Brill 2015.

Study characteristics
Methods	Design: randomised, single‐blind, placebo‐controlled, parallel‐group design Duration: 13 weeks. Location: single‐centre, UK‐based hospital (London)
Participants	Population: 99 adults with moderate to severe COPD were randomly assigned to moxifloxacin (n = 25), doxycycline (n = 25), azithromycin (n = 25), or placebo (n = 24) Baseline characteristics: age (mean years): 69.4 (SD 8.4); % male (mean): 69; % FEV₁ predicted (mean): 50 (SD 14); pack‐years (mean): 53 (SD 38); exacerbation history: participants had a mean of 2.5 (SD 2.1) exacerbations with moxifloxacin, 2.1 (SD 1.7) exacerbations with doxycycline, 2.8 (SD 4.0) exacerbations with azithromycin, and 1.5 (SD 1.4) exacerbations with placebo in the previous 12 months Inclusion criteria: mean % FEV₁ predicted: 52 (SD 13) (moxifloxacin), 53 (SD 14) (doxycyline), 44 (SD 17), (azithromycin), and 53 (SD 13) (placebo). Stable patients with chronic bronchitis (self‐reported sputum expectoration on most days when clinically stable) and spirometrically confirmed COPD (defined by FEV₁ < 80% predicted, FEV₁‐to‐FVC ratio < 0.7, and a history of smoking) Exclusion criteria: treatment for an exacerbation or an episode of symptom worsening in the 4 weeks before screening; unable to enrol for safety reasons (significant hepatic/renal impairment; QT prolongation; pre‐existing long‐term antibiotic use; hypersensitivity to treatments under investigation
Interventions	Moxifloxacin (400 mg daily for 5 days every 4 weeks) Doxycycline (100 mg daily) Azithromycin (250 mg 3 times a week) Placebo Allowed co‐medications: not reported
Outcomes	Change in sputum bacterial load, change in resistance to the 3 study antibiotics, change in FEV₁, adherence to therapy, health‐related quality of life (SGRQ),number of people with ≥ 1exacerbations,adverse events
Notes	Funding: National Institute for Health Research Identifier: NCT01398072
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Internet randomisation into groups of 1:1:1:1 was performed using a computer‐generated permutated block system of variable sizes (Sealed Envelope, UK)
Allocation concealment (selection bias)	Low risk	Internet randomisation into groups of 1:1:1:1 was performed using a computer‐generated permutated block system of variable sizes (Sealed Envelope, UK) "Patients remained blinded to treatment allocation"
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Patients remained blinded to treatment allocation. However, it is not clear whether study personnel were blinded. This was described as a single‐blind study
Blinding of outcome assessment (detection bias) All outcomes	High risk	No description of outcome assessor blinding was provided, although blinded participants assessed outcomes such as quality of life
Incomplete outcome data (attrition bias) All outcomes	Low risk	Dropout was low and balanced. All participants were accounted for in a flow diagram
Selective reporting (reporting bias)	Low risk	Planned outcomes according to trial registration relevant to this review were reported
Other bias	Low risk	No other bias was identified