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

BACKGROUND: According to international treatment guidelines, inhaled rapid-acting ß2 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 ß2 agonist (formoterol) with a short-acting ß2 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 ß2 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.