Brill 2015.

Methods	Prospective, randomised, single‐blind, placebo‐controlled clinical trial. Treatment duration of 13 weeks Intention‐to‐treat analysis
Participants	N = 99. Aged 45 to 80 years. Mean age (years) 70.0 (moxifloxacin), 70.4 (doxycyline), 67.9 (azithromycin) and 68.7 (placebo) Female: 32% (moxifloxacin), 28% (doxycyline), 36% (azithromycin), and 25% (placebo) 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) Exclusions: patients who reported either treatment for an exacerbation, an episode of symptoms worsening in the 4 weeks prior to screening, or were unable to enrol for safety reasons (significant hepatic/renal impairment, QT prolongation, pre‐existing long‐term antibiotic use, and hypersensitivity to the treatments under investigation)
Interventions	Prophylaxis: 1. Moxifloxacin 400 mg daily for 5 days every 4 weeks 2. Doxycyline 100 mg daily 3. Azithromycin 250 mg 3 times a week 4. Placebo
Outcomes	Primary: 1. Change in sputum bacterial load, as assessed by quantitative culture. Secondary: 1. Changes in resistance to the three tested antibiotics 2. Changes in FEV1 3. Adherence to therapy 4, Health status as measured by total SGRQ scores 5. Adverse events Exploratory: 1. Changes in sputum bacterial load as assessed by 16S rRNA gene‐targeted qPCR 2. Changes in sputum inflammation
Notes	Funding: funded by the National Institute for Health Research (NIHR) under the Programme Grants for Applied Research programme (RP‐PG‐0109‐10056) and the NIHR Royal Brompton Respiratory Biomedical Research Unit. The moxifloxacin for the study was provided by Bayer Pharma AG, Berlin, Germany and the study sponsor was University College, London, UK. Neither Bayer, the funder, nor the Sponsor had any influence in the study design, collection, analysis and interpretation of the data, the writing of the report, or the decision to submit for publication.
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 permuted 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 permuted block system of variable sizes (Sealed Envelope, UK). Participants remained blinded to treatment allocation".
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	"Patients remained blinded to treatment allocation". However, not clear if study personnel were blinded. Described as single‐blind study
Blinding of outcome assessment (detection bias) All outcomes	High risk	No description of outcome assessor blinding, although blinded participants assessed outcomes such as quality of life
Incomplete outcome data (attrition bias) All outcomes	Low risk	Dropout low and balanced. All participants accounted for in flow diagram
Selective reporting (reporting bias)	Low risk	Planned outcomes according to trial registration relevant to this review reported
Other bias	Low risk	No other bias identified