RELIEF 2003.

Methods	Study design: Multi‐national, multi‐centre, randomised, open, parallel‐group Study duration: 6 months Number of study centres and location: 1139 in 24 countries Date of study: 17 April 2000 to 24 June 2001
Participants	N randomised (males): formoterol 8924 (3924), salbutamol 8938 (3798) Withdrawals: formoterol 664, salbutamol 525 Age, mean (range): 39 (4 to 91) Asthma severity: any allowed, defined by use of maintenance treatment at entry as intermittent (no maintenance treatment), mild (ICS < 500 μg per day or regular LABA, cromone, theophylline or leukotriene modifier), moderate (ICS alone ≥ 500 μg per day or ICS 500 to 800 μg per day in combination with LABA, theophylline or leukotriene modifier) and severe (ICS > 800 μg per day in combination with LABA, theophylline or leukotriene modifier, or oral corticosteroids). Intermittent: 16%, mild: 35%, moderate: 35%, severe: 15% Diagnostic criteria: judged by asthma medication levels, GINA Baseline ICS use: 76% using ICS. Mean usage at baseline 753 μg (formoterol group), 763 μg (salbutamol group) Baseline LABA use: 31% Baseline lung function, FEV1 (% predicted): not reported Inclusion criteria: ≥ 6 years, previous use of or candidates for beta2‐agonist reliever therapy Exclusion criteria: women who were pregnant, breast‐feeding or not using appropriate contraception. Patients with concomitant cardiovascular diseases were included at physicians' discretion.
Interventions	Run‐in: none Intervention: formoterol 4.5 μg, Turbuhaler DPI Control: salbutamol 200 μg delivered by Turbuhaler dry powder inhaler in 6 countries and by pressurised metered dose inhaler in 18 countries Instructions provided for as‐needed therapy: patients instructed to contact investigator if they used more that 12 puffs reliever medication in adults and 8 in children in 1 day, with lower limits for those on LABA Average puffs per day used, mean (range): not reported Co‐medication: any ordinary asthma maintenance medication, except other reliever medication was allowed and investigators could change the maintenance medication according to clinical judgement Definition of asthma exacerbation: any of: 1) increase in maintenance asthma medication, 2) course of ICS ≥ 5 days, 3) emergency treatment with nebulised beta2‐agonist or corticosteroid injection, 4) hospitalisation Definition of severe asthma exacerbation: any of: 1) course of ICS ≥ 5 days, 2) emergency treatment with nebulised beta2‐agonist or corticosteroid injection, 3) hospitalisation
Outcomes	Efficacy outcomes collected: primary efficacy variable was time to first asthma exacerbation. Secondary variables: change in concomitant maintenance asthma medication, number of inhalations of study drug, number of days with asthma symptoms, health care resource utilisation, days restricted activity. Safety outcomes collected: primary safety variables were asthma‐related and non‐asthma‐related serious adverse events and adverse events resulting in discontinuations Time points: 1, 3 and 6 months
Funding	AstraZeneca
Notes	There were 305 serious adverse events in 278 patients on formoterol compared to 327 events in 299 patients on salbutamol
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer generated code"
Allocation concealment (selection bias)	Low risk	"At entry, patients were randomised in chronological order at each site, according to a computer generated code and treatment communicated via code envelope"
Blinding (performance bias and detection bias) Objective outcomes; hospitalisation, deaths, SAEs	Low risk	"Open label" Comment: the study was open‐label, but knowing the assignment of medication is unlikely to make a difference when judging when a participant experienced death, hospitalisation or all‐cause serious adverse event
Blinding (performance bias and detection bias) subjective outcomes; exacerbations requiring OCS, asthma‐related SAEs, withdrawal	Unclear risk	Comment: because the study was open‐label, this may introduce bias when investigators were subjectively judging whether a serious adverse event was related to asthma or required a course or oral corticosteroids. Knowledge of the treatment drug might influence a patient's decision to withdraw from the study.
Incomplete outcome data (attrition bias)	Low risk	All analyses were performed on intention‐to‐treat population and there were few withdrawals
Selective reporting (reporting bias)	Low risk	The number of outcomes measured was kept to a minimum as RELIEF was a large study and they were all reported
Other bias	Low risk	None noted