Abstract: Four studies randomly assigning 9130 people with asthma were included; two were six-month double-blind studies, and two were 12-month open-label studies. No trials included children younger than age 12. Trials included more women than men, with mean age ranging from 38 to 45, and mean baseline steroid dose (inhaled beclomethasone (BDP) equivalent) from 636 to 888 μg. Mean baseline forced expiratory volume in one second (FEV1) percentage predicted was between 70% and 73% in three of the trials, and 96% in another. All studies were funded by AstraZeneca and were generally free from methodological biases, although the two open-label studies were rated as having high risk for blinding, and some evidence of selective outcome reporting was found. These possible sources of bias did not lead us to downgrade the quality of the evidence. The quantity of inhaled steroids, including puffs taken for relief from symptoms, was consistently lower for SiT than for the comparison groups. Separate data for exacerbations leading to hospitalisations, to emergency room (ER) visits or to a course of oral steroids could not be obtained. Compared with higher fixed-dose combination inhalers, fewer people using SiT had exacerbations requiring hospitalisation or a visit to the ER (odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57 to 0.90; I2 = 0%, P = 0.66), and fewer had exacerbations requiring a course of oral corticosteroids (OR 0.75, 95% CI 0.65 to 0.87; I2 = 0%, P = 0.82). This translates to one less person admitted to hospital or visiting the ER (95% CI 0 to 2 fewer) and two fewer people needing oral steroids (95% CI 1 to 3 fewer) compared with fixed-dose combination treatment with a short-acting beta-agonist (SABA) reliever (per 100 treated over eight months). No statistical heterogeneity was observed in either outcome, and the evidence was rated of high quality. Although issues with blinding were evident in two of the studies, and one study recruited a less severe population, sensitivity analyses did not change the main results, so quality was not downgraded. We could not rule out the possibility that SiT increased rates of serious adverse events (OR 0.92, 95% CI 0.74 to 1.13; I2 = 0%, P = 0.98; moderate-quality evidence, downgraded owing to imprecision). We were unable to say whether SiT improved results for several secondary outcomes (morning and evening peak expiratory flow (PEF), rescue medication use, symptoms scales), and in cases where results were significant, the effect sizes were not considered clinically meaningful (predose FEV1, nocturnal awakenings and quality of life). SiT reduces the number of people having asthma exacerbations requiring oral steroids and the number requiring hospitalisation or an ER visit compared with fixed-dose combination inhalers. Evidence for serious adverse events was unclear. The mean daily dose of inhaled corticosteroids (ICS) in SiT, including the total dose administered with reliever use, was always lower than that of the other combination groups. This suggests that the flexibility in steroid administration that is possible with SiT might be more effective than a standard fixed-dose combination by increasing the dose only when needed and keeping it low during stable stages of the disease. Data for hospitalisations alone could not be obtained, and no studies have yet addressed this question in children younger than age 12.

Plain-language summary: Four studies including 9130 adults and adolescents were included. None of the studies included children younger than age 12. The studies lasted for six months to a year, and all were funded by one drug company. Studies included more women than men, with average age of about 40. Three studies recruited people with quite similar symptoms, but one study included people with less severe asthma. The studies were well conducted, although two did not hide which treatments were being taken (known as blinding), which might have affected the results. The amount of inhaled steroids, including puffs taken for relief from symptoms, was consistently lower for SiT than for the comparison groups using two types of inhalers. Overall, we believe that the quality of the evidence was high to moderate. Fewer people taking SiT had flare-ups that needed a hospital stay or a visit to the ER (one fewer per 100 treated than in the control group, 95% CI 0 to 2 fewer) or a course of oral steroids (two fewer per 100 treated, 95% CI one to three fewer). If more studies are published, it is unlikely that our opinions on these main findings will change. However, we could not tell whether one treatment caused more serious adverse events than the other. SiT had a small benefit on one measure of lung function (predose forced expiratory volume in one second (FEV1)). However, for several other measures, not enough information was available to show which treatment was better (amount of medication taken on an 'as needed' basis, various symptom measures and quality of life). In conclusion, SiT reduces the need for a hospital stay or an ER visit and for courses of oral steroids for asthma flare-ups. SiT did not increase the quantity of inhaled steroids taken overall, and it was unclear whether it increases or decreases serious side effects. Currently no data are available for the use of SiT in children younger than age 12.