Tattersfield 2001.

Methods	Study design: double‐blind, randomised, parallel‐group Study duration: 12 weeks Number of study centres and location: 35 centres in 4 countries (Greece, the Netherlands, Norway and Sweden).
Participants	N randomised: formoterol 182, terbutaline 180 Withdrawals: 21 formoterol, 32 terbutaline Age, mean (range): 47 (18 to 75) Asthma severity: FEV1 > 50% predicted (mild‐moderate according to GOLD definition by FEV1) Baseline ICS use: formoterol 890 μg (200 to 2800), terbutaline 860 (100 to 2400) Baseline lung function, FEV1 mean [range] (% predicted): formoterol 2.36 L [1.13 to 4.30] (74%), terbutaline 2.27 L [1.00 to 4.65] (74%) Inclusion criteria: ≥ 18 years, asthma for 6 months or more and been treated with ICS for > 4 weeks (mean dose 870 μg daily). FEV1 > 50% predicted, and increase in FEV1 of ≥ 12% after inhalation of 1.5 mg terbutaline dry‐powder inhaler and used the relief terbutaline turbuhaler on average 3 to 8 times per day on at least 7 days in the run‐in period Exclusion criteria: patients who needed more than 12 inhalations per day of relief medication during the run‐in period. Patients with a serum potassium value outside the reference range.
Interventions	Run‐in: 2 weeks on terbutaline Turbuhaler Intervention: formoterol 4.5 μg (metered dose 6 μg) Control: terbutaline Turbuhaler 0.5 mg Instructions provided for as‐needed therapy: patients told to take medication only when needed. Patients taking more than 12 inhalations per day were withdrawn. Average puffs per day used, mean: formoterol as‐needed 3.92, terbutaline as‐needed 5.52 Co‐medication: Patients were all on ICS. Patients were not allowed to take any oral or inhaled beta2‐agonists during the study period apart from the study medication. Other asthma medications (xanthines, sodium cromoglycate, nedocromil, antihistamines and diuretics) were allowed provided that they were kept at a constant dosage throughout the study. Definition of severe asthma exacerbation: the need for oral corticosteroid course, as judged by investigator, or decreased PEF of more than 30% from baseline on 2 consecutive days. All severe exacerbations were treated with a 7‐day course of oral prednisolone.
Outcomes	Primary: time to first severe exacerbation Secondary outcome measures included: morning/evening PEF, FEV1, symptoms, number of relief medication and safety data, including serum potassium concentration and changes in electrocardiogram Time points: start of run‐in, start of treatment and after 4, 8 and 12 weeks of treatment. Contacted by telephone between the last 4 visits to check for adverse events and study drug consumption.
Funding	AstraZeneca
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomly assigned to treatment groups in computer‐generated blocks. The randomisation sequence was generated by AstraZeneca research and Development, Lund."
Allocation concealment (selection bias)	Low risk	"Investigators assigned a number to each patient in order. The study drugs were sent to each centre’s pharmacy with a number allocated by randomisation before shipping."
Blinding (performance bias and detection bias) Objective outcomes; hospitalisation, deaths, SAEs	Low risk	"Investigators were unaware of study drug assignment throughout the study unless a SAE occurred."
Blinding (performance bias and detection bias) subjective outcomes; exacerbations requiring OCS, asthma‐related SAEs, withdrawal	Unclear risk	"double blind"
Incomplete outcome data (attrition bias)	Low risk	Analysed data on an intention‐to‐treat basis. Reasons for withdrawal provided, more withdrawals due to adverse events in the terbutaline group.
Selective reporting (reporting bias)	Low risk	None noted
Other bias	Unclear risk	None noted