Baloxavir marboxil, favipiravir, or oseltamivir in patients with non-severe symptomatic seasonal influenza (AD ASTRA): a phase 2, open-label, adaptive, randomised controlled trial

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BACKGROUND: The oral antiviral therapies baloxavir marboxil (hereafter baloxavir), favipiravir, and oseltamivir have not been simultaneously compared for the treatment of seasonal influenza. We aimed to determine their relative efficacies in accelerating viral clearance in patients with symptomatic influenza virus infection at low risk of progression to severe disease. METHODS: oropharyngeal viral densities from day 0 to day 5. Analyses were conducted in the modified intention-to-treat population (mITT), defined as patients with PCR-confirmed influenza with more than 250 viral RNA copies per mL at randomisation. Intervention groups were assessed for superiority over the no study drug group (posterior probability >0·9 that the relative increase in viral clearance was ≥20%); if superiority was met, intervention groups were assessed for non-inferiority relative to baloxavir (posterior probability >0·9 that the relative reduction in viral clearance was ≤10%). Secondary outcomes included time to resolution of fever and time to resolution of all symptoms. The trial is registered with ClinicalTrials.gov (NCT05648448) and is ongoing. FINDINGS: Between Feb 22, 2023, and Dec 12, 2025, 944 patients with influenza virus infection were randomly assigned to baloxavir (n=199; mITT 163 [82%]), favipiravir (n=223; mITT 196 [88%]), oseltamivir (n=200; mITT 170 [85%]), no study drug (n=228; mITT 200 [88%]) or other interventions (n=94). 120 patients were excluded based on baseline viral density (≤250 copies per mL), and one participant withdrew before collection of quantitative PCR results on day 0. 457 (63%) patients in the mITT population were female and 272 (37%) were male. Compared with no study drug, viral clearance rates were accelerated by 86% (95% credible interval [CrI] 60-117) with baloxavir, 66% (45-94) with favipiravir, and 49% (28-74) with oseltamivir. For all interventions, the posterior probability that the relative increase in viral clearance was 20% or more was 1·0. Compared with baloxavir, oseltamivir was inferior (20% slower clearance, 95% CrI 6 to 32; posterior probability 0·93 that the relative reduction in viral clearance was <10%); non-inferiority could not be shown for favipiravir (10% slower clearance, 95% CrI -4 to 22; posterior probability 0·55 that the relative reduction in viral clearance was <10%). Median time to fever resolution was accelerated with all three antivirals compared with no study drug (absolute differences ranging from 0·5 days to 0·9 days), whereas time to resolution of all symptoms was not significantly different between groups. 31 adverse events of grade 3 or above occurred, five of which were considered severe (one in the favipiravir group, one in the oseltamivir group, and three in the no study drug group). INTERPRETATION: Oral baloxavir, favipiravir, and oseltamivir accelerated influenza viral clearance rates in adults with early non-severe seasonal influenza at low risk of progression to severe disease. Baloxavir had the greatest in-vivo antiviral efficacy, followed by favipiravir and oseltamivir. These antivirals shortened fever duration but showed no clear effects on time to complete symptom resolution. This pharmacometric approach can inform prioritisation of antiviral agents for further study and potential inclusion in pandemic stockpiles. FUNDING: Wellcome Trust.

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