Trial Outcomes & Findings for Study to Assess the Safety, Pharmacokinetics, and Efficacy of Baloxavir Marboxil in Chinese Pediatric Participants 1 to <12 Years of Age With Influenza Symptoms (NCT NCT06774859)

A total of 100 participants aged 1 to \<12 years with influenza symptoms were randomized in the study at 16 investigative sites in China from 27 October 2024 to 08 May 2025.

Participants were randomized in a 2:1 ratio to receive either baloxavir marboxil or oseltamivir.

Study to Assess the Safety, Pharmacokinetics, and Efficacy of Baloxavir Marboxil in Chinese Pediatric Participants 1 to <12 Years of Age With Influenza Symptoms

An AE was defined as any untoward medical occurrence in a participant or clinical study participant temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An AE was therefore any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. An SAE was defined as any untoward medical occurrence that, at any dose, resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability or incapacity, was a congenital anomaly or birth defect.

TTAS was defined as the length of time taken from start of treatment to point at which all of following criteria were met \& remained so for at least 21.5 hours: * Score of 0 (no problem) or 1 (minor problem) for cough \& nasal symptoms (Items 14 \& 15 of Canadian Acute Respiratory Illness and Flu Scale \[CARIFS\]); * A "yes" response to following question- "Since last assessment has participant been able to return to day care/school, or resume his/her normal daily activity in same way as performed prior to developing flu?"; * Return to afebrile state (tympanic temperature ≤ 37.2 degree Celsius \[°C\]). Median time was estimated using Kaplan-Meier (K-M) method.

Duration of fever was defined as the length of time from start of treatment to return to afebrile state (tympanic temperature ≤ 37.2°C) and remaining so for at least 21.5 hours. Participants who were afebrile at baseline (tympanic temperature ≤ 37.2 °C) or whose body temperature was not collected were excluded from the analysis. Median time was estimated using K-M method.

Duration of symptoms was defined as the length of time from start of treatment to alleviation of all symptoms as defined by a score of 0 (no problem) or 1 (minor problem) and remaining so for at least 21.5 hours, for all 18 symptoms specified in the CARIFS questionnaire. Participants who withdrew prior to an event of interest or did not experience resolution of symptoms were censored at the last observation time point. Median time was estimated using K-M method.

Time to return to normal health and activity was defined as time from start of treatment to normal health and activity. Normal health \& activity was identified by a 'yes' response to the following question on the CARIFS: "Since the last assessment has the participant been able to return to day care/school, or resume his/her normal daily activity in the same way as performed prior to developing the flu?". Median time was estimated using K-M method.

Influenza-related complications included death, hospitalization, radiologically-confirmed pneumonia, bronchitis, sinusitis, otitis media, encephalitis/encephalopathy, febrile seizures, and myositis.

Influenza-related complications included death, hospitalization, radiologically-confirmed pneumonia, bronchitis, sinusitis, otitis media, encephalitis/encephalopathy, febrile seizures, and myositis. Percentages have been rounded off.

Time to cessation of viral shedding by virus titer was defined as the time, in hours, between the initiation of study treatment and the first time when the influenza virus titer was below the lower limit of detection (LLoD) (0.75 log10 tissue culture infectious dose \[TCID\] 50/milliliters \[mL\]). Participants whose virus ribonucleic acid (RNA) did not reach the limit by the last observation timepoint were treated as censored at that timepoint. Median time was estimated using K-M method.

Time to cessation of viral shedding by RT-PCR was defined as the time between the initiation of study treatment and the first time when the virus RNA by RT-PCR qualitative result is below the LLoD (qualitative assessment). For the participants with multiple virus types, time to cessation of viral shedding by RT-PCR was defined as the time between the initiation of the study treatment and first time when the virus RNA by RT-PCR qualitative result is negative for all virus types. Participants whose virus RNA did not reach the limit by the last observation timepoint were censored at that timepoint. Median time was estimated using K-M method.

Change from baseline in influenza virus titer (log10 TCID50/mL) on Days 2, 4, 6, 10, and 15 are presented. Influenza virus titer on specified time points was analysed with use of samples from respiratory swabs. If influenza virus titer was less than the lower limit of quantification (LLoQ), the virus titer was imputed as LLoQ - 0.001 (0.749 log10 TCID50/mL). Only participants with a positive virus titer on Day 1 were included in this analysis.

If the amount of virus RNA was less than the LLoQ, the amount of virus RNA was imputed as LLoQ - 0.001 (2.79 log10 vp/mL for influenza A and 2.63 log10 vp/mL for influenza B). If a participant was infected with multiple virus types, the sum of those amounts of virus RNA was used for analysis. Participants positive for virus RNA by RT-PCR on Day 1 were included in this analysis. log10 vp/mL=log 10 virus particles per milliliter.

Percentage of participants with positive influenza virus titer was defined as the percentage of participants whose influenza virus titer was not less than the LLoD (0.75 log10 TCID50/mL) or positive among those assessed for influenza virus titer on specified timepoints. Analyses were done with use of samples from respiratory swabs. Participants with a positive influenza virus titer on Day 1 were be included in this analysis. Percentages have been rounded off.

Percentage of participants with positive influenza virus titer was defined as the percentage of participants with a positive qualitative result among those assessed by RT-PCR on specified timepoints. Analyses were done with use of samples from respiratory swabs. Participants positive for virus RNA by RT-PCR on Day 1 were be included in this analysis. Percentages have been rounded off.

AUC was calculated using the trapezoidal method. Participants with a positive virus titer on Day 1 were included in this analysis. The lower limit was defined as 0.75 log10 TCID50/mL for flu A and flu B. If a participant was infected with multiple virus types, the sum of those virus titers was used for analysis. log10 TCID50/mL\*h=log10 TCID50 per milliliter-hours. Analyses were done with use of samples from respiratory swabs.

AUC in virus RNA (RT-PCR) AUC was calculated using the trapezoidal method. Participants positive for virus RNA by RT-PCR on Day 1 were included in this analysis. If a participant was infected with multiple virus types, the sum of the amount of virus RNA was used for analysis. log10 vp/mL\*h=log 10 virus particles per milliliter-hours.

S-033447 is an active metabolite of baloxavir marboxil.

S-033447 is an active metabolite of baloxavir marboxil.

S-033447 is an active metabolite of baloxavir marboxil.

S-033447 is an active metabolite of baloxavir marboxil.

S-033447 is an active metabolite of baloxavir marboxil.

Sanger sequencing of the influenza PA gene was performed to evaluate the incidence of polymorphic and treatment-emergent amino acid substitutions in baloxavir-treated participants with evaluable virus.

Drug susceptibility of the influenza virus, the 50% effective concentration (EC50) of baloxavir was measured by the ViroSpot™ assay using baseline swab samples for participants who received baloxavir marboxil. EC50 values were compared with EC50 values of reference strains and the respective ratio (EC50 / EC50 reference) was reported. The following influenza virus vaccines strains from the 2024/25 Northern hemisphere season were used as references: A/Wisconsin/67/2022 (H1N1) pdm09-like virus, A/Massachusetts/18/2022 (H3N2)-like virus and B/Austria/1359417/2021-like virus (B/Victoria/2/87 lineage). In the absence of established thresholds for baloxavir, reduced susceptibility was defined according to the WHO criteria for neurainidase inhibitor (NAI) as fold-changes in EC50 (EC50 / EC50 of reference) \> 10 for influenza A and \> 5 for influenza B viruses.

A two-question palatability and acceptability questionnaire was used to record palatability and acceptability. Palatability of baloxavir marboxil was evaluated by response to the following question, "How was the taste of the medicine? Please pick the face that best matches how you/the child felt about the taste". The responses ranged from: like very much, like a little, not sure, dislike a little, or dislike very much. Acceptability of baloxavir marboxil was evaluated by response to the following question, "Would you/the child be happy to take the medicine again?" The responses ranged from: Yes, No, or Not sure. The questionnaire was completed as soon as possible after swallowing the baloxavir marboxil drug solution on Day 1. Percentages have been rounded off.