Dal Negro 2003

Methods	Parallel group study. Trial duration: 12 months. Baseline characteristics: comparable. Intention‐to‐treat analysis: Yes.
Participants	Setting: Single centre in Italy. Participants randomised: 12 (FPS: 6; salmeterol: 6). Additional treatment groups not covered in this review: placebo: 6. Baseline characteristics: Age range: 53‐78; moderate COPD; mean FEV1 (L): 1.46; mean FEV1 (% predicted): 48; mean PEF (L/min): 180; mean reversibility (% baseline): 3.2. Inclusion criteria: baseline FEV1 % predicted: ≤ 80%; FEV1 > 800 mL; FEV1/FVC ratio: ≤ 70% predicted; FEV1 change of ≤ 12% predicted post 400 mg salmeterol; regular treatment with oral theophylline 20 mg BiD; SABA prn (for at least 6 months); current/ex‐smokers with smoking history of at least 10 pack years. Exclusion criteria: Current evidence of asthma or other pulmonary diseases; regular treatment with ICS; unstable respiratory disease requiring oral/parenteral CS within 4 weeks prior to the beginning of the study; changes in COPD medication in last 4 weeks before entering run‐in; upper/lower respiratory tract infection within 4 weeks before last screening visit; unstable angina/unstable arrhythmias; recent MI/heart failure; insulin‐dependent diabetes mellitus; neuropsychiatric disorders; concurrent use of medications that affect COPD (e.g. ß‐blockers), or interact with methylxanthine products, e.g. macrolides or fluoroquinolones; known/suspected hypersensitivity to ICS, ß‐agonist or lactose; evidence of alcohol abuse.
Interventions	Run‐in: 2 weeks treatment with theophylline and prn SABA. FPS 50/250 mcg bid. salmeterol 50mcg bid. Additional treatment groups not covered in this review placebo. Participants were on concomitant therapy: SABA prn and theophylline 400ug/day, for 12 months. Inhaler device: Diskus.
Outcomes	FEV1, Delta FEV1, PEF am, symptom scores, rescue medication use, exacerbations (event rate and mean number per year).
Notes	Classified as 'poorly reversible population'. Mild exacerbation: requirement for increase in SABA prn by >2 occasions/24hrs on two or more consecutive days compared with baseline mean of last seven days of run‐in Moderate exacerbation: condition requiring treatment with antibiotics and/or oral corticosteroids Severe exacerbation: Condition requiring emergency hospital treatment and/or hospitalisation.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised; no other information reported.
Allocation concealment (selection bias)	Unclear risk	Information not available.
Blinding (performance bias and detection bias) All outcomes	Low risk	Identical inhaler devices.
Incomplete outcome data (attrition bias) Mortality	Unclear risk	Only 12 participants.
Incomplete outcome data (attrition bias) All other outcomes	Unclear risk	Only 12 participants.
Selective reporting (reporting bias)	High risk	No data available for the primary outcomes.