Efficacy of azithromycin in severe asthma from the AMAZES randomised trial

Peter G Gibson^{1

2

3}, Ian A Yang^{4

5}, John W Upham^{4

6}, Paul N Reynolds^{7

8}, Sandra Hodge^{7

8}, Alan L James^{9

10}, Christine Jenkins^{11

12}, Matthew J Peters^{12

13}, Guy B Marks^{3

14}, Melissa Baraket¹⁵, Heather Powell^{1

2}, Jodie L Simpson²

Affiliations

¹ Dept of Respiratory and Sleep Medicine, Hunter Medical Research Institute, Newcastle, Australia.
² Priority Research Centre for Healthy Lungs, The University of Newcastle, Newcastle, Australia.
³ Woolcock Institute of Medical Research, Glebe, Australia.
⁴ Faculty of Medicine, The University of Queensland, St Lucia, Australia.
⁵ Dept of Thoracic Medicine, The Prince Charles Hospital, Chermside, Australia.
⁶ Dept of Respiratory Medicine, Princess Alexandra Hospital, Woolloongabba, Australia.
⁷ Dept of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia.
⁸ Dept of Medicine, The University of Adelaide, Adelaide, Australia.
⁹ Dept of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia.
¹⁰ School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia.
¹¹ Respiratory Trials, The George Institute for Global Health, Sydney, Australia.
¹² Faculty of Medicine and Health Sciences, Macquarie University, North Ryde, Australia.
¹³ Dept of Thoracic Medicine, Concord General Hospital, Concord, Australia.
¹⁴ South Western Sydney Clinical School, UNSW, Sydney, Australia.
¹⁵ Respiratory Medicine Dept and Ingham Institute Liverpool Hospital, University of New South Wales Medicine Faculty, Sydney, Australia.

PMID: 31886156
PMCID: PMC6926362
DOI: 10.1183/23120541.00056-2019

Efficacy of azithromycin in severe asthma from the AMAZES randomised trial

Peter G Gibson et al. ERJ Open Res. 2019.

. 2019 Dec 23;5(4):00056-2019.

doi: 10.1183/23120541.00056-2019. eCollection 2019 Oct.

Authors

Affiliations

¹ Dept of Respiratory and Sleep Medicine, Hunter Medical Research Institute, Newcastle, Australia.
² Priority Research Centre for Healthy Lungs, The University of Newcastle, Newcastle, Australia.
³ Woolcock Institute of Medical Research, Glebe, Australia.
⁴ Faculty of Medicine, The University of Queensland, St Lucia, Australia.
⁵ Dept of Thoracic Medicine, The Prince Charles Hospital, Chermside, Australia.
⁶ Dept of Respiratory Medicine, Princess Alexandra Hospital, Woolloongabba, Australia.
⁷ Dept of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia.
⁸ Dept of Medicine, The University of Adelaide, Adelaide, Australia.
⁹ Dept of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, Australia.
¹⁰ School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia.
¹¹ Respiratory Trials, The George Institute for Global Health, Sydney, Australia.
¹² Faculty of Medicine and Health Sciences, Macquarie University, North Ryde, Australia.
¹³ Dept of Thoracic Medicine, Concord General Hospital, Concord, Australia.
¹⁴ South Western Sydney Clinical School, UNSW, Sydney, Australia.
¹⁵ Respiratory Medicine Dept and Ingham Institute Liverpool Hospital, University of New South Wales Medicine Faculty, Sydney, Australia.

PMID: 31886156
PMCID: PMC6926362
DOI: 10.1183/23120541.00056-2019

Abstract

Background: Low-dose azithromycin is an effective therapy for persistent asthma; however, its benefit in severe asthma is not defined.

Methods: Participants with severe asthma were identified from the AMAZES randomised, placebo-controlled trial of long-term (48 weeks) low-dose azithromycin. Participants who met one of the following severe asthma definitions were included: 1) Global Initiative for Asthma step 4 treatment with poor asthma control (asthma control questionnaire score ≥0.75); 2) International Severe Asthma Registry definition; 3) American Thoracic Society and European Respiratory Society severe asthma definitions. The rate of total exacerbations was calculated for each subgroup and efficacy of azithromycin compared with placebo. Asthma-related quality of life was assessed before and after treatment along with adverse effects.

Results: Azithromycin significantly reduced asthma exacerbations in each group. In patients meeting the American Thoracic Society and European Respiratory Society task force definition of severe asthma (n=211), the rate of exacerbations with treatment was 1.2 per person-year, which was significantly less than for placebo (2.01 per person-year), giving an incidence rate ratio (95% CI) of 0.63 (0.41, 0.96). The proportion of participants experiencing at least one asthma exacerbation was reduced by azithromycin from 64% to 49% (p=0.021). A similar beneficial treatment effect was seen in participants poorly controlled with Global Initiative for Asthma step 4 treatment and those with International Severe Asthma Registry-defined severe asthma. Azithromycin also significantly improved the quality of life in severe asthma (p<0.05). Treatment was well tolerated, with gastrointestinal symptoms being the main adverse effect.

Conclusion: Long-term, low-dose azithromycin reduced asthma exacerbations and improved the quality of life in patients with severe asthma, regardless of how this was defined. These data support the addition of azithromycin as a treatment option for patients with severe asthma.

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Conflict of interest statement

Conflict of interest: P.G. Gibson reports grants and personal fees from AstraZeneca, GlaxoSmithKline, Novartis and Sanofi during the conduct of the study. Conflict of interest: I.A. Yang reports grants from the NHMRC during the conduct of the study. Conflict of interest: J.W. Upham reports a research grant, advisory boards, speaker fees and conference travel from Astra Zeneca, advisory boards from GSK, advisory boards, speaker fees and conference travel from Novartis, speaker fees and conference travel from Boehringer Ingelheim, and conference travel from Menarini, outside the submitted work. Conflict of interest: P.N. Reynolds reports grants from National Health and Medical Research Council, and personal fees from Boehringer Ingelheim, during the conduct of the study. Conflict of interest: S. Hodge has nothing to disclose. Conflict of interest: A.L. James has nothing to disclose. Conflict of interest: C. Jenkins reports grants and personal fees from GlaxoSmithKline, personal fees and nonfinancial support from AstraZeneca, personal fees and nonfinancial support from Boehringer Ingelheim, and personal fees from Novartis, outside the submitted work. Conflict of interest: M.J. Peters has nothing to disclose. Conflict of interest: G.B. Marks reports grants and nonfinancial support from GSK Australia, grants and other from AstraZeneca, outside the submitted work. Conflict of interest: M. Baraket has nothing to disclose. Conflict of interest: H.P. Powell has nothing to disclose. Conflict of interest: J.L. Simpson has nothing to disclose.

Figures

**FIGURE 1**
Trial profile. GINA: Global Initiative for Asthma; ISAR: International Severe Asthma Registry.

**FIGURE 2**
Effect of add-on azithromycin treatment on asthma exacerbations according to subgroup analyses. Severe asthma (ATS/ERS): ≥1000 µg of fluticasone equivalent inhaled corticosteroid and long-acting β agonist combination. No significant interaction was present between subgroup and treatment. AZM: azithromycin; IRR: incidence rate ratio; GINA: Global Initiative for Asthma; ATS: American Thoracic Society; ERS: European Respiratory Society; ISAR: International Severe Asthma Registry.

**FIGURE 3**
Total exacerbations in noneosinophilic severe asthma American Thoracic Society (ATS) criteria: high-dose inhaled corticosteroid and long-acting β₂-agonist (LABA) (≥1000 µg fluticasone and LABA combination). AZM: azithromycin; IRR: incidence rate ratio; GINA: Global Initiative for Asthma; ISAR: International Severe Asthma Registry; ERS: European Respiratory Society.

**FIGURE 4**
Total exacerbations in severe eosinophilic asthma. AZM: azithromycin; IRR: incidence rate ratio; GINA: Global Initiative for Asthma; ISAR: International Severe Asthma Registry; ATS: American Thoracic Society; ERS: European Respiratory Society.

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References

1. Hekking PP, Wener RR, Amelink M, et al. . The prevalence of severe refractory asthma. J Allergy Clin Immunol 2015; 135: 896–902. - PubMed
1. Chung KF, Wenzel SE, Brozek JL, et al. . International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43: 343–373. - PubMed
1. von Bulow A, Kriegbaum M, Backer V, et al. . The prevalence of severe asthma and low asthma control among Danish adults. J Allergy Clin Immunol Pract 2014; 2: 759–767. - PubMed
1. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med 2017; 377: 965–976. - PubMed
1. Brusselle GG, Vanderstichele C, Jordens P, et al. . Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013; 68: 322–329. - PubMed

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Efficacy of azithromycin in severe asthma from the AMAZES randomised trial

Affiliations

Efficacy of azithromycin in severe asthma from the AMAZES randomised trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources

Miscellaneous