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Randomized Controlled Trial
. 2013 May 30:346:f3039.
doi: 10.1136/bmj.f3039.

Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial

South East Asia Infectious Disease Clinical Research Network
Collaborators
Randomized Controlled Trial

Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial

South East Asia Infectious Disease Clinical Research Network. BMJ. .

Abstract

Objective: To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza.

Design: Double blind randomised trial.

Setting: Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam.

Participants: Patients aged ≥ 1 year admitted to hospital with confirmed severe influenza.

Interventions: Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent).

Main outcome measure: Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five.

Results: Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (-5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found.

Conclusions: There were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital.

Registration: Clinical Trials NCT00298233.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: Paul Anantharajah Tambyah has received financial support from Inviragen, Fabentech, Sanofi-Pasteur, GSK, MSD, AstraZeneca, and 3M; M d De Jong has received financial support from AIMM therapeutics, Crucell BV, and AviBiopharma. F Hayden received grants from National Institute of Allergy and Infectious Disease/SAIC during the conduct of the study; personal fees from law firms, Practice Point Communications, and the American Society for Microbiology; since 2008 he has provided non-compensated advice to multiple companies involved in the development and/or marketing of antiviral agents or biologics for influenza including Roche, GSK, Biocryst, Medivector, Romark, Nexbio, Theraclone, and others.

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Trial profile of participants in study of double or standard dose oseltamivir for treatment of severe influenza
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