Study characteristics
| Gibson et al. [5] | Brusselle et al. [7] | Hahn et al. [15] | |
| Design | Parallel-group, double-blind, placebo-controlled RCT | Parallel-group, double-blind, placebo-controlled RCT | Parallel-group, double-blind placebo-controlled RCT |
| Randomised to macrolide/placebo n | 213/207 | 55/54 | 38/37 |
| Macrolide type and regimen | Azithromycin, 500 mg, 3 times week | Azithromycin, 250 mg capsule, once daily for 5 days and then one capsule 3 times a week | Azithromycin, 600 mg tablet, once daily for 3 days then one tablet weekly for 11 weeks |
| Duration of treatment | 48 weeks | 26 weeks; with a study drug-free washout period of 4 weeks | 12 weeks; follow-up until 1 year after randomisation |
| Setting, country | Multicentre hospital-based, Australia | Multicentre hospital-based, Belgium | Primary care, practice-based, USA |
| Asthma criteria | Asthma (evidence of variable airflow limitation: post-bronchodilator reversibility ≥12% and at least 200 mL FEV1, airway hyperresponsiveness or increased peak flow variability >12% of amplitude above the lowest peak expiratory flow over at least 1 week of monitoring); currently symptomatic with at least partial loss of asthma control (ACQ6 ≥0.75) despite treatment with maintenance ICS and LABA | Severe asthma (GINA step 4 or 5 clinical features, received high doses of ICS (≥1000 µg fluticasone) plus inhaled LABA for at least 6 months prior to screening; at least two independent severe asthma exacerbations requiring systemic corticosteroids and/or LRTI requiring antibiotics within the previous 12 months) | Asthma (evidence of variable airflow limitation: a 12% and 200 mL change in FEV1 and/or a 25% and 60 L·min−1 change in peak expiratory flow rate; symptomatic ≥2 days·week−1 and/or ≥2 nights·month−1 or in exacerbation) |
| Primary efficacy outcome | Total number of asthma exacerbations (severe and moderate) and asthma quality of life. Severe exacerbations were defined as worsening of asthma symptoms that led to one of the following: 1) at least 3 days of systemic corticosteroid treatment of at least 10 mg·day−1 or a temporary increase in a stable OCS maintenance dosage of at least 10 mg·day−1 for at least 3 days; 2) an asthma-specific hospitalisation or 3) an emergency department visit requiring systemic corticosteroids. Moderate exacerbations were defined as any temporary increase in ICS or antibiotics in conjunction with a deterioration in asthma symptoms or both (change in ACQ6 of ≥0.5 or increased diary symptom score), or any increase in β2-agonist use for at least 2 days, or an emergency department visit not requiring systemic corticosteroids. | Rate of primary end-points (severe asthma exacerbations and/or LRTI requiring antibiotics). Severe asthma exacerbations were defined as deterioration in asthma leading to at least one of the following: 1) hospitalisation; 2) emergency department visit and/or 3) need for systemic corticosteroids for at least 3 days. | Overall asthma symptoms, measured on a 5-point scale. Exacerbation secondary outcome, which was used in the current meta-analysis: steroid bursts, unscheduled or emergency visit and/or a hospitalisation for asthma. |
| Patient characteristics | |||
| Age years | |||
| Azithromycin | 61 (51–69) | 53 (46–64) | 45.7 (15.5) |
| Placebo | 60 (50–68) | 53 (36–60) | 47.4 (14.2) |
| Female | |||
| Azithromycin | 134 (63) | 29 (53) | 27 (71) |
| Placebo | 121 (58) | 38 (70) | 24 (65) |
| Lung function# | |||
| FEV1¶ | |||
| Azithromycin | 72.3±20.7 | 80.1±21.9 | 2.33±1.05 |
| Placebo | 73.6±18.8 | 84.8±20.7 | 2.24±1.25 |
| FEV1/FVC % | |||
| Azithromycin | 67.5±12.9 | 66.8±12.3 | |
| Placebo | 68.3±11.9 | 67.8±12.1 |
Data for patient characteristics are presented as median (interquartile range), n (%) or mean±sd. RCT: randomised controlled trial; FEV1: forced expiratory volume in 1 s; ACQ: Asthma Control Questionnaire; ICS: inhaled corticosteroid; LABA: long-acting β2-agonist; GINA: Global Initiative for Asthma; LRTI: lower respiratory tract infection; OCS: oral corticosteroid; FVC: forced vital capacity. #: pre-bronchodilator; ¶: FEV1 % pred for Gibson et al. [5] and Brusselle et al. [7]; FEV1 L for Hahn et al. [15].