Study to Assess the Safety, Pharmacokinetics, and Efficacy of Baloxavir Marboxil in Healthy Pediatric Participants With Influenza-Like Symptoms

Study Overview
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Brief Summary
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This study will evaluate the safety, pharmacokinetics, and efficacy of baloxavir marboxil compared with oseltamivir in a single influenza episode in otherwise healthy pediatric participants (i.e., 1 to <12 years of age) with influenza-like symptoms.

Official Title
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A Multicenter, Randomized, Double-Blind, Active (Oseltamivir)-Controlled Study to Assess the Safety, Pharmacokinetics, and Efficacy of Baloxavir Marboxil in Otherwise Healthy Pediatric Patients 1 to <12 Years of Age With Influenza-Like Symptoms

Conditions
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Influenza

Intervention / Treatment
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* Drug: Baloxavir Marboxil
* Drug: Oseltamivir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 1 to < 12 years at randomization (Day 1). Written informed consent/assent for study participation obtained from participant's parents or legal guardian, with assent as appropriate by the participant, depending on the patient's level of understanding Participant able to comply with study requirements, depending on the patient's level of understanding Participant with a diagnosis of influenza virus infection confirmed by the presence of all of the following: Fever ≥ 38 degree celsius (tympanic temperature) at screening At least one respiratory symptom (either cough or nasal congestion) The time interval between the onset of symptoms and screening is ≤ 48 hours Exclusion Criteria: Severe symptoms of influenza virus infection requiring inpatient treatment Concurrent infections requiring systemic antiviral therapy at screening Require, in the opinion of the investigator, any of the prohibited medication during the study Previous treatment with peramivir, laninamivir, oseltamivir, zanamivir, or amantadine within 2 weeks prior to screening Immunization with a live/attenuated influenza vaccine in the 2 weeks prior to randomization Concomitant treatment with steroids or other immuno-suppressant therapy Known HIV infection or other immunosuppressive disorder Uncontrolled renal, vascular, neurologic, or metabolic disease (e.g., diabetes, thyroid disorders, adrenal disease), hepatitis, cirrhosis, or pulmonary disease or participants with known chronic renal failure. Active cancer at any site History of organ transplantation Known allergy to either study drug (i.e., baloxavir marboxil and oseltamivir) or to acetaminophen Females with child-bearing potential Participation in a clinical trial within 4 weeks or five half-lives of exposure to an investigational drug prior to screening, whichever is longer

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Baloxavir Marboxil<br>Participants will receive a single oral dose of baloxavir marboxil on Day 1 (based on body weight). Oseltamivir matching placebo will also be administered orally twice daily (BID) for 5 days. | Drug: Baloxavir Marboxil<br>* Baloxavir marboxil will be administered as oral suspension in a single dose on Day 1. Oseltamivir matching placebo will also be administered as oral suspension twice daily (BID) for 5 days.<br>|
| Active Comparator: Oseltamivir<br>Participants will receive oseltamivir orally BID for 5 days (based on body weight). Baloxavir marboxil matching placebo will also be administered orally on Day 1 | Drug: Oseltamivir<br>* Oseltamivir will be administered as oral suspension BID for 5 days. Participants receiving oseltamivir will also receive baloxavir marboxil matching placebo as oral suspension, single dose on Day 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. A serious adverse event (SAE) is any significant hazard, contraindication, side effect that is fatal or life-threatening, requires hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/ birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above. | Up to Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of Baloxavir Marboxil - Sparse PK Population | Results provided by body-weight groups for participants in the Baloxavir Marboxil arm. Values below lower limit of quantification (0.5 ng/mL) are set to zero. | Days 1 (Post-Dose), 2, 4, 6 and 10 | 
| Plasma Concentrations of S-033447 - Sparse PK Population | Results provided by body-weight groups for participants in the Baloxavir Marboxil arm. | Days 1 (Post-Dose), 2, 4, 6 and 10 | 
| Plasma Concentrations of Baloxavir Marboxil - Extensive PK Population | Results provided by body-weight groups for participants in the Baloxavir Marboxil arm. Values below lower limit of quantification (0.5 ng/mL) are set to zero. | Days 1 (Post-Dose), 2, 4, 6 and 10 | 
| Plasma Concentrations of S-033447 - Extensive PK Population | Results provided by body-weight groups for participants in the Baloxavir Marboxil arm. Values below lower limit of quantification (0.5 ng/mL) are set to zero. | Days 1 (Post-Dose), 2, 4, 6 and 10 | 
| Time to Alleviation of Influenza Signs and Symptoms | Time to alleviation of influenza signs and symptoms is defined as the length of time taken from the start of treatment to the point at which all of the following criteria are met and remain so for at least 21.5 hours: A score of 0 (no problem) or 1 (minor problem) for cough and nasal symptoms (items 14 and 15 of the Canadian Acute Respiratory Illness and Flu Scale [CARIFS]) A yes response to the following question on the CARIFS: Since the last assessment has the subject been able to return to day care/school, or resume his or her normal daily activity in the same way as performed prior to developing the flu? First return to afebrile state (tympanic temperature ≤37.2 degree Celsius [°C]) | Up to Day 15 | 
| Duration of Fever | Length of time taken by participants to return to afebrile state [tympanic temperature ≤ 37.2°C] and remaining so for at least 21.5 hours. | Up to Day 15 | 
| Duration of Symptoms | The clinical efficacy of baloxavir marboxil is evaluated by duration of symptoms i.e., 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. | Up to Day 15 | 
| Time to Return to Normal Health and Activity | Time to Return to Normal health and activity' is identified by a 'Yes' response to the following question on the CARIFS: Since the last assessment has the patient been able to return to day care/school, or resume his or her normal daily activity in the same way as performed prior to developing the flu? | Up to Day 15 | 
| Frequency of Influenza-Related Complications | Influenza related complications include death, hospitalization, radiologically confirmed pneumonia, bronchitis, sinusitis, otitis media, encephalitis/encephalopathy, febrile seizures, myositis. | Up to Day 29 | 
| Percentage of Participants With Influenza-Related Complications | Influenza related complications include death, hospitalization, radiologically confirmed pneumonia, bronchitis, sinusitis, otitis media, encephalitis/encephalopathy, febrile seizures, myositis. | Up to Day 29 | 
| Percentage of Participants Requiring Antibiotics |  | Up to Day 29 | 
| Time to Cessation of Viral Shedding by Virus Titer | Time to cessation of viral shedding by virus titer is defined as the time, in hours, between the initiation of any study treatment and first time when the influenza virus titer is below the limit of detection. | Day 1 - Day 29 | 
| Time to Cessation of Viral Shedding by RT-PCR | Time to cessation of viral shedding by RT-PCR, in hours, is defined as the time between the initiation of any study treatment and first time when the virus RNA by RT-PCR is below the limit of detection. | Day 1 - Day 29 | 
| Change From Baseline in Influenza Virus Titer at Day 2, 4, 6, 10, 15, 29 | Influenza virus titer (log10TCID50/ML) is the quantity of influenza virus in a given volume within the samples obtained from nasal swabs. If influenza virus titer was less than the lower limit of quantification, the virus titer was imputed as 0.749 (log10TCID50/mL). A lower value indicates lower viral titer. | Baseline, Day 2, 3 (optional), 4, 6, 10, 15 (optional), 29 | 
| Change From Baseline in the Amount of Virus RNA (RT-PCR) at Day 2, 4, 6, 10, 15, 29 | If the amount of virus RNA was less than the lower limit of quantification, the amount of virus RNA was imputed as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL) | Baseline, Day 2, 3 (optional), 4, 6, 10, 15 (optional), 29 | 
| Percentage of Participants With Positive Influenza Virus Titer at Day 2, 4, 6, 10 |  | Baseline, Day 2, 3 (optional), 4, 6, 10 | 
| Percentage of Participants Positive by RT-PCR at Day 2, 4, 6, 10, 15, 29 |  | Day 2, 3 (optional), 4, 6, 10, 15 (optional), 29 | 
| Area Under the Curve in Virus Titer | Area under the curve (AUC) in virus titer was calculated using the trapezoidal method. | Day 1 - Day 29 | 
| Area Under the Curve in the Amount of Virus RNA (RT-PCR) | AUC in virus RNA (RT-PCR) is defined as AUC of change from baseline in the amount of virus RNA (RT-PCR) from Day 1 to Day 10. AUC is calculated using the trapezoidal method similar to AUC in virus titer. | Day 1 - Day 10 | 
| Area Under the Concentration to Time Curve From Time 0 to Infinity (AUC0-inf) of Baloxavir Marboxil | Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs. | Up to Day 10 | 
| Area Under the Concentration to Time Curve From Time 0 to Infinity (AUC0-inf) of S-033447. | Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs. | Up to Day 10 | 
| Maximum Plasma Concentration (Cmax) of Baloxavir Marboxil | Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs. | Up to Day 10 | 
| Maximum Plasma Concentration (Cmax) of S-033447 | Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs. | Up to Day 10 | 
| Time to Maximum Plasma Concentration (Tmax) of Baloxavir Marboxil | Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs. | Up to Day 10 | 
| Time to Maximum Plasma Concentration (Tmax) of S-033447 | Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs. | Up to Day 10 | 
| Plasma Concentrations of Baloxavir Marboxil by Dosage | Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs. | 24, 72, 96 and 240 hours post-dose | 
| Plasma Concentrations of S-033447 by Dosage | Dose groups correspond to body-weight groups. 2mg/kg dose was used for subjects <20 kgs and 40 mg dose was used for subjects >20 kgs. | 24, 72, 96 and 240 hours post-dose |