Background: Baloxavir marboxil (baloxavir) rapidly reduces influenza virus shedding, which suggests that it may reduce transmission. Studies of treatment with neuraminidase inhibitors have not shown sufficient evidence that they prevent transmission to contacts.

Methods: We conducted a multicountry, phase 3b trial to assess the efficacy of single-dose baloxavir treatment to reduce influenza transmission from index patients to household contacts. Influenza-positive index patients 5 to 64 years of age were randomly assigned in a 1:1 ratio to receive baloxavir or placebo within 48 hours after symptom onset. The primary end point was transmission of influenza virus from an index patient to a household contact by day 5. The first secondary end point was transmission of influenza virus by day 5 that resulted in symptoms.

Results: Overall, 1457 index patients and 2681 household contacts were enrolled across the 2019-2024 influenza seasons; 726 index patients were assigned to the baloxavir group, and 731 to the placebo group. By day 5, transmission of laboratory-confirmed influenza was significantly lower with baloxavir than with placebo (adjusted incidence, 9.5% vs. 13.4%; adjusted odds ratio, 0.68; 95.38% confidence interval [CI], 0.50 to 0.93; P = 0.01), with an adjusted relative risk reduction of 29% (95.38% CI, 12 to 45). The adjusted incidence of transmission of influenza virus by day 5 that resulted in symptoms was 5.8% with baloxavir and 7.6% with placebo; however, the difference was not significant (adjusted odds ratio, 0.75; 95.38% CI, 0.50 to 1.12; P = 0.16). Emergence of drug-resistant viruses during the follow-up period occurred in 7.2% (95% CI, 4.1 to 11.6) of the index patients in the baloxavir group; no resistant viruses were detected in household contacts. No new safety signals were identified.

Conclusions: Treatment with a single oral dose of baloxavir led to a lower incidence of transmission of influenza virus to close contacts than placebo.