van Noord 2001

Methods	A randomised, double‐blind, double‐dummy, multi‐centre, placebo‐controlled, parallel‐group study over 3 months from December 1997 to March 1999, at 61 centres in 13 countries. Run‐in 2 weeks
Participants	Population: 509 adolescents and adults (12 to 82 years) with moderate to severe asthma Baseline characteristics: mean age 47 years; FEV₁ 72% predicted Concomitant ICS used by 100% of participants Inclusion criteria: 12 years old or older with documented clinical history of reversible airways obstruction and symptomatic on ICS therapy (beclomethasone dipropionate, budesonide, or flunisolide at a dose of 1500 to 2000 μg/d or fluticasone propionate 750 to 1000 μg d) for at least 4 weeks before the start of the study. FEV₁ % predicted between 50% and 100% During the last 7 days of the run‐in period, required to have had a mean morning PEF > 50% and < 85% of PEF measured 15 minutes after administration of 400 μg of salbutamol at the randomisation visit, and a cumulative total symptom score (daytime plus night‐time) in the daily record card ≥ 8   Exclusion criteria: received a LABA or an oral beta₂‐agonist with 2 weeks of the run‐in period, changed asthma medication, had a lower respiratory tract infection in the 4 weeks preceding the run‐in period, had an acute asthma exacerbation requiring hospitalisation in the 12 weeks preceding study entry
Interventions	• Fluticasone propionate and salmeterol 500/50 μg HFA twice daily via MDI • Fluticasone propionate and salmeterol 500/50 μg HFA twice daily via Diskus • Fluticasone propionate 500 μg  CFC twice daily via MDI
Outcomes	Primary efficacy variable: mean morning PEF over the 12‐week treatment period Paper reports 8 participants with SAE in fluticasone propionate/salmeterol groups and 2 on fluticasone propionate. These included 3 asthma exacerbations. Web report indicates that 2 of these were on fluticasone propionate/salmeterol and 1 on fluticasone propionate One death reported on fluticasone propionate/salmeterol via MDI due to leukaemia
Notes	Sponsored by GSK
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding (performance bias and detection bias) All outcomes	Low risk	Double‐blind, double‐dummy
Independent Assessment of causation (detection bias) Asthma‐related events	High risk	Causation of SAEs not independently assessed
Incomplete outcome data (attrition bias) All outcomes	Low risk	447/509 (88%) completed the study
Selective reporting (reporting bias)	Low risk	Full data on GSK website