Tashkin 2008.

Methods	Design: parallel group Randomisation: yes, computer generated Blinding: double‐blind, double‐dummy Withdrawals: stated
Participants	Setting: 194 centres in the US, Czech Republic, the Netherlands, Poland and South Africa Number eligible: 1942 Number enrolled: 1704 Number in groups: BUD/FM 320/9mcg 277, BUD/FM 160/9mcg 281, BUD 320mcg + FM 9mcg 287, BUD 320mcg 275, FM 9mcg 284, placebo 300 Number of withdrawals: BUD/FM 320/9mcg 39, BUD/FM 160/9mcg 38, BUD 320mcg + FM 9mcg 48, BUD 320mcg 63, FM 9mcg 61, placebo 77 Number completing trial: BUD/FM 320/9mcg 238, BUD/FM 160/9mcg 243, BUD 320mcg + FM 9mcg 239, BUD 320mcg 212, FM 9mcg 223, placebo 223 Age range: BUD/FM 320/9mcg 41‐86, BUD/FM 160/9mcg 40‐90, BUD 320mcg + FM 9mcg 40‐84, BUD 320mcg 40‐90, FM 9mcg 42‐89, placebo 40‐86 Sex (% male): BUD/FM 320/9mcg 67.9, BUD/FM 160/9mcg 64.4, BUD 320mcg + FM 9mcg 74.2, BUD 320mcg 67.6, FM 9mcg 65.5, placebo 69.0 Ethnicity (% white): BUD/FM 320/9mcg 94.2, BUD/FM 160/9mcg 93.2, BUD 320mcg + FM 9mcg 92.0, BUD 320mcg 94.2, FM 9mcg 92.3, placebo 94.7 COPD diagnosis: GOLD criteria Severity of COPD: as below Inclusion criteria: aged ≥40; symptoms for >2 years; history of at least one COPD exacerbation treated with a course of oral corticosteroids and/or antibacterials within 1–12 months before screening; documented use of an inhaled short acting bronchodilator as rescue medication; moderate to very severe COPD with a pre‐bronchodilator FEV1 of ≤50% of predicted normal and a pre‐bronchodilator FEV1/forced vital capacity of <70%; smoking history of ≥10 pack‐years; score of ≥2 on the Modified Medical Research Council dyspnoea scale at the time of screening; breathlessness, cough and sputum scale (BCSS) score of ≥2 per day for at least half of the 2‐week run‐in period Exclusion criteria: history of asthma; history of allergic rhinitis before 40 years of age; significant/unstable cardiovascular disorder; clinically significant respiratory tract disorder other than COPD; homozygous α‐1 antitrypsin deficiency or any other clinically significant co‐morbidities that could preclude participation in the study or interfere with the study results, as determined by the investigator; required additions or alterations to their usual COPD maintenance therapy or an increment in rescue therapy due to worsening symptoms within 30 days before screening or during the run‐in period; oral or ophthalmic non‐cardioselective β‐ adrenoceptor antagonists; oral corticosteroids; pregnancy; breast‐feeding Baseline characteristics of treatment/control groups: comparable
Interventions	After 2 weeks of treatment based on previous therapy (ICSs and short‐acting bronchodilators allowed during the run‐in period), patients received one of the following treatments administered twice daily, for 26 weeks: budesonide/formoterol pMDI 160/4.5 μg × two inhalations (320/9 μg); budesonide/formoterol pMDI 80/4.5 μg × two inhalations (160/9 μg); budesonide pMDI 160 μg × two inhalations (320 μg) plus formoterol DPI 4.5 μg × two inhalations (9 μg); budesonide pMDI 160 μg × two inhalations (320 μg); formoterol DPI 4.5 μg × two inhalations (9 μg); or placebo.
Outcomes	Primary: Pre‐dose forced expiratory volume in 1 second (FEV1), 1‐hour post‐dose FEV1 Secondary: morning and evening PEF (L/min)
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "randomised". Computer generated code
Allocation concealment (selection bias)	Unclear risk	Method not stated
Blinding (performance bias and detection bias) All outcomes	Low risk	Quote: "double blind"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Similar rates of withdrawal between ICS and placebo arms
Selective reporting (reporting bias)	Low risk	All outcomes reported