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

Chest. 2017 May;151(5):1069-1080. doi: 10.1016/j.chest.2016.11.012. Epub 2016 Nov 22.


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.

Keywords: A(H3N2); clarithromycin; hospitalized; naproxen; oseltamivir.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Anti-Bacterial Agents / therapeutic use*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Antiviral Agents / therapeutic use*
  • Clarithromycin / therapeutic use*
  • Drug Resistance, Viral
  • Drug Therapy, Combination
  • Female
  • Hospitalization
  • Humans
  • Influenza A Virus, H3N2 Subtype
  • Influenza, Human / drug therapy*
  • Influenza, Human / immunology
  • Length of Stay
  • Male
  • Mortality
  • Naproxen / therapeutic use*
  • Nasopharynx / virology
  • Oseltamivir / therapeutic use*
  • Severity of Illness Index
  • Treatment Outcome
  • Viral Load


  • Anti-Bacterial Agents
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antiviral Agents
  • Oseltamivir
  • Naproxen
  • Clarithromycin

Associated data

  • ISRCTN/ISRCTN11273879