugansk, State Medical Institute Lugansk, Regional Clinical Hospital
city: Yalta
country: Ukraine
facility: Department Therapy of Bronchopulmonary Pathology in Adults, Crimean Republic Research Institute of Physical Methods of Therapy and Medical Climatology
Study officials:
affiliation: Department of Respiartory 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: Gerzeli S, Rognoni C, Quaglini S, Cavallo MC, Cremonesi G, Papi A. Cost-effectiveness and cost-utility of beclomethasone/formoterol versus fluticasone propionate/salmeterol in patients with moderate to severe asthma. Clin Drug Investig. 2012 Apr 1;32(4):253-65. doi: 10.2165/11598940-000000000-00000.
citation: Papi A, Paggiaro P, Nicolini G, Vignola AM, Fabbri LM; ICAT SE study group. Beclomethasone/formoterol vs fluticasone/salmeterol inhaled combination in moderate to severe asthma. Allergy. 2007 Oct;62(10):1182-8. doi: 10.1111/j.1398-9995.2007.01493.x.