Koenig 2008

Methods	A randomised, double‐blind, multi‐centre, parallel‐group study over 40 weeks from February 2003 to October 2004, at 55 sites (50 in the USA, 3 in Latin America, 2 in Latvia). Run‐in 2 weeks
Participants	Population: 466 adolescents and adults (12 to 81 years) with asthma   Baseline characteristics: mean age 34 years; FEV₁ 78% predicted Concomitant ICS used by 100% of participants  Inclusion criteria: 12 years of age or older, with a diagnosis of asthma, as defined by the ATS, for ≥ 3 months before visit 1; must have been treated with a short‐acting beta₂‐agonist, an anticholinergic, or an allowed ICS at a fixed dosing regimen (within an allowed total daily dose) for at least 4 weeks before screening visit; FEV₁ % predicted between 60% and 95%; bronchodilator reversibility by an increase of ≥ 12% in FEV₁ over baseline within 30 minutes of inhalation of 2 puffs of inhaled albuterol (180 μg) Exclusion criteria: pregnancy, life‐threatening asthma, hospitalisation attributable to asthma within the last 6 months, current smoker or > 10‐pack‐year history of smoking, recent (within 2 weeks) upper or lower respiratory tract infection or significant concurrent disease. Medications that could confound evaluation of study treatments or treatment strategies were prohibited before and throughout the study, including inhaled (up to 250 μg fluticasone propionate allowed before randomisation), oral, or parenteral corticosteroids (with the exception of protocol‐defined use of oral corticosteroids following second consecutive assignment to highest dose of fluticasone propionate/salmeterol), theophylline or other bronchodilators, leukotriene modifiers, anticholinergics, cromolyn, and nedocromil
Interventions	• Fluticasone propionate and salmeterol 100/50, 250/50, or 500/50 μg twice daily (BHR strategy) • Fluticasone propionate 100, 250, or 500 μg (BHR strategy) • Fluticasone propionate 100, 250, or 500 μg (reference strategy) ‐ data from this arm not used Delivery was Diskus device
Outcomes	Primary efficacy variable: average inhaled corticosteroid treatment dose over the treatment period Paper reports: "There were no non‐fatal serious adverse events in any treatment group that were considered to be drug related. One patient in the fluticasone propionateBHR treatment group died due to convulsions and cardiac arrest following deep vein thrombosis" Web report indicates 1 participant with SAE related to asthma on fluticasone propionate/salmeterolBHR and 1 with ear infection and sinusitis on fluticasone propionateBHR
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
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	321/466 (69%) completed the study
Selective reporting (reporting bias)	Low risk	Full data on GlaxoSmithKline website