Methods	Study design: a randomised, open-label, multicentre, parallel-group, Phase III study over 7 months at 145 centres in the United States. Run-in 10 to 14 days. The study comprised 3 phases: run-in (10 to 14 days), treatment period 1 (1 month, fixed-dose regimens), treatment period 2 (6 months, adjustable-dose or fixed-dose regimens).
Participants	Population: 1225 adolescents and adults (12 to 87) years with moderate-to-severe persistent asthma Baseline characteristics: mean age 39 years. FEV1 78.7% predicted. Concomitant inhaled corticosteroids used by 100% of participants. Mean dose 550 μg/day. Run-in on previous asthma therapy (ICS or LABA/ICS) Inclusion criteria: patients aged 12 years and older with a documented diagnosis of asthma, as defined by the American Thoracic Society for 6 months or more before screening and who were in stable condition. To have been maintained on a daily medium-dose ICS or ICS/LABA combination for 12 weeks or longer before screening. FEV1 % predicted of 50% or greater 6 or more hours after short-acting beta2-adrenergic agonist use and 24 or more hours after LABA use, had received 8 or more inhalations of albuterol during the last 10 days of the run-in period and demonstrated a mean morning peak expiratory flow (PEF) of between 50% and 85% of the PEF value obtained 15 minutes after albuterol pMDI (2 to 4 inhalations (90 μg per inhalation)) during the last 7 days of the run-in period. Exclusion criteria: systemic corticosteroid use within 30 days before screening, a 20 or more pack-year smoking history at screening, or a significant disease, respiratory tract infection, or illness that might interfere with the patient’s lung function or participation in the study
Interventions	1. Fluticasone/salmeterol 250/50 μg BD DPI 2. Budesonide/formoterol 320/9 μg BD pMDI The AMD treatment arm was not included in this review
Outcomes	The primary efficacy variable was asthma control, as assessed by asthma exacerbations SAE results reported on the sponsor’s website. Uncertainty over the 2 participants mentioned in the footnotes to table S4 in the report from the trial register was resolved after correspondence with the sponsors. The participant who suffered a SAE after finishing treatment had already been counted in the formoterol/budesonide arm due to another SAE whilst on treatment, but the patient who was admitted to hospital for an episode that was judged to have started during run-in had not been included in the 9 participants on formoterol/budesonide. After discussion we therefore used 10 for this arm in our primary analysis
Notes	Sponsored by AstraZeneca
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomisation schedule was computer-generated
Allocation concealment (selection bias)	Low risk	The site called in to an IVRS which assigned subjects the next lowest available randomisation number
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding in 6-month study extension
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No details
Incomplete outcome data (attrition bias) All outcomes	Low risk	1052/1225 (86%) completed the study
Selective reporting (reporting bias)	Low risk	SAE data found on website
Independent Outcome Assessment Asthma-related serious adverse events	High risk	No independent outcome assessment