Influenza
Conditions
Brief summary
This study will evaluate the safety, pharmacokinetics and efficacy of baloxavir marboxil in healthy pediatric participants from birth to \<1 year with influenza like symptoms
Interventions
Participants will receive single oral dose of baloxavir marboxil on Day 1 based on body weight and age. Participants aged ≥ 3 months to \<12 months old received baloxavir marboxil, 2 milligrams per kilograms (mg/kg). Participants from birth to \< 4 weeks old and ≥ 4 weeks to \< 3 months old received baloxavir marboxil, 1 mg/kg.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 1 Years
Healthy volunteers
No
Inclusion criteria
* Age from birth to \< 1 year at screening * Written informed consent for study participation obtained from participant's parents or legal guardian * Parent/guardian willing and able to comply with study requirements, in the investigator's judgment * Participants with a diagnosis of influenza virus infection confirmed by the presence of all of the following: 1. In the investigator's judgement there is a clinical suspicion of influenza 2. At least one respiratory symptom (either cough or coryza) (b) Positive prescreening influenza test (RIDT or PCR) performed within 48 hours of screening * Participants with a negative prescreening COVID-19 test (RAT or PCR) within 48 hours of screening * The time interval between the onset of symptoms and screening is ≤ 96 hours (the onset of symptoms is defined as the time when body temperature first exceeded 37.5°C if known, or the time when the first symptom was noticed by the parent or caregiver)
Exclusion criteria
* Hospitalized for complications of influenza or significant comorbidities * Concurrent infections requiring systemic antiviral therapy at screening * Require, in the opinion of the investigator, any of the prohibited medication during the study * Preterm neonates (born at \< 37 weeks gestation) and/or weighing \< 2.5 kg at screening * Previous treatment with peramivir, laninamivir, oseltamivir, zanamivir, or amantadine within 2 weeks prior to screening * Immunization with a live/attenuated influenza vaccine during the 2 weeks prior to screening * 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 transplant * Known hypersensitivity to study drug (i.e., baloxavir marboxil) or to acetaminophen * Participation in a clinical trial within 4 weeks or five half-lives of exposure to an investigational drug prior to screening, whichever is longer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From Day 1 up to Day 29 | An 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 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration to Time Curve From Time 0 to Infinity (AUC0-inf) of Baloxavir Marboxil and S-033447 | Up to Day 10 | S-033447 is an active metabolite of baloxavir marboxil. |
| Maximum Plasma Concentration (Cmax) of Baloxavir Marboxil and S-033447 | Up to Day 10 | S-033447 is an active metabolite of baloxavir marboxil. |
| Time to Maximum Plasma Concentration (Tmax) of Baloxavir Marboxil and S-033447 | Up to Day 10 | S-033447 is an active metabolite of baloxavir marboxil. |
| Apparent Half-Life (T1/2) of Baloxavir Marboxil and S-033447 | Up to Day 10 | S-033447 is an active metabolite of baloxavir marboxil. |
| Time to Alleviation of Influenza Signs and Symptoms | Day 1 up to Day 15 | Time to alleviation of influenza signs and symptoms was defined as the length of time taken from the start of treatment to the point at which all of the following criteria were met and remained for at least 21.5 hours: * A score of 0 (no problem) or 1 (minor problem) for cough and nasal symptoms for 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 participant 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 \[°C\]). Median time was estimated from the Kaplan-Meier curve. Participants who withdrew prior to an event of interest or did not experience resolution of symptoms were censored at the last observation time point. |
| Duration of Fever | Day 1 up to Day 15 | Duration of fever was defined as the 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 after onset. Participants who did not have fever at baseline or whose body temperature was not collected were excluded from the analysis. Median time was estimated from the Kaplan-Meier curve. |
| Duration of Symptoms | Day 1 up to Day 15 | The efficacy of baloxavir marboxil was 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 (Poor appetite; Not sleeping well; Irritable, cranky, fussy; Feels unwell; Low energy, tired; Not playing well; Crying more than usual; Needing extra care; Clinginess; Headache; Sore throat; Muscle aches or pains; Fever; Cough; Nasal congestion, runny nose; Vomiting; Not interested in what's going on; Unable to get out of bed) specified in the CARIFS questionnaire. Median time was estimated from the Kaplan-Meier curve. Participants who withdrew prior to an event of interest or did not experience resolution of symptoms were censored at the last observation time point. |
| Time to Return to Normal Health and Activity | Day 1 up to Day 15 | Time to return to normal health and activity was defined 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? and remaining so for at least 21.5 hours. Median time was estimated from the Kaplan-Meier curve.Participants who withdrew prior to an event of interest or did not experience resolution of symptoms were censored at the last observation time point. |
| Number of Participants With Influenza-Related Complications | Day 1 up to Day 29 | The influenza related complications include death, hospitalization, radiologically confirmed pneumonia, bronchitis, sinusitis, otitis media, encephalitis/encephalopathy, febrile seizures, myositis |
| Plasma Concentrations of Baloxavir Marboxil and S-033447 | 0.5 to 2 hours post dose on Day 1; 24 hours (Day 2) and 72 hours (Day 4) post dose, Day 6 and Day 10 | S-033447 is an active metabolite of baloxavir marboxil. |
| Time to Cessation of Viral Shedding by Virus Titer | Day 1 up to Day 29 | Time to cessation of viral shedding by virus titer was defined as the time, in hours, between the initiation of any study treatment and first time when the influenza virus titer was below the limit of detection (0.75 log10 tissue culture infectious dose (TCID)50/milliliters \[mL\]). Participants whose virus titers did not reach the limit by the last observation time point were treated as censored at that time point. One day was converted into 24 hours. Median time was estimated from the Kaplan-Meier curve. |
| Time to Cessation of Viral Shedding by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) | Day 1 up to Day 29 | Time to cessation of viral shedding by RT-PCR, in hours, was defined as the time between the initiation of study treatment and first time when the virus ribonucleic acid (RNA) by RT-PCR qualitative result was negative (no cycle threshold \[Ct\]-value detectable). Participants who did not have a negative result by the last observation time point were treated as censored at that time point. For the participants with multiple virus types, this endpoint was defined as the time between the initiation of the study treatment and first time when the virus RNA by RT-PCR qualitative result was negative for all virus types. One day was converted into 24 hours. Median time was estimated from the Kaplan -Meier curve. Participants with a positive virus RNA on Day 1 are included in this analysis. |
| Change From Baseline in Influenza Virus Titer Over Time | Baseline, Days 2, 4, 6, 10, and 29 | Change from baseline in influenza virus titer (log10TCID50/mL) was defined as the change from baseline in influenza virus titer on Days 2, 4, 6, 10, and 29. If influenza virus titer was less than the lower limit of quantification (LLOQ), the virus titer was imputed as 0.749 (log10TCID50/mL). Only participants with a positive virus titer on Day 1 were included in this analysis. |
| Change From Baseline in the Amount of Virus RNA (RT-PCR) Over Time | Baseline, Days 2, 4, 6, and 10 | Change from baseline in the amount of virus RNA was defined as the change from baseline in the amount of virus RNA on Days 2, 4, 6 and 10. If the amount of virus RNA is less than the lower limit of quantification, the amount of virus RNA was imputed as the relevant LLOQ (log10 viral particles per mililiter (vp/mL)). If a participant was infected with multiple virus types, the sum of virus RNA (log10 vp/mL) was used for analysis. Participants with a positive virus RNA by RT-PCR on Day 1 were included in this analysis. |
| Percentage of Participants With Positive Influenza Virus Titer Over Time | Baseline, Days 2, 4, 6, 10, and 29 | Percentage of participants positive for influenza virus titer at each visit were defined as the percentage of participants whose influenza virus titer was not less than the LLOQ (0.75 log10TCID50/mL) or positive among those assessed for influenza virus titer on Days 2, 4, 6, 10 and 29. Participants with a positive influenza virus titer on Day 1 were included in this analysis. |
| Percentage of Participants Positive by RT-PCR Over Time | Baseline, Days 2, 4, 6, 10, and 29 | Percentage of participants positive by RT-PCR at each visit was defined as the percentage of participants with a positive qualitative result among those assessed by RT-PCR on Days 2, 4, 6, 10 and 29. Participants with a positive RT-PCR result on Day 1 were included in this analysis. Percentages are rounded off. |
| Area Under the Concentration-Time Curve (AUC) in Virus Titer | Day 1 up to Day 29 | AUC in virus titer was calculated using the trapezoidal method. Twenty-four hours of time was converted into one day. Participants with a positive virus titer on Day 1 were included in this analysis. The LLOQ and lower limit of detection was defined as 0.75 log10TCID50/mL for flu A and 0.75 log10TCID50/mL for flu B. If a participant was infected with multiple virus types, the sum of those virus titers will be used for analysis. |
| Area Under the Curve in the Amount of Virus RNA (RT-PCR) | Day 1 up to Day 29 | AUC in virus RNA (RT-PCR) was defined as AUC of change from baseline in the amount of virus RNA (RT-PCR). AUC was calculated using the trapezoidal method similar to AUC in virus titer. Participants with a positive RT-PCR result on Day 1 were subjected to this analysis. If the amount of virus RNA is less than the lower limit of quantification, the amount of virus RNA was imputed as the relevant LLOQ (log10 viral particles per mililiter (vp/mL)). If a participant was infected with multiple virus types, the sum of those the amount of virus RNA was used for analysis. |
| Number of Participants Requiring Antibiotics | Day 1 up to Day 29 | The number of participants who required antibiotics for influenza related complication are reported here. |
Countries
Bulgaria, Costa Rica, Finland, Israel, Poland, Russia, South Africa, Spain, United States
Participant flow
Recruitment details
Participants were enrolled in this study at 15 investigative sites in 7 countries (Costa Rica, Finland, Mexico, Poland, South Africa, Spain, and the United States) from 23 January 2019 to 03 April 2023.
Pre-assignment details
A total of 49 pediatric participants from birth to \<1 year with influenza-like symptoms were enrolled in this study to receive baloxavir marboxil. Out of the 49 participants, one participant was screened and enrolled by accident but was not dosed.
Participants by arm
| Arm | Count |
|---|---|
| Baloxavir Marboxil Participants received a single oral dose of baloxavir marboxil on Day 1 based on body weight and age. | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Enrolled in Error | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Baloxavir Marboxil |
|---|---|
| Age, Continuous | 206.5 days STANDARD_DEVIATION 106.08 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 26 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 21 Participants |
| Sex: Female, Male Female | 23 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 48 |
| other Total, other adverse events | 11 / 48 |
| serious Total, serious adverse events | 2 / 48 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An 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 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.
Time frame: From Day 1 up to Day 29
Population: Safety-evaluable population included all participants who received at least one dose of treatment regardless of whether they had any follow-up assessments.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Baloxavir Marboxil | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 23 Participants |
| Baloxavir Marboxil | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
Secondary
Apparent Half-Life (T1/2) of Baloxavir Marboxil and S-033447
S-033447 is an active metabolite of baloxavir marboxil.
Time frame: Up to Day 10
Population: PK-evaluable population included all participants in the ITT population who had at least one post-dose drug concentration measurement at a scheduled visit timepoint. Overall number analyzed is the number of participants with data available for analysis. Since baloxavir marboxil was barely measurable in plasma, baloxavir marboxil pharmacokinetic parameters were not determined.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Baloxavir Marboxil | Apparent Half-Life (T1/2) of Baloxavir Marboxil and S-033447 | S-033447 | 23.1 hours |
| Baloxavir Marboxil | Apparent Half-Life (T1/2) of Baloxavir Marboxil and S-033447 | Baloxavir Marboxil | NA hours |
Secondary
Area Under the Concentration-Time Curve (AUC) in Virus Titer
AUC in virus titer was calculated using the trapezoidal method. Twenty-four hours of time was converted into one day. Participants with a positive virus titer on Day 1 were included in this analysis. The LLOQ and lower limit of detection was defined as 0.75 log10TCID50/mL for flu A and 0.75 log10TCID50/mL for flu B. If a participant was infected with multiple virus types, the sum of those virus titers will be used for analysis.
Time frame: Day 1 up to Day 29
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study. Overall number analyzed is the number of participants with a positive virus titer on Day 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baloxavir Marboxil | Area Under the Concentration-Time Curve (AUC) in Virus Titer | 405.23 log10 TCID 50/mL*hours | Standard Deviation 184.72 |
Secondary
Area Under the Concentration to Time Curve From Time 0 to Infinity (AUC0-inf) of Baloxavir Marboxil and S-033447
S-033447 is an active metabolite of baloxavir marboxil.
Time frame: Up to Day 10
Population: PK-evaluable population included all participants in the ITT population who had at least one post-dose drug concentration measurement at a scheduled visit timepoint. Overall number analyzed is the number of participants with data available for analysis. Since baloxavir marboxil was barely measurable in plasma, baloxavir marboxil pharmacokinetic parameters were not determined.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Area Under the Concentration to Time Curve From Time 0 to Infinity (AUC0-inf) of Baloxavir Marboxil and S-033447 | Baloxavir Marboxil | NA nanograms/milliters*hour (ng/mL*hr) | — |
| Baloxavir Marboxil | Area Under the Concentration to Time Curve From Time 0 to Infinity (AUC0-inf) of Baloxavir Marboxil and S-033447 | S-033447 | 5070 nanograms/milliters*hour (ng/mL*hr) | Standard Deviation 3520 |
Secondary
Area Under the Curve in the Amount of Virus RNA (RT-PCR)
AUC in virus RNA (RT-PCR) was defined as AUC of change from baseline in the amount of virus RNA (RT-PCR). AUC was calculated using the trapezoidal method similar to AUC in virus titer. Participants with a positive RT-PCR result on Day 1 were subjected to this analysis. If the amount of virus RNA is less than the lower limit of quantification, the amount of virus RNA was imputed as the relevant LLOQ (log10 viral particles per mililiter (vp/mL)). If a participant was infected with multiple virus types, the sum of those the amount of virus RNA was used for analysis.
Time frame: Day 1 up to Day 29
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study. Overall number analyzed is the number of participants with a positive virus titer on Day 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baloxavir Marboxil | Area Under the Curve in the Amount of Virus RNA (RT-PCR) | 779.06 log10 vp/mL*hours | Standard Deviation 426.83 |
Secondary
Change From Baseline in Influenza Virus Titer Over Time
Change from baseline in influenza virus titer (log10TCID50/mL) was defined as the change from baseline in influenza virus titer on Days 2, 4, 6, 10, and 29. If influenza virus titer was less than the lower limit of quantification (LLOQ), the virus titer was imputed as 0.749 (log10TCID50/mL). Only participants with a positive virus titer on Day 1 were included in this analysis.
Time frame: Baseline, Days 2, 4, 6, 10, and 29
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study. Number analyzed per timepoint are unique number of participants out of all the assessed participants with data available for analysis at specified timepoint. Different participants may have contributed data for each timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Change From Baseline in Influenza Virus Titer Over Time | Baseline | 3.58 log10 TCID 50/mL | Standard Deviation 1.81 |
| Baloxavir Marboxil | Change From Baseline in Influenza Virus Titer Over Time | Change From Baseline at Day 2 | -2.50 log10 TCID 50/mL | Standard Deviation 1.7 |
| Baloxavir Marboxil | Change From Baseline in Influenza Virus Titer Over Time | Change From Baseline at Day 4 | -2.60 log10 TCID 50/mL | Standard Deviation 1.95 |
| Baloxavir Marboxil | Change From Baseline in Influenza Virus Titer Over Time | Change From Baseline at Day 6 | -2.43 log10 TCID 50/mL | Standard Deviation 1.4 |
| Baloxavir Marboxil | Change From Baseline in Influenza Virus Titer Over Time | Change From Baseline at Day 10 | -2.83 log10 TCID 50/mL | Standard Deviation 1.81 |
| Baloxavir Marboxil | Change From Baseline in Influenza Virus Titer Over Time | Change From Baseline at Day 29 | -1.69 log10 TCID 50/mL | Standard Deviation 1.71 |
Secondary
Change From Baseline in the Amount of Virus RNA (RT-PCR) Over Time
Change from baseline in the amount of virus RNA was defined as the change from baseline in the amount of virus RNA on Days 2, 4, 6 and 10. If the amount of virus RNA is less than the lower limit of quantification, the amount of virus RNA was imputed as the relevant LLOQ (log10 viral particles per mililiter (vp/mL)). If a participant was infected with multiple virus types, the sum of virus RNA (log10 vp/mL) was used for analysis. Participants with a positive virus RNA by RT-PCR on Day 1 were included in this analysis.
Time frame: Baseline, Days 2, 4, 6, and 10
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study. Number analyzed per timepoint are unique number of participants out of all the assessed participants with data available for analysis at specified timepoint. Different participants may have contributed data for each timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Change From Baseline in the Amount of Virus RNA (RT-PCR) Over Time | Baseline | 6.46 log10 vp/mL | Standard Deviation 1.91 |
| Baloxavir Marboxil | Change From Baseline in the Amount of Virus RNA (RT-PCR) Over Time | Change From Baseline at Day 2 | -2.26 log10 vp/mL | Standard Deviation 1 |
| Baloxavir Marboxil | Change From Baseline in the Amount of Virus RNA (RT-PCR) Over Time | Change From Baseline at Day 4 | -1.93 log10 vp/mL | Standard Deviation 1.99 |
| Baloxavir Marboxil | Change From Baseline in the Amount of Virus RNA (RT-PCR) Over Time | Change From Baseline at Day 6 | -1.76 log10 vp/mL | Standard Deviation 2.4 |
| Baloxavir Marboxil | Change From Baseline in the Amount of Virus RNA (RT-PCR) Over Time | Change From Baseline at Day 10 | -3.30 log10 vp/mL | Standard Deviation 3.46 |
Secondary
Duration of Fever
Duration of fever was defined as the 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 after onset. Participants who did not have fever at baseline or whose body temperature was not collected were excluded from the analysis. Median time was estimated from the Kaplan-Meier curve.
Time frame: Day 1 up to Day 15
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study. Overall number analyzed is the number of participants available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Duration of Fever | 23.1 hours |
Secondary
Duration of Symptoms
The efficacy of baloxavir marboxil was 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 (Poor appetite; Not sleeping well; Irritable, cranky, fussy; Feels unwell; Low energy, tired; Not playing well; Crying more than usual; Needing extra care; Clinginess; Headache; Sore throat; Muscle aches or pains; Fever; Cough; Nasal congestion, runny nose; Vomiting; Not interested in what's going on; Unable to get out of bed) specified in the CARIFS questionnaire. Median time was estimated from the Kaplan-Meier curve. Participants who withdrew prior to an event of interest or did not experience resolution of symptoms were censored at the last observation time point.
Time frame: Day 1 up to Day 15
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Duration of Symptoms | 163.7 hours |
Secondary
Maximum Plasma Concentration (Cmax) of Baloxavir Marboxil and S-033447
S-033447 is an active metabolite of baloxavir marboxil.
Time frame: Up to Day 10
Population: PK-evaluable population included all participants in the ITT population who had at least one post-dose drug concentration measurement at a scheduled visit timepoint. Overall number analyzed is the number of participants with data available for analysis. Since baloxavir marboxil was barely measurable in plasma, baloxavir marboxil pharmacokinetic parameters were not determined.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Maximum Plasma Concentration (Cmax) of Baloxavir Marboxil and S-033447 | Baloxavir Marboxil | NA nanograms/ milliters (ng/ml) | — |
| Baloxavir Marboxil | Maximum Plasma Concentration (Cmax) of Baloxavir Marboxil and S-033447 | S-033447 | 127 nanograms/ milliters (ng/ml) | Standard Deviation 81 |
Secondary
Number of Participants Requiring Antibiotics
The number of participants who required antibiotics for influenza related complication are reported here.
Time frame: Day 1 up to Day 29
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Baloxavir Marboxil | Number of Participants Requiring Antibiotics | 0 Participants |
Secondary
Number of Participants With Influenza-Related Complications
The influenza related complications include death, hospitalization, radiologically confirmed pneumonia, bronchitis, sinusitis, otitis media, encephalitis/encephalopathy, febrile seizures, myositis
Time frame: Day 1 up to Day 29
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Baloxavir Marboxil | Number of Participants With Influenza-Related Complications | 0 Participants |
Secondary
Percentage of Participants Positive by RT-PCR Over Time
Percentage of participants positive by RT-PCR at each visit was defined as the percentage of participants with a positive qualitative result among those assessed by RT-PCR on Days 2, 4, 6, 10 and 29. Participants with a positive RT-PCR result on Day 1 were included in this analysis. Percentages are rounded off.
Time frame: Baseline, Days 2, 4, 6, 10, and 29
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study. Overall number analyzed is the number of participants with a positive RT-PCR result on Day 1. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants Positive by RT-PCR Over Time | Day 10 | 42.9 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Positive by RT-PCR Over Time | Day 29 | 0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Positive by RT-PCR Over Time | Baseline | 100 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Positive by RT-PCR Over Time | Day 2 | 92.3 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Positive by RT-PCR Over Time | Day 4 | 92.3 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Positive by RT-PCR Over Time | Day 6 | 64.3 percentage of participants |
Secondary
Percentage of Participants With Positive Influenza Virus Titer Over Time
Percentage of participants positive for influenza virus titer at each visit were defined as the percentage of participants whose influenza virus titer was not less than the LLOQ (0.75 log10TCID50/mL) or positive among those assessed for influenza virus titer on Days 2, 4, 6, 10 and 29. Participants with a positive influenza virus titer on Day 1 were included in this analysis.
Time frame: Baseline, Days 2, 4, 6, 10, and 29
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study. Overall number analyzed is the number of participants with a positive influenza virus titer on Day 1. Number analyzed is the number of participants with data available for analysis at the specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer Over Time | Baseline | 100 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer Over Time | Day 2 | 40 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer Over Time | Day 4 | 20 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer Over Time | Day 6 | 30 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer Over Time | Day 10 | 0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer Over Time | Day 29 | 0 percentage of participants |
Secondary
Plasma Concentrations of Baloxavir Marboxil and S-033447
S-033447 is an active metabolite of baloxavir marboxil.
Time frame: 0.5 to 2 hours post dose on Day 1; 24 hours (Day 2) and 72 hours (Day 4) post dose, Day 6 and Day 10
Population: Pharmacokinetics (PK)-evaluable population included all participants in the ITT population who had at least one post-dose drug concentration measurement at a scheduled visit timepoint. Overall number analyzed is the number of participants with data available for analysis. Number analyzed per timepoint are unique number of participants out of all the assessed participants with data available for analysis at specified timepoint. Different participants may have contributed data for each timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Plasma Concentrations of Baloxavir Marboxil and S-033447 | Baloxavir Marboxil: 0.5 to 2 hours | 0.93 nanograms per milliliters (ng/mL) | Standard Deviation 2.301 |
| Baloxavir Marboxil | Plasma Concentrations of Baloxavir Marboxil and S-033447 | Baloxavir Marboxil: 24 hours | 0 nanograms per milliliters (ng/mL) | Standard Deviation 0 |
| Baloxavir Marboxil | Plasma Concentrations of Baloxavir Marboxil and S-033447 | Baloxavir Marboxil: 72 hours | 0 nanograms per milliliters (ng/mL) | Standard Deviation 0 |
| Baloxavir Marboxil | Plasma Concentrations of Baloxavir Marboxil and S-033447 | Baloxavir Marboxil: Day 6 | 0 nanograms per milliliters (ng/mL) | Standard Deviation 0 |
| Baloxavir Marboxil | Plasma Concentrations of Baloxavir Marboxil and S-033447 | Baloxavir Marboxil: Day 10 | 0 nanograms per milliliters (ng/mL) | Standard Deviation 0 |
| Baloxavir Marboxil | Plasma Concentrations of Baloxavir Marboxil and S-033447 | S-033447: 0.5 to 2 hours | 81.98 nanograms per milliliters (ng/mL) | Standard Deviation 89.412 |
| Baloxavir Marboxil | Plasma Concentrations of Baloxavir Marboxil and S-033447 | S-033447: 24 hours | 49.75 nanograms per milliliters (ng/mL) | Standard Deviation 40.987 |
| Baloxavir Marboxil | Plasma Concentrations of Baloxavir Marboxil and S-033447 | S-033447: 72 hours | 17.88 nanograms per milliliters (ng/mL) | Standard Deviation 17.438 |
| Baloxavir Marboxil | Plasma Concentrations of Baloxavir Marboxil and S-033447 | S-033447: Day 6 | 4.72 nanograms per milliliters (ng/mL) | Standard Deviation 3.649 |
| Baloxavir Marboxil | Plasma Concentrations of Baloxavir Marboxil and S-033447 | S-033447: Day 10 | 1.35 nanograms per milliliters (ng/mL) | Standard Deviation 1.547 |
Secondary
Time to Alleviation of Influenza Signs and Symptoms
Time to alleviation of influenza signs and symptoms was defined as the length of time taken from the start of treatment to the point at which all of the following criteria were met and remained for at least 21.5 hours: * A score of 0 (no problem) or 1 (minor problem) for cough and nasal symptoms for 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 participant 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 \[°C\]). Median time was estimated from the Kaplan-Meier curve. Participants who withdrew prior to an event of interest or did not experience resolution of symptoms were censored at the last observation time point.
Time frame: Day 1 up to Day 15
Population: Intent-to-Treat Influenza-Infected (ITTi) population is a subset of ITT participants who had a laboratory confirmation of influenza infection (polymerase chain reaction \[PCR\] result) from any swab sample collected at baseline or during the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Alleviation of Influenza Signs and Symptoms | 163.7 hours |
Secondary
Time to Cessation of Viral Shedding by Reverse Transcription-Polymerase Chain Reaction (RT-PCR)
Time to cessation of viral shedding by RT-PCR, in hours, was defined as the time between the initiation of study treatment and first time when the virus ribonucleic acid (RNA) by RT-PCR qualitative result was negative (no cycle threshold \[Ct\]-value detectable). Participants who did not have a negative result by the last observation time point were treated as censored at that time point. For the participants with multiple virus types, this endpoint was defined as the time between the initiation of the study treatment and first time when the virus RNA by RT-PCR qualitative result was negative for all virus types. One day was converted into 24 hours. Median time was estimated from the Kaplan -Meier curve. Participants with a positive virus RNA on Day 1 are included in this analysis.
Time frame: Day 1 up to Day 29
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study. Overall number analyzed is the number of participants with a positive virus RNA on Day 1.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Cessation of Viral Shedding by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) | 219.1 hours |
Secondary
Time to Cessation of Viral Shedding by Virus Titer
Time to cessation of viral shedding by virus titer was defined as the time, in hours, between the initiation of any study treatment and first time when the influenza virus titer was below the limit of detection (0.75 log10 tissue culture infectious dose (TCID)50/milliliters \[mL\]). Participants whose virus titers did not reach the limit by the last observation time point were treated as censored at that time point. One day was converted into 24 hours. Median time was estimated from the Kaplan-Meier curve.
Time frame: Day 1 up to Day 29
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study. Overall number analyzed is the number of participants with data available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Cessation of Viral Shedding by Virus Titer | 24.5 hours |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Baloxavir Marboxil and S-033447
S-033447 is an active metabolite of baloxavir marboxil.
Time frame: Up to Day 10
Population: PK-evaluable population included all participants in the ITT population who had at least one post-dose drug concentration measurement at a scheduled visit timepoint. Overall number analyzed is the number of participants with data available for analysis. Since baloxavir marboxil was barely measurable in plasma, baloxavir marboxil pharmacokinetic parameters were not determined.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Baloxavir Marboxil | Time to Maximum Plasma Concentration (Tmax) of Baloxavir Marboxil and S-033447 | Baloxavir Marboxil | NA hours |
| Baloxavir Marboxil | Time to Maximum Plasma Concentration (Tmax) of Baloxavir Marboxil and S-033447 | S-033447 | 4.5 hours |
Secondary
Time to Return to Normal Health and Activity
Time to return to normal health and activity was defined 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? and remaining so for at least 21.5 hours. Median time was estimated from the Kaplan-Meier curve.Participants who withdrew prior to an event of interest or did not experience resolution of symptoms were censored at the last observation time point.
Time frame: Day 1 up to Day 15
Population: ITTi population is a subset of ITT participants who had a laboratory confirmation of influenza infection (PCR result) from any swab sample collected at baseline or during the study. Overall number analyzed is the number of participants with data available for analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Return to Normal Health and Activity | 140.7 hours |