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Original Research: Chest Infections |

Efficacy of Clarithromycin-Naproxen-Oseltamivir Combination in the Treatment of Patients Hospitalized for Influenza A(H3N2) Infection: An Open-label Randomized, Controlled, Phase IIb/III Trial

Ivan F.N. Hung, MD; Kelvin K.W. To, MD; Jasper F.W. Chan, MBBS; Vincent C.C. Cheng, MD; Kevin S.H. Liu, MBChB; Anthony Tam, MBBS; Tuen-Ching Chan, MD; Anna Jinxia Zhang, PhD; Patrick Li, MSc; Tin-Lun Wong, BSc; Ricky Zhang, MSc; Michael K.S. Cheung, MBBS; William Leung, MBBS; Johnson Y.N. Lau, MD; Manson Fok, MD; Honglin Chen, PhD; Kwok-Hung Chan, PhD; Kwok-Yung Yuen, MD
Author and Funding Information

FUNDING/SUPPORT: This study was funded by the Shaw Foundation, Providence Foundation Limited in memory of the late Dr Lui Hac Minh, Larry Chi-Kin Yung, the University Grant Council, and the Health and Medical Research Fund of the Food and Health Bureau of the Hong Kong Special Administrative Region government.

aCarol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China

bDepartment of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China

cLKS Faculty of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China

dCollaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China

CORRESPONDENCE TO: Kwok-Yung Yuen, MD, Carol Yu Centre for Infection and Division of Infectious Diseases, State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, the University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Rd, Pokfulam, Hong Kong Special Administrative Region, China


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(5):1069-1080. doi:10.1016/j.chest.2016.11.012
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Background  Influenza causes excessive hospitalizations and deaths. The study assessed the efficacy and safety of a clarithromycin-naproxen-oseltamivir combination for treatment of serious influenza.

Methods  From February to April 2015, we conducted a prospective open-label, randomized, controlled trial. Adult patients hospitalized for A(H3N2) influenza were randomly assigned to a 2-day combination of clarithromycin 500 mg, naproxen 200 mg, and oseltamivir 75 mg twice daily, followed by 3 days of oseltamivir or to oseltamivir 75 mg twice daily without placebo for 5 days as a control method (1:1). The primary end point was 30-day mortality. The secondary end points were 90-day mortality, serial nasopharyngeal aspirate (NPA) virus titer, percentage of neuraminidase-inhibitor-resistant A(H3N2) virus (NIRV) quasispecies, pneumonia severity index (PSI), and duration of hospital stay.

Results  Among the 217 patients with influenza A(H3N2) enrolled, 107 were randomly assigned to the combination treatment. The median age was 80 years, and 53.5% were men. Adverse events were uncommon. Ten patients died during the 30-day follow-up. The combination treatment was associated with lower 30-day mortality (P = .01), less frequent high dependency unit admission (P = .009), and shorter hospital stay (P < .0001). The virus titer and PSI (days 1-3; P < .01) and the NPA specimens with NIRV quasispecies ≥ 5% (days 1-2; P < .01) were significantly lower in the combination treatment group. Multivariate analysis showed that combination treatment was the only independent factor associated with lower 30-day mortality (OR, 0.06; 95% CI, 0.004-0.94; P = .04).

Conclusions  Combination treatment reduced both 30- and 90-day mortality and length of hospital stay. Further study of the antiviral and immunomodulatory effects of this combination treatment of severe influenza is warranted.

Trial Registry  BioMed Central; No.: ISRCTN11273879 DOI 10.1186/ISRCTN11273879; URL: www.isrctn.com/ISRCTN11273879

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