Methods	This was a double-blind, double-dummy, randomised, active-controlled, parallel-group, Multicentre study comparing the efficacy and safety of Symbicort 160/4.5 μg/inhalation, two inhalations once daily + Symbicort 160/4.5 μg/inhalation as-needed (Symbicort single-inhaler therapy (SiT)) with Pulmicort 160 μg/inhalation, two inhalations bid + Bricanyl 0.4 mg/inhalation as-needed, in adults and adolescents (12-80 years) for a period of 12 months in the treatment of asthma.(Carried out between May 2001 and January 2003). The run-in period was on usual ICS dose but LABA was withdrawn This was a Multicentre study with 211 centres participating from the following 18 countries: Argentina (6 centres), Australia (10 centres), Canada (22 centres), Czech republic (5 centres), Finland (6 centres), France (29 centres), Germany (20 centres) , Hungary (7 centres), Israel (17 centres), Italy (11 centres), Mexico (5 centres), the Netherlands (24 centres), New Zealand (4 centres), Norway (13 centres), Portugal (7 centres), Russia (6 centres), South Africa (11 centres) and Turkey (8 centres)
Participants	Population: Mean age: 43 years. FEV1 70% predicted. Mean ICS dose at enrolment 746mcg/day. Hospital admission for asthma in the past year: unknown%. Course of oral steroids for asthma in past year: unknown%. Previous clinically important exacerbation required for eligibility. 45% of enrolled patients were already on LABA as well as ICS Inclusion criteria: Male and female subjects, 12 to 80 years with asthma, previously treated with inhaled glucocorticosteroids (IGCS) 400-1600 μg per day, with a forced expiratory volume in one second (FEV1 ) of 50-90% of predicted normal (% P.N. ), a history of at least one clinical important asthma exacerbation 1-12 months prior to inclusion, a reversibility in FEV1 from baseline of at least 12%, and who had an asthma symptom score ≥ 1 during 4 of the last 7 days of the run-in period (in which usual dose of ICS was used but LABA was withdrawn from the 45% taking LABA previously)
Interventions	1. Budesonide/formoterol 200/6 mcg two inhalation in the evening [400 mcg budesonide/day], with additional doses as needed as reliever (3 turbuhalers formorning, evening and relief ) 2. Budesonide 200 mcg two inhalations twice daily [800 mcg budesonide/day], with terbutaline reliever (3 turbuhalers as above with placebo in the morning) Maximum of 10 as needed inhalations could be used per day before contacting the investigator *200/6 mcg actuator dose is described as 160/4.5 mcg delivered dose in the paper
Outcomes	Primary efficacy variable Severe asthma exacerbations. The associated primary efficacy outcome variable was time to first severe asthma exacerbation. Additional secondary efficacy variables The number of severe asthma exacerbations was a secondary outcome variable Morning and evening peak expiratory flow (mPEF and ePEF) Asthma symptom scores Nights with awakening(s) due to asthma symptom Inhalations of as-needed medication Asthma-control days Mild asthma exacerbation days As-needed-free days Symptom-free days, FEV1, overall treatment evaluation, and asthma quality of life questionnaire, standardised version (AQLQ(S)) overall and domain scores N.B. As-needed-free days and symptom-free days were added as variables to the statistical analyses to conform with previous Symbicort studies. It was done after finalisation of the study protocol, but before un blinding of study data Safety Safety assessments including physical examination, adverse events (AEs), pulse and blood pressure, were obtained in all subjects Definition of severe exacerbation Included PEF less than 70% baseline on two consecutive days, severe exacerbations requiring medical intervention were also reported (hospitalisation, ED visit or course of oral steroids), but all severe exacerbations were to be treated with a 10 day course of oral prednisolone Additional Data Data on file from AstraZeneca indicated the number patients given at least one course of oral steroids was 129/947 on SMART and 204/943 on Pulmicort. For Hospitalisation/ER treatment there were 12/947 and 20/947 respectively. Asthma SAE was 5/947 and 11/943 which have been used as the hospital admission outcomes for this study
Notes	There were three deaths reported in the study, two in the Pulmicort group and one in the Symbicort SiT group. None of the deaths were related to asthma or, as judged by the investigator causally related to investigational product.
Risk of bias
Item	Authors’ judgement	Description
Adequate sequence generation?	Unclear	No details
Allocation concealment?	Unclear	No details
Blinding? All outcomes	Yes	Double blind
Incomplete outcome data addressed? All outcomes	Yes	1573/1890 completed (83%)