Methods	Study design: a randomised, double-blind, double-dummy, multicentre, parallel-group study over 12 weeks from May 1998 to June 1999 at 52 primary care practices and hospital respiratory units in 11 countries (Austria (4), Belgium (4), Croatia (2), Denmark (4), Finland (2), Germany (7), Italy (3), Norway (5), Russia (2), Slovakia (3), United Kingdom (16)). Run-in 2 weeks
Participants	Population: 428 adolescents and adults (16 to 75) years with moderate-to-severe asthma who were uncontrolled on existing corticosteroid therapy Baseline characteristics: mean age 47 years. FEV1 69% predicted. Concomitant inhaled corticosteroids used by 100% of participants. Run-in on previous dose of ICS (no LABA allowed in previous 2 weeks before recruitment). Inclusion criteria: aged 16 to 75 years with a documented clinical history of asthma currently receiving 1000 to 1600 μg/day of budesonide, beclomethasone dipropionate or flunisolide, or 500 to 800 μg/day fluticasone propionate, for at least 4 weeks before Visit 1 At the end of run-in, FEV1 % predicted of 50% to 85% at any of Visits 1 or 2/2A (bronchodilators withheld for 6 hours), bronchodilator reversibility by an increase of at least 15% in FEV1 over baseline 15 minutes after inhaling 400 μg of salbutamol at Visit 1 or 2/2A, and a symptom score (day and night combined) of at least 2 or relief bronchodilator use on at least 2 separate occasions (any dose) per day on at least 4 of the last 7 days of the run-in period Exclusion criteria: a smoking history of 10 pack-years or more, an asthma exacerbation or upper or lower respiratory tract infection within the previous month, systemic or nasal steroids or anti leukotrienes within the previous 4 weeks, or long-acting/oral/slow-release beta2-agonists in the previous 2 weeks before Visit 1
Interventions	1. Salmeterol/fluticasone 50/250 μg bd via Diskus 2. Formoterol (12 μg bd) + budesonide (800 μg bd) via separate turbohalers
Outcomes	The primary efficacy measure was mean PEFam over the week prior to the end of treatment (Week 12) SAE data obtained from sponsor’s website and also reported in the paper publication
Notes	Sponsored by GSK
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A randomisation code was generated using the Glaxo Wellcome computer program ‘Patient Allocation for Clinical Trials’ (block size of 4) and non-overlapping sets of treatment numbers were allocated to each centre. Treatment numbers were allocated at Visit 2 in consecutive order, starting with the lowest number available at that centre
Allocation concealment (selection bias)	Low risk	Numbered treatment packs of study drugs were labelled to ensure that both patients and investigators were blinded to the treatment allocation, and the randomisation codes were not revealed to investigators or other study participants until after recruitment, treatment, data collection and analyses were complete
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double-blind, double-dummy
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double-blind, double-dummy
Incomplete outcome data (attrition bias) All outcomes	Low risk	379/428 (89%) completed the study
Selective reporting (reporting bias)	Low risk	SAE reported in paper and on sponsor’s trial report
Independent Outcome Assessment Asthma-related serious adverse events	High risk	No independent outcome assessment