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Randomized Controlled Trials for Prevention and Treatment

Frederick G. Hayden, MD; John J. Treanor, MD; R. Scott Fritz, PhD; Monica Lobo, MD; Robert F. Betts, MD; Madeline Miller, DVM; Nelson Kinnersley, MSc; Roger G. Mills, MD; Penelope Ward, MD; Stephen E. Straus, MD

JAMA. 1999;282:1240-1246.

Context  Influenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered.

Objective  To determine the safety, tolerability, and antiviral activity of oral neuraminidase inhibitor oseltamivir (GS4104/Ro64-0796) for prevention and the early treatment of influenza in experimentally infected humans.

Design  Two randomized, double-blind, placebo-controlled trials conducted between June and July 1997.

Setting  Individual hotel rooms; 2 large US university medical schools.

Participants  A total of 117 healthy adult volunteers (aged 18-40 years; median age, 21 years) who were susceptible (hemagglutination-inhibition antibody titer 1:8).

Interventions  All subjects were inoculated intranasally with influenza A/Texas/36/91(H1N1) virus. For the prophylaxis study, oral oseltamivir (100 mg once daily [n=12], 100 mg twice daily [n=12], or matching placebo [n=13], starting 26 hours before virus inoculation) was administered. For the treatment study, the same drug was given (20 mg, 100 mg, or 200 mg twice daily, 200 mg once daily, or matching placebo [n=16], in each group starting 28 hours after inoculation). All regimens were continued for 5 days.

Main Outcome Measures  Comparing placebo groups with pooled treatment groups, for prophylaxis, outcomes included frequency of infection and viral shedding; for treatment, viral shedding in titers.

Results  In the prophylaxis study, 8 (67%) of 12 placebo and 8 (38%) of 21 oseltamivir recipients became infected (P=.16; efficacy, 61%); 6 (50%) placebo compared with 0 oseltamivir recipients shed virus (P<.001; efficacy, 100%), and 33% of placebo but no oseltamivir recipient had infection-related respiratory illness (P<.01). Among infected subjects in the treatment study (n=69), the viral titer area under the curve of the combined oseltamivir groups (n=56) was lower (median [interquartile range {IQR}], 80 [23-151] vs 273 [79-306] log₁₀ tissue culture-infective doses₅₀ per milliliterxhour; P=.02) than the placebo group (n=13), and the median (IQR) duration of viral shedding with therapy was reduced from 107 (83-131) to 58 (35-59) hours (P=.003). Oseltamivir treatment also reduced symptom scores (median [IQR] score-hours, 225 [97-349] vs 400 [189-645]; P=.05), and nasal proinflammatory cytokine levels. Transient mild to moderate nausea after dosing was observed in 15 (17%) of 88 oseltamivir and 2 (7%) of 29 placebo recipients (95% confidence interval for difference, -11% to 68%), which was largely prevented by ingestion with food.

Conclusions  In these trials, prophylaxis and early treatment with oral oseltamivir were both associated with significant antiviral and clinical effects in experimental human influenza.

Author Affiliations: University of Virginia School of Medicine, Charlottesville (Drs Hayden and Lobo); University of Rochester School of Medicine, Rochester, NY (Drs Treanor and Betts); SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Md (Dr Fritz); Gilead Sciences, Foster City, Calif (Drs Miller and Mills); Roche Discovery Welwyn, Hoffman-LaRoche and Company, Welwyn Garden City, England (Mr Kinnersley and Dr Ward); and Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md (Dr Straus).

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