Ind 2002.

Methods	Study design: randomised, double‐blind, parallel‐group Study duration: 12 weeks Number of study centres and location: 42 centres in 5 countries (the UK, Spain, Israel, Finland and Hungary)
Participants	N randomised (males): formoterol maintenance plus formoterol as‐needed 176 (67), formoterol maintenance plus terbutaline as‐needed 181 (76) Withdrawals: formoterol maintenance plus formoterol as‐needed 7 and formoterol maintenance plus terbutaline as‐needed 1 Age mean (range): 47 Asthma severity: patients had to have been stable on an adequate constant dose of ICS for > 4 weeks. Patients were also included if ≤ 10 mg per day of oral prednisolone or equivalent. Diagnostic criteria: ATS Baseline ICS use: formoterol maintenance plus formoterol as‐needed 1034 μg (200 to 2900), formoterol maintenance plus terbutaline as‐needed1030 μg (200 to 3200) Baseline lung function, FEV1 (% predicted): formoterol maintenance plus formoterol as‐needed 2.23 L (76%), formoterol maintenance plus terbutaline as‐needed 2.24 L (76%) Inclusion criteria: patients > 18 years with FEV1 > 50% predicted normal. Patients requiring 2 to 5 inhalations per day of as‐needed terbutaline during run‐in. Patients must have completed the run‐in according to protocol. Exclusion criteria: patients with significant cardiovascular disease, pregnant or breastfeeding women or patients with hypersensitivity to lactose or beta2‐agonists. Beta2‐agonist, anticholinergics, leukotriene receptor agonists, cromones or immunotherapy were not permitted. Patients who used > 8 inhalations during a single day during run‐in.
Interventions	Run‐in: 2 weeks on formoterol 9 μg twice a day and terbutaline Turbuhaler 0.5 mg as‐needed Intervention: formoterol 9 μg twice a day plus formoterol Turbuhaler 4.5 μg as‐needed Control: formoterol 9 μg twice a day plus terbutaline Turbuhaler 0.5 mg as‐needed Instructions provided for as‐needed therapy: "use as‐needed medication for either relief of asthma symptoms or prevention of bronchoconstriction (e.g. before exercise) and to appraise the effect of each inhalation before proceeding with as second" Average puffs per day used, mean (range): formoterol as‐needed 2.16 (0.0 to 6.3), terbutaline as‐needed 2.34 (0.1 to 7.5) Co‐medication: all on inhaled or oral corticosteroids at a constant dose
Outcomes	Primary outcomes: serum potassium levels, ECG, vital signs, lung function, adverse events Secondary outcomes: number of inhalations of as‐needed medication, severe asthma exacerbations, lung function, asthma symptoms Time points: attended clinic on 5 occasions with telephone calls to check on usage of reliever medication and adverse events between visits Definition of severe asthma exacerbation: either a requirement for oral glucocorticosteroids, either as judged by the investigator or following a drop in PEF on 2 consecutive days to < 70% of mean baseline value. Treated with 30 mg/day oral prednisolone for 10 days reducing dose by 5 mg/day over the next 5 days. Patients withdrawn after a second exacerbation.
Funding	AstraZeneca
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomised"
Allocation concealment (selection bias)	Low risk	From correspondence: "Patients received an enrolment code in consecutive order per centre at visit 1. Eligible patients... were allocated a randomised patient No. in consecutive order, per centre, at visit 2."
Blinding (performance bias and detection bias) Objective outcomes; hospitalisation, deaths, SAEs	Low risk	"Double blind". Both study drugs administered by identical inhalers.
Blinding (performance bias and detection bias) subjective outcomes; exacerbations requiring OCS, asthma‐related SAEs, withdrawal	Low risk	"Double blind"
Incomplete outcome data (attrition bias)	Unclear risk	The numbers of withdrawals in each treatment arm were not described adequately in the text
Selective reporting (reporting bias)	Low risk	Outcomes reported, although numerical data not given for PEF and FEV1 apart from a graph that no data could be obtained from
Other bias	Low risk	None noted