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BackgroundThe Global Initiative for Asthma recommends as-needed inhaled corticosteroid (ICS)-formoterol as an alternative to maintenance ICS plus short-acting beta2-agonist (SABA) reliever at Step 2 of their stepwise treatment algorithm. Our aim was to assess the efficacy and safety of these two treatment regimens, with a focus on severe exacerbation prevention.MethodsWe performed a systematic review and meta-analysis of all randomised controlled trials (RCTs) comparing as-needed ICS-formoterol with maintenance ICS plus SABA. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from database inception to 12 December 2019. The primary outcome was time to first severe exacerbation. RCTs were excluded if they used as-needed budesonide-formoterol as part of a maintenance and reliever regimen, or did not report on severe exacerbations. The review is registered with PROSPERO (CRD42020154680).ResultsFour RCTs (n=8065 participants) were included in the analysis. As-needed ICS-formoterol was associated with a prolonged time to first severe exacerbation (hazard ratio 0.85, 95%CI 0.73 to 1.00; p=0.048) and reduced daily ICS dose (mean difference −177.3 mcg, 95%CI −182.2 to −172.4). Asthma symptom control was worse in the as-needed group (ACQ-5 mean difference 0.12, 95%CI 0.09 to 0.14), though did not meet the minimal clinically important difference of 0.50 units. There was no significant difference in serious adverse events (odds ratio 1.07 95%CI 0.84 to 1.36).ConclusionAs-needed ICS-formoterol offers a therapeutic alternative to maintenance low-dose ICS plus SABA in asthma and may be the preferred option if severe exacerbation prevention is the primary aim of treatment.

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ObjectiveTo compare bronchodilator response after to salbutamol and budesonide/formoterol in adults with stable asthma.MethodsA double-blind, cross-over, single-centre, placebo-controlled, non-inferiority trial. Adults with stable asthma were randomised to different orders of two treatment regimens: two actuations of placebo via MDI and one actuation of budesonide/formoterol 200/6 µg via turbuhaler; and one actuation of placebo turbuhaler and two actuations of salbutamol 100 µg via MDI. The primary outcome measure was FEV1 after 2 min. Secondary outcome measures included FEV1, mBorg Dyspnoea Scale score and visual analogue score for breathlessness over 30 min.ResultsForty-nine of 50 potential participants were randomised. One participant withdrew following the first intervention visit and another could not be randomised due to COVID-19 restrictions. The mean (SD) change from baseline FEV1 2 min after treatment administration for budesonide/formoterol and salbutamol was 0.08 (0.14) L, n=49, and 0.17 (0.18) L, n=48, respectively, mean (95% CI) paired difference of −0.097 L (−0.147 to −0.047), p=0.07, against a non-inferiority bound of −0.06 L. In the secondary analysis, FEV1 over 30 min was lower for budesonide/formoterol compared with salbutamol, difference (95% CI): −0.10 (−0.12 to −0.08) L, p<0.001. There were no differences in Visual Analogue Scale score or mBorg Dyspnoea Scale score between treatments.ConclusionThe results do not support the primary hypothesis of non-inferiority at the boundary of −0.06 L for the difference between budesonide/formoterol 200/6 µg compared with salbutamol 200 µg for FEV1 at 2 min, and could be consistent with inferiority with a p value of 0.07. For the secondary analysis of FEV1 measurements over time, the FEV1 was higher with salbutamol.Trial registration numberAustralian and New Zealand Clinical Trials Registry (ACTRN 12619001387112).

BackgroundAsthma is the most common chronic disease in children, many of whom are managed solely with a short-acting β2-agonist (SABA). In adults, the evidence that budesonide-formoterol as sole reliever therapy markedly reduces the risk of severe exacerbations compared with SABA alone has contributed to the Global Initiative for Asthma recommending against SABA monotherapy in this population. The lack of current evidence in children means it is unknown whether these findings are also relevant to this demographic. High-quality randomised controlled trials (RCTs) are needed.ObjectiveTo determine the efficacy and safety of as-needed budesonide-formoterol therapy compared with as-needed salbutamol in children aged five to 15 years with mild asthma, who only use a SABA.MethodsA 52-week, open-label, parallel group, phase III, RCT will recruit 380 children aged five to 15 years with mild asthma (ACTRN12620001091998). Participants will be randomised 1:1 to either budesonide-formoterol (Symbicort Rapihaler®) 50/3mcg, two actuations as needed or salbutamol (Ventolin®) 100mcg, two actuations as needed. The primary outcome is asthma attacks as rate per participant per year. Secondary outcomes assess asthma control, lung function, exhaled nitric oxide, and treatment step change. A cost-effectiveness analysis is also planned.ConclusionThis is the first RCT to assess the safety and efficacy of as-needed budesonide-formoterol in children with mild asthma. The results will provide a much-needed evidence base for the treatment of mild asthma in children.