COMbination therapy with baloxavir and oseltamivir 1 for hospitalized patients with influenza: The pragmatic COMBO 1 randomized controlled trial

Background COMBO 1 compared time to cessation of viral shedding (TCVS) among hospitalized influenza patients treated with oseltamivir plus a single dose of baloxavir vs. oseltamivir alone. Methods In a quadruple-blinded, placebo-controlled parallel group multicenter randomized controlled trial, hospitalized patients with laboratory-confirmed influenza were randomly enrolled in a 1:1 ratio to Group 1 (oseltamivir+placebo) or Group 2 (oseltamivir+baloxavir). All patients were treated with oseltamivir for 5 days; one dose of baloxavir or placebo was given in identical capsules. Primary efficacy and safety outcomes were TCVS by virus titer with qCulture TCID 50 agglutination and 30-day severe adverse event (SAE) rate, respectively. Secondary virology, clinical, and safety outcomes were assessed. Continuous and categorical data were analyzed with Wilcoxon Rank-Sum and Fisher’s Exact Tests, respectively. Results 14 participants were randomized and received study drug (Group 1: n=6, Group 2: n=8); the study was stopped early due to slow accrual. Baseline characteristics were balanced. Median TCVS with qCulture was 53.3 hours in Group 1 and 25.3 hours in Group 2 (p=0.13). 30-day overall SAE rates were 16.7% and 12.5%, respectively. All patients achieved negative qCulture. Median TCVS with quantitative PCR (RT-qPCR) was 115.6 and 34.4 hours (p=0.24); % achieving viral negative by RT-qPCR was 33.3% and 75.0% (p=0.28), respectively. Conclusions Combination therapy with oseltamivir and a single dose of baloxavir was inconclusive with non-significant trends towards shorter median TCVS vs. monotherapy with oseltamivir in hospitalized patients with influenza. Interpretation is limited by small sample size and early termination.