Baloxavir marboxil (baloxavir) is a polymerase acidic protein (PA) endonuclease inhibitor with clinical

efficacy in the treatment of uncomplicated influenza, including in outpatients at increased risk for
complications. The postexposure prophylactic efficacy of baloxavir in the household setting is unclear.

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We conducted a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the

postexposure prophylactic efficacy of baloxavir in household contacts of index patients with confirmed
influenza during the 2018–2019 season in Japan. The participants were assigned in a 1:1 ratio to receive
either a single dose of baloxavir or placebo. The primary end point was clinical influenza, as confirmed by
reverse-transcriptase–polymerase-chain-reaction testing, over a period of 10 days. The occurrence of
baloxavir-selected PA substitutions associated with reduced susceptibility was assessed.

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A total of 752 household contacts of 545 index patients were randomly assigned to receive baloxavir or
placebo. Among the index patients, 95.6% had influenza A virus infection, 73.6% were younger than 12
years of age, and 52.7% received baloxavir. Among the participants who could be evaluated (374 in the
baloxavir group and 375 in the placebo group), the percentage in whom clinical influenza developed was
significantly lower in the baloxavir group than in the placebo group (1.9% vs. 13.6%) (adjusted risk ratio,
0.14; 95% confidence interval [CI], 0.06 to 0.30; P<0.001). Baloxavir was effective in high-risk, pediatric,
and unvaccinated subgroups of participants. The risk of influenza infection, regardless of symptoms, was
lower with baloxavir than with placebo (adjusted risk ratio, 0.43; 95% CI, 0.32 to 0.58). The incidence of
adverse events was similar in the two groups (22.2% in the baloxavir group and 20.5% in the placebo
group). In the baloxavir group, the viral PA substitutions I38T/M or E23K were detected in 10 (2.7%) and
5 (1.3%) participants, respectively. No transmission of these variants from baloxavir-treated index
patients to participants in the placebo group was detected; however, several instances of transmission to
participants in the baloxavir group could not be ruled out.

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Single-dose baloxavir showed significant postexposure prophylactic efficacy in preventing influenza in

household contacts of patients with influenza. (Funded by Shionogi; Japan Primary Registries Network
number, JapicCTI-184180.)