Influenza
Conditions
Brief summary
This study will evaluate the efficacy, safety, and pharmacokinetics of baloxavir marboxil in combination with a standard-of-care (SOC) neuraminidase inhibitor (NAI) (i.e., oseltamivir, zanamivir, or peramivir) compared with a matching placebo in combination with a SOC NAI in hospitalized patients with influenza.
Interventions
Baloxavir marboxil will be administered as a weight-based dose on Days 1 and 4. A third dose will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5.
OTHERPlacebo
Participants will receive matching placebo on Days 1, 4 and 7.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult participants: Signed informed consent by any participant capable of giving consent, or, where the participant is not capable of giving consent, by his or her legal/authorized representative * Adolescent participants not able to legally consent: written informed consent for study participation is obtained from participant's parents or legal guardian, with assent as appropriate by the participant, depending on the participant's level of understanding and capability to provide assent * Participants who require hospitalization for severe influenza or acquire influenza during hospitalization, the severity of which requires an extension of hospitalization * Diagnosis of influenza A and/or B by a positive Rapid Influenza Diagnostic Test (RIDT) or reverse transcriptase-polymerase chain reaction (RT-PCR) * The time interval between the onset of symptoms and randomization is within 96 hours * A score of ≥4 based on the National Early Warning Score 2 (NEWS2) * Participants will require objective criteria of seriousness defined by at least one of the following criteria: * Requires ventilation or supplemental oxygen to support respiration * Has a complication related to influenza that requires hospitalization (e.g., pneumonia, central nervous system involvement, myositis, rhabdomyolysis, acute exacerbation of chronic kidney disease, asthma or chronic obstructive pulmonary disease (COPD), severe dehydration, myocarditis, pericarditis, exacerbation of ischemic heart disease) * For women of childbearing potential: Agreement to remain abstinent or use contraceptive methods with a failure rate of \< 1% per year during the treatment period and for 28 days after the last dose of study treatment. Hormonal contraceptive methods must be supplemented by a barrier method.
Exclusion criteria
* Participants who have received more than 48 hours of antiviral treatment for the current influenza infection prior to screening * Participants who have received baloxavir marboxil for the current influenza infection * Known contraindication to neuraminidase inhibitors * Participants hospitalized for exclusively social reasons (e.g., lack of caregivers at home) * Participants expected to die or be discharged within 48 hours, according to the investigator's judgement * Participants weighing \< 40 kg * Participants with known severe renal impairment (estimated glomerular filtration rate \< 30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis * Participants with any of the following laboratory abnormalities detected within 24 hours prior to or during screening (according to local laboratory reference ranges: * Alanine Transaminase (ALT) or Aspartate Transaminase (AST) level \> 5 times the upper limit of normal (ULN) OR * ALT or AST \> 3 times the ULN and total bilirubin level \> 2 times the ULN * Pregnant or breastfeeding, or positive pregnancy test in a predose examination, or intending to become pregnant during the study or within 28 days after the last dose of study treatment * Exposure to an investigational drug within 5 half-lives or 30 days (whichever is longer) of randomization * Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study * Known hypersensitivity to baloxavir marboxil or the drug product excipients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinical Improvement | Up to Day 35 | Time to Clinical Improvement (TTCI) is defined as Time to Hospital Discharge OR Time to NEWS2 (National Early Warning Score 2) of ≤ 2 maintained for 24 hours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Clinical Response | Up to Day 35 | Time to Clinical Response is based on temperature ranges, oxygen saturation, respiratory status, heart rate, and hospitalization status. |
| Percentage of Participants on Mechanical Ventilation | Up to Day 35 | — |
| Duration of Mechanical Ventilation | Up to Day 35 | — |
| Percentage of Participants Requiring ICU Stay | Up to Day 35 | — |
| Duration of ICU Stay | Up to Day 35 | — |
| Time to Clinical Failure | Up to Day 35 | Time to clinical failure, defined as the time to death, mechanical ventilation, or ICU admission, corresponding to ordinal scale categories 6, 5, and 4, respectively, from baseline |
| Time to Hospital Discharge | Up to Day 35 | — |
| Percentage of Participants With Post-Treatment Influenza-Related Complications | Up to Day 35 | Influenza-related complications included pneumonia, myositis or rhabdomyolysis, encephalitis or encephalopathy, myocarditis and/or pericarditis, otitis media, sinusitis, exacerbation of COPD/asthma, sepsis, acute lung injury or acute respiratory distress syndrome. |
| Mortality Rate at Day 7 | Up to Day 7 | — |
| Mortality Rate at Day 28 | Up to Day 28 | — |
| Time to NEWS2 of ≤ 2 Maintained for 24 Hours | Up to Day 35 | A score of 0 (Range 0 - 3) indicates normal health conditions. |
| Time to Cessation of Viral Shedding by Virus Titer | Screening (baseline) and on Days 2, 3, 4, 5, 7, and 10 | Time to cessation of viral shedding by virus titer is defined as the time, in hours, between the initiation of study treatment and first time when the influenza virus titer is below the limit of detection (0.75 log10 TCID50/mL) |
| Change From Baseline in Influenza Virus Titer at Each Timepoint | Days 2, 3, 4, 5, 7, and 10 | Influenza virus titer 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. |
| Response Rates of the 6-Point Ordinal Scale at Day 7 | Day 7 | The ordinal scale categories are: Category 1) Discharged (or ready for discharge) Category 2) Non-ICU hospital ward (or ready for hospital ward) not requiring supplemental oxygen/non-invasive ventilation Category 3) Non-ICU hospital ward (or ready for hospital ward) requiring supplemental oxygen/non-invasive ventilation Category 4) ICU without mechanical (invasive) ventilation (or ready for ICU admission) Category 5) Mechanical (invasive) ventilation Category 6) Death |
| Area Under the Curve in Virus Titer | Days 1, 2, 3, 4, 5, 7, and 10 | — |
| Time to Cessation of Viral Shedding by RT-PCR | Screening (baseline) and on Days 2, 3, 4, 5, 7, and 10 | Time to cessation of viral shedding by RT-PCR, in hours, is defined as the time between the initiation of study treatment and first time when the virus RNA by RT-PCR is below the limit of detection (2.05 for flu A and 2.83 for flu B log10 virus particles/mL) |
| Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Days 2, 3, 4, 5, 7, and 10 | 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) |
| Percentage of Participants Positive by RT-PCR at Each Timepoint | Days 2, 3, 4, 5, 7, and 10 | 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) |
| Area Under the Curve in the Amount of Virus RNA (RT-PCR) | Days 1, 2, 3, 4, 5, 7, and 10 | — |
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to Day 35 | 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. |
| Percentage of Participants With AEs and SAEs Leading to Discontinuation From Treatment | Up to Day 35 | Discontinuation from study treatment. |
| Percentage of Participants With Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN | Up to Day 35 | ALT = alanine aminotransferase AST = aspartate transaminase |
| Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 1, 2, 4, 5, 7 and 8 | — |
| Area Under the Concentration to Time Curve From Time 0 to 72 Hours (AUC0-72) of Baloxavir | 0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8 | — |
| Maximum Plasma Concentration (Cmax) of Baloxavir | 0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8 | — |
| Apparent Half-Life (T1/2) of Baloxavir | 0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8 | — |
| Concentration at 24 Hours (C24) of Baloxavir | 0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8 | — |
| Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Days 2, 3, 4, 5, 7, and 10 | Influenza virus titer 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 (log10 TCID50/mL). A lower value indicates lower viral titer. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czechia, Estonia, Finland, France, Germany, Hong Kong, Israel, Japan, Mexico, Netherlands, New Zealand, Peru, Romania, Serbia, Singapore, South Korea, Spain, Sweden, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
A total of 363 patients received at least one dose of study treatment and were included in the analyses of safety and efficacy.
Participants by arm
| Arm | Count |
|---|---|
| Baloxavir Marboxil Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice. | 239 |
| Placebo Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice. | 124 |
| Total | 363 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 0 |
| Overall Study | Death | 4 | 7 |
| Overall Study | Lost to Follow-up | 3 | 2 |
| Overall Study | Patient Not Available | 0 | 2 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 11 | 9 |
Baseline characteristics
| Characteristic | Total | Placebo | Baloxavir Marboxil |
|---|---|---|---|
| Age, Continuous | 59.2 Years STANDARD_DEVIATION 20 | 61.6 Years STANDARD_DEVIATION 20.3 | 58.0 Years STANDARD_DEVIATION 19.8 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 61 Participants | 22 Participants | 39 Participants |
| Race/Ethnicity, Customized Black or African American | 9 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 46 Participants | 16 Participants | 30 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 309 Participants | 106 Participants | 203 Participants |
| Race/Ethnicity, Customized Not Stated | 5 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 5 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 276 Participants | 95 Participants | 181 Participants |
| Sex: Female, Male Female | 173 Participants | 56 Participants | 117 Participants |
| Sex: Female, Male Male | 190 Participants | 68 Participants | 122 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 239 | 7 / 124 |
| other Total, other adverse events | 44 / 239 | 27 / 124 |
| serious Total, serious adverse events | 29 / 239 | 19 / 124 |
Outcome results
Primary
Time to Clinical Improvement
Time to Clinical Improvement (TTCI) is defined as Time to Hospital Discharge OR Time to NEWS2 (National Early Warning Score 2) of ≤ 2 maintained for 24 hours.
Time frame: Up to Day 35
Population: Participants were reverse transcriptase-polymerase chain reaction (RT-PCR) positive for influenza at any time point
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Clinical Improvement | 97.5 hours |
| Placebo | Time to Clinical Improvement | 100.2 hours |
p-value: 0.466695% CI: [-53.4, 25.9]Gehan Wilcoxon
Secondary
Apparent Half-Life (T1/2) of Baloxavir
Time frame: 0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8
Population: Participants who provided informed consent to intensive PK sampling and had a sufficient number of samples available for analysis
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Apparent Half-Life (T1/2) of Baloxavir | Day 1 | 18.9 Hours (h) | — |
| Baloxavir Marboxil | Apparent Half-Life (T1/2) of Baloxavir | Day 4 | 23.4 Hours (h) | Geometric Coefficient of Variation 12.8 |
Secondary
Area Under the Concentration to Time Curve From Time 0 to 72 Hours (AUC0-72) of Baloxavir
Time frame: 0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8
Population: Participants who provided informed consent to intensive pharmacokinetic (PK) sampling in the Baloxavir Marboxil arm.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Area Under the Concentration to Time Curve From Time 0 to 72 Hours (AUC0-72) of Baloxavir | Day 1 | 2820 Hours(h)*nanogram(ng)/milliliter (mL) | Geometric Coefficient of Variation 70.5 |
| Baloxavir Marboxil | Area Under the Concentration to Time Curve From Time 0 to 72 Hours (AUC0-72) of Baloxavir | Day 4 | 3170 Hours(h)*nanogram(ng)/milliliter (mL) | Geometric Coefficient of Variation 53.5 |
Secondary
Area Under the Curve in the Amount of Virus RNA (RT-PCR)
Time frame: Days 1, 2, 3, 4, 5, 7, and 10
Population: Participants were RT-PCR positive for influenza on Day 1.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baloxavir Marboxil | Area Under the Curve in the Amount of Virus RNA (RT-PCR) | 676.40 log10 virus particles/mL*hours | Standard Deviation 371.72 |
| Placebo | Area Under the Curve in the Amount of Virus RNA (RT-PCR) | 740.15 log10 virus particles/mL*hours | Standard Deviation 484.07 |
Secondary
Area Under the Curve in Virus Titer
Time frame: Days 1, 2, 3, 4, 5, 7, and 10
Population: Participants with a positive virus titer on Day 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baloxavir Marboxil | Area Under the Curve in Virus Titer | 291.68 log10 TCID50/mL*hours | Standard Deviation 176.68 |
| Placebo | Area Under the Curve in Virus Titer | 332.04 log10 TCID50/mL*hours | Standard Deviation 183.63 |
Secondary
Change From Baseline in Influenza Virus Titer at Each Timepoint
Influenza virus titer 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.
Time frame: Days 2, 3, 4, 5, 7, and 10
Population: Participants were RT-PCR positive for influenza at any time point and with a positive virus titer on Day 1
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Change From Baseline in Influenza Virus Titer at Each Timepoint | Day 2 | -2.36 log10 TCID50/ml |
| Baloxavir Marboxil | Change From Baseline in Influenza Virus Titer at Each Timepoint | Day 3 | -2.70 log10 TCID50/ml |
| Baloxavir Marboxil | Change From Baseline in Influenza Virus Titer at Each Timepoint | Day 4 | -2.88 log10 TCID50/ml |
| Baloxavir Marboxil | Change From Baseline in Influenza Virus Titer at Each Timepoint | Day 5 | -3.01 log10 TCID50/ml |
| Baloxavir Marboxil | Change From Baseline in Influenza Virus Titer at Each Timepoint | Day 7 | -3.00 log10 TCID50/ml |
| Baloxavir Marboxil | Change From Baseline in Influenza Virus Titer at Each Timepoint | Day 10 | -3.02 log10 TCID50/ml |
| Placebo | Change From Baseline in Influenza Virus Titer at Each Timepoint | Day 7 | -2.95 log10 TCID50/ml |
| Placebo | Change From Baseline in Influenza Virus Titer at Each Timepoint | Day 2 | -1.00 log10 TCID50/ml |
| Placebo | Change From Baseline in Influenza Virus Titer at Each Timepoint | Day 5 | -2.81 log10 TCID50/ml |
| Placebo | Change From Baseline in Influenza Virus Titer at Each Timepoint | Day 3 | -1.93 log10 TCID50/ml |
| Placebo | Change From Baseline in Influenza Virus Titer at Each Timepoint | Day 10 | -3.06 log10 TCID50/ml |
| Placebo | Change From Baseline in Influenza Virus Titer at Each Timepoint | Day 4 | -2.50 log10 TCID50/ml |
Secondary
Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint
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)
Time frame: Days 2, 3, 4, 5, 7, and 10
Population: Participants were RT-PCR positive for influenza on Day 1
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Day 2 | -0.98 log10 virus particles/mL |
| Baloxavir Marboxil | Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Day 3 | -1.54 log10 virus particles/mL |
| Baloxavir Marboxil | Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Day 4 | -2.35 log10 virus particles/mL |
| Baloxavir Marboxil | Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Day 5 | -2.91 log10 virus particles/mL |
| Baloxavir Marboxil | Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Day 7 | -3.15 log10 virus particles/mL |
| Baloxavir Marboxil | Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Day 10 | -3.69 log10 virus particles/mL |
| Placebo | Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Day 7 | -2.96 log10 virus particles/mL |
| Placebo | Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Day 2 | -0.66 log10 virus particles/mL |
| Placebo | Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Day 5 | -2.39 log10 virus particles/mL |
| Placebo | Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Day 3 | -1.19 log10 virus particles/mL |
| Placebo | Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Day 10 | -3.21 log10 virus particles/mL |
| Placebo | Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint | Day 4 | -1.84 log10 virus particles/mL |
Secondary
Concentration at 24 Hours (C24) of Baloxavir
Time frame: 0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8
Population: Participants who provided informed consent to intensive PK sampling in the Baloxavir Marboxil arm
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Concentration at 24 Hours (C24) of Baloxavir | Day 1 | 43.9 ng/mL | Geometric Coefficient of Variation 74.4 |
| Baloxavir Marboxil | Concentration at 24 Hours (C24) of Baloxavir | Day 4 | 67.1 ng/mL | Geometric Coefficient of Variation 66.8 |
| Baloxavir Marboxil | Concentration at 24 Hours (C24) of Baloxavir | Day 7 | 105 ng/mL | — |
Secondary
Duration of ICU Stay
Time frame: Up to Day 35
Population: Participants were RT-PCR positive for influenza at any time point
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Duration of ICU Stay | 138.55 hours |
| Placebo | Duration of ICU Stay | 71.78 hours |
Secondary
Duration of Mechanical Ventilation
Time frame: Up to Day 35
Population: Participants were RT-PCR positive for influenza at any time point
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Duration of Mechanical Ventilation | 150.25 hours |
| Placebo | Duration of Mechanical Ventilation | 91.00 hours |
Secondary
Maximum Plasma Concentration (Cmax) of Baloxavir
Time frame: 0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8
Population: Participants who provided informed consent to intensive PK sampling in the Baloxavir Marboxil arm.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Maximum Plasma Concentration (Cmax) of Baloxavir | Day 1 | 86.3 ng/mL | Geometric Coefficient of Variation 64.6 |
| Baloxavir Marboxil | Maximum Plasma Concentration (Cmax) of Baloxavir | Day 4 | 123 ng/mL | Geometric Coefficient of Variation 51.7 |
Secondary
Mortality Rate at Day 28
Time frame: Up to Day 28
Population: Participants were RT-PCR positive for influenza at any time point
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Baloxavir Marboxil | Mortality Rate at Day 28 | 1.9 percentage of participants |
| Placebo | Mortality Rate at Day 28 | 5.3 percentage of participants |
Secondary
Mortality Rate at Day 7
Time frame: Up to Day 7
Population: Participants were RT-PCR positive for influenza at any time point
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Baloxavir Marboxil | Mortality Rate at Day 7 | 0.5 percentage of participants |
| Placebo | Mortality Rate at Day 7 | 2.6 percentage of participants |
Secondary
Percentage of Participants on Mechanical Ventilation
Time frame: Up to Day 35
Population: Participants were RT-PCR positive for influenza at any time point
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Baloxavir Marboxil | Percentage of Participants on Mechanical Ventilation | 5.3 percentage of participants |
| Placebo | Percentage of Participants on Mechanical Ventilation | 6.1 percentage of participants |
Secondary
Percentage of Participants Positive by RT-PCR at Each Timepoint
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)
Time frame: Days 2, 3, 4, 5, 7, and 10
Population: Participants were RT-PCR positive for influenza on Day 1
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants Positive by RT-PCR at Each Timepoint | Day 2 | 95.6 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Positive by RT-PCR at Each Timepoint | Day 3 | 90.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Positive by RT-PCR at Each Timepoint | Day 4 | 88.1 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Positive by RT-PCR at Each Timepoint | Day 5 | 79.9 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Positive by RT-PCR at Each Timepoint | Day 7 | 69.6 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Positive by RT-PCR at Each Timepoint | Day 10 | 46.7 percentage of participants |
| Placebo | Percentage of Participants Positive by RT-PCR at Each Timepoint | Day 7 | 68.0 percentage of participants |
| Placebo | Percentage of Participants Positive by RT-PCR at Each Timepoint | Day 2 | 96.3 percentage of participants |
| Placebo | Percentage of Participants Positive by RT-PCR at Each Timepoint | Day 5 | 85.4 percentage of participants |
| Placebo | Percentage of Participants Positive by RT-PCR at Each Timepoint | Day 3 | 93.3 percentage of participants |
| Placebo | Percentage of Participants Positive by RT-PCR at Each Timepoint | Day 10 | 50.5 percentage of participants |
| Placebo | Percentage of Participants Positive by RT-PCR at Each Timepoint | Day 4 | 87.9 percentage of participants |
Secondary
Percentage of Participants Requiring ICU Stay
Time frame: Up to Day 35
Population: Participants were RT-PCR positive for influenza at any time point
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Baloxavir Marboxil | Percentage of Participants Requiring ICU Stay | 4.3 percentage of participants |
| Placebo | Percentage of Participants Requiring ICU Stay | 3.5 percentage of participants |
Secondary
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.
Time frame: Up to Day 35
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 45.2 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 12.1 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 50.0 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 15.3 percentage of participants |
Secondary
Percentage of Participants With AEs and SAEs Leading to Discontinuation From Treatment
Discontinuation from study treatment.
Time frame: Up to Day 35
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants With AEs and SAEs Leading to Discontinuation From Treatment | AEs | 1.3 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With AEs and SAEs Leading to Discontinuation From Treatment | SAEs | 0.8 percentage of participants |
| Placebo | Percentage of Participants With AEs and SAEs Leading to Discontinuation From Treatment | AEs | 3.2 percentage of participants |
| Placebo | Percentage of Participants With AEs and SAEs Leading to Discontinuation From Treatment | SAEs | 1.6 percentage of participants |
Secondary
Percentage of Participants With Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN
ALT = alanine aminotransferase AST = aspartate transaminase
Time frame: Up to Day 35
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants With Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN | AST(U/L) or ALT (U/L) >3 x ULN | 4.6 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN | AST(U/L) or ALT (U/L) >5 x ULN | 0.8 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN | AST(U/L) or ALT (U/L) >10 x ULN | 0 percentage of participants |
| Placebo | Percentage of Participants With Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN | AST(U/L) or ALT (U/L) >3 x ULN | 8.9 percentage of participants |
| Placebo | Percentage of Participants With Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN | AST(U/L) or ALT (U/L) >5 x ULN | 3.2 percentage of participants |
| Placebo | Percentage of Participants With Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN | AST(U/L) or ALT (U/L) >10 x ULN | 1.6 percentage of participants |
Secondary
Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint
Influenza virus titer 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 (log10 TCID50/mL). A lower value indicates lower viral titer.
Time frame: Days 2, 3, 4, 5, 7, and 10
Population: Participants were RT-PCR positive for influenza at any time point and with a positive virus titer on Day 1.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Day 2 | 37.7 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Day 3 | 18.6 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Day 4 | 7.9 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Day 5 | 1.3 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Day 7 | 2.7 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Day 10 | 1.4 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Day 7 | 5.8 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Day 2 | 80.3 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Day 5 | 20.8 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Day 3 | 53.4 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Day 10 | 1.4 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint | Day 4 | 26.7 percentage of participants |
Secondary
Percentage of Participants With Post-Treatment Influenza-Related Complications
Influenza-related complications included pneumonia, myositis or rhabdomyolysis, encephalitis or encephalopathy, myocarditis and/or pericarditis, otitis media, sinusitis, exacerbation of COPD/asthma, sepsis, acute lung injury or acute respiratory distress syndrome.
Time frame: Up to Day 35
Population: Participants were RT-PCR positive for influenza at any time point
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Baloxavir Marboxil | Percentage of Participants With Post-Treatment Influenza-Related Complications | 10.6 percentage of participants |
| Placebo | Percentage of Participants With Post-Treatment Influenza-Related Complications | 14.0 percentage of participants |
Secondary
Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points
Time frame: Day 1, 2, 4, 5, 7 and 8
Population: Participants who provided informed consent to intensive PK sampling in the Baloxavir Marboxil arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 4 - 4 hours postdose | 117.69 ng/mL | Standard Deviation 60.54 |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 1 - 30 minutes postdose | 37.82 ng/mL | Standard Deviation 23.61 |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 1 - 2 hours postdose | 75.06 ng/mL | Standard Deviation 52.16 |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 1 - 4 hours postdose | 95.85 ng/mL | Standard Deviation 58.36 |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 1 - 10 hours postdose | 64.47 ng/mL | Standard Deviation 39.47 |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 2 - 24 hours postdose | 53.36 ng/mL | Standard Deviation 37.42 |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 4 - Predose | 24.26 ng/mL | Standard Deviation 15.87 |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 4 - 30 minutes postdose | 49.16 ng/mL | Standard Deviation 52.07 |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 4 - 2 hours postdose | 109.66 ng/mL | Standard Deviation 95.22 |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 4 - 10 hours postdose | 94.08 ng/mL | Standard Deviation 49.71 |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 5 - 24 hours postdose | 77.98 ng/mL | Standard Deviation 42.89 |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 7 - predose | 23.31 ng/mL | Standard Deviation 25.87 |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Day 8 - 24 hours postdose | 105.00 ng/mL | — |
| Baloxavir Marboxil | Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points | Visit 8 | 28.37 ng/mL | Standard Deviation 61.61 |
Secondary
Response Rates of the 6-Point Ordinal Scale at Day 7
The ordinal scale categories are: Category 1) Discharged (or ready for discharge) Category 2) Non-ICU hospital ward (or ready for hospital ward) not requiring supplemental oxygen/non-invasive ventilation Category 3) Non-ICU hospital ward (or ready for hospital ward) requiring supplemental oxygen/non-invasive ventilation Category 4) ICU without mechanical (invasive) ventilation (or ready for ICU admission) Category 5) Mechanical (invasive) ventilation Category 6) Death
Time frame: Day 7
Population: All participants who were RT-PCR positive for influenza and were not discontinued or lost to follow up prior to day 7.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Response Rates of the 6-Point Ordinal Scale at Day 7 | Category 1 | 49.2 percentage of participants |
| Baloxavir Marboxil | Response Rates of the 6-Point Ordinal Scale at Day 7 | Category 2 | 22.6 percentage of participants |
| Baloxavir Marboxil | Response Rates of the 6-Point Ordinal Scale at Day 7 | Category 3 | 20.1 percentage of participants |
| Baloxavir Marboxil | Response Rates of the 6-Point Ordinal Scale at Day 7 | Category 4 | 4.0 percentage of participants |
| Baloxavir Marboxil | Response Rates of the 6-Point Ordinal Scale at Day 7 | Category 5 | 3.5 percentage of participants |
| Baloxavir Marboxil | Response Rates of the 6-Point Ordinal Scale at Day 7 | Category 6 | 0.5 percentage of participants |
| Placebo | Response Rates of the 6-Point Ordinal Scale at Day 7 | Category 5 | 4.6 percentage of participants |
| Placebo | Response Rates of the 6-Point Ordinal Scale at Day 7 | Category 1 | 45.4 percentage of participants |
| Placebo | Response Rates of the 6-Point Ordinal Scale at Day 7 | Category 4 | 1.9 percentage of participants |
| Placebo | Response Rates of the 6-Point Ordinal Scale at Day 7 | Category 2 | 24.1 percentage of participants |
| Placebo | Response Rates of the 6-Point Ordinal Scale at Day 7 | Category 6 | 1.9 percentage of participants |
| Placebo | Response Rates of the 6-Point Ordinal Scale at Day 7 | Category 3 | 22.2 percentage of participants |
p-value: 0.6326Cochran-Mantel-Haenszel
Secondary
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 study treatment and first time when the virus RNA by RT-PCR is below the limit of detection (2.05 for flu A and 2.83 for flu B log10 virus particles/mL)
Time frame: Screening (baseline) and on Days 2, 3, 4, 5, 7, and 10
Population: Participants were RT-PCR positive for influenza on Day 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Cessation of Viral Shedding by RT-PCR | 216.3 hours |
| Placebo | Time to Cessation of Viral Shedding by RT-PCR | 261.1 hours |
Secondary
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 study treatment and first time when the influenza virus titer is below the limit of detection (0.75 log10 TCID50/mL)
Time frame: Screening (baseline) and on Days 2, 3, 4, 5, 7, and 10
Population: Participants were RT-PCR positive for influenza at any time point and with a positive virus titer on Day 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Cessation of Viral Shedding by Virus Titer | 23.9 hours |
| Placebo | Time to Cessation of Viral Shedding by Virus Titer | 63.7 hours |
Secondary
Time to Clinical Failure
Time to clinical failure, defined as the time to death, mechanical ventilation, or ICU admission, corresponding to ordinal scale categories 6, 5, and 4, respectively, from baseline
Time frame: Up to Day 35
Population: Participants were RT-PCR positive for influenza at any time point
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Clinical Failure | NA hours |
| Placebo | Time to Clinical Failure | NA hours |
Secondary
Time to Clinical Response
Time to Clinical Response is based on temperature ranges, oxygen saturation, respiratory status, heart rate, and hospitalization status.
Time frame: Up to Day 35
Population: Participants were RT-PCR positive for influenza at any time point
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Clinical Response | 138.3 hours |
| Placebo | Time to Clinical Response | 145.1 hours |
p-value: 0.327295% CI: [-50.9, 17.7]Gehan Wilcoxon
Secondary
Time to Hospital Discharge
Time frame: Up to Day 35
Population: Participants were RT-PCR positive for influenza at any time point
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Hospital Discharge | 166.7 hours |
| Placebo | Time to Hospital Discharge | 167.3 hours |
Secondary
Time to NEWS2 of ≤ 2 Maintained for 24 Hours
A score of 0 (Range 0 - 3) indicates normal health conditions.
Time frame: Up to Day 35
Population: Participants were RT-PCR positive for influenza at any time point
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to NEWS2 of ≤ 2 Maintained for 24 Hours | 106.3 hours |
| Placebo | Time to NEWS2 of ≤ 2 Maintained for 24 Hours | 127.2 hours |