Antiviral treatment in adult patients hospitalized for influenza: study protocol for a multi-center, randomized, placebo-controlled trial on the efficacy of baloxavir marboxil to reduce time to clinical improvement and the risk for severe complications (the INFLUENT trial).

backgroundSeasonal influenza virus leads to more than half a million deaths each year worldwide. Due to its capacity to evolve, it is considered the most likely pathogen to cause a future pandemic. Antiviral treatment options are currently limited, with the most widely used drugs being neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir marboxil. In adult hospitalized patients, due to the lack of placebo-controlled trials, current available evidence on antiviral treatment benefits is essentially based on observational studies. A placebo-controlled clinical trial is needed to fill this knowledge gap.

methodsThis is an investigator-initiated, randomized, triple-blind, placebo-controlled, superiority, multi-center trial to assess the clinical efficacy of single-dose baloxavir in decreasing time to clinical improvement in adult immunocompetent patients hospitalized with influenza. Patients (n = 484) with confirmed, severe infection (NEWS2 score ≥ 4) will be recruited over three influenza seasons in four large Swiss hospitals. PRIMARY OUTCOME: time to clinical improvement (in hours), calculated from treatment administration until NEWS2 score ≤ 2 maintained for 24 h or until hospital discharge, whichever comes first. The primary outcome is calculated in all patients independently of the duration of symptoms at treatment administration, as well as in participants treated early (<72 h) post onset of symptoms. The main secondary outcomes are the risk of serious influenza complications, length of hospitalization, and difference in viral load at D3 post-treatment administration. DISCUSSION: This trial's results, whether positive or negative, will impact clinical guidance. If baloxavir's clinical benefit is demonstrated, a single-dose pill would be the easiest implementable treatment option in case of large seasonal outbreaks or a new influenza pandemic. If a clear treatment benefit is not shown, antiviral treatment administration in the hospitalized patient population could be reconsidered to prevent unnecessary medication, lower the risk of resistance development linked to treatment overuse, and ultimately save unnecessary treatment-related expenses.

trial registrationClinicalTrials.gov NCT06653569. Registered on October 22, 2024, https://clinicaltrials.gov/study/NCT06653569?term=NCT06653569&rank=1 .