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

• Baloxavir Marboxil (Drug): Baloxavir marboxil will be administered as oral suspension: 2 milligrams per kilograms (mg/kg) (if weight < 20 kg), 40 mg (if weight ≥ 20 kg to < 80 kg), or 80 mg (if weight ≥ 80 kg).
• Oseltamivir (Drug): Oseltamivir will be administered as oral capsule: 30 mg (if weight ≤15 kg), 45 mg (if weight > 15 kg to ≥ 23 kg), 60 mg (if weight > 23 kg to ≤ 40 kg) or 75 mg (if weight > 40 kg), twice daily (BID) for 5 days.

Primary outcomes

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up to Day 29]: 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.

Secondary outcomes

• Time to Alleviation of Influenza Signs and Symptoms (TTAS) [Up to Day 15]: 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 [Up to Day 15]: 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 [Up to Day 15]: 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 Based on the CARIFS Questionnaire [Up to Day 15]: 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.
• Number of Participants With Influenza-related Complications [Up to Day 29]: Influenza-related complications included death, hospitalization, radiologically-confirmed pneumonia, bronchitis, sinusitis, otitis media, encephalitis/encephalopathy, febrile seizures, and myositis.
• Percentage of Participants Requiring Antibiotics for Influenza-related Complications [Up to Day 29]: 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 [Up to Day 29]: 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 Reverse Transcriptase - Polymerase Chain Reaction (RT-PCR) Using Samples From Respiratory Swabs [Up to Day 29]: 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 Over Time Using Samples From Respiratory Swabs [Baseline, Days 2, 4, 6, 10, and 15]: 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.
• Change From Baseline in Amount of Virus RNA (RT-PCR) at Each Timepoint Using Samples From Respiratory Swabs [Baseline, Days 2, 4, 6, 10, and 15]: 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 Over Time [Baseline, Days 2, 4, 6, 10, and 15]: 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 Positive by RT-PCR at Each Timepoint Using Samples From Respiratory Swabs [Baseline, Days 2, 4, 6, 10, and 15]: 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.
• Area Under the Curve (AUC) in Virus Titer [Up to Day 10]: 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 the Amount of Virus RNA (RT-PCR) Using Samples From Respiratory Swabs [Up to Day 10]: 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.
• Plasma Concentrations of S-033447 (Active Metabolite) [Post-dose on Days 1, 2, 4, and 6]: S-033447 is an active metabolite of baloxavir marboxil.
• Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) of S-033447 [Post-dose on Days 1, 2, 4, and 6]: S-033447 is an active metabolite of baloxavir marboxil.
• Maximum Observed Concentration (Cmax) of S-033447 [Post-dose on Days 1, 2, 4, and 6]: S-033447 is an active metabolite of baloxavir marboxil.
• Time of Maximum Observed Concentration (Tmax) of S-033447 [Post-dose on Days 1, 2, 4, and 6]: S-033447 is an active metabolite of baloxavir marboxil.
• Elimination Half-life (t1/2) of S-033447 [Post-dose on Days 1, 2, 4, and 6]: S-033447 is an active metabolite of baloxavir marboxil.
• Percentage of Participants With Polymorphic and Treatment-emergent Amino Acid Substitutions in the Polymerase Acidic (PA) Gene [Up to Day 29]: 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 in Participants With Evaluable Virus [Up to Day 29]: 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.
• Percentage of Participants With Responses to Palatability and Acceptability Questionnaire [On Day 1]: 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.

Sex: All, ages: 1 Year to 11 Years

Inclusion Criteria:

* A participant who has a diagnosis of influenza virus infection and meets all the following conditions:

  * Fever ≥ 38°C (tympanic temperature) at screening
  * At least one of the respiratory symptoms of influenza virus infection
* A rapid influenza diagnostic test (RIDT) or polymerase chain reaction (PCR) shows positive for influenza A/B, e.g., point-of-care/local laboratory results with use of nasal aspirate, throat swab, or nasal drip/droplet (or other appropriate sample)
* The time interval between the onset of symptoms and screening is ≤ 48 hours
* PCR (-) or antigen test (-) for severe acute respiratory virus-coronavirus 2 (SARS-CoV-2) using point-of-care/local laboratory test with nasal aspirate, throat swab, or nasal drip/droplet (or other appropriate sample)

Exclusion Criteria:

* A participant having severe influenza virus infection symptoms requiring inpatient treatment
* Received systemic corticosteroid or immunosuppressive therapy
* Primary immunodeficiency syndrome
* History of organ transplantation
* Human immunodeficiency virus (HIV) infection
* Immunization with a live/attenuated influenza vaccine in 2 weeks prior to randomization
* Previous malignancy within the last 5 years or has an active cancer at any site
* A participant who received any medications with anti-flu effect such as baloxavir, peramivir, oseltamivir, zanamivir, favipiravir, arbidol, amantadine or traditional Chinese anti-influenza medicines within 30 days before screening
* Diagnosed with or suspected SARS-CoV-2 infection, or close contacts of diagnosed or suspected SARS-CoV-2 infected patients
* Severe underlying disease or condition potentially affecting study evaluation in the opinion of the investigator/sub-investigator
* A participant who received an investigational or unapproved drug product within 30 days or 5 x the half-life before screening, whichever is longer

Participant flow

Outcome results

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) (Primary), Count of participants, Participants: Baloxavir Marboxil 24; Oseltamivir 12
• Time to Alleviation of Influenza Signs and Symptoms (TTAS) (Secondary), Median, hours: Baloxavir Marboxil 126.1 (92.2 to 141.1); Oseltamivir 119.5 (90.5 to 160.0)
• Duration of Fever (Secondary), Median, hours: Baloxavir Marboxil 28.3 (23.3 to 38.9); Oseltamivir 36.1 (29.3 to 44.0)
• Duration of Symptoms (Secondary), Median, hours: Baloxavir Marboxil 43.9 (35.0 to 76.6); Oseltamivir 51.9 (34.5 to 71.0)
• Time to Return to Normal Health and Activity Based on the CARIFS Questionnaire (Secondary), Median, hours: Baloxavir Marboxil 126.0 (81.8 to 137.8); Oseltamivir 115.3 (88.4 to 136.7)
• Number of Participants With Influenza-related Complications (Secondary), Count of participants, Participants: Baloxavir Marboxil 2; Oseltamivir 0
• Percentage of Participants Requiring Antibiotics for Influenza-related Complications (Secondary), Number, percentage of participants: Baloxavir Marboxil 1.6; Oseltamivir 0
• Time to Cessation of Viral Shedding by Virus Titer (Secondary), Median, hours: Baloxavir Marboxil 23.2 (21.9 to 24.4); Oseltamivir 100.7 (70.9 to 120.3)
• Time to Cessation of Viral Shedding by Reverse Transcriptase - Polymerase Chain Reaction (RT-PCR) Using Samples From Respiratory Swabs (Secondary), Median, hours: Baloxavir Marboxil 218.4 (214.8 to 242.7); Oseltamivir 238.6 (214.8 to NA)
• Change From Baseline in Influenza Virus Titer Over Time Using Samples From Respiratory Swabs (Secondary), Mean, log10 TCID 50/mL: Baloxavir Marboxil 4.41 +/- 1.32; Oseltamivir 5.21 +/- 1.11
• Change From Baseline in Amount of Virus RNA (RT-PCR) at Each Timepoint Using Samples From Respiratory Swabs (Secondary), Mean, log10 vp/mL: Baloxavir Marboxil 7.00 +/- 1.25; Oseltamivir 7.43 +/- 1.20
• Percentage of Participants With Positive Influenza Virus Titer Over Time (Secondary), Number, percentage of participants: Baloxavir Marboxil 100.0; Oseltamivir 100.0
• Percentage of Participants Positive by RT-PCR at Each Timepoint Using Samples From Respiratory Swabs (Secondary), Number, percentage of participants: Baloxavir Marboxil 100.0; Oseltamivir 100.0
• Area Under the Curve (AUC) in Virus Titer (Secondary), Mean, log10 TCID 50/mL*h: Baloxavir Marboxil -536.09 +/- 312.86; Oseltamivir -610.11 +/- 414.54
• AUC in the Amount of Virus RNA (RT-PCR) Using Samples From Respiratory Swabs (Secondary), Mean, log10 vp/mL*h: Baloxavir Marboxil -390.08 +/- 263.39; Oseltamivir -388.13 +/- 325.99
• Plasma Concentrations of S-033447 (Active Metabolite) (Secondary), Mean, nanograms per milliliter (ng/mL): Baloxavir Marboxil 75.49 +/- 77.283
• Area Under the Concentration-time Curve Extrapolated to Infinity (AUCinf) of S-033447 (Secondary), Mean, nanograms-hour per milliliter (ng*h/mL): Baloxavir Marboxil 9550 +/- 4230
• Maximum Observed Concentration (Cmax) of S-033447 (Secondary), Mean, ng/mL: Baloxavir Marboxil 182 +/- 68.2
• Time of Maximum Observed Concentration (Tmax) of S-033447 (Secondary), Median, hours: Baloxavir Marboxil 3.75 (1.00 to 15.0)
• Elimination Half-life (t1/2) of S-033447 (Secondary), Median, hours: Baloxavir Marboxil 30.0 (21.8 to 56.0)
• 3 more outcome measures not shown.

Adverse events

Time frame: Up to Day 29

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2024-02-02)
• Statistical Analysis Plan (PDF, 2025-03-20)

• Clinical Trials, Study director, Hoffmann-La Roche