Elsevier

The Lancet

Volume 390, Issue 10095, 12–18 August 2017, Pages 659-668
The Lancet

Articles
Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(17)31281-3Get rights and content

Summary

Background

Exacerbations of asthma cause a substantial global illness burden. Adults with uncontrolled persistent asthma despite maintenance treatment require additional therapy. Since macrolide antibiotics can be used to treat persistent asthma, we aimed to assess the efficacy and safety of oral azithromycin as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high dose inhaled corticosteroids plus a long-acting bronchodilator.

Methods

We did a randomised, double-blind, placebo controlled parallel group trial to determine whether oral azithromycin decreases the frequency of asthma exacerbations in adults (≥18 years) with symptomatic asthma despite current use of inhaled corticosteroid and long-acting bronchodilator, and who had no hearing impairment or abnormal prolongation of the corrected QT interval. Patients were randomly assigned (1:1) to receive azithromycin 500 mg or placebo three times per week for 48 weeks. Patients were centrally allocated using concealed random allocation from a computer-generated random numbers table with permuted blocks of 4 or 6 and stratification for centre and past smoking. Primary efficacy endpoints were the rate of total (severe and moderate) asthma exacerbations over 48 weeks and asthma quality of life. Data were analysed on an intention-to-treat basis. The trial is registered at the Australian and New Zealand Clinical Trials Registry (ANZCTR), number 12609000197235.

Findings

Between June 12, 2009, and Jan 31, 2015, 420 patients were randomly assigned (213 in the azithromycin group and 207 in the placebo group). Azithromycin reduced asthma exacerbations (1·07 per patient-year [95% CI 0·85–1·29]) compared with placebo (1·86 per patient-year [1·54–2·18]; incidence rate ratio [IRR] 0·59 [95% CI 0·47–0·74]; p<0·0001). The proportion of patients experiencing at least one asthma exacerbation was reduced by azithromycin treatment (127 [61%] patients in the placebo group vs 94 [44%] patients in the azithromycin group, p<0·0001). Azithromycin significantly improved asthma-related quality of life (adjusted mean difference, 0·36 [95% CI 0·21–0·52]; p=0·001). Diarrhoea was more common in azithromycin-treated patients (72 [34%] vs 39 [19%]; p=0·001).

Interpretation

Adults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma.

Funding

National Health and Medical Research Council of Australia, John Hunter Hospital Charitable Trust.

Introduction

Asthma is a common global chronic disease, and over 50 million people are estimated to have moderate-to-severe uncontrolled asthma.1 Patients with uncontrolled asthma are at risk of severe exacerbations that result in frequent visits to physicians' offices, hospitalisations, days lost from work, and—rarely—death.2, 3 Asthma exacerbations can still occur despite maintenance treatment with inhaled corticosteroids and long-acting bronchodilators, indicating a need for additional treatment options in uncontrolled persistent asthma.2, 3

Asthma is characterised by chronic airway inflammation, increased susceptibility to respiratory viral infection, and altered airway microbiology. The airway inflammatory response is heterogeneous in asthma, with eosinophilic and non-eosinophilic phenotypes being recognised.4 These phenotypes have different mechanisms and different responses to inhaled corticosteroids. The eosinophilic phenotype involves the Th2/allergic pathways and is usually corticosteroid-sensitive, whereas the non-eosinophilic phenotype exhibits innate immune dysfunction and corticosteroid insensitivity.

Macrolide antibiotics have antibacterial, antiviral, and anti-inflammatory effects,5, 6, 7, 8 and are reported to be beneficial in both eosinophilic6 and non-eosinophilic subtypes.7, 8 Systematic reviews of randomised controlled trials report benefits of macrolides on asthma symptoms but are unable to draw conclusions about the effects on other endpoints, including exacerbations, due to lack of data, heterogeneity of results, and inadequate study design and sample size.9, 10, 11, 12 Therefore, we did a randomised trial to test the hypothesis that azithromycin reduces asthma exacerbations and improves quality of life in patients with symptomatic asthma on inhaled maintenance therapy.

Research in context

Evidence before this study

Asthma is a common chronic inflammatory airway disease worldwide. Severe exacerbations and poor control persist in people treated with maintenance asthma therapy, showing a need for additional therapeutic options. Macrolide antibiotics have anti-inflammatory, antibacterial, and antiviral effects that might be beneficial in asthma. We searched PubMed on Dec 12, 2016, for randomised controlled clinical trials of macrolides for asthma in adults that were published in English, using the search terms “asthma AND (macrolide OR azithromycin) AND clinical trial AND adult”. The search was done from Jan 1, 1980 onwards and identified randomised controlled trials and systematic reviews of clinical trials. These studies identified a potential benefit of macrolides on asthma symptoms, but gave inconsistent results for an effect on asthma exacerbations and for phenotype-specific effects. Systematic reviews were unable to draw conclusions about the effects on other endpoints, including exacerbations, due to lack of data, heterogeneity of results, and inadequate study design.

Added value of this study

Our study provides clear evidence of benefit of add-on azithromycin in reducing asthma exacerbations in adults with uncontrolled asthma who are taking maintenance inhaled corticosteroid and a long-acting bronchodilator. We also show improved quality of life with azithromycin treatment of persistent asthma. Additionally, we identify a beneficial effect of azithromycin in reducing episodes of respiratory infection. The treatment was well tolerated.

Implications of all the available evidence

Using azithromycin in addition to inhaled corticosteroids and long-acting bronchodilators could substantially improve the health of people with uncontrolled persistent asthma.

Section snippets

Study design and participants

We used a multicentre, randomised, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of oral azithromycin 500 mg, three times weekly for 48 weeks, as add-on therapy in adults with persistent symptomatic asthma despite maintenance controller therapy with an inhaled corticosteroid and a long-acting bronchodilator.

Patients were eligible if they had asthma defined as a compatible history and documented objective evidence of variable airflow obstruction from

Results

Between June 12, 2009, and Jan 31, 2015, 582 patients were screened for participation, and 420 were randomly assigned across eight sites. The reasons for screen failure are listed in the appendix. We allocated 213 (51%) to azithromycin treatment and 207 (49%) to placebo. The trial was completed by 334 (80%) patients. There were similar numbers of trial withdrawals in each group, and similar withdrawals due to adverse effects (15 [4%] in the azithromycin group and 10 [2%] in the placebo group;

Discussion

Patients with symptomatic asthma on combination maintenance therapy with inhaled corticosteroid and a long-acting bronchodilator remain at risk of asthma exacerbations. We report that the addition of oral azithromycin 500 mg, three times per week, for 48 weeks, led to a decrease in the frequency of asthma exacerbations and improved asthma-related quality of life. With azithromycin there were also fewer respiratory infections overall. The treatment was well tolerated, but there was an increase

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