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Original Investigation |

Azithromycin for Acute Exacerbations of Asthma  The AZALEA Randomized Clinical Trial ONLINE FIRST

Sebastian L. Johnston, MBBS, PhD1; Matyas Szigeti, MSc2; Mary Cross, BA (Hons)2; Christopher Brightling, MBBS, PhD3; Rekha Chaudhuri, MBBS, MD4,5; Timothy Harrison, MBBS, PhD6; Adel Mansur, MBBS, PhD7,8; Laura Robison, BSc2; Zahid Sattar, BSc, PhD2; David Jackson, MBBS, PhD1; Patrick Mallia, MBBS, PhD1; Ernie Wong, MBBS, BSc1; Christopher Corrigan, MA, PhD9,10; Bernard Higgins, MBBS11; Philip Ind, MB, BChir, PhD1,12; Dave Singh, MB, BChir, MD13; Neil C. Thomson, MBChB, MD4; Deborah Ashby, PhD, CStat2; Anoop Chauhan, MBBS, PhD14 ; For the AZALEA Trial Team
[+] Author Affiliations
1National Heart and Lung Institute, Imperial College London, London, England
2Imperial Clinical Trials Unit, School of Public Health, Imperial College London, London, England
3Institute for Lung Health, University of Leicester, Leicester, England
4Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, Scotland
5Respiratory Medicine, NHS Greater Glasgow and Clyde, Glasgow, Scotland
6Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, England
7Respiratory Medicine, Heart of England Foundation Trust, Birmingham, England
8Severe and Brittle Asthma Unit, University of Birmingham, Birmingham, England
9Respiratory Medicine and Allergy, King’s College London School of Medicine, London, England
10Department of Asthma, Allergy and Respiratory Science, Guy’s and St. Thomas’ NHS Foundation Trust, London, England
11Respiratory Medicine, Newcastle University, Newcastle, England
12Respiratory Medicine, Imperial College Healthcare NHS Trust, London, England
13Centre for Respiratory Medicine and Allergy, Medicines Evaluation Unit, University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, England
14Respiratory Medicine, Portsmouth Hospitals NHS Trust, Portsmouth, England
JAMA Intern Med. Published online September 19, 2016. doi:10.1001/jamainternmed.2016.5664
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Importance  Guidelines recommend against antibiotic use to treat asthma attacks. A study with telithromycin reported benefit, but adverse reactions limit its use.

Objective  To determine whether azithromycin added to standard care for asthma attacks in adults results in clinical benefit.

Design, Setting, and Participants  The Azithromycin Against Placebo in Exacerbations of Asthma (AZALEA) randomized, double-blind, placebo-controlled clinical trial, a United Kingdom–based multicenter study in adults requesting emergency care for acute asthma exacerbations, ran from September 2011 to April 2014. Adults with a history of asthma for more than 6 months were recruited within 48 hours of presentation to medical care with an acute deterioration in asthma control requiring a course of oral and/or systemic corticosteroids.

Interventions  Azithromycin 500 mg daily or matched placebo for 3 days.

Main Outcomes and Measures  The primary outcome was diary card symptom score 10 days after randomization, with a hypothesized treatment effect size of −0.3. Secondary outcomes were diary card symptom score, quality-of-life questionnaires, and lung function changes, all between exacerbation and day 10, and time to a 50% reduction in symptom score.

Results  Of 4582 patients screened at 31 centers, 199 of a planned 380 were randomized within 48 hours of presentation. The major reason for nonrecruitment was receipt of antibiotics (2044 [44.6%] screened patients). Median time from presentation to drug administration was 22 hours (interquartile range, 14-28 hours). Exacerbation characteristics were well balanced across treatment arms and centers. The primary outcome asthma symptom scores were mean (SD), 4.14 (1.38) at exacerbation and 2.09 (1.71) at 10 days for the azithromycin group and 4.18 (1.48) and 2.20 (1.51) for the placebo group, respectively. Using multilevel modeling, there was no significant difference in symptom scores between azithromycin and placebo at day 10 (difference, −0.166; 95% CI, −0.670 to 0.337), nor on any day between exacerbation and day 10. No significant between-group differences were observed in quality-of-life questionnaires or lung function between exacerbation and day 10, or in time to 50% reduction in symptom score.

Conclusions and Relevance  In this randomized population, azithromycin treatment resulted in no statistically or clinically significant benefit. For each patient randomized, more than 10 were excluded because they had already received antibiotics.

Trial Registration  clinicaltrials.gov Identifier: NCT01444469

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Figure 1.
Consolidated Standards of Reporting Trials Diagram of the Azithromycin for Acute Exacerbations of Asthma (AZALEA) Trial

AQLQ indicates Asthma Quality of Life Questionnaire.

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Figure 2.
Primary Outcome Symptom Diary Scores From Randomization to Day 10

Error bars indicate standard error.

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Figure 3.
Secondary Outcome Acute and Mini Asthma Quality of Life Questionnaire (AQLQ) Scores From Randomization to Day 10 and Time to 50% Reduction in Symptom Diary Score

A and B, Acute and Mini AQLQ mean scores by visits for each treatment arm. Error bars indicate standard error. C, Kaplan-Meier curves of time to a 50% reduction in symptom diary score for each treatment arm (truncated at 10 days).

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