Articles
Beclometasone–formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial

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Summary

Background

According to international treatment guidelines, inhaled rapid-acting β2 agonists should be used for the control of symptoms in patients with asthma. We compared the efficacy and safety of an extrafine combination inhaler containing a corticosteroid (beclometasone) plus a rapid-onset, long-acting β2 agonist (formoterol) with a short-acting β2 agonist (salbutamol) as reliever strategies in patients taking beclometasone–formoterol combination as maintenance treatment.

Methods

In a double-blind trial undertaken in 183 centres in 14 European countries over 48 weeks, patients (aged ≥18 years) with asthma that was not fully controlled, with a forced expiratory volume in 1 s (FEV1) of at least 60% predicted, had a 2-week run in. During this period, patients were treated with a combination of beclometasone 100 μg and formoterol 6 μg per one inhalation twice daily plus salbutamol 100 μg as required delivered by use of a pressurised metered-dose inhaler. They were then randomly assigned in a 1:1 ratio with a computer-generated randomisation list to receive beclometasone 100 μg plus formoterol 6 μg or salbutamol 100 μg as reliever in addition to maintenance with beclometasone 100 μg plus formoterol 6 μg twice daily. Primary outcome was the time to first severe exacerbation (admission to hospital or visit to emergency department, or use of systemic steroids for ≥3 consecutive days). Secondary outcomes were number of severe exacerbations (events per 100 patients per year), time to and number of mild exacerbations, additional exacerbation variables, lung function, symptom scores, and asthma control. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00861926.

Findings

1714 patients were randomly assigned to the as-needed beclometasone–formoterol (n=857) and as-needed salbutamol groups (n=857), and 1701 were analysed (852 and 849, respectively). 326 severe exacerbations were reported by 251 patients during the study, and 99 versus 152 patients had at least one exacerbation during the 48 weeks, respectively. Compared with beclometasone–formoterol plus salbutamol as needed, beclometasone–formoterol for both maintenance and reliever treatment significantly increased the time to first exacerbation (209 days vs 134 days) by 75 days, with a 36% reduction in risk (hazard ratio 0·64 [95% CI 0·49 to 0·82]; p=0·0005), and the estimated probability was 12% and 18%, respectively (p=0·0003). The number of days with mild asthma exacerbations was also lower with as-needed beclometasone–formoterol than with as-needed salbutamol (56·04 days per patient per year vs 65·11 days per patient per year; 0·86 [0·76 to 0·98]; p=0·021). From the run-in period to week 48, both treatments improved symptoms (mean change −1·59 [–1·94 to −1·25] in the as-needed beclometasone–formoterol group vs −1·44 [–1·78 to −1·10] in the as-needed salbutamol group, difference −0·15 [–0·60 to 0·30]; p=0·507), percentage of asthma control days (9·5% [7·3 to 11·8] vs 10·9% [8·7 to 13·1], respectively, −1·4 [–4·3 to 1·6]; p=0·359), use of reliever (–0·29 [–0·38 to −0·20] vs −0·27 [–0·36 to −0·19], respectively, −0·02 [–0·13 to 0·10]; p=0·794), and lung function (FEV1, 0·090 [0·060 to 0·120] vs 0·090 [0·060–0·120], respectively, 0·001 [–0·040 to 0·040]; p=0·969), and were well tolerated (patients with serious adverse events, 32 [4%] and 41 [5%], respectively).

Interpretation

Our results lend support to the use of the combination of a single inhaled corticosteroid plus a rapid-onset, long-acting β2 agonist for maintenance and relief in patients with moderate to severe asthma and provide encouraging data for the formulation of beclometasone–formoterol for this use.

Funding

Chiesi Farmaceutici.

Introduction

International treatment guidelines for asthma1, 2 recommend the combination of an inhaled corticosteroid and a long-acting β2 agonist with the addition of a short-acting β2 agonist for relief of symptoms in patients who are not adequately controlled with an inhaled corticosteroid alone. All available combinations of inhaled corticosteroid plus long-acting β2 agonist have similar efficacies in patients with moderate-to-severe asthma when given with a short-acting β2 agonist as reliever.3, 4

Budesonide–formoterol is more effective in reducing asthma exacerbations when given as maintenance and reliever than when given regularly as maintenance with a short-acting β2 agonist terbutaline or the rapid-onset, long-acting β2 agonist formoterol as reliever.5, 6 These findings suggest that treatment of symptoms with an inhaled corticosteroid and rapid-onset, long-acting β2 agonist combination might provide better clinical control than a short-acting β2 agonist alone for symptom relief. Whether patients should be left in need of rescue medication is debatable,7 partly because of concerns about the safety of a long-acting β2 agonist in asthma.8

The use of regular inhaled beclometasone dipropionate–formoterol combination in an extrafine hydrofluoroalkane formulation plus salbutamol as a reliever is non-inferior to equivalent doses of both regular inhaled budesonide–formoterol3 or fluticasone–salmeterol combinations plus salbutamol as reliever4 in improving lung function in patients with asthma uncontrolled with inhaled corticosteroid alone. The clinical effectiveness of low-dose extrafine beclometasone–formoterol combination in a single pressurised metered-dose inhaler (pMDI) as maintenance led us to speculate that a similar effectiveness could also be shown if this combination was used as a reliever medication, particularly considering the increased penetration of particles in the peripheral airways, a site of important acute inflammation during exacerbations. This method of treating asthma, initially introduced as SMART (Single inhaler Maintenance And Reliever Therapy), seems to be a generally effective management strategy in patients with asthma, with particular effectiveness in the prevention of exacerbations. It might also have ramifications for the development of other affordable formulations worldwide. However, whether the extrafine beclometasone–formoterol combination is suitable as both maintenance and relief of asthma exacerbations has never been tested.

The main objective in our study was to investigate whether the inhaled extrafine hydrofluoroalkane fixed combination of beclometasone 100 μg and formoterol 6 μg was more effective when given as both maintenance and reliever than when given as maintenance with a short-acting β2 agonist as reliever in adults with asthma that was not fully controlled by inhaled corticosteroid alone or low-dose inhaled corticosteroid plus a long-acting β2 agonist.

Section snippets

Study design and patients

The study was a multinational, multicentre, double-blind, randomised, parallel group, active-controlled trial. Additional details about the study design are provided in the appendix p 3. Patients were recruited between March 20, and Nov 20, 2009, in 183 centres in 14 European countries (appendix p 2). They were eligible for inclusion if they were aged 18 years or older, and had a clinical diagnosis of asthma for at least 6 months, prebronchodilator forced expiratory volume in 1 s (FEV1) of at

Results

The start and end dates for the study were March 20, 2009, and Dec 7, 2010, respectively. Figure 1 shows the trial profile; 2079 patients signed the informed consent and entered the study, 1714 were randomly assigned to the as-needed beclometasone–formoterol and as-needed salbutamol groups, and 1701 patients were included in the efficacy analysis (intention-to-treat population). The safety population consisted of all randomly assigned patients who took at least one dose of study medication (854

Discussion

We have shown that an extrafine inhaled combination of beclometasone 100 μg and formoterol 6 μg is more effective in reducing asthma exacerbations when given as both maintenance and reliever treatment than when given only as maintenance with salbutamol 100 μg as needed to patients who do not have fully controlled asthma. The two treatment regimens are equally safe and well tolerated. These findings confirm the efficacy of the inhaled corticosteroid (beclometasone) given as reliever with a

References (30)

  • A Papi et al.

    Beclomethasone/formoterol vs fluticasone/salmeterol inhaled combination in moderate to severe asthma

    Allergy

    (2007)
  • PM O'Byrne et al.

    Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma

    Am J Respir Crit Care Med

    (2005)
  • KR Chapman et al.

    Single maintenance and reliever therapy (SMART) of asthma: a critical appraisal

    Thorax

    (2010)
  • ST Weiss

    FDA LABA warning: is there anything new here?

    Clin Pharmacol Ther

    (2010)
  • HK Reddel et al.

    An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice

    Am J Respir Crit Care Med

    (2009)
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