Table 3.

Clinical trials of long-term macrolide treatment for COPD.

Study	Design and Treatment Groups	Patient Population	Results
Suzuki et al, 2001 [62]	Randomized, non-blinded study of 109 patients, 55 treated with erythromycin 200–400 mg/day and 54 in the control group for 1 year	Mean age 70 years, mean FEV1 between 1.3 to 1.47 L	Reduction in common colds and exacerbations in the antibiotic group.
Seemungal et al, 2008 [63]	Randomized, double-blind, placebo-controlled study. 109 patients, 53 treated with erythromycin 250 b.i.d and 56 with placebo for 1 year	Mean age 67.2 years, mean FEV1(%) = 50%	35% reduction of exacerbation frequency with antibiotic (p = 0.006). Median time to first exacerbation was 271 vs. 89 days in the placebo arm (p = 0.02). Reduction in duration of the exacerbation with macrolide.
Pomares et al, 2011 [68]	Retrospective study of 24 COPD patients treated with azithromycin 500 mg three times per week for 1 year	Mean age 70.9 years, mean FEV1(%) = 32.2%, a mean of 3.3 hospitalization and 7 exacerbations the previous year	A 58.9% reduction in exacerbations and 61.2% reduction in hospitalizations compared with previous year without macrolides.
He et al, 2010 [69]	Randomized, double-blind, placebo-controlled study of 36 patients, 18 treated with erythromycin 125 mg t.i.d and 18 with placebo for 6 months.	Mean age 69 years. Mean FEV1(%) = 43%	Reduction in total numbers of sputum cells and neutrophil elastase. A reduction of 44% in relative risk of exacerbation with the antibiotic. Delayed time to first exacerbation with macrolide.
Blasi et al, 2010 [70]	Open label, randomized, uncontrolled trial of 22 patients with COPD and tracheostomy, 11 treated with azithromycin 500 mg 3 days a week for 6 months and 11 in standard care group	Mean age 72 and 73 years. No lung function available. 91% and 73% were colonized.	Longer time to the first exacerbation with the macrolide. Estimated hazard ratio for first exacerbation associated with standard care 5.41 (95% CI: 1.67–17.5). Reduction in hospitalization with azithromycin.
Albert et al, 2011 [64]	Randomized, double-blind, placebo-controlled trial of 1142 patients. 570 assigned to azithromycin 250 mg daily and 572 to placebo for a year.	Mean age 66 years. Mean FEV1(%) 39-40%, up to 50% required hospital visit for exacerbation the previous year.	Reduction in risk of exacerbation with azithromycin (p <0.001). Median time to first exacerbation prolonged from 174 with placebo to 266 with macrolide. Hazard ratio for time to the first exacerbation was 0.71 (95% CI: 0.61 to 0.83; p <0.001)
Uzun et al., 2014 [58]	Randomized, double-blind, placebo-controlled study of 92 patients, 47 assigned to azithromycin 500 mg 3 times a week for 12 months and 45 to placebo	Mean age 65 years, mean FEV1(%) = 45%, at least 3 exacerbations the previous year. Patients with bronchiectasis in CT were excluded.	Reduction of exacerbation of 42% with azithromycin (reduction risk 0.58, 95% CI: 0.42–0.79; p = 0.001). Median time to first exacerbation was 59 days with placebo and 130 with azithromycin (p = 0.001).
Vermeersch et al., 2019 [30]	Randomized, double-blind, placebo-controlled trial of 301 patients admitted for an exacerbation of COPD. 147 assigned to azithromycin 500 mg 3 for days and 250 mg every 2 days for 3 months and 154 assigned to placebo	Mean age 67 years, mean FEV1(%) = 37%, at least 1 exacerbation the previous year.	There was no change in the treatment success. Azithromycin decreased treatment failure: 49% azithromycin and 60% placebo (HR 0.73; 95% CI: 0.53–1.01; p = 0.052). Clinical benefits were lost 6 months after withdrawal.

FEV1: forced expiratory volume in 1 s; bid: bis in die; COPD: chronic obstructive pulmonary disease; tid: ter in die.