Influenza
Conditions
Keywords
Tamiflu®, Influenza, Oseltamivir, Flu, S-033188
Brief summary
The primary objective of this study is to evaluate the efficacy of a single, oral dose of baloxavir marboxil compared with placebo by measuring the time to improvement of influenza symptoms in patients with influenza presenting within 48 hours of symptom onset.
Interventions
Tablets taken orally
Matching tablets taken orally
DRUGOseltamivir
Capsules taken orally
Matching placebo capsules taken orally
Sponsors
Shionogi
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
1. Patients or their legal guardians who provide written informed consent to participate in the study on a voluntary basis. For adolescent patients, informed consent/assent of voluntary participation should be obtained in accordance with local requirements. 2. Male or female patients ≥ 12 years at the time of signing the informed consent/assent form. 3. Patients with a diagnosis of influenza confirmed by all of the following: 1. Fever ≥ 38ºC (axillary) during the predose examinations or within the 4 hours prior if antipyretics were taken 2. A positive rapid influenza diagnostic test (RIDT) result OR A patient with a negative RIDT may be enrolled if the patient reports contact with a known case of influenza within the prior 7 days and all other inclusion criteria are met. 3. At least 1 each of the following general and respiratory symptoms associated with influenza is present with a severity of moderate or greater: i. General symptoms (headache, feverishness or chills, muscle or joint pain, or fatigue) ii. Respiratory symptoms (cough, sore throat, or nasal congestion) 4. The time interval between the onset of symptoms and the predose examinations is 48 hours or less. The onset of symptoms is defined as either: 1. Time of the first increase in body temperature (an increase of at least 1ºC from normal body temperature) 2. Time when the patient experiences at least 1 new general or respiratory symptom 5. If a women of childbearing potential, agrees to use a highly effective method of contraception for 3 months after the first dose of study drug 6. Patients will be considered at high risk\* of influenza complications due to the presence of at least 1 of the following inclusion criteria: 1. Asthma or chronic lung disease (such as chronic obstructive pulmonary disease or cystic fibrosis) 2. Endocrine disorders (including diabetes mellitus) 3. Residents of long-term care facilities (eg, nursing homes) 4. Compromised immune system (including patients receiving corticosteroids not exceeding 20 mg of prednisolone or equivalent, and patients being treated for human immunodeficiency virus \[HIV\] infection with a CD4 count \> 350 cells/mm³ within the last 6 months) 5. Neurological and neurodevelopmental disorders (including disorders of the brain, spinal cord, peripheral nerve, and muscle, eg, cerebral palsy, epilepsy \[seizure disorders\], stroke, muscular dystrophy, or spinal cord injury) 6. Heart disease (such as congenital heart disease, congestive heart failure, or coronary artery disease), excluding hypertension without any other heart-related symptoms 7. Adults aged ≥ 65 years 8. American Indians and Alaskan Natives 9. Blood disorders (such as sickle cell disease) 10. Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders) 11. Morbid obesity (body mass index ≥ 40 kg/m²) 12. Women who are within 2 weeks postpartum and are not breastfeeding
Exclusion criteria
1. Patients with severe influenza virus infection requiring inpatient treatment. 2. Patients with known allergy to oseltamivir (Tamiflu®). 3. Patients unable to swallow tablets or capsules. 4. Patients who have previously received baloxavir marboxil. 5. Patients weighing ≤ 40 kg. 6. Patients who have been exposed to an investigational drug within 30 days prior to the predose examinations. 7. Women who are pregnant, breastfeeding, or have a positive pregnancy test at the predose examinations. The following female patients who have documentation of either a or b below do not need to undergo a pregnancy test at the predose examinations: 1. Postmenopausal women (defined as cessation of regular menstrual periods for 2 years or more and confirmed by a follicle-stimulating hormone test) 2. Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or tubal ligation 8. Patients with concurrent infections at the predose examinations requiring systemic antimicrobial therapy. 9. Patients with liver disease associated with hepatic impairment. 10. Patients with cancer within the last 5 years (unless nonmelanoma skin cancer). 11. Patients with untreated HIV infection or treated HIV infection with a CD4 count below 350 cells/mm3 in the last 6 months. 12. Patients with immunosuppression following organ or bone marrow transplants. 13. Patients exceeding 20 mg of prednisolone or equivalent dose of chronic systemic corticosteroids. 14. Patients who have received peramivir, laninamivir, oseltamivir, zanamivir, rimantadine, umifenovir or amantadine within 30 days prior to the predose examinations. 15. Patients who have received an investigational monoclonal antibody for a viral disease in the last year. 16. Patients with known creatinine clearance ≤ 60 mL/min. 17. Patients who, in the opinion of the investigator, would be unlikely to comply with required study visits, self-assessments, and interventions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Improvement of Influenza Symptoms | From Day 1 pretreatment up to Day 14 | Participants assessed the severity of 7 influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness/chills, muscle/joint pain, and fatigue) on a 4-point scale (0 = no symptoms, 1= mild, 2 = moderate, and 3 = severe). Time to improvement of symptoms was defined as the time from the start of treatment to the time when all influenza symptoms were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: * Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline * Preexisting symptoms not worse at baseline must have maintained baseline severity * New symptoms must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of symptoms was analyzed using Kaplan-Meier (KM) methods; participants who did not experience improvement of symptom s were censored at the last observation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Days 2, 3, 4 (optional), 5, 6 (optional), and 9. | Influenza virus ribonucleic acid (RNA) was quantified from nasopharyngeal swabs (or throat swabs, if nasopharyngeal swabbing was not feasible). The percentage of participants with detectable virus RNA (2.05 for flu A and 2.83 for flu B log₁₀ virus particles/mL) measured by reverse transcription polymerase chain reaction (RT-PCR) among those assessed on Days 2, 3, 4, 5, 6 and 9. |
| Change From Baseline in Virus Titer at Each Time Point | Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9 | Virus titer was quantified from nasopharyngeal swabs (or throat swabs if nasopharyngeal swabbing was not feasible) by tissue culture methods. If virus titer was less than the lower limit of quantification, the virus titer was imputed 0.7 (TCID₅₀/mL). |
| Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9 | Nasopharyngeal swabs (or throat swabs, if nasopharyngeal swabbing was not feasible) were obtained for viral quantitation. Virus RNA was measured by reverse transcription polymerase chain reaction (RT-PCR). |
| Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer | Day 1 to Day 9 | This endpoint was defined as AUC of change from Baseline in virus titer from Day 1 to Day 9. AUC was calculated using the trapezoidal method. |
| Area Under the Curve (AUC) Adjusted by Baseline in Viral RNA | Day 1 to Day 9 | This endpoint was defined as AUC of change from baseline in the amount of virus RNA (RT-PCR) from Day 1 to Day 9. The AUC was calculated using the trapezoidal method. |
| Time to Cessation of Viral Shedding Determined by Virus Titer | Day 1 to Day 9 | Time to cessation of viral shedding by virus titer was defined as the time between the initiation of the study treatment and first time when the virus titer was below the limit of detection (0.7 log₁₀\[TCID₅₀/mL\]). The median and 95% confidence interval (CI) for time to cessation of viral shedding determined by virus titer was analyzed using the Kaplan-Meier (KM) method; participants whose virus titer had not reached cessation by the last observation time point were treated as censored at that time point. |
| Time to Cessation of Viral Shedding Determined by Virus RNA | Day 1 to Day 9 | Time to cessation of viral shedding by RT-PCR was defined as the time between the initiation of the study treatment and first time when the virus RNA was below the limit of detection measured by RT-PCR. Time to cessation of viral shedding by RT-PCR was analyzed using the KM method; participants whose virus RNA had not reached cessation by the last observation time point were treated as censored at that time point. |
| Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the initial dose of study treatment | Participants assessed the severity of 7 influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (0 = no symptoms, 1= mild, 2 = moderate, and 3 = severe). Improvement of symptoms was defined as all influenza symptoms alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: * Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) judged to be worse at baseline must have improved at least 1 point from baseline severity * Preexisting symptoms judged not to be worse at baseline must have maintained baseline severity * New symptoms at baseline must have alleviated, defined as a symptom score of none (0) or mild (1). |
| Time to Alleviation of Symptoms | Initiation of study treatment up to Day 14 | Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms). Time to alleviation of symptoms was defined as the time from the start of the study treatment to the time when all seven influenza-related symptoms were assessed by the participant as absent (0) or mild (1) for at least 21.5 hours. Time to alleviation of symptoms was analyzed using Kaplan-Meier (KM) methods; participants who did not experience alleviation of symptoms were censored at the last observation time point. |
| Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Days 2, 3, 4 (optional), 5, 6 (optional), and 9 | Virus titer was quantified from nasopharyngeal swabs (or throat swabs if nasopharyngeal swabbing was not feasible) using tissue culture methods. Positive influenza virus titer was defined as virus titer not less than the lower limit of quantification (0.7 log₁₀ of the 50% tissue culture infective dose (TCID₅₀/mL) among those assessed for virus titer on Days 2, 3, 4, 5, 6, and 9. |
| Time to Improvement of the Three Respiratory Symptoms | Initiation of study treatment up to Day 14 | Participants assessed the severity of 7 influenza-associated symptoms on a 4-point scale (from 0 = no symptoms to 3 = severe symptoms). Time to improvement of the 3 respiratory symptoms was defined as the time from the start of study treatment to the time when all 3 respiratory symptoms (cough, sore throat, and nasal congestion) were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: * Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline * Preexisting symptoms not worse at baseline must have maintained baseline severity * New symptoms at baseline must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of the 3 respiratory symptoms was analyzed using KM methods; participants who did not experience improvement of symptoms were censored at the last observation time point. |
| Time to Resolution of Fever | Initiation of study treatment up to Day 14 | Time to resolution of fever was defined as the time between the initiation of the study treatment and the resolution of fever. The resolution of fever was defined as the time when the participant's self-measured axillary temperature became less than 37ºC and was maintained at less than 37ºC for at least 12 hours. Time to resolution of fever was analyzed using KM methods; participants who did not experience resolution of fever by the last observation time point were censored at that time point. |
| Percentage of Participants Reporting Normal Temperature at Each Time Point | 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the initial dose of study treatment | Defined as the percentage of patrticipants whose axillary body temperature dropped to less than 37ºC after the initiation of the study treatment. |
| Body Temperature at Each Time Point | 12, 24, 36, 48, 72, 96 and 120 hours after the initial dose of study treatment | Participant's self-measured axillary temperature using an electronic thermometer. |
| Time to Improvement of Individual Symptoms | Initiation of study treatment up to Day 14 | Participants assessed the severity of 7 influenza-associated symptoms on a 4-point scale (0 = no symptoms to 3 = severe). Time to improvement of cough, fatigue, and muscle/joint pain was defined as the time from the start of treatment to the time when each symptom was alleviated, maintained, or improved, as defined below, for at least 21.5 hours: * Preexisting symptoms that were worse at baseline must have improved at least 1 point from baseline * Preexisting symptoms not worse at baseline must have maintained baseline severity * New symptoms must have alleviated, defined as a score of 0 (None) or 1 (Mild). Time to improvement of sore throat, headache, nasal congestion, and feverish/chills was defined as the time from the start of treatment to the time when the symptom was assessed as 0 (None) or 1 (Mild) for at least 21.5 hours. Time to improvement of symptoms was analyzed using KM methods; participants with no improvement of symptoms were censored at the last observation. |
| Time to Return to Preinfluenza Health Status | Baseline to Day 14 | Participants were asked to record their preinfluenza health status on a scale from 0 (worst possible health) to 10 (normal health \[for someone your age and condition\]), and their health status at baseline and every day after initiation of study treatment on the same scale. Return to preinfluenza health status was defined as time from the initiation of the study treatment to the first time when the health status score was equal to or higher than the preinfluenza health status score. Time to return to preinfluenza health status was analyzed using KM methods; participants with a smaller number on the scale for health status by the last observation time point were censored at that time point. |
| Percentage of Participants Requiring Systemic Antibiotics for Infections Secondary to Influenza Infection | Day 2 to Day 22 | The percentage of participants who received systemic antibiotics for any of the predefined complications (sinusitis, otitis media, bronchitis and pneumonia). |
| Percentage of Participants With Influenza-related Complications | Day 1 to Day 22 | Defined as the percentage of patients who experience each influenza-related complication (hospitalization, death, sinusitis, otitis media, bronchitis, and radiologically-confirmed pneumonia) as an adverse event after the initiation of study treatment. |
| Percentage of Participants With Adverse Events (AEs) | From first dose of study drug to Day 22 | — |
| Time to Improvement of the Four Systemic Symptoms | Initiation of study treatment up to Day 14 | Participants assessed the severity of 7 influenza-associated symptoms on a 4-point scale (from 0 = no symptoms to 3 = severe symptoms). Time to improvement of the 4 systemic symptoms was defined as the time between the initiation of study treatment to the time when all 4 systemic symptoms (headache, feverishness or chills, muscle or joint pain, and fatigue) were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: * Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline * Preexisting symptoms not worse at baseline must have maintained baseline severity * New symptoms at baseline must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of the 4 systemic symptoms was analyzed using KM methods; participants who did not experience improvement of symptoms were censored at the last observation. |
Participant flow
Recruitment details
This was a multicenter study conducted at 551 sites, including 242 sites in the United States, 142 sites in Japan, 48 sites in APAC (including Australia, New Zealand, Philippines, and South Korea), 98 sites in Europe (Belgium, Germany, Hungary, Latvia, Poland, Romania, and Spain), and 21 sites in South Africa.
Pre-assignment details
Eligible patients were randomized in a 1:1:1 ratio to 1 of 3 treatment groups. Participants were stratified by baseline symptom score (≤ 14 or ≥ 15), preexisting and worsened symptom (Yes or No), region (Asia, North America/Europe, or Southern Hemisphere), and patient's weight (\< 80 kg or ≥ 80 kg).
Participants by arm
| Arm | Count |
|---|---|
| Baloxavir Marboxil Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of \< 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. | 388 |
| Placebo Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. | 386 |
| Oseltamivir Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1. | 389 |
| Total | 1,163 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 7 | 3 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Failed Inclusion/Exclusion Criteria | 0 | 0 | 3 |
| Overall Study | Lack of Efficacy | 0 | 2 | 0 |
| Overall Study | Lost to Follow-up | 7 | 5 | 5 |
| Overall Study | Miscellaneous | 2 | 4 | 6 |
| Overall Study | Protocol Deviation | 5 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 13 | 13 | 21 |
Baseline characteristics
| Characteristic | Total | Placebo | Oseltamivir | Baloxavir Marboxil |
|---|---|---|---|---|
| Age, Continuous | 51.8 years STANDARD_DEVIATION 16.8 | 51.9 years STANDARD_DEVIATION 16.7 | 51.1 years STANDARD_DEVIATION 17 | 52.3 years STANDARD_DEVIATION 16.8 |
| Age, Customized ≥ 12 to ≤ 19 years | 58 Participants | 17 Participants | 22 Participants | 19 Participants |
| Age, Customized ≥ 20 to ≤ 29 years | 78 Participants | 22 Participants | 27 Participants | 29 Participants |
| Age, Customized ≥ 30 to ≤ 39 years | 144 Participants | 58 Participants | 44 Participants | 42 Participants |
| Age, Customized ≥ 40 to ≤ 49 years | 193 Participants | 55 Participants | 75 Participants | 63 Participants |
| Age, Customized ≥ 50 to ≤ 59 years | 267 Participants | 101 Participants | 83 Participants | 83 Participants |
| Age, Customized ≥ 60 to ≤ 64 years | 104 Participants | 30 Participants | 35 Participants | 39 Participants |
| Age, Customized ≥ 65 to ≤ 74 years | 239 Participants | 76 Participants | 78 Participants | 85 Participants |
| Age, Customized ≥ 75 years | 80 Participants | 27 Participants | 25 Participants | 28 Participants |
| Composite Symptom Score ≤ 14 | 577 Participants | 188 Participants | 201 Participants | 188 Participants |
| Composite Symptom Score ≥ 15 | 586 Participants | 198 Participants | 188 Participants | 200 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 177 Participants | 59 Participants | 56 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 983 Participants | 327 Participants | 331 Participants | 325 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 2 Participants | 1 Participants |
| Influenza Virus Ribonucleic Acid (RNA) Load | 6.80 log₁₀ virus particles/mL STANDARD_DEVIATION 1.45 | 6.87 log₁₀ virus particles/mL STANDARD_DEVIATION 1.54 | 6.81 log₁₀ virus particles/mL STANDARD_DEVIATION 1.37 | 6.72 log₁₀ virus particles/mL STANDARD_DEVIATION 1.43 |
| Influenza Virus Subtype Based on RT-PCR Assay A/H1N1pdm | 80 Participants | 17 Participants | 35 Participants | 28 Participants |
| Influenza Virus Subtype Based on RT-PCR Assay A/H3 | 557 Participants | 185 Participants | 190 Participants | 182 Participants |
| Influenza Virus Subtype Based on RT-PCR Assay B | 484 Participants | 168 Participants | 149 Participants | 167 Participants |
| Influenza Virus Subtype Based on RT-PCR Assay Mixed infection | 14 Participants | 5 Participants | 5 Participants | 4 Participants |
| Influenza Virus Subtype Based on RT-PCR Assay Other | 28 Participants | 11 Participants | 10 Participants | 7 Participants |
| Influenza Virus Titer | 5.16 log₁₀[TCID₅₀/mL] STANDARD_DEVIATION 2.32 | 5.27 log₁₀[TCID₅₀/mL] STANDARD_DEVIATION 2.39 | 5.25 log₁₀[TCID₅₀/mL] STANDARD_DEVIATION 2.27 | 4.96 log₁₀[TCID₅₀/mL] STANDARD_DEVIATION 2.28 |
| Preexisting Symptom Status No | 947 Participants | 310 Participants | 320 Participants | 317 Participants |
| Preexisting Symptom Status Yes | 216 Participants | 76 Participants | 69 Participants | 71 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 6 Participants | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 487 Participants | 157 Participants | 163 Participants | 167 Participants |
| Race/Ethnicity, Customized Black or African American | 98 Participants | 30 Participants | 29 Participants | 39 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 3 Participants | 6 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 560 Participants | 194 Participants | 188 Participants | 178 Participants |
| Region Asia | 462 Participants | 151 Participants | 152 Participants | 159 Participants |
| Region North America/Europe | 648 Participants | 216 Participants | 220 Participants | 212 Participants |
| Region Southern Hemisphere | 53 Participants | 19 Participants | 17 Participants | 17 Participants |
| Sex: Female, Male Female | 599 Participants | 206 Participants | 198 Participants | 195 Participants |
| Sex: Female, Male Male | 564 Participants | 180 Participants | 191 Participants | 193 Participants |
| Time to Treatment From Influenza Onset ≥ 0 to ≤ 12 hours | 106 Participants | 42 Participants | 37 Participants | 27 Participants |
| Time to Treatment From Influenza Onset > 12 to ≤ 24 hours | 420 Participants | 150 Participants | 119 Participants | 151 Participants |
| Time to Treatment From Influenza Onset > 24 to ≤ 36 hours | 375 Participants | 120 Participants | 141 Participants | 114 Participants |
| Time to Treatment From Influenza Onset > 36 to ≤ 48 hours | 261 Participants | 74 Participants | 92 Participants | 95 Participants |
| Time to Treatment From Influenza Onset Missing | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Weight < 80 kg | 704 Participants | 232 Participants | 233 Participants | 239 Participants |
| Weight ≥ 80 kg | 459 Participants | 154 Participants | 156 Participants | 149 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 730 | 0 / 727 | 1 / 721 |
| other Total, other adverse events | 70 / 730 | 92 / 727 | 90 / 721 |
| serious Total, serious adverse events | 5 / 730 | 9 / 727 | 8 / 721 |
Outcome results
Primary
Time to Improvement of Influenza Symptoms
Participants assessed the severity of 7 influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness/chills, muscle/joint pain, and fatigue) on a 4-point scale (0 = no symptoms, 1= mild, 2 = moderate, and 3 = severe). Time to improvement of symptoms was defined as the time from the start of treatment to the time when all influenza symptoms were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: * Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline * Preexisting symptoms not worse at baseline must have maintained baseline severity * New symptoms must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of symptoms was analyzed using Kaplan-Meier (KM) methods; participants who did not experience improvement of symptom s were censored at the last observation.
Time frame: From Day 1 pretreatment up to Day 14
Population: Participants in the intention-to-treat infected population with available time to improvement of symptoms data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Improvement of Influenza Symptoms | 73.2 hours |
| Placebo | Time to Improvement of Influenza Symptoms | 102.3 hours |
| Oseltamivir | Time to Improvement of Influenza Symptoms | 81.0 hours |
Comparison: The primary analysis of the primary endpoint was a comparison between the baloxavir marboxil and placebo groups.p-value: <0.000195% CI: [-42.8, -14.6]Stratified generalized Wilcoxon test
Comparison: The comparison between the baloxavir marboxil and the oseltamivir groups was conducted as a secondary analysis only if a statistically significant difference was observed in the primary analysis in order to maintain control of overall type I error.p-value: 0.834795% CI: [-22.7, 7.9]Stratified generalized Wilcoxon test
Comparison: Analysis using the stratified log rank test was performed as a sensitivity analysis.p-value: 0.0008Log Rank
Comparison: Analysis using the stratified log rank test was performed as a sensitivity analysis.p-value: 0.8449Log Rank
Secondary
Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer
This endpoint was defined as AUC of change from Baseline in virus titer from Day 1 to Day 9. AUC was calculated using the trapezoidal method.
Time frame: Day 1 to Day 9
Population: Participants in the intention-to-treat infected population with a positive virus titer on Day 1 and available sample on Day 9.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baloxavir Marboxil | Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer | -727.7 log₁₀[TCID₅₀/mL]*hours | Standard Deviation 367.2 |
| Placebo | Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer | -660.2 log₁₀[TCID₅₀/mL]*hours | Standard Deviation 372.3 |
| Oseltamivir | Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer | -695.5 log₁₀[TCID₅₀/mL]*hours | Standard Deviation 360.5 |
p-value: 0.034van Elteren test
p-value: 0.2766van Elteren test
Secondary
Area Under the Curve (AUC) Adjusted by Baseline in Viral RNA
This endpoint was defined as AUC of change from baseline in the amount of virus RNA (RT-PCR) from Day 1 to Day 9. The AUC was calculated using the trapezoidal method.
Time frame: Day 1 to Day 9
Population: Participants in the intention-to-treat infected population with a positive virus RNA determined by RT-PCR at baseline and available sample on Day 9.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baloxavir Marboxil | Area Under the Curve (AUC) Adjusted by Baseline in Viral RNA | -490.9 log₁₀ virus particles/mL*hours | Standard Deviation 249.3 |
| Placebo | Area Under the Curve (AUC) Adjusted by Baseline in Viral RNA | -434.9 log₁₀ virus particles/mL*hours | Standard Deviation 269.3 |
| Oseltamivir | Area Under the Curve (AUC) Adjusted by Baseline in Viral RNA | -482.2 log₁₀ virus particles/mL*hours | Standard Deviation 233.2 |
p-value: 0.0072van Elteren test
p-value: 0.733van Elteren test
Secondary
Body Temperature at Each Time Point
Participant's self-measured axillary temperature using an electronic thermometer.
Time frame: 12, 24, 36, 48, 72, 96 and 120 hours after the initial dose of study treatment
Population: Participants in the intention-to-treat infected population with available temperature data at each time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Body Temperature at Each Time Point | 36 hours | 36.58 °C | Standard Error 0.06 |
| Baloxavir Marboxil | Body Temperature at Each Time Point | 24 hours | 36.84 °C | Standard Error 0.06 |
| Baloxavir Marboxil | Body Temperature at Each Time Point | 12 hours | 37.39 °C | Standard Error 0.07 |
| Baloxavir Marboxil | Body Temperature at Each Time Point | 72 hours | 36.30 °C | Standard Error 0.05 |
| Baloxavir Marboxil | Body Temperature at Each Time Point | 48 hours | 36.44 °C | Standard Error 0.06 |
| Baloxavir Marboxil | Body Temperature at Each Time Point | 120 hours | 36.26 °C | Standard Error 0.05 |
| Baloxavir Marboxil | Body Temperature at Each Time Point | 96 hours | 36.26 °C | Standard Error 0.05 |
| Placebo | Body Temperature at Each Time Point | 12 hours | 37.53 °C | Standard Error 0.07 |
| Placebo | Body Temperature at Each Time Point | 96 hours | 36.35 °C | Standard Error 0.05 |
| Placebo | Body Temperature at Each Time Point | 120 hours | 36.27 °C | Standard Error 0.05 |
| Placebo | Body Temperature at Each Time Point | 72 hours | 36.46 °C | Standard Error 0.05 |
| Placebo | Body Temperature at Each Time Point | 24 hours | 37.02 °C | Standard Error 0.06 |
| Placebo | Body Temperature at Each Time Point | 36 hours | 36.94 °C | Standard Error 0.06 |
| Placebo | Body Temperature at Each Time Point | 48 hours | 36.77 °C | Standard Error 0.06 |
| Oseltamivir | Body Temperature at Each Time Point | 24 hours | 36.80 °C | Standard Error 0.06 |
| Oseltamivir | Body Temperature at Each Time Point | 120 hours | 36.21 °C | Standard Error 0.05 |
| Oseltamivir | Body Temperature at Each Time Point | 48 hours | 36.50 °C | Standard Error 0.06 |
| Oseltamivir | Body Temperature at Each Time Point | 96 hours | 36.24 °C | Standard Error 0.05 |
| Oseltamivir | Body Temperature at Each Time Point | 12 hours | 37.43 °C | Standard Error 0.07 |
| Oseltamivir | Body Temperature at Each Time Point | 36 hours | 36.62 °C | Standard Error 0.06 |
| Oseltamivir | Body Temperature at Each Time Point | 72 hours | 36.29 °C | Standard Error 0.05 |
Comparison: 12 hoursp-value: 0.040895% CI: [-0.28, -0.01]ANCOVA
Comparison: 12 hoursp-value: 0.532495% CI: [-0.18, 0.09]ANCOVA
Comparison: 24 hoursp-value: 0.002595% CI: [-0.3, -0.06]ANCOVA
Comparison: 24 hoursp-value: 0.487495% CI: [-0.08, 0.16]ANCOVA
Comparison: 36 hoursp-value: <0.000195% CI: [-0.47, -0.24]ANCOVA
Comparison: 36 hoursp-value: 0.541495% CI: [-0.15, 0.08]ANCOVA
Comparison: 48 hoursp-value: <0.000195% CI: [-0.44, -0.22]ANCOVA
Comparison: 48 hoursp-value: 0.318595% CI: [-0.17, 0.05]ANCOVA
Comparison: 72 hoursp-value: 0.002595% CI: [-0.26, -0.06]ANCOVA
Comparison: 72 hoursp-value: 0.829995% CI: [-0.09, 0.11]ANCOVA
Comparison: 96 hoursp-value: 0.087895% CI: [-0.19, 0.01]ANCOVA
Comparison: 96 hoursp-value: 0.749895% CI: [-0.09, 0.12]ANCOVA
Comparison: 120 hoursp-value: 0.80395% CI: [-0.11, 0.09]ANCOVA
Comparison: 120 hoursp-value: 0.357795% CI: [-0.05, 0.15]ANCOVA
Secondary
Change From Baseline in Virus RNA (RT-PCR) at Each Time Point
Nasopharyngeal swabs (or throat swabs, if nasopharyngeal swabbing was not feasible) were obtained for viral quantitation. Virus RNA was measured by reverse transcription polymerase chain reaction (RT-PCR).
Time frame: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Population: Participants in the intention-to-treat infected population with positive RT-PCR on Day 1 and with available virus RNA data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 2 | -1.13 log₁₀ virus particles/mL | Standard Deviation 1.2 |
| Baloxavir Marboxil | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 6 | -3.33 log₁₀ virus particles/mL | Standard Deviation 1.48 |
| Baloxavir Marboxil | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 4 | -2.77 log₁₀ virus particles/mL | Standard Deviation 1.42 |
| Baloxavir Marboxil | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 5 | -3.09 log₁₀ virus particles/mL | Standard Deviation 1.58 |
| Baloxavir Marboxil | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 9 | -3.89 log₁₀ virus particles/mL | Standard Deviation 1.51 |
| Baloxavir Marboxil | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 3 | -2.09 log₁₀ virus particles/mL | Standard Deviation 1.45 |
| Placebo | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 4 | -2.09 log₁₀ virus particles/mL | Standard Deviation 1.84 |
| Placebo | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 5 | -2.77 log₁₀ virus particles/mL | Standard Deviation 1.67 |
| Placebo | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 2 | -0.62 log₁₀ virus particles/mL | Standard Deviation 1.34 |
| Placebo | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 3 | -1.57 log₁₀ virus particles/mL | Standard Deviation 1.66 |
| Placebo | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 6 | -3.19 log₁₀ virus particles/mL | Standard Deviation 1.77 |
| Placebo | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 9 | -3.78 log₁₀ virus particles/mL | Standard Deviation 1.65 |
| Oseltamivir | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 3 | -1.77 log₁₀ virus particles/mL | Standard Deviation 1.45 |
| Oseltamivir | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 9 | -3.99 log₁₀ virus particles/mL | Standard Deviation 1.39 |
| Oseltamivir | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 6 | -3.41 log₁₀ virus particles/mL | Standard Deviation 1.38 |
| Oseltamivir | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 2 | -0.76 log₁₀ virus particles/mL | Standard Deviation 1.18 |
| Oseltamivir | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 4 | -2.34 log₁₀ virus particles/mL | Standard Deviation 1.63 |
| Oseltamivir | Change From Baseline in Virus RNA (RT-PCR) at Each Time Point | Day 5 | -3.04 log₁₀ virus particles/mL | Standard Deviation 1.46 |
Comparison: Day 2p-value: <0.0001van Elteren test
Comparison: Day 2p-value: <0.0001van Elteren test
Comparison: Day 3p-value: <0.0001van Elteren test
Comparison: Day 3p-value: 0.0015van Elteren test
Comparison: Day 4p-value: 0.0028van Elteren test
Comparison: Day 4p-value: 0.0265van Elteren test
Comparison: Day 5p-value: 0.0247van Elteren test
Comparison: Day 5p-value: 0.5298van Elteren test
Comparison: Day 6p-value: 0.9554van Elteren test
Comparison: Day 6p-value: 0.9075van Elteren test
Comparison: Day 9p-value: 0.7624van Elteren test
Comparison: Day 9p-value: 0.6156van Elteren test
Secondary
Change From Baseline in Virus Titer at Each Time Point
Virus titer was quantified from nasopharyngeal swabs (or throat swabs if nasopharyngeal swabbing was not feasible) by tissue culture methods. If virus titer was less than the lower limit of quantification, the virus titer was imputed 0.7 (TCID₅₀/mL).
Time frame: Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Population: Participants in the intention-to-treat infected population with positive influenza virus titer on Day 1 and with available virus titer data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Baloxavir Marboxil | Change From Baseline in Virus Titer at Each Time Point | Day 2 | -3.36 log₁₀[TCID₅₀/mL] | Standard Deviation 2.21 |
| Baloxavir Marboxil | Change From Baseline in Virus Titer at Each Time Point | Day 3 | -3.92 log₁₀[TCID₅₀/mL] | Standard Deviation 2.22 |
| Baloxavir Marboxil | Change From Baseline in Virus Titer at Each Time Point | Day 4 | -3.99 log₁₀[TCID₅₀/mL] | Standard Deviation 2 |
| Baloxavir Marboxil | Change From Baseline in Virus Titer at Each Time Point | Day 5 | -4.32 log₁₀[TCID₅₀/mL] | Standard Deviation 2.16 |
| Baloxavir Marboxil | Change From Baseline in Virus Titer at Each Time Point | Day 6 | -4.07 log₁₀[TCID₅₀/mL] | Standard Deviation 2.05 |
| Baloxavir Marboxil | Change From Baseline in Virus Titer at Each Time Point | Day 9 | -4.53 log₁₀[TCID₅₀/mL] | Standard Deviation 2.11 |
| Placebo | Change From Baseline in Virus Titer at Each Time Point | Day 9 | -4.91 log₁₀[TCID₅₀/mL] | Standard Deviation 2.08 |
| Placebo | Change From Baseline in Virus Titer at Each Time Point | Day 2 | -1.25 log₁₀[TCID₅₀/mL] | Standard Deviation 2.27 |
| Placebo | Change From Baseline in Virus Titer at Each Time Point | Day 5 | -4.38 log₁₀[TCID₅₀/mL] | Standard Deviation 2.31 |
| Placebo | Change From Baseline in Virus Titer at Each Time Point | Day 6 | -4.68 log₁₀[TCID₅₀/mL] | Standard Deviation 2.22 |
| Placebo | Change From Baseline in Virus Titer at Each Time Point | Day 3 | -2.99 log₁₀[TCID₅₀/mL] | Standard Deviation 2.55 |
| Placebo | Change From Baseline in Virus Titer at Each Time Point | Day 4 | -3.79 log₁₀[TCID₅₀/mL] | Standard Deviation 2.75 |
| Oseltamivir | Change From Baseline in Virus Titer at Each Time Point | Day 3 | -3.26 log₁₀[TCID₅₀/mL] | Standard Deviation 2.5 |
| Oseltamivir | Change From Baseline in Virus Titer at Each Time Point | Day 4 | -3.75 log₁₀[TCID₅₀/mL] | Standard Deviation 2.26 |
| Oseltamivir | Change From Baseline in Virus Titer at Each Time Point | Day 9 | -4.78 log₁₀[TCID₅₀/mL] | Standard Deviation 2.07 |
| Oseltamivir | Change From Baseline in Virus Titer at Each Time Point | Day 5 | -4.41 log₁₀[TCID₅₀/mL] | Standard Deviation 2.12 |
| Oseltamivir | Change From Baseline in Virus Titer at Each Time Point | Day 2 | -1.76 log₁₀[TCID₅₀/mL] | Standard Deviation 2.2 |
| Oseltamivir | Change From Baseline in Virus Titer at Each Time Point | Day 6 | -4.39 log₁₀[TCID₅₀/mL] | Standard Deviation 1.97 |
Comparison: Day 2p-value: <0.0001van Elteren test
Comparison: Day 2p-value: <0.0001van Elteren test
Comparison: Day 3p-value: <0.0001van Elteren test
Comparison: Day 3p-value: 0.0024van Elteren test
Comparison: Day 4p-value: 0.9127ven Elteren test
Comparison: Day 4p-value: 0.5361van Elteren test
Comparison: Day 5p-value: 0.5739van Elteren test
Comparison: Day 5p-value: 0.5466van Elteren test
Comparison: Day 6p-value: 0.0543van Elteren test
Comparison: Day 6p-value: 0.4677van Elteren test
Comparison: Day 9p-value: 0.0266van Elteren test
Comparison: Day 9p-value: 0.1281van Elteren test
Secondary
Percentage of Participants Reporting Normal Temperature at Each Time Point
Defined as the percentage of patrticipants whose axillary body temperature dropped to less than 37ºC after the initiation of the study treatment.
Time frame: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the initial dose of study treatment
Population: Participants in the intention-to-treat infected population whose body temperature at baseline was more than 37°C and with available body temperature data at each time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants Reporting Normal Temperature at Each Time Point | 96 hours | 87.5 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Reporting Normal Temperature at Each Time Point | 192 hours | 89.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Reporting Normal Temperature at Each Time Point | 72 hours | 84.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Reporting Normal Temperature at Each Time Point | 24 hours | 51.1 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Reporting Normal Temperature at Each Time Point | 168 hours | 87.9 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Reporting Normal Temperature at Each Time Point | 144 hours | 90.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Reporting Normal Temperature at Each Time Point | 36 hours | 68.1 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Reporting Normal Temperature at Each Time Point | 216 hours | 89.1 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Reporting Normal Temperature at Each Time Point | 120 hours | 86.2 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Reporting Normal Temperature at Each Time Point | 48 hours | 77.4 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Reporting Normal Temperature at Each Time Point | 12 hours | 29.7 percentage of participants |
| Placebo | Percentage of Participants Reporting Normal Temperature at Each Time Point | 48 hours | 59.3 percentage of participants |
| Placebo | Percentage of Participants Reporting Normal Temperature at Each Time Point | 96 hours | 79.8 percentage of participants |
| Placebo | Percentage of Participants Reporting Normal Temperature at Each Time Point | 144 hours | 86.1 percentage of participants |
| Placebo | Percentage of Participants Reporting Normal Temperature at Each Time Point | 192 hours | 87.5 percentage of participants |
| Placebo | Percentage of Participants Reporting Normal Temperature at Each Time Point | 216 hours | 89.9 percentage of participants |
| Placebo | Percentage of Participants Reporting Normal Temperature at Each Time Point | 120 hours | 86.6 percentage of participants |
| Placebo | Percentage of Participants Reporting Normal Temperature at Each Time Point | 12 hours | 24.6 percentage of participants |
| Placebo | Percentage of Participants Reporting Normal Temperature at Each Time Point | 24 hours | 43.2 percentage of participants |
| Placebo | Percentage of Participants Reporting Normal Temperature at Each Time Point | 36 hours | 47.4 percentage of participants |
| Placebo | Percentage of Participants Reporting Normal Temperature at Each Time Point | 168 hours | 88.1 percentage of participants |
| Placebo | Percentage of Participants Reporting Normal Temperature at Each Time Point | 72 hours | 71.7 percentage of participants |
| Oseltamivir | Percentage of Participants Reporting Normal Temperature at Each Time Point | 216 hours | 89.6 percentage of participants |
| Oseltamivir | Percentage of Participants Reporting Normal Temperature at Each Time Point | 48 hours | 76.4 percentage of participants |
| Oseltamivir | Percentage of Participants Reporting Normal Temperature at Each Time Point | 120 hours | 88.4 percentage of participants |
| Oseltamivir | Percentage of Participants Reporting Normal Temperature at Each Time Point | 168 hours | 87.7 percentage of participants |
| Oseltamivir | Percentage of Participants Reporting Normal Temperature at Each Time Point | 192 hours | 90.5 percentage of participants |
| Oseltamivir | Percentage of Participants Reporting Normal Temperature at Each Time Point | 12 hours | 25.9 percentage of participants |
| Oseltamivir | Percentage of Participants Reporting Normal Temperature at Each Time Point | 24 hours | 54.3 percentage of participants |
| Oseltamivir | Percentage of Participants Reporting Normal Temperature at Each Time Point | 36 hours | 64.1 percentage of participants |
| Oseltamivir | Percentage of Participants Reporting Normal Temperature at Each Time Point | 72 hours | 82.6 percentage of participants |
| Oseltamivir | Percentage of Participants Reporting Normal Temperature at Each Time Point | 96 hours | 85.8 percentage of participants |
| Oseltamivir | Percentage of Participants Reporting Normal Temperature at Each Time Point | 144 hours | 87.4 percentage of participants |
Comparison: 12 hoursp-value: 0.1713Mantel Haenszel
Comparison: 12 hoursp-value: 0.2249Mantel Haenszel
Comparison: 24 hoursp-value: 0.0387Mantel Haenszel
Comparison: 24 hoursp-value: 0.3915Mantel Haenszel
Comparison: 36 hoursp-value: <0.0001Mantel Haenszel
Comparison: 36 hoursp-value: 0.2617Mantel Haenszel
Comparison: 48 hoursp-value: <0.0001Mantel Haenszel
Comparison: 48 hoursp-value: 0.8808Mantel Haenszel
Comparison: 72 hoursp-value: 0.0001Mantel Haenszel
Comparison: 72 hoursp-value: 0.5923Mantel Haenszel
Comparison: 96 hoursp-value: 0.0064Mantel Haenszel
Comparison: 96 hoursp-value: 0.6746Mantel Haenszel
Comparison: 120 hoursp-value: 0.8167Mantel Haenszel
Comparison: 120 hoursp-value: 0.3773Mantel Haenszel
Comparison: 144 hoursp-value: 0.1041Mantel Haenszel
Comparison: 144 hoursp-value: 0.3328Mantel Haenszel
Comparison: 168 hoursp-value: 0.7867Mantel Haenszel
Comparison: 168 hoursp-value: 0.864Mantel Haenszel
Comparison: 192 hoursp-value: 0.6465Mantel Haenszel
Comparison: 192 hoursp-value: 0.4265Mantel Haenszel
Comparison: 216 hoursp-value: 0.6568Mantel Haenszel
Comparison: 216 hoursp-value: 0.6102Mantel Haenszel
Secondary
Percentage of Participants Requiring Systemic Antibiotics for Infections Secondary to Influenza Infection
The percentage of participants who received systemic antibiotics for any of the predefined complications (sinusitis, otitis media, bronchitis and pneumonia).
Time frame: Day 2 to Day 22
Population: Intention-to-treat infected population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Baloxavir Marboxil | Percentage of Participants Requiring Systemic Antibiotics for Infections Secondary to Influenza Infection | 3.4 percentage of participants |
| Placebo | Percentage of Participants Requiring Systemic Antibiotics for Infections Secondary to Influenza Infection | 7.5 percentage of participants |
| Oseltamivir | Percentage of Participants Requiring Systemic Antibiotics for Infections Secondary to Influenza Infection | 3.9 percentage of participants |
p-value: 0.0112Fisher Exact
p-value: 0.8478Fisher Exact
Secondary
Percentage of Participants Whose Symptoms Were Improved at Each Time Point
Participants assessed the severity of 7 influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (0 = no symptoms, 1= mild, 2 = moderate, and 3 = severe). Improvement of symptoms was defined as all influenza symptoms alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: * Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) judged to be worse at baseline must have improved at least 1 point from baseline severity * Preexisting symptoms judged not to be worse at baseline must have maintained baseline severity * New symptoms at baseline must have alleviated, defined as a symptom score of none (0) or mild (1).
Time frame: 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the initial dose of study treatment
Population: Participants in the intention-to-treat infected population with available symptoms data at each time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 48 hours | 38.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 168 hours | 80.1 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 216 hours | 85.8 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 192 hours | 83.6 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 36 hours | 33.9 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 24 hours | 18.8 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 120 hours | 72.3 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 72 hours | 56.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 12 hours | 9.1 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 144 hours | 78.1 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 96 hours | 65.9 percentage of participants |
| Placebo | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 168 hours | 72.7 percentage of participants |
| Placebo | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 96 hours | 53.4 percentage of participants |
| Placebo | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 120 hours | 64.6 percentage of participants |
| Placebo | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 144 hours | 69.6 percentage of participants |
| Placebo | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 192 hours | 78.0 percentage of participants |
| Placebo | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 216 hours | 78.7 percentage of participants |
| Placebo | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 48 hours | 28.8 percentage of participants |
| Placebo | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 12 hours | 8.6 percentage of participants |
| Placebo | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 24 hours | 14.2 percentage of participants |
| Placebo | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 36 hours | 21.1 percentage of participants |
| Placebo | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 72 hours | 41.8 percentage of participants |
| Oseltamivir | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 24 hours | 19.6 percentage of participants |
| Oseltamivir | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 120 hours | 72.4 percentage of participants |
| Oseltamivir | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 72 hours | 56.0 percentage of participants |
| Oseltamivir | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 12 hours | 8.1 percentage of participants |
| Oseltamivir | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 96 hours | 61.1 percentage of participants |
| Oseltamivir | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 192 hours | 85.6 percentage of participants |
| Oseltamivir | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 168 hours | 79.6 percentage of participants |
| Oseltamivir | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 48 hours | 39.9 percentage of participants |
| Oseltamivir | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 216 hours | 88.2 percentage of participants |
| Oseltamivir | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 36 hours | 31.0 percentage of participants |
| Oseltamivir | Percentage of Participants Whose Symptoms Were Improved at Each Time Point | 144 hours | 77.6 percentage of participants |
Comparison: 12 hoursp-value: 0.7698Mantel Haenszel
Comparison: 12 hoursp-value: 0.5777Mantel Haenszel
Comparison: 24 hoursp-value: 0.1112Mantel Haenszel
Comparison: 24 hoursp-value: 0.6483Mantel Haenszel
Comparison: 36 hoursp-value: 0.0004Mantel Haenszel
Comparison: 36 hoursp-value: 0.5625Mantel Haenszel
Comparison: 48 hoursp-value: 0.0072Mantel Haenszel
Comparison: 48 hoursp-value: 0.6234Mantel Haenszel
Comparison: 72 hoursp-value: 0.0002Mantel Haenszel
Comparison: 72 hoursp-value: 0.9547Mantel Haenszel
Comparison: 96 hoursp-value: 0.0012Mantel Haenszel
Comparison: 96 hoursp-value: 0.186Mantel Haenszel
Comparison: 120 hoursp-value: 0.0274Mantel Haenszel
Comparison: 120 hoursp-value: 0.9635Mantel Haenszel
Comparison: 144 hoursp-value: 0.0081Mantel Haenszel
Comparison: 144 hoursp-value: 0.7425Mantel Haenszel
Comparison: 168 hoursp-value: 0.0209Mantel Haenszel
Comparison: 168 hoursp-value: 0.7448Mantel Haenszel
Comparison: 192 hoursp-value: 0.0644Mantel Haenszel
Comparison: 192 hoursp-value: 0.4931Mantel Haenszel
Comparison: 216 hoursp-value: 0.0708Mantel Haenszel
Comparison: 216 hoursp-value: 0.4024Mantel Haenszel
Secondary
Percentage of Participants With Adverse Events (AEs)
Time frame: From first dose of study drug to Day 22
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants With Adverse Events (AEs) | Serious adverse events | 0.7 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Adverse Events (AEs) | Any adverse event (AE) | 25.1 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Adverse Events (AEs) | AEs leading to withdrawal of study drug | 0.7 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Adverse Events (AEs) | TRAEs leading to withdrawal of study drug | 0.3 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Adverse Events (AEs) | Fatal adverse events | 0.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Adverse Events (AEs) | Treatment-related serious adverse events | 0.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Adverse Events (AEs) | Treatment-related adverse events (TRAEs) | 5.6 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Adverse Events (AEs) | Fatal treatment-related adverse events | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Serious adverse events | 1.2 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Any adverse event (AE) | 29.7 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Treatment-related serious adverse events | 0.3 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | TRAEs leading to withdrawal of study drug | 0.3 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Fatal treatment-related adverse events | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | AEs leading to withdrawal of study drug | 0.7 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Treatment-related adverse events (TRAEs) | 8.3 percentage of participants |
| Placebo | Percentage of Participants With Adverse Events (AEs) | Fatal adverse events | 0.0 percentage of participants |
| Oseltamivir | Percentage of Participants With Adverse Events (AEs) | TRAEs leading to withdrawal of study drug | 0.4 percentage of participants |
| Oseltamivir | Percentage of Participants With Adverse Events (AEs) | Any adverse event (AE) | 28.0 percentage of participants |
| Oseltamivir | Percentage of Participants With Adverse Events (AEs) | Fatal adverse events | 0.1 percentage of participants |
| Oseltamivir | Percentage of Participants With Adverse Events (AEs) | Serious adverse events | 1.1 percentage of participants |
| Oseltamivir | Percentage of Participants With Adverse Events (AEs) | AEs leading to withdrawal of study drug | 0.6 percentage of participants |
| Oseltamivir | Percentage of Participants With Adverse Events (AEs) | Treatment-related adverse events (TRAEs) | 7.9 percentage of participants |
| Oseltamivir | Percentage of Participants With Adverse Events (AEs) | Fatal treatment-related adverse events | 0.0 percentage of participants |
| Oseltamivir | Percentage of Participants With Adverse Events (AEs) | Treatment-related serious adverse events | 0.3 percentage of participants |
Secondary
Percentage of Participants With Influenza-related Complications
Defined as the percentage of patients who experience each influenza-related complication (hospitalization, death, sinusitis, otitis media, bronchitis, and radiologically-confirmed pneumonia) as an adverse event after the initiation of study treatment.
Time frame: Day 1 to Day 22
Population: Intention-to-treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants With Influenza-related Complications | Death | 0.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Influenza-related Complications | Otitis media | 0.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Influenza-related Complications | Sinusitis | 0.3 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Influenza-related Complications | Any Complications | 2.8 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Influenza-related Complications | Pneumonia | 0.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Influenza-related Complications | Bronchitis | 1.8 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Influenza-related Complications | Hospitalization | 0.8 percentage of participants |
| Placebo | Percentage of Participants With Influenza-related Complications | Sinusitis | 2.1 percentage of participants |
| Placebo | Percentage of Participants With Influenza-related Complications | Any Complications | 10.4 percentage of participants |
| Placebo | Percentage of Participants With Influenza-related Complications | Death | 0.0 percentage of participants |
| Placebo | Percentage of Participants With Influenza-related Complications | Hospitalization | 1.3 percentage of participants |
| Placebo | Percentage of Participants With Influenza-related Complications | Otitis media | 0.8 percentage of participants |
| Placebo | Percentage of Participants With Influenza-related Complications | Bronchitis | 6.0 percentage of participants |
| Placebo | Percentage of Participants With Influenza-related Complications | Pneumonia | 0.8 percentage of participants |
| Oseltamivir | Percentage of Participants With Influenza-related Complications | Otitis media | 0.3 percentage of participants |
| Oseltamivir | Percentage of Participants With Influenza-related Complications | Death | 0.3 percentage of participants |
| Oseltamivir | Percentage of Participants With Influenza-related Complications | Pneumonia | 0.5 percentage of participants |
| Oseltamivir | Percentage of Participants With Influenza-related Complications | Bronchitis | 2.3 percentage of participants |
| Oseltamivir | Percentage of Participants With Influenza-related Complications | Sinusitis | 0.5 percentage of participants |
| Oseltamivir | Percentage of Participants With Influenza-related Complications | Hospitalization | 1.0 percentage of participants |
| Oseltamivir | Percentage of Participants With Influenza-related Complications | Any Complications | 4.6 percentage of participants |
Comparison: Any Complicationsp-value: <0.0001Fisher Exact
Comparison: Any Complicationsp-value: 0.2558Fisher Exact
Secondary
Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point
Influenza virus ribonucleic acid (RNA) was quantified from nasopharyngeal swabs (or throat swabs, if nasopharyngeal swabbing was not feasible). The percentage of participants with detectable virus RNA (2.05 for flu A and 2.83 for flu B log₁₀ virus particles/mL) measured by reverse transcription polymerase chain reaction (RT-PCR) among those assessed on Days 2, 3, 4, 5, 6 and 9.
Time frame: Days 2, 3, 4 (optional), 5, 6 (optional), and 9.
Population: Participants in the intention-to-treat infected population with positive influenza virus RNA determined by RT-PCR on Day 1 and with available data at each time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 6 | 71.8 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 2 | 96.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 9 | 54.5 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 3 | 92.5 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 4 | 86.5 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 5 | 84.9 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 3 | 95.4 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 9 | 64.9 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 5 | 88.6 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 4 | 91.0 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 2 | 96.3 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 6 | 78.0 percentage of participants |
| Oseltamivir | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 2 | 96.0 percentage of participants |
| Oseltamivir | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 6 | 71.8 percentage of participants |
| Oseltamivir | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 4 | 86.4 percentage of participants |
| Oseltamivir | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 3 | 95.1 percentage of participants |
| Oseltamivir | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 5 | 86.1 percentage of participants |
| Oseltamivir | Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point | Day 9 | 57.7 percentage of participants |
Comparison: Day 2p-value: 0.7383Mantel Haenszel
Comparison: Day 2p-value: 0.9619Mantel Haenszel
Comparison: Day 3p-value: 0.0576Mantel Haenszel
Comparison: Day 3p-value: 0.1237Mantel Haenszel
Comparison: Day 4p-value: 0.3071Mantel Haenszel
Comparison: Day 4p-value: 0.9603Mantel Haenszel
Comparison: Day 5p-value: 0.0784Mantel Haenszel
Comparison: Day 5p-value: 0.5547Mantel Haenszel
Comparison: Day 6p-value: 0.3087Mantel Haenszel
Comparison: Day 6p-value: 0.9106Mantel Haenszel
Comparison: Day 9p-value: 0.0017Mantel Haenszel
Comparison: Day 9p-value: 0.3068Mantel Haenszel
Secondary
Percentage of Participants With Positive Influenza Virus Titer at Each Time Point
Virus titer was quantified from nasopharyngeal swabs (or throat swabs if nasopharyngeal swabbing was not feasible) using tissue culture methods. Positive influenza virus titer was defined as virus titer not less than the lower limit of quantification (0.7 log₁₀ of the 50% tissue culture infective dose (TCID₅₀/mL) among those assessed for virus titer on Days 2, 3, 4, 5, 6, and 9.
Time frame: Days 2, 3, 4 (optional), 5, 6 (optional), and 9
Population: Participants in the intention-to-treat infected population with a positive influenza virus titer on Day 1 and with available virus titer data at each time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 2 | 58.6 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 3 | 31.7 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 4 | 18.5 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 5 | 16.0 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 6 | 4.3 percentage of participants |
| Baloxavir Marboxil | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 9 | 2.8 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 9 | 5.3 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 2 | 86.9 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 5 | 30.7 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 6 | 16.0 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 3 | 72.7 percentage of participants |
| Placebo | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 4 | 50.0 percentage of participants |
| Oseltamivir | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 3 | 60.0 percentage of participants |
| Oseltamivir | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 4 | 33.1 percentage of participants |
| Oseltamivir | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 9 | 0.9 percentage of participants |
| Oseltamivir | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 5 | 20.4 percentage of participants |
| Oseltamivir | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 2 | 86.9 percentage of participants |
| Oseltamivir | Percentage of Participants With Positive Influenza Virus Titer at Each Time Point | Day 6 | 11.4 percentage of participants |
Comparison: Day 2p-value: <0.0001Mantel Haenszel
Comparison: Day 2p-value: <0.0001Mantel Haenszel
Comparison: Day 3p-value: <0.0001Mantel Haenszel
Comparison: Day 3p-value: <0.0001Mantel Haenszel
Comparison: Day 4p-value: <0.0001Mantel Haenszel
Comparison: Day 4p-value: 0.0044Mantel Haenszel
Comparison: Day 5p-value: <0.0001Mantel Haenszel
Comparison: Day 5p-value: 0.1146Mantel Haenszel
Comparison: Day 6p-value: 0.0046Mantel Haenszel
Comparison: Day 6p-value: 0.441Mantel Haenszel
Comparison: Day 9p-value: 0.0929Mantel Haenszel
Comparison: Day 9p-value: 0.0907Mantel Haenszel
Secondary
Time to Alleviation of Symptoms
Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms). Time to alleviation of symptoms was defined as the time from the start of the study treatment to the time when all seven influenza-related symptoms were assessed by the participant as absent (0) or mild (1) for at least 21.5 hours. Time to alleviation of symptoms was analyzed using Kaplan-Meier (KM) methods; participants who did not experience alleviation of symptoms were censored at the last observation time point.
Time frame: Initiation of study treatment up to Day 14
Population: Participants in the intention-to-treat infected population with available time to alleviation of symptoms data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Alleviation of Symptoms | 77.0 hours |
| Placebo | Time to Alleviation of Symptoms | 102.8 hours |
| Oseltamivir | Time to Alleviation of Symptoms | 85.6 hours |
p-value: <0.0001Generalized Wilcoxon test
p-value: 0.9127Generalized Wilcoxon test
Secondary
Time to Cessation of Viral Shedding Determined by Virus RNA
Time to cessation of viral shedding by RT-PCR was defined as the time between the initiation of the study treatment and first time when the virus RNA was below the limit of detection measured by RT-PCR. Time to cessation of viral shedding by RT-PCR was analyzed using the KM method; participants whose virus RNA had not reached cessation by the last observation time point were treated as censored at that time point.
Time frame: Day 1 to Day 9
Population: Participants in the intention-to-treat infected population with positive influenza virus RNA determined by RT-PCR on Day 1 whose time to cessation of viral shedding by RT-PCR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Cessation of Viral Shedding Determined by Virus RNA | 216.0 hours |
| Placebo | Time to Cessation of Viral Shedding Determined by Virus RNA | 240.0 hours |
| Oseltamivir | Time to Cessation of Viral Shedding Determined by Virus RNA | 216.0 hours |
p-value: 0.000695% CI: [-96, 0]Generalized Wilcoxon test
p-value: 0.23795% CI: [-48, 24]Generalized Wilcoxon test
Secondary
Time to Cessation of Viral Shedding Determined by Virus Titer
Time to cessation of viral shedding by virus titer was defined as the time between the initiation of the study treatment and first time when the virus titer was below the limit of detection (0.7 log₁₀\[TCID₅₀/mL\]). The median and 95% confidence interval (CI) for time to cessation of viral shedding determined by virus titer was analyzed using the Kaplan-Meier (KM) method; participants whose virus titer had not reached cessation by the last observation time point were treated as censored at that time point.
Time frame: Day 1 to Day 9
Population: Participants in the intention-to-treat infected population with a positive virus titer on Day 1 whose time to cessation of viral shedding by virus titer was not missing.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Cessation of Viral Shedding Determined by Virus Titer | 48.0 hours |
| Placebo | Time to Cessation of Viral Shedding Determined by Virus Titer | 96.0 hours |
| Oseltamivir | Time to Cessation of Viral Shedding Determined by Virus Titer | 96.0 hours |
p-value: <0.000195% CI: [-48, -48]Generalized Wilcoxon test
p-value: <0.000195% CI: [-48, -24]Generalized Wilcoxon test
Secondary
Time to Improvement of Individual Symptoms
Participants assessed the severity of 7 influenza-associated symptoms on a 4-point scale (0 = no symptoms to 3 = severe). Time to improvement of cough, fatigue, and muscle/joint pain was defined as the time from the start of treatment to the time when each symptom was alleviated, maintained, or improved, as defined below, for at least 21.5 hours: * Preexisting symptoms that were worse at baseline must have improved at least 1 point from baseline * Preexisting symptoms not worse at baseline must have maintained baseline severity * New symptoms must have alleviated, defined as a score of 0 (None) or 1 (Mild). Time to improvement of sore throat, headache, nasal congestion, and feverish/chills was defined as the time from the start of treatment to the time when the symptom was assessed as 0 (None) or 1 (Mild) for at least 21.5 hours. Time to improvement of symptoms was analyzed using KM methods; participants with no improvement of symptoms were censored at the last observation.
Time frame: Initiation of study treatment up to Day 14
Population: Participants in the intention-to-treat infected population; the analysis of each individual symptom includes participants with new or preexisting and worsened symptom scores of moderate (2) or severe (3) at baseline, and with available time to improvement of symptom data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Baloxavir Marboxil | Time to Improvement of Individual Symptoms | Cough | 47.3 hours |
| Baloxavir Marboxil | Time to Improvement of Individual Symptoms | Muscle or Joint Pain | 37.2 hours |
| Baloxavir Marboxil | Time to Improvement of Individual Symptoms | Headache | 33.4 hours |
| Baloxavir Marboxil | Time to Improvement of Individual Symptoms | Fatigue | 41.3 hours |
| Baloxavir Marboxil | Time to Improvement of Individual Symptoms | Nasal Congestion | 45.6 hours |
| Baloxavir Marboxil | Time to Improvement of Individual Symptoms | Sore Throat | 40.2 hours |
| Baloxavir Marboxil | Time to Improvement of Individual Symptoms | Feverishness or Chills | 28.3 hours |
| Placebo | Time to Improvement of Individual Symptoms | Cough | 70.4 hours |
| Placebo | Time to Improvement of Individual Symptoms | Sore Throat | 46.5 hours |
| Placebo | Time to Improvement of Individual Symptoms | Nasal Congestion | 57.7 hours |
| Placebo | Time to Improvement of Individual Symptoms | Headache | 43.9 hours |
| Placebo | Time to Improvement of Individual Symptoms | Feverishness or Chills | 31.9 hours |
| Placebo | Time to Improvement of Individual Symptoms | Muscle or Joint Pain | 44.9 hours |
| Placebo | Time to Improvement of Individual Symptoms | Fatigue | 48.8 hours |
| Oseltamivir | Time to Improvement of Individual Symptoms | Feverishness or Chills | 29.1 hours |
| Oseltamivir | Time to Improvement of Individual Symptoms | Cough | 47.5 hours |
| Oseltamivir | Time to Improvement of Individual Symptoms | Fatigue | 43.2 hours |
| Oseltamivir | Time to Improvement of Individual Symptoms | Sore Throat | 39.3 hours |
| Oseltamivir | Time to Improvement of Individual Symptoms | Muscle or Joint Pain | 33.2 hours |
| Oseltamivir | Time to Improvement of Individual Symptoms | Nasal Congestion | 44.0 hours |
| Oseltamivir | Time to Improvement of Individual Symptoms | Headache | 31.3 hours |
Comparison: Coughp-value: 0.0009Generalized Wilcoxon test
Comparison: Coughp-value: 0.4074Generalized Wilcoxon test
Comparison: Sore Throatp-value: 0.2496Generalized Wilcoxon test
Comparison: Sore Throatp-value: 0.2963Generalized Wilcoxon test
Comparison: Headachep-value: 0.039Generalized Wilcoxon test
Comparison: Headachep-value: 0.7877Generalized Wilcoxon test
Comparison: Nasal Congestionp-value: 0.0017Generalized Wilcoxon test
Comparison: Nasal Congestionp-value: 0.8119Generalized Wilcoxon test
Comparison: Feverishness or Chillsp-value: 0.007Generalized Wilcoxon test
Comparison: Feverishness or Chillsp-value: 0.9191Generalized Wilcoxon test
Comparison: Muscle or Joint Painp-value: 0.0232Generalized Wilcoxon test
Comparison: Muscle or Joint Painp-value: 0.5436Generalized Wilcoxon test
Comparison: Fatiguep-value: 0.0207Generalized Wilcoxon test
Comparison: Fatiguep-value: 0.371Generalized Wilcoxon test
Secondary
Time to Improvement of the Four Systemic Symptoms
Participants assessed the severity of 7 influenza-associated symptoms on a 4-point scale (from 0 = no symptoms to 3 = severe symptoms). Time to improvement of the 4 systemic symptoms was defined as the time between the initiation of study treatment to the time when all 4 systemic symptoms (headache, feverishness or chills, muscle or joint pain, and fatigue) were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: * Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline * Preexisting symptoms not worse at baseline must have maintained baseline severity * New symptoms at baseline must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of the 4 systemic symptoms was analyzed using KM methods; participants who did not experience improvement of symptoms were censored at the last observation.
Time frame: Initiation of study treatment up to Day 14
Population: Participants in the intention-to-treat infected population with available time to improvement of the 4 systemic symptoms data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Improvement of the Four Systemic Symptoms | 51.7 hours |
| Placebo | Time to Improvement of the Four Systemic Symptoms | 66.8 hours |
| Oseltamivir | Time to Improvement of the Four Systemic Symptoms | 49.4 hours |
p-value: 0.0013Generalized Wilcoxon test
p-value: 0.8498Generalized Wilcoxon test
Secondary
Time to Improvement of the Three Respiratory Symptoms
Participants assessed the severity of 7 influenza-associated symptoms on a 4-point scale (from 0 = no symptoms to 3 = severe symptoms). Time to improvement of the 3 respiratory symptoms was defined as the time from the start of study treatment to the time when all 3 respiratory symptoms (cough, sore throat, and nasal congestion) were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: * Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline * Preexisting symptoms not worse at baseline must have maintained baseline severity * New symptoms at baseline must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of the 3 respiratory symptoms was analyzed using KM methods; participants who did not experience improvement of symptoms were censored at the last observation time point.
Time frame: Initiation of study treatment up to Day 14
Population: Participants in the intention-to-treat infected population with available time to improvement of the 3 respiratory symptoms data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Improvement of the Three Respiratory Symptoms | 63.6 hours |
| Placebo | Time to Improvement of the Three Respiratory Symptoms | 87.8 hours |
| Oseltamivir | Time to Improvement of the Three Respiratory Symptoms | 62.1 hours |
p-value: 0.0001Generalized Wilcoxon test
p-value: 0.9237Generalized Wilcoxon test
Secondary
Time to Resolution of Fever
Time to resolution of fever was defined as the time between the initiation of the study treatment and the resolution of fever. The resolution of fever was defined as the time when the participant's self-measured axillary temperature became less than 37ºC and was maintained at less than 37ºC for at least 12 hours. Time to resolution of fever was analyzed using KM methods; participants who did not experience resolution of fever by the last observation time point were censored at that time point.
Time frame: Initiation of study treatment up to Day 14
Population: Participants in the intention-to-treat infected population whose body temperature at baseline was more than 37°C and time to resolution of fever was not missing
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Resolution of Fever | 30.8 hours |
| Placebo | Time to Resolution of Fever | 50.7 hours |
| Oseltamivir | Time to Resolution of Fever | 34.3 hours |
p-value: <0.000195% CI: [-28.8, -12.5]Generalized Wilcoxon test
p-value: 0.242595% CI: [-9.1, 2.7]Generalized Wilcoxon test
Secondary
Time to Return to Preinfluenza Health Status
Participants were asked to record their preinfluenza health status on a scale from 0 (worst possible health) to 10 (normal health \[for someone your age and condition\]), and their health status at baseline and every day after initiation of study treatment on the same scale. Return to preinfluenza health status was defined as time from the initiation of the study treatment to the first time when the health status score was equal to or higher than the preinfluenza health status score. Time to return to preinfluenza health status was analyzed using KM methods; participants with a smaller number on the scale for health status by the last observation time point were censored at that time point.
Time frame: Baseline to Day 14
Population: Participants in the intention-to-treat infected population whose health status score at baseline was lower than the preinfluenza health status score and with available time to return to preinfluenza health status data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baloxavir Marboxil | Time to Return to Preinfluenza Health Status | 126.4 hours |
| Placebo | Time to Return to Preinfluenza Health Status | 149.8 hours |
| Oseltamivir | Time to Return to Preinfluenza Health Status | 126.9 hours |
p-value: 0.4634Generalized Wilcoxon test
p-value: 0.6386Generalized Wilcoxon test