A randomised, double-blind, placebo-controlled study to evaluate the efficacy of oral azithromycin as a supplement to standard care for adult patients with acute exacerbations of asthma (the AZALEA trial)

BackgroundBacterial infections are implicated in the pathogenesis of asthma exacerbation but guidelines recommend that antibiotics should not be administered. Telithromycin shows clinical benefit compared with placebo but toxicity limits its use.ObjectiveTo evaluate the efficacy of azithromycin compared with placebo in reducing the severity of asthma exacerbations.DesignMulticentre, randomised, double-blind, placebo-controlled study.SettingAccident and emergency and acute medical units, and one primary care centre.ParticipantsAdults with a history of asthma presenting within 48 hours (of initial presentation requesting medical care) with an acute deterioration in asthma control [increased wheeze, dyspnoea and/or cough with reduced peak expiratory flow (PEF)] requiring treatment with corticosteroids.InterventionsAzithromycin (500 mg once daily) or two placebo capsules once a day for 3 days.Main outcome measureDiary card summary symptom score assessed at 10 days after randomisation.ResultsIn total, 4582 patients were screened at 31 centres, of whom 199 were randomised to the study (azithromycin,n = 97; placebo,n = 102) (of the intended 380). The major reasons for non-recruitment were already receiving antibiotics (n = 2044; 44.6% of screened subjects), unable to contact (n = 315; 6.9%), declined participation (n = 191; 4.2%) and other (e.g. underlying health condition, on steroids;n = 1833; 40.0%). The mean age of participants was 39.9 years and 69.8% were female; 61.1% had never smoked, 22.7% were former smokers and 16.2% were current smokers (mean pack-years 3.45). The median time from presentation to drug administration was 22 hours. Lung function at baseline (exacerbation) was PEF 69.4% predicted, forced expiratory volume in 1 second (FEV1) 64.8% predicted and FEV1/forced vital capacity ratio 69.2%. Baseline characteristics were well balanced across treatment arms and centres. The mean (standard deviation) scores on the primary outcome asthma symptom score were 4.14 (1.38) at baseline and 2.09 (1.71) at the end of treatment for the azithromycin group, and 4.18 (1.48) at baseline and 2.20 (1.51) at the end of treatment for the placebo group. Using multilevel modelling there was no statistically significant difference in symptom scores between groups at day 10 (unbiased estimated mean difference –0.166, 95% confidence interval –0.670 to 0.337); similarly, no significant between-group differences were seen in symptom scores on any other day between baseline and day 10. No significant between-group differences were seen in the Acute Asthma Quality of Life Questionnaire (AQLQ) score, Mini AQLQ score or any measure of lung function on any day, and there were no differences in time to a 50% reduction in symptom score. Sputum bacterial culture was positive in 6% of subjects, atypical pathogen polymerase chain reaction (PCR) and/or serology was positive in 4.5% of subjects and virus PCR analysis was positive in 18.1% of subjects. There was no difference in the primary outcome between the active group and the placebo group among those with a positive sputum bacterial test, although numbers for these analyses were small.ConclusionsIn the population of patients randomised to treatment, the addition of azithromycin to standard medical care demonstrated no statistically significant or clinically important benefit, although this could not be ruled out based on the confidence intervals. A limitation of this study was that, for each subject randomised, > 10 failed screening because they had already been prescribed antibiotic therapy. Further clinical trials are needed in settings of less antibiotic usage.Trial registrationClinicalTrials.gov NCT01444469; EudraCT 2011–001093–26.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.