Trial Outcomes & Findings for Study of S-033188 (Baloxavir Marboxil) Compared With Placebo or Oseltamivir in Patients With Influenza at High Risk of Influenza Complications (NCT NCT02949011)

Last Updated: 2019-11-19

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2184 participants

Primary outcome timeframe

From Day 1 pretreatment up to Day 14

Results posted on

2019-11-19

Participant Flow

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.

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).

Participant milestones

Participant milestones
Measure	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.	Placebo Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Overall Study STARTED	730	729	725
Overall Study Received Study Drug	728	728	722
Overall Study Intention to Treat Infected Population	388	386	389
Overall Study COMPLETED	697	695	683
Overall Study NOT COMPLETED	33	34	42

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	Placebo Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Overall Study Adverse Event	6	7	3
Overall Study Failed Inclusion/Exclusion Criteria	0	0	3
Overall Study Protocol Deviation	5	3	3
Overall Study Lack of Efficacy	0	2	0
Overall Study Withdrawal by Subject	13	13	21
Overall Study Lost to Follow-up	7	5	5
Overall Study Death	0	0	1
Overall Study Miscellaneous	2	4	6

Baseline Characteristics

Participants with available virus titer data

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Baloxavir Marboxil n=388 Participants 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.	Placebo n=386 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=389 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.	Total n=1163 Participants Total of all reporting groups
Age, Continuous	52.3 years STANDARD_DEVIATION 16.8 • n=388 Participants	51.9 years STANDARD_DEVIATION 16.7 • n=386 Participants	51.1 years STANDARD_DEVIATION 17.0 • n=389 Participants	51.8 years STANDARD_DEVIATION 16.8 • n=1163 Participants
Age, Customized ≥ 12 to ≤ 19 years	19 Participants n=388 Participants	17 Participants n=386 Participants	22 Participants n=389 Participants	58 Participants n=1163 Participants
Age, Customized ≥ 20 to ≤ 29 years	29 Participants n=388 Participants	22 Participants n=386 Participants	27 Participants n=389 Participants	78 Participants n=1163 Participants
Age, Customized ≥ 30 to ≤ 39 years	42 Participants n=388 Participants	58 Participants n=386 Participants	44 Participants n=389 Participants	144 Participants n=1163 Participants
Age, Customized ≥ 40 to ≤ 49 years	63 Participants n=388 Participants	55 Participants n=386 Participants	75 Participants n=389 Participants	193 Participants n=1163 Participants
Age, Customized ≥ 50 to ≤ 59 years	83 Participants n=388 Participants	101 Participants n=386 Participants	83 Participants n=389 Participants	267 Participants n=1163 Participants
Age, Customized ≥ 60 to ≤ 64 years	39 Participants n=388 Participants	30 Participants n=386 Participants	35 Participants n=389 Participants	104 Participants n=1163 Participants
Age, Customized ≥ 65 to ≤ 74 years	85 Participants n=388 Participants	76 Participants n=386 Participants	78 Participants n=389 Participants	239 Participants n=1163 Participants
Age, Customized ≥ 75 years	28 Participants n=388 Participants	27 Participants n=386 Participants	25 Participants n=389 Participants	80 Participants n=1163 Participants
Sex: Female, Male Female	195 Participants n=388 Participants	206 Participants n=386 Participants	198 Participants n=389 Participants	599 Participants n=1163 Participants
Sex: Female, Male Male	193 Participants n=388 Participants	180 Participants n=386 Participants	191 Participants n=389 Participants	564 Participants n=1163 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	62 Participants n=388 Participants	59 Participants n=386 Participants	56 Participants n=389 Participants	177 Participants n=1163 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	325 Participants n=388 Participants	327 Participants n=386 Participants	331 Participants n=389 Participants	983 Participants n=1163 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=388 Participants	0 Participants n=386 Participants	2 Participants n=389 Participants	3 Participants n=1163 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=388 Participants	2 Participants n=386 Participants	3 Participants n=389 Participants	6 Participants n=1163 Participants
Race/Ethnicity, Customized Asian	167 Participants n=388 Participants	157 Participants n=386 Participants	163 Participants n=389 Participants	487 Participants n=1163 Participants
Race/Ethnicity, Customized Black or African American	39 Participants n=388 Participants	30 Participants n=386 Participants	29 Participants n=389 Participants	98 Participants n=1163 Participants
Race/Ethnicity, Customized White	178 Participants n=388 Participants	194 Participants n=386 Participants	188 Participants n=389 Participants	560 Participants n=1163 Participants
Race/Ethnicity, Customized Other	3 Participants n=388 Participants	3 Participants n=386 Participants	6 Participants n=389 Participants	12 Participants n=1163 Participants
Weight < 80 kg	239 Participants n=388 Participants	232 Participants n=386 Participants	233 Participants n=389 Participants	704 Participants n=1163 Participants
Weight ≥ 80 kg	149 Participants n=388 Participants	154 Participants n=386 Participants	156 Participants n=389 Participants	459 Participants n=1163 Participants
Time to Treatment From Influenza Onset ≥ 0 to ≤ 12 hours	27 Participants n=388 Participants	42 Participants n=386 Participants	37 Participants n=389 Participants	106 Participants n=1163 Participants
Time to Treatment From Influenza Onset > 12 to ≤ 24 hours	151 Participants n=388 Participants	150 Participants n=386 Participants	119 Participants n=389 Participants	420 Participants n=1163 Participants
Time to Treatment From Influenza Onset > 24 to ≤ 36 hours	114 Participants n=388 Participants	120 Participants n=386 Participants	141 Participants n=389 Participants	375 Participants n=1163 Participants
Time to Treatment From Influenza Onset > 36 to ≤ 48 hours	95 Participants n=388 Participants	74 Participants n=386 Participants	92 Participants n=389 Participants	261 Participants n=1163 Participants
Time to Treatment From Influenza Onset Missing	1 Participants n=388 Participants	0 Participants n=386 Participants	0 Participants n=389 Participants	1 Participants n=1163 Participants
Influenza Virus Subtype Based on RT-PCR Assay A/H1N1pdm	28 Participants n=388 Participants	17 Participants n=386 Participants	35 Participants n=389 Participants	80 Participants n=1163 Participants
Influenza Virus Subtype Based on RT-PCR Assay A/H3	182 Participants n=388 Participants	185 Participants n=386 Participants	190 Participants n=389 Participants	557 Participants n=1163 Participants
Influenza Virus Subtype Based on RT-PCR Assay B	167 Participants n=388 Participants	168 Participants n=386 Participants	149 Participants n=389 Participants	484 Participants n=1163 Participants
Influenza Virus Subtype Based on RT-PCR Assay Mixed infection	4 Participants n=388 Participants	5 Participants n=386 Participants	5 Participants n=389 Participants	14 Participants n=1163 Participants
Influenza Virus Subtype Based on RT-PCR Assay Other	7 Participants n=388 Participants	11 Participants n=386 Participants	10 Participants n=389 Participants	28 Participants n=1163 Participants
Influenza Virus Titer	4.96 log₁₀[TCID₅₀/mL] STANDARD_DEVIATION 2.28 • n=378 Participants • Participants with available virus titer data	5.27 log₁₀[TCID₅₀/mL] STANDARD_DEVIATION 2.39 • n=377 Participants • Participants with available virus titer data	5.25 log₁₀[TCID₅₀/mL] STANDARD_DEVIATION 2.27 • n=380 Participants • Participants with available virus titer data	5.16 log₁₀[TCID₅₀/mL] STANDARD_DEVIATION 2.32 • n=1135 Participants • Participants with available virus titer data
Influenza Virus Ribonucleic Acid (RNA) Load	6.72 log₁₀ virus particles/mL STANDARD_DEVIATION 1.43 • n=385 Participants • Participants with available influenza virus RNA data	6.87 log₁₀ virus particles/mL STANDARD_DEVIATION 1.54 • n=378 Participants • Participants with available influenza virus RNA data	6.81 log₁₀ virus particles/mL STANDARD_DEVIATION 1.37 • n=387 Participants • Participants with available influenza virus RNA data	6.80 log₁₀ virus particles/mL STANDARD_DEVIATION 1.45 • n=1150 Participants • Participants with available influenza virus RNA data
Region Asia	159 Participants n=388 Participants	151 Participants n=386 Participants	152 Participants n=389 Participants	462 Participants n=1163 Participants
Region North America/Europe	212 Participants n=388 Participants	216 Participants n=386 Participants	220 Participants n=389 Participants	648 Participants n=1163 Participants
Region Southern Hemisphere	17 Participants n=388 Participants	19 Participants n=386 Participants	17 Participants n=389 Participants	53 Participants n=1163 Participants
Composite Symptom Score ≤ 14	188 Participants n=388 Participants	188 Participants n=386 Participants	201 Participants n=389 Participants	577 Participants n=1163 Participants
Composite Symptom Score ≥ 15	200 Participants n=388 Participants	198 Participants n=386 Participants	188 Participants n=389 Participants	586 Participants n=1163 Participants
Preexisting Symptom Status Yes	71 Participants n=388 Participants	76 Participants n=386 Participants	69 Participants n=389 Participants	216 Participants n=1163 Participants
Preexisting Symptom Status No	317 Participants n=388 Participants	310 Participants n=386 Participants	320 Participants n=389 Participants	947 Participants n=1163 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=385 Participants 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.	Placebo n=385 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=388 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Time to Improvement of Influenza Symptoms	73.2 hours Interval 67.2 to 85.1	102.3 hours Interval 92.7 to 113.1	81.0 hours Interval 69.4 to 91.5

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=355 Participants 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.	Placebo n=353 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=360 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Percentage of Participants With Positive Influenza Virus Titer at Each Time Point Day 9	2.8 percentage of participants Interval 1.3 to 5.2	5.3 percentage of participants Interval 3.1 to 8.3	0.9 percentage of participants Interval 0.2 to 2.7
Percentage of Participants With Positive Influenza Virus Titer at Each Time Point Day 2	58.6 percentage of participants Interval 53.2 to 63.9	86.9 percentage of participants Interval 82.9 to 90.3	86.9 percentage of participants Interval 82.9 to 90.3
Percentage of Participants With Positive Influenza Virus Titer at Each Time Point Day 3	31.7 percentage of participants Interval 26.7 to 36.9	72.7 percentage of participants Interval 67.6 to 77.4	60.0 percentage of participants Interval 54.6 to 65.2
Percentage of Participants With Positive Influenza Virus Titer at Each Time Point Day 4	18.5 percentage of participants Interval 12.2 to 26.2	50.0 percentage of participants Interval 40.8 to 59.2	33.1 percentage of participants Interval 24.9 to 42.1
Percentage of Participants With Positive Influenza Virus Titer at Each Time Point Day 5	16.0 percentage of participants Interval 12.1 to 20.4	30.7 percentage of participants Interval 25.7 to 36.1	20.4 percentage of participants Interval 16.2 to 25.2
Percentage of Participants With Positive Influenza Virus Titer at Each Time Point Day 6	4.3 percentage of participants Interval 1.4 to 9.9	16.0 percentage of participants Interval 9.6 to 24.4	11.4 percentage of participants Interval 6.0 to 19.1

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=388 Participants 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.	Placebo n=386 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=389 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point Day 3	92.5 percentage of participants Interval 89.4 to 95.0	95.4 percentage of participants Interval 92.8 to 97.3	95.1 percentage of participants Interval 92.4 to 97.1
Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point Day 6	71.8 percentage of participants Interval 63.2 to 79.3	78.0 percentage of participants Interval 69.7 to 85.0	71.8 percentage of participants Interval 62.7 to 79.7
Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point Day 2	96.0 percentage of participants Interval 93.4 to 97.7	96.3 percentage of participants Interval 93.8 to 97.9	96.0 percentage of participants Interval 93.5 to 97.7
Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point Day 4	86.5 percentage of participants Interval 79.9 to 91.5	91.0 percentage of participants Interval 85.1 to 95.1	86.4 percentage of participants Interval 79.6 to 91.6
Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point Day 5	84.9 percentage of participants Interval 80.8 to 88.4	88.6 percentage of participants Interval 84.9 to 91.7	86.1 percentage of participants Interval 82.2 to 89.5
Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point Day 9	54.5 percentage of participants Interval 49.3 to 59.8	64.9 percentage of participants Interval 59.7 to 69.8	57.7 percentage of participants Interval 52.3 to 62.9

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=355 Participants 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.	Placebo n=353 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=360 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Change From Baseline in Virus Titer at Each Time Point Day 4	-3.99 log₁₀[TCID₅₀/mL] Standard Deviation 2.00	-3.79 log₁₀[TCID₅₀/mL] Standard Deviation 2.75	-3.75 log₁₀[TCID₅₀/mL] Standard Deviation 2.26
Change From Baseline in Virus Titer at Each Time Point Day 2	-3.36 log₁₀[TCID₅₀/mL] Standard Deviation 2.21	-1.25 log₁₀[TCID₅₀/mL] Standard Deviation 2.27	-1.76 log₁₀[TCID₅₀/mL] Standard Deviation 2.20
Change From Baseline in Virus Titer at Each Time Point Day 3	-3.92 log₁₀[TCID₅₀/mL] Standard Deviation 2.22	-2.99 log₁₀[TCID₅₀/mL] Standard Deviation 2.55	-3.26 log₁₀[TCID₅₀/mL] Standard Deviation 2.50
Change From Baseline in Virus Titer at Each Time Point Day 5	-4.32 log₁₀[TCID₅₀/mL] Standard Deviation 2.16	-4.38 log₁₀[TCID₅₀/mL] Standard Deviation 2.31	-4.41 log₁₀[TCID₅₀/mL] Standard Deviation 2.12
Change From Baseline in Virus Titer at Each Time Point Day 6	-4.07 log₁₀[TCID₅₀/mL] Standard Deviation 2.05	-4.68 log₁₀[TCID₅₀/mL] Standard Deviation 2.22	-4.39 log₁₀[TCID₅₀/mL] Standard Deviation 1.97
Change From Baseline in Virus Titer at Each Time Point Day 9	-4.53 log₁₀[TCID₅₀/mL] Standard Deviation 2.11	-4.91 log₁₀[TCID₅₀/mL] Standard Deviation 2.08	-4.78 log₁₀[TCID₅₀/mL] Standard Deviation 2.07

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=388 Participants 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.	Placebo n=386 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=389 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Change From Baseline in Virus RNA (RT-PCR) at Each Time Point Day 6	-3.33 log₁₀ virus particles/mL Standard Deviation 1.48	-3.19 log₁₀ virus particles/mL Standard Deviation 1.77	-3.41 log₁₀ virus particles/mL Standard Deviation 1.38
Change From Baseline in Virus RNA (RT-PCR) at Each Time Point Day 9	-3.89 log₁₀ virus particles/mL Standard Deviation 1.51	-3.78 log₁₀ virus particles/mL Standard Deviation 1.65	-3.99 log₁₀ virus particles/mL Standard Deviation 1.39
Change From Baseline in Virus RNA (RT-PCR) at Each Time Point Day 2	-1.13 log₁₀ virus particles/mL Standard Deviation 1.20	-0.62 log₁₀ virus particles/mL Standard Deviation 1.34	-0.76 log₁₀ virus particles/mL Standard Deviation 1.18
Change From Baseline in Virus RNA (RT-PCR) at Each Time Point Day 3	-2.09 log₁₀ virus particles/mL Standard Deviation 1.45	-1.57 log₁₀ virus particles/mL Standard Deviation 1.66	-1.77 log₁₀ virus particles/mL Standard Deviation 1.45
Change From Baseline in Virus RNA (RT-PCR) at Each Time Point Day 4	-2.77 log₁₀ virus particles/mL Standard Deviation 1.42	-2.09 log₁₀ virus particles/mL Standard Deviation 1.84	-2.34 log₁₀ virus particles/mL Standard Deviation 1.63
Change From Baseline in Virus RNA (RT-PCR) at Each Time Point Day 5	-3.09 log₁₀ virus particles/mL Standard Deviation 1.58	-2.77 log₁₀ virus particles/mL Standard Deviation 1.67	-3.04 log₁₀ virus particles/mL Standard Deviation 1.46

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=355 Participants 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.	Placebo n=353 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=360 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer	-727.7 log₁₀[TCID₅₀/mL]*hours Standard Deviation 367.2	-660.2 log₁₀[TCID₅₀/mL]*hours Standard Deviation 372.3	-695.5 log₁₀[TCID₅₀/mL]*hours Standard Deviation 360.5

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=360 Participants 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.	Placebo n=349 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=349 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Area Under the Curve (AUC) Adjusted by Baseline in Viral RNA	-490.9 log₁₀ virus particles/mL*hours Standard Deviation 249.3	-434.9 log₁₀ virus particles/mL*hours Standard Deviation 269.3	-482.2 log₁₀ virus particles/mL*hours Standard Deviation 233.2

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=352 Participants 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.	Placebo n=352 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=356 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Time to Cessation of Viral Shedding Determined by Virus Titer	48.0 hours Could not be estimated because lower limit of 95% CI of KM survival function just before the median survival time was higher than 50% and an upper limit of 95% CI of KM survival function just after the median survival time was lower than 50%.	96.0 hours Could not be estimated because lower limit of 95% CI of KM survival function just before the median survival time was higher than 50% and an upper limit of 95% CI of KM survival function just after the median survival time was lower than 50%.	96.0 hours Interval 72.0 to 96.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=385 Participants 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.	Placebo n=385 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=384 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Time to Cessation of Viral Shedding Determined by Virus RNA	216.0 hours Interval 192.0 to 240.0	240.0 hours Interval 216.0 to 312.0	216.0 hours Interval 216.0 to 240.0

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=388 Participants 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.	Placebo n=386 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=389 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Percentage of Participants Whose Symptoms Were Improved at Each Time Point 24 hours	18.8 percentage of participants Interval 14.9 to 23.2	14.2 percentage of participants Interval 10.8 to 18.3	19.6 percentage of participants Interval 15.7 to 24.1
Percentage of Participants Whose Symptoms Were Improved at Each Time Point 36 hours	33.9 percentage of participants Interval 28.6 to 39.5	21.1 percentage of participants Interval 16.6 to 26.1	31.0 percentage of participants Interval 25.8 to 36.6
Percentage of Participants Whose Symptoms Were Improved at Each Time Point 72 hours	56.0 percentage of participants Interval 50.7 to 61.2	41.8 percentage of participants Interval 36.6 to 47.1	56.0 percentage of participants Interval 50.6 to 61.3
Percentage of Participants Whose Symptoms Were Improved at Each Time Point 96 hours	65.9 percentage of participants Interval 60.7 to 70.9	53.4 percentage of participants Interval 47.9 to 58.8	61.1 percentage of participants Interval 55.8 to 66.3
Percentage of Participants Whose Symptoms Were Improved at Each Time Point 120 hours	72.3 percentage of participants Interval 67.4 to 76.9	64.6 percentage of participants Interval 59.3 to 69.7	72.4 percentage of participants Interval 67.2 to 77.1
Percentage of Participants Whose Symptoms Were Improved at Each Time Point 144 hours	78.1 percentage of participants Interval 73.4 to 82.3	69.6 percentage of participants Interval 64.4 to 74.4	77.6 percentage of participants Interval 72.7 to 82.0
Percentage of Participants Whose Symptoms Were Improved at Each Time Point 192 hours	83.6 percentage of participants Interval 79.2 to 87.3	78.0 percentage of participants Interval 73.2 to 82.3	85.6 percentage of participants Interval 81.3 to 89.2
Percentage of Participants Whose Symptoms Were Improved at Each Time Point 216 hours	85.8 percentage of participants Interval 80.1 to 90.3	78.7 percentage of participants Interval 71.9 to 84.6	88.2 percentage of participants Interval 82.5 to 92.5
Percentage of Participants Whose Symptoms Were Improved at Each Time Point 12 hours	9.1 percentage of participants Interval 6.1 to 13.0	8.6 percentage of participants Interval 5.7 to 12.3	8.1 percentage of participants Interval 5.3 to 11.8
Percentage of Participants Whose Symptoms Were Improved at Each Time Point 48 hours	38.0 percentage of participants Interval 33.0 to 43.2	28.8 percentage of participants Interval 24.2 to 33.7	39.9 percentage of participants Interval 34.9 to 45.2
Percentage of Participants Whose Symptoms Were Improved at Each Time Point 168 hours	80.1 percentage of participants Interval 75.5 to 84.2	72.7 percentage of participants Interval 67.5 to 77.5	79.6 percentage of participants Interval 74.8 to 83.8

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=385 Participants 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.	Placebo n=385 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=388 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Time to Alleviation of Symptoms	77.0 hours Interval 68.4 to 88.3	102.8 hours Interval 93.2 to 113.4	85.6 hours Interval 71.5 to 94.8

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=385 Participants 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.	Placebo n=385 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=388 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Time to Improvement of the Four Systemic Symptoms	51.7 hours Interval 45.0 to 55.4	66.8 hours Interval 60.1 to 70.0	49.4 hours Interval 44.2 to 56.8

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=385 Participants 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.	Placebo n=385 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=388 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Time to Improvement of the Three Respiratory Symptoms	63.6 hours Interval 55.9 to 68.2	87.8 hours Interval 76.3 to 98.9	62.1 hours Interval 54.0 to 69.1

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=380 Participants 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.	Placebo n=385 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=383 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Time to Resolution of Fever	30.8 hours Interval 28.2 to 35.4	50.7 hours Interval 44.6 to 58.8	34.3 hours Interval 30.0 to 38.9

SECONDARY outcome

Timeframe: 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.

Defined as the percentage of patrticipants whose axillary body temperature dropped to less than 37ºC after the initiation of the study treatment.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=385 Participants 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.	Placebo n=386 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=386 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Percentage of Participants Reporting Normal Temperature at Each Time Point 12 hours	29.7 percentage of participants Interval 24.9 to 34.9	24.6 percentage of participants Interval 20.1 to 29.5	25.9 percentage of participants Interval 21.3 to 30.8
Percentage of Participants Reporting Normal Temperature at Each Time Point 24 hours	51.1 percentage of participants Interval 45.8 to 56.4	43.2 percentage of participants Interval 38.1 to 48.5	54.3 percentage of participants Interval 49.1 to 59.5
Percentage of Participants Reporting Normal Temperature at Each Time Point 36 hours	68.1 percentage of participants Interval 62.9 to 73.0	47.4 percentage of participants Interval 42.1 to 52.8	64.1 percentage of participants Interval 58.8 to 69.2
Percentage of Participants Reporting Normal Temperature at Each Time Point 48 hours	77.4 percentage of participants Interval 72.8 to 81.6	59.3 percentage of participants Interval 54.1 to 64.3	76.4 percentage of participants Interval 71.7 to 80.7
Percentage of Participants Reporting Normal Temperature at Each Time Point 72 hours	84.0 percentage of participants Interval 79.6 to 87.7	71.7 percentage of participants Interval 66.6 to 76.5	82.6 percentage of participants Interval 78.0 to 86.6
Percentage of Participants Reporting Normal Temperature at Each Time Point 96 hours	87.5 percentage of participants Interval 83.5 to 90.9	79.8 percentage of participants Interval 75.0 to 84.0	85.8 percentage of participants Interval 81.5 to 89.5
Percentage of Participants Reporting Normal Temperature at Each Time Point 120 hours	86.2 percentage of participants Interval 82.0 to 89.8	86.6 percentage of participants Interval 82.4 to 90.1	88.4 percentage of participants Interval 84.3 to 91.7
Percentage of Participants Reporting Normal Temperature at Each Time Point 144 hours	90.0 percentage of participants Interval 86.1 to 93.0	86.1 percentage of participants Interval 81.9 to 89.7	87.4 percentage of participants Interval 83.1 to 90.9
Percentage of Participants Reporting Normal Temperature at Each Time Point 168 hours	87.9 percentage of participants Interval 83.8 to 91.2	88.1 percentage of participants Interval 84.0 to 91.5	87.7 percentage of participants Interval 83.4 to 91.2
Percentage of Participants Reporting Normal Temperature at Each Time Point 192 hours	89.0 percentage of participants Interval 85.0 to 92.2	87.5 percentage of participants Interval 83.3 to 91.0	90.5 percentage of participants Interval 86.5 to 93.6
Percentage of Participants Reporting Normal Temperature at Each Time Point 216 hours	89.1 percentage of participants Interval 85.1 to 92.3	89.9 percentage of participants Interval 85.9 to 93.1	89.6 percentage of participants Interval 85.7 to 92.8

SECONDARY outcome

Timeframe: 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.

Participant's self-measured axillary temperature using an electronic thermometer.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=388 Participants 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.	Placebo n=386 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=389 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Body Temperature at Each Time Point 120 hours	36.26 °C Standard Error 0.05	36.27 °C Standard Error 0.05	36.21 °C Standard Error 0.05
Body Temperature at Each Time Point 12 hours	37.39 °C Standard Error 0.07	37.53 °C Standard Error 0.07	37.43 °C Standard Error 0.07
Body Temperature at Each Time Point 24 hours	36.84 °C Standard Error 0.06	37.02 °C Standard Error 0.06	36.80 °C Standard Error 0.06
Body Temperature at Each Time Point 36 hours	36.58 °C Standard Error 0.06	36.94 °C Standard Error 0.06	36.62 °C Standard Error 0.06
Body Temperature at Each Time Point 48 hours	36.44 °C Standard Error 0.06	36.77 °C Standard Error 0.06	36.50 °C Standard Error 0.06
Body Temperature at Each Time Point 72 hours	36.30 °C Standard Error 0.05	36.46 °C Standard Error 0.05	36.29 °C Standard Error 0.05
Body Temperature at Each Time Point 96 hours	36.26 °C Standard Error 0.05	36.35 °C Standard Error 0.05	36.24 °C Standard Error 0.05

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=388 Participants 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.	Placebo n=386 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=389 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Time to Improvement of Individual Symptoms Cough	47.3 hours Interval 42.8 to 52.7	70.4 hours Interval 56.5 to 79.5	47.5 hours Interval 43.0 to 55.4
Time to Improvement of Individual Symptoms Sore Throat	40.2 hours Interval 32.4 to 46.1	46.5 hours Interval 39.0 to 53.5	39.3 hours Interval 30.1 to 42.8
Time to Improvement of Individual Symptoms Headache	33.4 hours Interval 29.1 to 40.5	43.9 hours Interval 33.6 to 46.2	31.3 hours Interval 28.6 to 37.0
Time to Improvement of Individual Symptoms Nasal Congestion	45.6 hours Interval 37.4 to 54.3	57.7 hours Interval 48.7 to 67.8	44.0 hours Interval 36.4 to 50.3
Time to Improvement of Individual Symptoms Feverishness or Chills	28.3 hours Interval 24.2 to 31.8	31.9 hours Interval 28.6 to 41.2	29.1 hours Interval 25.2 to 30.8
Time to Improvement of Individual Symptoms Muscle or Joint Pain	37.2 hours Interval 31.5 to 41.6	44.9 hours Interval 42.2 to 52.0	33.2 hours Interval 30.2 to 39.5
Time to Improvement of Individual Symptoms Fatigue	41.3 hours Interval 35.2 to 46.1	48.8 hours Interval 42.7 to 55.4	43.2 hours Interval 39.3 to 47.4

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=274 Participants 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.	Placebo n=274 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=286 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Time to Return to Preinfluenza Health Status	126.4 hours Interval 104.6 to 153.4	149.8 hours Interval 124.7 to 175.7	126.9 hours Interval 104.9 to 152.7

SECONDARY outcome

Timeframe: Day 2 to Day 22

Population: Intention-to-treat infected population

The percentage of participants who received systemic antibiotics for any of the predefined complications (sinusitis, otitis media, bronchitis and pneumonia).

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=388 Participants 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.	Placebo n=386 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=389 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Percentage of Participants Requiring Systemic Antibiotics for Infections Secondary to Influenza Infection	3.4 percentage of participants Interval 1.8 to 5.7	7.5 percentage of participants Interval 5.1 to 10.6	3.9 percentage of participants Interval 2.2 to 6.3

SECONDARY outcome

Timeframe: Day 1 to Day 22

Population: Intention-to-treat population

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.

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=388 Participants 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.	Placebo n=386 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=389 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Percentage of Participants With Influenza-related Complications Hospitalization	0.8 percentage of participants Interval 0.2 to 2.2	1.3 percentage of participants Interval 0.4 to 3.0	1.0 percentage of participants Interval 0.3 to 2.6
Percentage of Participants With Influenza-related Complications Any Complications	2.8 percentage of participants Interval 1.4 to 5.0	10.4 percentage of participants Interval 7.5 to 13.8	4.6 percentage of participants Interval 2.8 to 7.2
Percentage of Participants With Influenza-related Complications Death	0.0 percentage of participants Interval 0.0 to 0.9	0.0 percentage of participants Interval 0.0 to 1.0	0.3 percentage of participants Interval 0.0 to 1.4
Percentage of Participants With Influenza-related Complications Sinusitis	0.3 percentage of participants Interval 0.0 to 1.4	2.1 percentage of participants Interval 0.9 to 4.0	0.5 percentage of participants Interval 0.1 to 1.8
Percentage of Participants With Influenza-related Complications Otitis media	0.0 percentage of participants Interval 0.0 to 0.9	0.8 percentage of participants Interval 0.2 to 2.3	0.3 percentage of participants Interval 0.0 to 1.4
Percentage of Participants With Influenza-related Complications Bronchitis	1.8 percentage of participants Interval 0.7 to 3.7	6.0 percentage of participants Interval 3.8 to 8.8	2.3 percentage of participants Interval 1.1 to 4.3
Percentage of Participants With Influenza-related Complications Pneumonia	0.0 percentage of participants Interval 0.0 to 0.9	0.8 percentage of participants Interval 0.2 to 2.3	0.5 percentage of participants Interval 0.1 to 1.8

SECONDARY outcome

Timeframe: From first dose of study drug to Day 22

Population: All participants who received at least 1 dose of study drug

Outcome measures

Outcome measures
Measure	Baloxavir Marboxil n=730 Participants 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.	Placebo n=727 Participants Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=721 Participants Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Percentage of Participants With Adverse Events (AEs) TRAEs leading to withdrawal of study drug	0.3 percentage of participants	0.3 percentage of participants	0.4 percentage of participants
Percentage of Participants With Adverse Events (AEs) Any adverse event (AE)	25.1 percentage of participants	29.7 percentage of participants	28.0 percentage of participants
Percentage of Participants With Adverse Events (AEs) Fatal adverse events	0.0 percentage of participants	0.0 percentage of participants	0.1 percentage of participants
Percentage of Participants With Adverse Events (AEs) Serious adverse events	0.7 percentage of participants	1.2 percentage of participants	1.1 percentage of participants
Percentage of Participants With Adverse Events (AEs) AEs leading to withdrawal of study drug	0.7 percentage of participants	0.7 percentage of participants	0.6 percentage of participants
Percentage of Participants With Adverse Events (AEs) Treatment-related adverse events (TRAEs)	5.6 percentage of participants	8.3 percentage of participants	7.9 percentage of participants
Percentage of Participants With Adverse Events (AEs) Fatal treatment-related adverse events	0.0 percentage of participants	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants With Adverse Events (AEs) Treatment-related serious adverse events	0.0 percentage of participants	0.3 percentage of participants	0.3 percentage of participants

Adverse Events

Baloxavir Marboxil

Serious events: 5 serious events

Other events: 70 other events

Deaths: 1 deaths

Placebo

Serious events: 9 serious events

Other events: 92 other events

Deaths: 0 deaths

Oseltamivir

Serious events: 8 serious events

Other events: 90 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Baloxavir Marboxil n=730 participants at risk 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.	Placebo n=727 participants at risk Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.	Oseltamivir n=721 participants at risk Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
Gastrointestinal disorders Nausea	2.7% 20/730 • All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events). One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.	3.9% 28/727 • All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events). One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.	4.7% 34/721 • All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events). One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.
Infections and infestations Bronchitis	2.9% 21/730 • All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events). One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.	4.5% 33/727 • All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events). One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.	4.2% 30/721 • All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events). One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.
Infections and infestations Sinusitis	1.9% 14/730 • All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events). One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.	2.9% 21/727 • All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events). One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.	3.1% 22/721 • All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events). One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.
Gastrointestinal disorders Diarrhoea	2.7% 20/730 • All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events). One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.	2.9% 21/727 • All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events). One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.	3.2% 23/721 • All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events). One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.

Additional Information

Shionogi Clinical Trials Administrator

Shionogi Inc.

Phone: 800-849-9707

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.
Publication restrictions are in place

Restriction type: OTHER