1. Characteristics of studies including prior exacerbation details.

Author	Class comparison	Concomitant treatments (%, antibiotic/ placebo)	Dose/regimen	COPD severity	Included in NMA?	Exacberations in the previous 12 months before participation in study	Exacerbation definition	Risk of bias
Albert 2011 (N = 1142); USA (12 academic health centres) 52 weeks	Macrolide vs placebo	ICS only (4%/6%) LAMAs only (6%/8%) LABAs only (3%/1%) ICS + LAMA (19%/22%) ICS + LABA (4%/5%) LABA + LAMA (5%/4%) ICS + LABA + LAMA (49%/46%) None (10%/8%)	AZM 250 mg daily continuous	Moderate to severe FEV₁ 1.11 L	Yes	Approximately 50% of participants in each treatment arm had required hospitalisation or an ED visit in the previous 12 months	Acute exacerbation of COPD: “a complex of respiratory symptoms (increased or new onset) of more than one of the following: cough, sputum, wheezing, dyspnoea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids"	Low risk of bias across all domains except attrition (unclear reasoning of missing data for HRQoL)
Banerjee 2005 (N = 67); UK (clinics and lung function units from 2 hospitals) 13 weeks	Macrolide vs placebo	All participants: ICS (100%), LABAs (18%), inhaled anticholinergics (63%)	CLR 500 mg daily continuous	Moderate to severe	No	NR	Not included in exacerbation analysis	Low risk of bias across all domains except detection bias, which was unclear
Berkhof 2013 (N = 84); Netherlands (1 teaching hospital) 12 weeks	Macrolide vs placebo	LABAs (81%/80%) Long‐acting anticholinergics (64%/57%) ICS (98%/83%)	AZM 250 mg 3 times a week Intermittent	Moderate FEV₁ 1.36 L	Yes	Participants had a median for 1 exacerbation (range 0 to 13) in the previous 12 months	Time to first exacerbation of COPD: sustained worsening of COPD, from stable state and beyond normal day‐to‐day variations, requiring treatment with prednisolone, antibiotics, or a combination of both	Unclear selection bias (allocation) but assumed done, low risk across all other domains
Blasi 2010 (N = 22); Italy (multi‐centre) 26 weeks	Macrolide vs placebo	Inhaled medication NR LTOT (46% in both groups)	AZM 500 mg 3 times a week Intermittent	Severe FEV₁ (not reported)	Yes	Participants in each treatment arm had a mean of 3 exacerbations in the previous 12 months	Worsening of symptoms requiring both a change in regular respiratory medication or medical assistance, or resulting in hospitalisation or ED treatment	Judged as high risk of bias for allocation concealment, performance, detection, attrition, and selective reporting; open‐label
Brill 2015 (N = 99); UK (1 outpatient hospital department) 13 weeks	Quinolone Tetracycline Macrolide vs placebo	ICS (84%/76%/72%) ICS in placebo group 57%	MOX 400 mg daily for 5 days every 4 weeks (pulsed) DOX 100 mg daily (continuous) AZM 250 mg 3 times a week (intermittent)	Moderate to severe FEV₁ 1.4 L	Yes	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 previous 12 months	Exacerbations during the study: using diary card criteria, patient reporting to clinical health professionals or study team. Exacerbation was not the primary outcome of the study	Unclear performance bias; detection bias judged as high
He 2010 (N = 36); China (1 university hospital) 26 weeks	Macrolide vs placebo	ICS (44%/38%) Theophylline (61%/55%) Inhaled anticholinergic (50%/55%) Inhaled beta‐adrenergic (72%/77%)	ERY 125 mg 3 times daily (continuous)	Severe FEV₁ 1.07 L at baseline	Yes	NR	Moderate exacerbation: sustained worsening of baseline respiratory symptoms for at least 2 days requiring increased treatment or additional therapy (e.g. OCS, antibiotics) Severe exacerbation: all of the above plus requiring hospital admission	Randomisation and allocation unclear. Double‐blind study, but outcome assessment unclear. Funding not stated
Mygind 2010 (N = 575); Denmark 156 weeks	Macrolide vs placebo	NR	AZM 500 mg for 3 days every month (pulsed)	NR	No	NR	Not included in exacerbation analysis	Unclear randomisation, allocation concealment, attrition domains. Blinding of participants, personnel, and outcome assessors were judged as low risk of bias
Seemungal 2008 (N = 109); UK (2 outpatient clinics in 2 hospitals) 52 weeks	Macrolide vs placebo	ICS (77% in both groups) LABAs (66%/61%) LAMAs (28%/38%) Theophylline (7.5%/14%)	ERY 250 mg twice daily (continuous)	Moderate to severe FEV₁ 1.31 L at baseline	Yes	35% of participants had 3 or more exacerbations in the previous 12 months	Moderate exacerbation: sustained worsening of baseline respiratory symptoms for at least 2 days requiring treatment with OCS (prednisolone) and/or antibiotics Severe exacerbation: requiring admission to hospital	Low risk of bias across all domains. Funded by British Lung Foundation
Sethi 2010 (N = 1157); (international multi‐centre) 48 weeks	Quinolone vs placebo	SABAs (71%/72%) LABAs (44%/45%) ICS (41%/43%) Theophylline (29%/26%) Systemic steroids (0.4%/0.2%) Others (4.7%/5.7%) ICS + long‐acting bronchodilators (25%/26%)	MOX 400 mg daily for 5 days every 8 weeks (pulsed)	Mild to severe FEV₁ 1.2 L at baseline	Yes	NR	Any confirmed AECB: requiring intervention (start of systemic antibiotic and/or start of systemic steroid and/or hospitalisation within 7 days of the start date of exacerbation) and with a minimum of 2 weeks between the start of 2 consecutive exacerbations	Unclear risk for selection bias (random sequence generation and allocation concealment). Low risk for performance bias and selective reporting
Shafuddin 2015 (N = 292); Australia and New Zealand (multi‐ centre) 12 weeks	Macrolide Macrolide plus tetracycline vs placebo	NR	ROX 300 mg daily (continuous) DOX + ROX 100 mg daily plus 300 mg daily (continuous)	Moderate to severe FEV₁ 0.935 L at baseline	Yes	Mean 5.11 (SD 2.4) exacerbations within 2 years	Not included in exacerbation analysis	Low risk of bias across all domain except attrition, which was unclear
Simpson 2014 (N = 30); Australia (1 tertiary care respiratory and sleep ambulatory care service, hospital) 12 weeks	Macrolide vs placebo	ICS (% NR)	AZM 250 mg daily (continuous)	Moderate	Yes	NR	Severe exacerbations of COPD: requiring unscheduled medical attention with treatment of OCS and/or antibiotics	Low risk of bias across all domains
Singh 2019 (N = 60); India (1 outpatient department) 13 weeks	Tetracycline vs placebo	NR	DOX 100 mg daily (continuous)	Moderate to severe	No (sensitivity analysis)	NR	Not included in exacerbation analysis	Low risk of bias for allocation concealment, high risk of bias for blinding of participants, personnel, and outcome assessors. Randomisation and selective reporting domains were unclear
Suzuki 2001 (N = 109); Japan (setting NR) 13 weeks	Macrolide vs placebo	NR	ERY 200 to 400 mg daily (continuous)	FEV₁ 1.47 L at baseline	No (sensitivity analysis)	NR	Not included in exacerbation analysis	Low risk of bias across most domains except for blinding of participants, personnel, and outcome assessors, which were judged as high risk of bias
Tan 2016 (N = 49); China (1 regional hospital) 52 weeks	Macrolide vs placebo	ICS (44%/38%/44%) Theophylline (55%/55%/61%) Inhaled anticholinergic (55%/50%/50%) Inhaled beta2‐adrenergic agonist (66%/66%/72%)	ERY 125 mg 3 times daily (continuous) ERY 125 mg 3 times daily with 6 months' follow‐up (continuous)	Moderate to severe FEV₁ 1.04 to 1.08 L	Yes	NR	Not included in exacerbation analysis	Unclear risk of bias across most domains, high risk of bias for blinding of participants, personnel, and outcome assessors
Uzun 2014 (N = 92); Netherlands (1 regional hospital) 52 weeks	Macrolide vs placebo	LABA (96%/91%) LAMA (89%/71%) ICS (89%/96%) SABA (68%/73%) Prednisolone (28%/20%)	AZM 500 mg 3 times a week (intermittent)	Mild to severe FEV₁ 1.1 L at baseline	Yes	Participants had a mean of 4 (SD 1.1) acute exacerbations in the previous 12 months	All exacerbations: defined according to Anthonisen criteria, and whether the patient needed treatment with steroids or antibiotics, or both. Severe exacerbation: requiring hospital admission. Mild exacerbation: requiring treatment at the outpatient department	Low risk of bias across all domains
Vermeersch 2019 (N = 301); Italy (5 centres across Italy) 13 weeks	Macrolide vs placebo	LABA (93%/94%) LAMA (80%/80%) ICS (80%/80%) SABA (73%/71%)	AZM 500 mg once daily (loading dose) for 3 days, followed by 250 mg every 2 days for 13 weeks (intermittent)	FEV₁ 0.925 L	Yes	NR	Not included in exacerbation analysis	Low risk of bias across all domains
Wang 2017 (N = 86); China (1 regional hospital) 26 weeks	Macrolide vs placebo	NR	AZM 250 mg once daily plus 20 mg once daily simvastatin (continuous)	FEV₁ 0.67 L	No	NR	Not included in exacerbation analysis	Low risk of bias for randomisation, high risk of bias for blinding of participants, personnel, and outcome assessors

Abbreviations

AECB: acute exacerbation of chronic bronchitis; AZM: azithromycin; CLR: clarithromycin; COPD: chronic obstructive pulmonary disease; DOX: doxycycline; ED: emergency department; ERY: erythromycin; FEV₁: forced expiratory volume in one second; HRQoL: health‐related quality of life; ICS: inhaled corticosteroid; LABA: long‐acting beta agonist; LAMA: long‐acting muscarinic antagonist; LTOT: long‐term oxygen therapy; MOX: moxifloxacin; NMA: network meta‐analysis; NR: not reported; OCS: oral corticosteroids;ROX: roxithromycin; SABA: short‐acting beta agonist; SD: standard deviation.