Bateman 2001

Methods	A randomised, double‐blind, double‐dummy, multi‐centre, parallel‐group study over 12 weeks from March 1998 to June 1999, at 69 centres in 10 countries. Run‐in 2 weeks and 2 weeks' follow‐up
Participants	Population: 497 adolescents and adults (12 to 79 years) with documented clinical history of reversible airways obstruction Baseline characteristics: mean age 40 years; FEV₁ 76% predicted Concomitant ICS used by 100% of participants Inclusion criteria: 12 years or older with documented clinical history of reversible airway obstruction, smoking history < 10 pack‐years, and using ICS (beclomethasone dipropionate, budesonide, or flunisolide 400 to 500 μg/d or fluticasone propionate 200 to 250 μg/d) for ≥ 4 weeks before entering the run‐in period; FEV₁ % predicted ≥ 50%. Mean PEF over last 7 days of run‐in period between 50% and 85% measured after inhalation of salbutamol (400 mg); symptomatic (i.e. cumulative total symptom score (daytime plus night‐time) > 8 for last 7 days of the run‐in period; and taking salbutamol up to 800 μg/d   Exclusion criteria: received a long‐acting beta₂‐agonist or an oral beta₂‐agonist within 2 weeks of the run‐in period, changed asthma medication, had a lower respiratory tract infection within 4 weeks of the run‐in period, or had an acute asthma exacerbation requiring hospitalisation within 12 weeks of study entry. Other exclusion criteria were prior treatment with oral, depot, or parenteral corticosteroids or combination therapy (containing a beta₂‐agonist and/or ICS)
Interventions	• Fluticasone propionate and salmeterol 100/50 μg HFA MDI • Fluticasone propionate and salmeterol 100/50 μg Diskus • Fluticasone propionate 100 μg CFC MDI
Outcomes	Primary efficacy variable: mean morning PEF over the 12‐week treatment period A serious adverse event was described as any event that was fatal, life‐threatening, disabling, or incapacitating, or that required or prolonged hospitalisation Paper reports: "During treatment, serious adverse events were reported by three patients (2%) in each group. These included asthma exacerbations (n.5), breast neoplasia (n.1) and events associated with the gastrointestinal system (n.2) and ear, nose and throat (n.1). The only serious adverse events considered by the investigator to be drug‐related were asthma exacerbations in two patients (one each in the fluticasone propionate/salmeterol MDI and Diskus groups)" SFCB3022 reports 5 participants with asthma SAE in fluticasone propionate/salmeterol groups (333 participants) and none in the fluticasone propionate alone group (165 participants) Bateman reports 4 asthma hospitalisations in fluticasone propionate/salmeterol groups
Notes	Sponsored by GSK
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
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	430/497 (87%) completed the study
Selective reporting (reporting bias)	Low risk	Full data on GlaxoSmithKline website