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Original Research |

Efficacy of clarithromycin-naproxen-oseltamivir combination in the treatment of patients hospitalized for influenza A(H3N2) infection: an open-label, randomized controlled, phase 2b/3 trial

Ivan FN. Hung, MD; Kelvin KW. To, MD; Jasper FW. Chan, MBBS; Vincent CC. Cheng, MD; Kevin SH. Liu, MBChB; Anthony Tam, MBBS; Tuen-Ching Chan, MD; Anna Jinxia Zhang, PhD; Patrick Li, MSc; Tin-Lun Wong, BSc; Ricky Zhang, MSc; Michael KS. Cheung; William Leung, MBBS; Johnson YN. Lau, MD; Manson Fok, MD; Honglin Chen, PhD; Kwok-Hung Chan, PhD; Kwok-Yung Yuen, MD
Author and Funding Information

Conflicts of Interest: JFW Chan has received travel grants from Pfizer Corporation Hong Kong Ltd. and Astellas Pharma Hong Kong Co., Ltd. and was an invited speaker by Gilead Sciences Hong Kong Ltd. JYN Lau and M Fok are partners of Avelon Biomedical Management. All others declare no conflicts of interest.

Clinical trial registered with www.isrctn.com/ISRCTN11273879

1Carol 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

2Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong Special Administrative Region, China

3LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China

4Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China

Correspondence to: Kwok-Yung Yuen, Carol Yu Centre for Infection and Division of Infectious Diseases, Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong Special Administrative Region, China.


Copyright 2016, . All Rights Reserved.


Chest. 2016. doi:10.1016/j.chest.2016.11.012
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Abstract

Background  Influenza causes excessive hospitalizations and deaths. Single agent treatment with oseltamivir in severe influenza might be insufficient. The study assessed the efficacy and safety of oseltamivir-clarithromycin-naproxen 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 500mg, naproxen 200mg and oseltamivir 75mg twice daily, followed by 3 days of oseltamivir; or oseltamivir 75mg twice daily without placebos for 5 days as control (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 by pyrosequencing, pneumonia-severity-index (PSI), and duration of hospital-stay.

Results  Among the 217 influenza A(H3N2) patients enrolled, 107 were randomly assigned to the combination treatment. The median age was 80 years and 56% were men. Adverse events were uncommon. Ten patients succumbed during the 30-day follow-up. The combination treatment was associated with lower 30-day mortality (P=0.01), less frequent ICU/HDU admission (P<0.001), and shorter hospital-stay (P<0.0001). The virus titer, PSI (day 1-3;P<0.01), and NPA specimens with NIRV quasispecies ≥5% (day 1-2;P<0.01) 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 (odds-ratio:0.06; 95%,confidence-interval, 0.004-0.94;P=0.04).

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


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