Shafuddin 2015.

Study characteristics
Methods	Design: randomised, double‐blind, placebo‐controlled, double‐dummy, parallel‐group design Duration: 12 weeks Location: 16 centres across Australia and New Zealand
Participants	Population: 292 adults with moderate to severe COPD were randomly assigned to roxithromycin plus doxycycline (n = 101), roxithromycin (n = 97), or matched placebo (n = 94) Baseline characteristics: age (mean) 67 (SD 8.5); % male (mean): 73; % FEV₁ predicted (mean): 34 (SD 10); pack‐years (mean): 55.6 (SD 33); exacerbation history: participants had a mean 5.11 (SD 2.4) exacerbations in the last 24 months Inclusion criteria: mean % FEV₁ predicted, mean: 32.53 (SD 13.55) (roxithromycin/doxycyline), 33.93 (SD 15.3) (doxycyline), 35.8 (SD 15.2) (placebo); meeting spirometric criteria for COPD (FEV₁ ≤ 70% predicted, FEV₁‐to‐FVC ≤ 60%; reversibility of ≤ 10% of predicted FEV₁ or ≤ 200 mL if predicted FEV₁ ≤ 2 L); smoking history ≥ 20 pack‐years; ≥ 3 confirmed moderate or severe COPD exacerbations in the past 2 years (i.e. requiring treatment with antibiotics and/or OCS and/or hospitalisation); positive serology for C pneumoniae (IgG antibody titre ≥ 1:64) Exclusion criteria: pulmonary disease other than COPD; treatment with antibiotics; exacerbation or an investigational drug in the 4 weeks before randomisation; pregnancy (serum pregnancy test) or breast‐feeding; history of hypersensitivity to macrolides, tetracyclines, beta‐lactams, or sulphamethoxazole:trimethoprim; serious cardiovascular, hepatic, renal, or other systemic disease; known long QT syndrome or QTc > 450 ms; sick sinus syndrome; bradycardia (< 50 bpm) or severe hypokalaemia; epilepsy; treatment with medicine known to have important interaction with macrolides or tetracyclines; impaired hepatic function (aspartate aminotransferase or alanine aminotransferase ≥ 2 times the ULN, alkaline phosphatase ≥ 1.25 times the ULN, bilirubin > 2 times the ULN, and albumin < 30 g/L); unlikely to comply
Interventions	Roxithromycin (300 mg daily) Doxycycline (100 mg daily) plus roxithromycin (300 mg daily) Matching placebo Allowed co‐medications: not stated
Outcomes	Exacerbations, quality of life, lung function, adverse events
Notes	Funding: Sanofi‐Aventis Australia Pty Ltd. Identifier: ANZCTRN 12615000052538
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Each eligible participant was assigned to a sequential subject number followed by randomisation number provided by Hoescht Marion Roussel, Australia. Participants were supplied with one of three treatments according to their randomisation number" Clinical trials registry clarifies: computer sequence generation used for randomisation of participants into treatment arms at 1:1:1 ratio
Allocation concealment (selection bias)	Low risk	Study medication was packed by Hoechst Marion Roussel in bottles labelled with randomisation and batch numbers. Investigators, pharmacists, and subjects were blinded to study medication in these bottles
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Triallists confirm that all participants, personnel, and outcome assessors remained blinded until data had been analysed
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Triallists confirm that all participants, personnel, and outcome assessors remained blinded until data had been analysed
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	More patients dropped out of combined antibiotics treatment arm (21 vs 13 in single antibiotic arm and 10 in placebo arm), although according to triallists, reasons were not related to study medication. All patients were included in the ITT analysis
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