Table 3 Outcome measures and endpoints

Efficacy

Primary clinical endpoints

 Time to illness alleviation of influenza, defined as the time from baloxavir or oseltamivir administration until the following criteria were reached and sustained for at least 21.5 h (24 h—10%): both cough and nasal discharge/nasal congestion assessed as 0 (absent) or 1 (mild) and axillary temperature less than 37.5 °C

Secondary endpoints

 Time to sustained resolution of influenza symptoms (cough, nasal discharge/nasal congestion) rated using the Influenza Symptom Severity Scale as absent (grade 0) or mild (grade 1) and resolution of fever (normal body temperature < 37.5 °C) for at least 72 h

 Time to resolution of fever (< 37.5 °C) for at least 12 h

 Time to sustained resolution of fever for at least 72 h

 Proportion of subjects with resolution of fever at each time point

 Time to resolution of all seven influenza symptoms (cough, sore throat, headache, nasal discharge/nasal congestion, feverish or chills, muscle ache or joint pain, and fatigue), rated using the Influenza  Symptom Severity Scale as absent (grade 0) or mild (grade 1) for at least 21.5 h

 Time to resolution of each influenza symptom for at least 21.5 h

 Incidence of influenza-related complications (pneumonia determined by X-ray, bronchitis, sinusitis, otitis media)

 Incidence of influenza-related complications seen particularly in children (influenza-associated encephalitis or encephalopathy, febrile seizures, myositis)

 Incidence of death and hospitalization from influenza-related complications or influenza-related complications seen particularly in children

 Use of antibiotics

 Virological endpoints

  Infectious influenza virus titer and the amount of virus RNA (determined by RT-PCR) at each time point

  Change from baseline in infectious influenza virus titer and amount of virus RNA (determined by RT-PCR) at each time point

  Proportion of participants whose influenza virus titer and quantitative RT-PCR are above and below the lower limits of quantification at each time point

  Time to the first cessation of viral shedding based on the influenza virus titer, defined as the time postdose until virus titers reach the lower limit of quantification for the first time

  Time to sustained cessation of viral shedding based on influenza virus titer, defined as the time from the last positive virus titer postdose to the first virus titer that is below the lower limit of quantification

Exploratory endpoints

 Emergence of amino-acid substitutions (PA/I38X and NA/H275Y) in subjects who are RT-PCR positive for influenza infection pre- and postdose. Treatment-emergent influenza virus substitutions in PA/I38 or NA/H275 will be defined as amino-acid substitution occurring between Day 1 and the last time point where the influenza virus RT-PCR cycle threshold is < 31 for the H1 subtype or < 29 for the H3 subtype

 Rate of intrahousehold influenza infection

Safety

 AEs, AEs possibly related to baloxavir or oseltamivir, SAEs, vital signs