Study to Assess Efficacy and Safety of Baloxavir Marboxil In Combination With Standard-of-Care Neuraminidase Inhibitor In Hospitalized Participants With Severe Influenza

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03684044
• Collaborator: (none)
• Enrollment: 363
• Locations: 170
• Arms: 2
• Actual Duration (Months): 14.2
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy, safety, and pharmacokinetics of baloxavir marboxil in combination with a standard-of-care (SOC) neuraminidase inhibitor (NAI) (i.e., oseltamivir, zanamivir, or peramivir) compared with a matching placebo in combination with a SOC NAI in hospitalized patients with influenza.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Drug: Baloxavir Marboxil; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 363 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-Blind Placebo-Controlled, Multicenter Study To Evaluate the Efficacy and Safety of Baloxavir Marboxil in Combination With Standard-of-Care Neuraminidase Inhibitor in Hospitalized Participants With Severe Influenza
• Actual Study Start Date: Jan 8, 2019
• Actual Primary Completion Date: Mar 16, 2020
• Actual Study Completion Date: Mar 16, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Baloxavir Marboxil Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Drug: Baloxavir Marboxil; Baloxavir marboxil will be administered as a weight-based dose on Days 1 and 4. A third dose will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5.
Placebo Comparator: Placebo Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Other: Placebo; Participants will receive matching placebo on Days 1, 4 and 7.

Outcome Measures

Primary Outcome Measures

1. Time to Clinical Improvement [Up to Day 35]

   Time to Clinical Improvement (TTCI) is defined as Time to Hospital Discharge OR Time to NEWS2 (National Early Warning Score 2) of ≤ 2 maintained for 24 hours.

Secondary Outcome Measures

1. Response Rates of the 6-Point Ordinal Scale at Day 7 [Day 7]

   The ordinal scale categories are: Category 1) Discharged (or "ready for discharge") Category 2) Non-ICU hospital ward (or "ready for hospital ward") not requiring supplemental oxygen/non-invasive ventilation Category 3) Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen/non-invasive ventilation Category 4) ICU without mechanical (invasive) ventilation (or "ready for ICU admission") Category 5) Mechanical (invasive) ventilation Category 6) Death

2. Time to Clinical Response [Up to Day 35]

   Time to Clinical Response is based on temperature ranges, oxygen saturation, respiratory status, heart rate, and hospitalization status.

3. Percentage of Participants on Mechanical Ventilation [Up to Day 35]

4. Duration of Mechanical Ventilation [Up to Day 35]

5. Percentage of Participants Requiring ICU Stay [Up to Day 35]

6. Duration of ICU Stay [Up to Day 35]

7. Time to Clinical Failure [Up to Day 35]

   Time to clinical failure, defined as the time to death, mechanical ventilation, or ICU admission, corresponding to ordinal scale categories 6, 5, and 4, respectively, from baseline

8. Time to Hospital Discharge [Up to Day 35]

9. Percentage of Participants With Post-Treatment Influenza-Related Complications [Up to Day 35]

   Influenza-related complications included pneumonia, myositis or rhabdomyolysis, encephalitis or encephalopathy, myocarditis and/or pericarditis, otitis media, sinusitis, exacerbation of COPD/asthma, sepsis, acute lung injury or acute respiratory distress syndrome.

10. Mortality Rate at Day 7 [Up to Day 7]

11. Mortality Rate at Day 28 [Up to Day 28]

12. Time to NEWS2 of ≤ 2 Maintained for 24 Hours [Up to Day 35]

    A score of 0 (Range 0 - 3) indicates normal health conditions.

13. Time to Cessation of Viral Shedding by Virus Titer [Screening (baseline) and on Days 2, 3, 4, 5, 7, and 10]

    Time to cessation of viral shedding by virus titer is defined as the time, in hours, between the initiation of study treatment and first time when the influenza virus titer is below the limit of detection (0.75 log10 TCID50/mL)

14. Change From Baseline in Influenza Virus Titer at Each Timepoint [Days 2, 3, 4, 5, 7, and 10]

    Influenza virus titer is the quantity of influenza virus in a given volume within the samples obtained from nasal swabs. If influenza virus titer was less than the lower limit of quantification, the virus titer was imputed as 0.749 (log10TCID50/mL). A lower value indicates lower viral titer.

15. Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint [Days 2, 3, 4, 5, 7, and 10]

    Influenza virus titer is the quantity of influenza virus in a given volume within the samples obtained from nasal swabs. If influenza virus titer was less than the lower limit of quantification, the virus titer was imputed as 0.749 (log10 TCID50/mL). A lower value indicates lower viral titer.

16. Area Under the Curve in Virus Titer [Days 1, 2, 3, 4, 5, 7, and 10]

17. Time to Cessation of Viral Shedding by RT-PCR [Screening (baseline) and on Days 2, 3, 4, 5, 7, and 10]

    Time to cessation of viral shedding by RT-PCR, in hours, is defined as the time between the initiation of study treatment and first time when the virus RNA by RT-PCR is below the limit of detection (2.05 for flu A and 2.83 for flu B log10 virus particles/mL)

18. Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint [Days 2, 3, 4, 5, 7, and 10]

    If the amount of virus RNA was less than the lower limit of quantification, the amount of virus RNA was imputed as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL)

19. Percentage of Participants Positive by RT-PCR at Each Timepoint [Days 2, 3, 4, 5, 7, and 10]

    If the amount of virus RNA was less than the lower limit of quantification, the amount of virus RNA was imputed as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL)

20. Area Under the Curve in the Amount of Virus RNA (RT-PCR) [Days 1, 2, 3, 4, 5, 7, and 10]

21. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up to Day 35]

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

22. Percentage of Participants With AEs and SAEs Leading to Discontinuation From Treatment [Up to Day 35]

    Discontinuation from study treatment.

23. Percentage of Participants With Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN [Up to Day 35]

    ALT = alanine aminotransferase AST = aspartate transaminase

24. Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points [Day 1, 2, 4, 5, 7 and 8]

25. Area Under the Concentration to Time Curve From Time 0 to 72 Hours (AUC0-72) of Baloxavir [0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8]

26. Maximum Plasma Concentration (Cmax) of Baloxavir [0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8]

27. Apparent Half-Life (T1/2) of Baloxavir [0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8]

28. Concentration at 24 Hours (C24) of Baloxavir [0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult participants: Signed informed consent by any participant capable of giving consent, or, where the participant is not capable of giving consent, by his or her legal/authorized representative

• Adolescent participants not able to legally consent: written informed consent for study participation is obtained from participant's parents or legal guardian, with assent as appropriate by the participant, depending on the participant's level of understanding and capability to provide assent

• Participants who require hospitalization for severe influenza or acquire influenza during hospitalization, the severity of which requires an extension of hospitalization

• Diagnosis of influenza A and/or B by a positive Rapid Influenza Diagnostic Test (RIDT) or reverse transcriptase-polymerase chain reaction (RT-PCR)

• The time interval between the onset of symptoms and randomization is within 96 hours

• A score of ≥4 based on the National Early Warning Score 2 (NEWS2)

• Participants will require objective criteria of seriousness defined by at least one of the following criteria:

• Requires ventilation or supplemental oxygen to support respiration

• Has a complication related to influenza that requires hospitalization (e.g., pneumonia, central nervous system involvement, myositis, rhabdomyolysis, acute exacerbation of chronic kidney disease, asthma or chronic obstructive pulmonary disease (COPD), severe dehydration, myocarditis, pericarditis, exacerbation of ischemic heart disease)

• For women of childbearing potential: Agreement to remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 28 days after the last dose of study treatment. Hormonal contraceptive methods must be supplemented by a barrier method.

Exclusion Criteria:

• Participants who have received more than 48 hours of antiviral treatment for the current influenza infection prior to screening

• Participants who have received baloxavir marboxil for the current influenza infection

• Known contraindication to neuraminidase inhibitors

• Participants hospitalized for exclusively social reasons (e.g., lack of caregivers at home)

• Participants expected to die or be discharged within 48 hours, according to the investigator's judgement

• Participants weighing < 40 kg

• Participants with known severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis

• Participants with any of the following laboratory abnormalities detected within 24 hours prior to or during screening (according to local laboratory reference ranges:

• Alanine Transaminase (ALT) or Aspartate Transaminase (AST) level > 5 times the upper limit of normal (ULN) OR

• ALT or AST > 3 times the ULN and total bilirubin level > 2 times the ULN

• Pregnant or breastfeeding, or positive pregnancy test in a predose examination, or intending to become pregnant during the study or within 28 days after the last dose of study treatment

• Exposure to an investigational drug within 5 half-lives or 30 days (whichever is longer) of randomization

• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study

• Known hypersensitivity to baloxavir marboxil or the drug product excipients

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Torrance Memorial Medical Center	Torrance	California	United States	90505
2	Denver Health Medical Center	Denver	Colorado	United States	80204
3	Atlanta Institute For Medical Research, Inc; DeKalb Medical Pharmacy	Decatur	Georgia	United States	30030
4	University of Chicago; Oncology Dept	Chicago	Illinois	United States	60637
5	NorthShore University HealthSystem	Evanston	Illinois	United States	60201
6	Barnum Medical Research, Inc.	Natchitoches	Louisiana	United States	71457
7	Detroit Receiving Hospital	Detroit	Michigan	United States	48201
8	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
9	Mercury Street Medical Group	Butte	Montana	United States	59701
10	Creighton University Medical Center	Omaha	Nebraska	United States	68131
11	New York-Presbyterian Brooklyn Methodist Hospital; Department of Emergency Medicine	Brooklyn	New York	United States	11215
12	Temple University Hospital ; Lung Center	Philadelphia	Pennsylvania	United States	19140
13	Salem Veterans Affairs Medical Center - NAVREF; Pharmacy	Salem	Virginia	United States	24153
14	Froedtert and The Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
15	Instituto Medico Platense	La Plata		Argentina	1900
16	Royal Brisbane & Womens Hospital; Pharmacy Department	Herston	Queensland	Australia	4029
17	Royal Children's Hospital Melbourne - PIN	Parkville	Victoria	Australia	3052
18	Hopital Erasme; Chest Medicine, Cardiac & Thoracic Surgery	Bruxelles		Belgium	1070
19	Cliniques Universitaires Saint-Luc; Hematology	Bruxelles		Belgium	1200
20	UZ Leuven	Leuven		Belgium	3000
21	Santa Casa de Misericordia; de Belo Horizonte	Belo Horizonte	MG	Brazil	30150-221
22	Hospital Sao Vicente de Paulo	Passo Fundo	RS	Brazil	99010-090
23	Centro de Estudos Clinicos do Interior Paulista	JAU	SP	Brazil	17201-130
24	Multiprofile Hospital For Active Treatment Sveta Ekaterina Dimitrovgrad EOOD; Internal Diseases	Dimitrovgrad		Bulgaria	6400
25	Specialized Hospital for Active Treatment of Pneumophthisiatric Diseases - Haskovo EOOD	Haskovo		Bulgaria	6305
26	MHAT Stamen Iliev AD; Pharmacy	Montana		Bulgaria	3400
27	University Mulitiprofile Hospital for Active Treatment Sveti Georgi EAD; Pharmacy	Plovdiv		Bulgaria	4002
28	Specialized Hospital for Active Treatment of Pneumophthisiatric Diseases Dr. D. Gramatikov - Ruse	Ruse		Bulgaria	7002
29	Multiprofile Hospital for Active Treatment - Samokov EOOD	Samokov		Bulgaria	2000
30	Multiprofile Hospital For Active Treatment Sliven То Military Hospital Sofia; Pharmacy	Sliven		Bulgaria	8800
31	Multiprofile Hospital For Active Treatment - Dr. Bratan Shukerov AD; Pharmacy	Smolyan		Bulgaria	4700
32	First Multiprofile Hospital for Active Treatment - Sofia EAD	Sofia		Bulgaria	1142
33	Fifth Multiprofile Hospital for Active Treatment - Sofia EAD; Pharmacy	Sofia		Bulgaria	1233
34	Military Medical Academy Multiprofile Hospital for Active Treatment - Sofia; Pharmacy	Sofia		Bulgaria	1606
35	National Multiprofile Transport Hospital Tzar Boris Ill; Clinic of Internal Diseases	Sofia		Bulgaria	2233
36	Multiprofile District Hospital for Active Treatment Dr. Stefan Cherkezov AD; Pharmacy	Veliko Tarnovo		Bulgaria	5000
37	Specialized Hospital for Active Treatment of Pneumophthisiatric Diseases-Vratsa; Pharmacy	Vratsa		Bulgaria	3000
38	Peter Lougheed Centre	Calgary	Alberta	Canada	T1Y 6J4
39	Foothills Medical Centre	Calgary	Alberta	Canada	T2N-2T9
40	Carlson Urology	Calgary	Alberta	Canada	T2V 1P9
41	South Health Campus	Calgary	Alberta	Canada	T3M 1M4
42	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 1Z1
43	Toronto East General Hospital; Main Pharmacy G Wing Basement	East York	Ontario	Canada	M4C 3E7
44	London Health Sciences Center; Pharmacy Dept.	London	Ontario	Canada	N6A 5W9
45	Institut Universitaire de Cardiologie et de Pneumologie	Quebec		Canada	G1V 4G5
46	Beijing Youan Hospital, Capital Medical University; Center for Infectious Diseases	Beijing City		China	100069
47	Beijing Ditan Hospital Capital Medical University	Beijing		China	100015
48	China-Japan Friendship Hospital	Beijing		China	10029
49	West China Hospital, Sichuan University	Chengdu		China	610041
50	The First Affiliated Hospital of Guangzhou Medical University	Guangzhou		China	510120
51	The First Affiliated Hospital of College of Medicine, Zhejiang University	Hangzhou		China	310003
52	The 1st Affiliated Hospital of Nanchang Unversity	Nanchang		China	330006
53	Shanghai Jiao Tong University School of Medicine (SJTUSM) - Ruijin Hospital (GuangCi Hospital)	Shanghai		China	200025
54	Zhongshan Hospital Fudan University	Shanghai		China	200032
55	Shanghai Public Health Clinical Center	Shanghai		China	201508
56	Fakultni nemocnice Brno; Interni hematologicka a onkologicka klinika	Brno		Czechia	625 00
57	Nemocnice Kyjov, prispevkova organizace	Kyjov		Czechia	697 33
58	East Tallinn Central Hospital	Tallinn		Estonia	10138
59	Kuopion Yliopistollinen Sairaala; Silmätaudit	Kuopio		Finland	70210
60	Oulun Yliopistollinen Sairaala; Teho-osasto	Oulu		Finland	90220
61	Turku University Hospital	Turku		Finland	20521
62	Centre Hospitalier Victor Dupouy	Argenteuil		France	95107
63	CHRU Dijon Complexe Du Bocage	Dijon		France	21079
64	Centre Hospitalier Departemental de Vendee	La Roche Sur Yon		France	85925
65	Hôpital Universitaire Dupuytren	Limoges		France	87042
66	CHRU Nantes	Nantes		France	44093
67	CHU de Nîmes - Hôpital Carémeau	Nimes		France	30029
68	Hopital de La Source	Orleans		France	45067
69	Groupe Hospitalier Pitie Salpetriere; Service De Pneumologie	Paris		France	75651
70	Nouvel Hopital Civil - CHU Strasbourg	Strasbourg		France	67091
71	CHRU Bretonneau	Tours		France	37044
72	Krankenhaus Donaustauf der LVA Niederbayern Oberpfalz	Donaustauf		Germany	93093
73	Universitätsklinikum Carl Gustav Carus an der TU Dresden	Dresden		Germany	01307
74	St. Josefskrankenhaus - Freiburg; Klinik fur Pneumologieund Beatmungsmedizin	Freiburg im Breisgau		Germany	79104
75	Medizinische Hochschule Hannover	Hannover		Germany	30625
76	Uniklinik Koln; Klinik I fur Innere Medizin	Köln		Germany	50937
77	Universitatsklinikum Schleswig-Holstein; Klinik fuer Innere Medizin I	Lubeck		Germany	23538
78	Klinikum Mannheim GmbH Universitätsklinikum	Mannheim		Germany	68167
79	Klinikum der Universität Regensburg	Regensburg		Germany	93053
80	Universitatsklinikum Tubingen	Tübingen		Germany	72076
81	Princess Margaret Hospital	Hong Kong		Hong Kong
82	Queen Mary Hospital	Hong Kong		Hong Kong
83	Prince of Wales Hospital	Shatin, New Territories		Hong Kong
84	Soroka University Medical Centre	Beer Sheva		Israel	8410101
85	Edith Wolfson Medical Center	Holon		Israel	58100
86	Galilee Medical Center	Nahariya		Israel	22100
87	Chaim Sheba Medical Center; Allergy and Clinical Immunology Unit	Ramat Gan		Israel	5266202
88	Rambam Health Corporation; Oncology Institute	Rambam		Israel	3525408
89	ZIV Medical Center; Department Of Internal Medicine A	Safed		Israel	13100
90	Tel Aviv Sourasky Medical Center; Pharmacy	Tel Aviv		Israel	6423906
91	Baruch Padeh Poria Medical Center; Pharmacy	Tiberias		Israel	15208
92	Fujita General Hospital	Dategun Kunimimachi		Japan	969-1793
93	Shin Komonji Hospital	Fukuoka		Japan	800-0057
94	Fukuoka Shin Mizumaki Hospital	Fukuoka		Japan	807-0051
95	Fukuoka Wajiro Hospital	Fukuoka		Japan	811-0213
96	Rinku General Medical Center	Izumisano		Japan	598-0048
97	National Hospital Organization Minami Kyoto Hospital	Joyo		Japan	610-0113
98	National Hospital Organization Kanazawa Medical Center	Kanazawa		Japan	920-8650
99	Japanese Red Cross Kumamoto Hospital	Kumamoto-shi		Japan	861-8520
100	Naha City Hospital	Naha		Japan	902-8511
101	National Hospital Organization Ibarakihigashi National Hospital; Center for Clinical Research	Naka-gun		Japan	319-1113
102	Japan Community Health care Organization Nihonmatsu hospital	Nihonmatsu		Japan	964-8501
103	Social Corporation Keigakukai Minamiosaka Hosupital	Osaka		Japan	559-0012
104	National Hospital Organaization Shibukawa Medical Center	Shibukawa		Japan	377-0280
105	Tokyo Shinagawa Hospital Medical Corporation Association Tokyokyojuno-kai	Shinagawa		Japan	140-8522
106	Saka General Hospital	Shiogama		Japan	985-8506
107	Local incorporated administrative agency Shizuoka City Shizuoka Hospital	Shizuoka		Japan	420-8630
108	Iwase General Hospital	Sukagawa		Japan	962-8503
109	Center Hospital of the National Center for Global Health and Medicine	Tokyo		Japan	162-0052
110	Nagata Hospital; Department of pulmonary medicine	Yanagawa-shi		Japan	832-0059
111	The Catholic University of Korea Incheon St. Mary's Hospital	Incheon		Korea, Republic of	21431
112	Seoul National University Bundang Hospital	Seongnam-si		Korea, Republic of	13605
113	Korea University Anam Hospital	Seoul		Korea, Republic of	02841
114	Seoul National University Hospital	Seoul		Korea, Republic of	03080
115	Asan Medical Center	Seoul		Korea, Republic of	05505
116	ChungAng University Hospital	Seoul		Korea, Republic of	06973
117	Hallym University Kangnam Sacred Heart Hospital	Seoul		Korea, Republic of	07441
118	Instituto Nacional de Ciencias Médicas y Nutricion Dr. Salvador Zubiran; Hamatologia y Oncologia	Mexico	Mexico CITY (federal District)	Mexico	14000
119	Hospital Civil Fray Antonio Alcalde; Instituto de Patologia Infecciosa	Guadalajara		Mexico	44280
120	Hospital Universitario Dr. Jose Eleuterio González; Enfermedades Pulmonares Crónicas	Monterrey		Mexico	64460
121	Hospital General de Tijuana	Tijuana		Mexico	22320
122	Leids Universitair Medisch Centrum; C5-P Stafcentrum Hartziekten	Leiden		Netherlands	2333 ZA
123	Canisius Wilhelmina Ziekenhuis; Department Hematology	Nijmegen		Netherlands	6532 SZ
124	Ikazia Ziekenhuis	Rotterdam		Netherlands	3083 AN
125	Zuyderland Medisch Centrum - Sittard Geleen	Sittard-Geleen		Netherlands	6162 BG
126	Universitair Medisch Centrum Utrecht	Utrecht		Netherlands	3584 CX
127	Wellington Hospital	Wellington		New Zealand	6012
128	Hospital Alberto Sabogal Sologuren	Callao		Peru	Callao 02
129	Hospital Nacional Adolfo Guevara Velasco - ESSALUD; Servicio de Cardiología	Cusco		Peru	08006
130	Prof. Dr. Matei Bals Institute of Infectious Diseases	Bucharest		Romania	21105
131	Dr. Victor Babes Clinical Hospital For Tropical and Infectious Diseases	Bucharest		Romania	30303
132	Spitalul Clinic de Boli Infectioase	Cluj Napoca		Romania	400000
133	Sf.Cuv. Parascheva Infectious Diseases Clinical Hospital	Galati		Romania	800179
134	Spitalul Clinic de Boli Infectioase "Sfanta Parascheva" Iasi	Iasi		Romania	700116
135	Sibiu Emergency Clinical County Hospital	Sibiu		Romania	550245
136	Sf. Ioan cel Nou Emergency County Hospital	Suceava		Romania	720224
137	Clinical Center of Serbia	Belgrade		Serbia	11000
138	Clinical Hospital Center Zvezdara	Belgrade		Serbia	11000
139	Clinical Center Kragujevac	Kragujevac		Serbia	34000
140	Clinical Center Nis; Clinic for Pulmonary Diseases and Tuberculosis Knez Selo	Nis		Serbia	18204
141	Clinical Centre of Vojvodina	Nova Sad		Serbia	21000
142	General Hospital Dr Radivoj Simonovic Sombor	Sombor		Serbia	25000
143	Institute of Lung Diseases Vojvodina	Sremska Kamenica		Serbia	21204
144	Tan Tock Seng Hospital	Singapore		Singapore	308433
145	Hospital Universitario Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
146	Hospital Sant Joan de Deu - PIN; Unitat de Recerca - Farmacia	Esplugues de Llobregat	Barcelona	Spain	08950
147	Hospital Mutua de Terrassa	Terrassa	Barcelona	Spain	08221
148	Hospital Universitario Marques de Valdecilla	Santander	Cantabria	Spain	39008
149	Hospital Universitario de Torrejon	Torrejon de Ardoz	Madrid	Spain	28850
150	Hospital General Universitario de Alicante	Alicante		Spain	03010
151	Hospital del Mar	Barcelona		Spain	08003
152	Hospital Universitario Vall d'Hebron - PPDS	Barcelona		Spain	08035
153	Hospital Universitario Fundacion Jimenez Diaz.	Madrid		Spain	28040
154	Hospital General Universitario Reina Sofia; Servicio de Nefrologia	Murcia		Spain	30003
155	Hospital Universitario Virgen Macarena	Sevilla		Spain	41009
156	Hospital de La Ribera	Valencia		Spain	46600
157	Sahlgrenska Universitetssjukhuset	Goteborg		Sweden	413 45
158	Skånes Universitetssjukhus Malmö; Infektionskliniken	Malmö		Sweden	SE-20502
159	Hacettepe University Medical Faculty	Ankara		Turkey	06100
160	Akdeniz University Medical Faculty	Antalya		Turkey	07059
161	Selcuk University Medical Faculty; Internal Medicine	Konya		Turkey	42050
162	Karadeniz Technical University Faculty of Medicine	Trabzon		Turkey	61080
163	Regional Municipal Institution Chernivtsi Regional Clinical Hospital	Chernivtsi	Chernihiv Governorate	Ukraine	58005
164	Kyiv Oleksandrivska Clinical Hospital; Infectious Box Department #2	Kyiv	Katerynoslav Governorate	Ukraine	01601
165	Regional Municipal Institution Sumy Regional Infectious Clinical Hospital n.a. Z.Y. Krasovytskyi	Sumy	Katerynoslav Governorate	Ukraine	40021
166	Ternopil City Municipal Emergency Hospital; Infectious Department	Ternopil	KIEV Governorate	Ukraine	46008
167	Communal Non-Commercial Enterprise "Vinnytsia City Clinical Hospital №1"; Infectious Department	Vinnytsia	KIEV Governorate	Ukraine	21029
168	MI Vinnytsia Regional Clinical Children's Infectious Hospital; Infectiuos Box department	Vinnytsia	KIEV Governorate	Ukraine	21032
169	MI Dnipropetrovsk City Clinical Hospital #21 n.a. Prof. Popkova of DRC; The First Department	Dnipro	Podolia Governorate	Ukraine	49006
170	Municipal Institution City Clinical Infectious Diseases Hospital	Odesa		Ukraine	65023

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - May 30, 2019
• Statistical Analysis Plan - May 7, 2020

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03684044
• Other Study ID Numbers: CP40617; 2018-001416-30
• First Posted: Sep 25, 2018
• Last Update Posted: Jan 6, 2021
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Influenza, Human; Baloxavir

Study Results

Participant Flow

Recruitment Details	A total of 363 patients received at least one dose of study treatment and were included in the analyses of safety and efficacy.

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Period Title: Overall Study
STARTED	239	124
COMPLETED	217	104
NOT COMPLETED	22	20

Baseline Characteristics

Arm/Group Title	Baloxavir Marboxil	Placebo	Total
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Total of all reporting groups
Overall Participants	239	124	363
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	58.0 (19.8)	61.6 (20.3)	59.2 (20.0)
Sex: Female, Male (Count of Participants)
Female	117 49%	56 45.2%	173 47.7%
Male	122 51%	68 54.8%	190 52.3%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	30 12.6%	16 12.9%	46 12.7%
Not Hispanic or Latino	203 84.9%	106 85.5%	309 85.1%
Not Stated	4 1.7%	1 0.8%	5 1.4%
Unknown	2 0.8%	1 0.8%	3 0.8%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	4 1.7%	0 0%	4 1.1%
Asian	39 16.3%	22 17.7%	61 16.8%
Black or African American	7 2.9%	2 1.6%	9 2.5%
Native Hawaiian or other Pacific Islander	1 0.4%	0 0%	1 0.3%
White	181 75.7%	95 76.6%	276 76%
Unknown	7 2.9%	5 4%	12 3.3%

Outcome Measures

1. Primary Outcome

Title	Time to Clinical Improvement
Description	Time to Clinical Improvement (TTCI) is defined as Time to Hospital Discharge OR Time to NEWS2 (National Early Warning Score 2) of ≤ 2 maintained for 24 hours.
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

Participants were reverse transcriptase-polymerase chain reaction (RT-PCR) positive for influenza at any time point

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	208	114
Median (95% Confidence Interval) [hours]	97.5	100.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Baloxavir Marboxil, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4666
	Comments
	Method	Gehan Wilcoxon
	Comments	The Gehan Wilcoxon test was used to analyze the TTCI data because the proportional hazards assumption was violated
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-2.7
	Confidence Interval	(2-Sided) 95%; -53.4 to 25.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Response Rates of the 6-Point Ordinal Scale at Day 7
Description	The ordinal scale categories are: Category 1) Discharged (or "ready for discharge") Category 2) Non-ICU hospital ward (or "ready for hospital ward") not requiring supplemental oxygen/non-invasive ventilation Category 3) Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen/non-invasive ventilation Category 4) ICU without mechanical (invasive) ventilation (or "ready for ICU admission") Category 5) Mechanical (invasive) ventilation Category 6) Death
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

All participants who were RT-PCR positive for influenza and were not discontinued or lost to follow up prior to day 7.

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	199	108
Category 1	49.2 20.6%	45.4 36.6%
Category 2	22.6 9.5%	24.1 19.4%
Category 3	20.1 8.4%	22.2 17.9%
Category 4	4.0 1.7%	1.9 1.5%
Category 5	3.5 1.5%	4.6 3.7%
Category 6	0.5 0.2%	1.9 1.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Baloxavir Marboxil, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6326
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Statistic was stratified by region, NEWS2 at baseline (≤7, >7), and time from symptom onset to study treatment (≤48 hours, >48 hours)

3. Secondary Outcome

Title	Time to Clinical Response
Description	Time to Clinical Response is based on temperature ranges, oxygen saturation, respiratory status, heart rate, and hospitalization status.
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	208	114
Median (95% Confidence Interval) [hours]	138.3	145.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Baloxavir Marboxil, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3272
	Comments
	Method	Gehan Wilcoxon
	Comments	The Gehan Wilcoxon test was used to analyze the TTCI data because the proportional hazards assumption was violated
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-6.8
	Confidence Interval	(2-Sided) 95%; -50.9 to 17.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants on Mechanical Ventilation
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	208	114
Number [percentage of participants]	5.3 2.2%	6.1 4.9%

5. Secondary Outcome

Title	Duration of Mechanical Ventilation
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	208	114
Median (Full Range) [hours]	150.25	91.00

6. Secondary Outcome

Title	Percentage of Participants Requiring ICU Stay
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	208	114
Number [percentage of participants]	4.3 1.8%	3.5 2.8%

7. Secondary Outcome

Title	Duration of ICU Stay
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	208	114
Median (Full Range) [hours]	138.55	71.78

8. Secondary Outcome

Title	Time to Clinical Failure
Description	Time to clinical failure, defined as the time to death, mechanical ventilation, or ICU admission, corresponding to ordinal scale categories 6, 5, and 4, respectively, from baseline
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	208	114
Median (95% Confidence Interval) [hours]	NA	NA

9. Secondary Outcome

Title	Time to Hospital Discharge
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	208	114
Median (95% Confidence Interval) [hours]	166.7	167.3

10. Secondary Outcome

Title	Percentage of Participants With Post-Treatment Influenza-Related Complications
Description	Influenza-related complications included pneumonia, myositis or rhabdomyolysis, encephalitis or encephalopathy, myocarditis and/or pericarditis, otitis media, sinusitis, exacerbation of COPD/asthma, sepsis, acute lung injury or acute respiratory distress syndrome.
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	208	114
Number [percentage of participants]	10.6 4.4%	14.0 11.3%

11. Secondary Outcome

Title	Mortality Rate at Day 7
Time Frame	Up to Day 7

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	208	114
Number (95% Confidence Interval) [percentage of participants]	0.5 0.2%	2.6 2.1%

12. Secondary Outcome

Title	Mortality Rate at Day 28
Time Frame	Up to Day 28

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	208	114
Number (95% Confidence Interval) [percentage of participants]	1.9 0.8%	5.3 4.3%

13. Secondary Outcome

Title	Time to NEWS2 of ≤ 2 Maintained for 24 Hours
Description	A score of 0 (Range 0 - 3) indicates normal health conditions.
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	208	114
Median (95% Confidence Interval) [hours]	106.3	127.2

14. Secondary Outcome

Title	Time to Cessation of Viral Shedding by Virus Titer
Description	Time to cessation of viral shedding by virus titer is defined as the time, in hours, between the initiation of study treatment and first time when the influenza virus titer is below the limit of detection (0.75 log10 TCID50/mL)
Time Frame	Screening (baseline) and on Days 2, 3, 4, 5, 7, and 10

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point and with a positive virus titer on Day 1

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	159	78
Median (95% Confidence Interval) [hours]	23.9	63.7

15. Secondary Outcome

Title	Change From Baseline in Influenza Virus Titer at Each Timepoint
Description	Influenza virus titer is the quantity of influenza virus in a given volume within the samples obtained from nasal swabs. If influenza virus titer was less than the lower limit of quantification, the virus titer was imputed as 0.749 (log10TCID50/mL). A lower value indicates lower viral titer.
Time Frame	Days 2, 3, 4, 5, 7, and 10

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point and with a positive virus titer on Day 1

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	159	78
Day 2	-2.36	-1.00
Day 3	-2.70	-1.93
Day 4	-2.88	-2.50
Day 5	-3.01	-2.81
Day 7	-3.00	-2.95
Day 10	-3.02	-3.06

16. Secondary Outcome

Title	Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint
Description	Influenza virus titer is the quantity of influenza virus in a given volume within the samples obtained from nasal swabs. If influenza virus titer was less than the lower limit of quantification, the virus titer was imputed as 0.749 (log10 TCID50/mL). A lower value indicates lower viral titer.
Time Frame	Days 2, 3, 4, 5, 7, and 10

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza at any time point and with a positive virus titer on Day 1.

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	159	78
Day 2	37.7 15.8%	80.3 64.8%
Day 3	18.6 7.8%	53.4 43.1%
Day 4	7.9 3.3%	26.7 21.5%
Day 5	1.3 0.5%	20.8 16.8%
Day 7	2.7 1.1%	5.8 4.7%
Day 10	1.4 0.6%	1.4 1.1%

17. Secondary Outcome

Title	Area Under the Curve in Virus Titer
Time Frame	Days 1, 2, 3, 4, 5, 7, and 10

Outcome Measure Data

Analysis Population Description

Participants with a positive virus titer on Day 1

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	159	77
Mean (Standard Deviation) [log10 TCID50/mL*hours]	291.68 (176.68)	332.04 (183.63)

18. Secondary Outcome

Title	Time to Cessation of Viral Shedding by RT-PCR
Description	Time to cessation of viral shedding by RT-PCR, in hours, is defined as the time between the initiation of study treatment and first time when the virus RNA by RT-PCR is below the limit of detection (2.05 for flu A and 2.83 for flu B log10 virus particles/mL)
Time Frame	Screening (baseline) and on Days 2, 3, 4, 5, 7, and 10

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza on Day 1

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	205	111
Median (95% Confidence Interval) [hours]	216.3	261.1

19. Secondary Outcome

Title	Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint
Description	If the amount of virus RNA was less than the lower limit of quantification, the amount of virus RNA was imputed as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL)
Time Frame	Days 2, 3, 4, 5, 7, and 10

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza on Day 1

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	205	111
Day 2	-0.98	-0.66
Day 3	-1.54	-1.19
Day 4	-2.35	-1.84
Day 5	-2.91	-2.39
Day 7	-3.15	-2.96
Day 10	-3.69	-3.21

20. Secondary Outcome

Title	Percentage of Participants Positive by RT-PCR at Each Timepoint
Description	If the amount of virus RNA was less than the lower limit of quantification, the amount of virus RNA was imputed as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL)
Time Frame	Days 2, 3, 4, 5, 7, and 10

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza on Day 1

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	205	111
Day 2	95.6 40%	96.3 77.7%
Day 3	90.0 37.7%	93.3 75.2%
Day 4	88.1 36.9%	87.9 70.9%
Day 5	79.9 33.4%	85.4 68.9%
Day 7	69.6 29.1%	68.0 54.8%
Day 10	46.7 19.5%	50.5 40.7%

21. Secondary Outcome

Title	Area Under the Curve in the Amount of Virus RNA (RT-PCR)
Time Frame	Days 1, 2, 3, 4, 5, 7, and 10

Outcome Measure Data

Analysis Population Description

Participants were RT-PCR positive for influenza on Day 1.

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	197	106
Mean (Standard Deviation) [log10 virus particles/mL*hours]	676.40 (371.72)	740.15 (484.07)

22. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. A serious adverse event (SAE) is any significant hazard, contraindication, side effect that is fatal or life-threatening, requires hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/ birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above.
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	239	124
AEs	45.2 18.9%	50.0 40.3%
SAEs	12.1 5.1%	15.3 12.3%

23. Secondary Outcome

Title	Percentage of Participants With AEs and SAEs Leading to Discontinuation From Treatment
Description	Discontinuation from study treatment.
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	239	124
AEs	1.3 0.5%	3.2 2.6%
SAEs	0.8 0.3%	1.6 1.3%

24. Secondary Outcome

Title	Percentage of Participants With Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN
Description	ALT = alanine aminotransferase AST = aspartate transaminase
Time Frame	Up to Day 35

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Baloxavir Marboxil	Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.	Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	239	124
AST(U/L) or ALT (U/L) >3 x ULN	4.6 1.9%	8.9 7.2%
AST(U/L) or ALT (U/L) >5 x ULN	0.8 0.3%	3.2 2.6%
AST(U/L) or ALT (U/L) >10 x ULN	0 0%	1.6 1.3%

25. Secondary Outcome

Title	Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points
Time Frame	Day 1, 2, 4, 5, 7 and 8

Outcome Measure Data

Analysis Population Description

Participants who provided informed consent to intensive PK sampling in the Baloxavir Marboxil arm.

Arm/Group Title	Baloxavir Marboxil
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	8
Day 1 - 30 minutes postdose	37.82 (23.61)
Day 1 - 2 hours postdose	75.06 (52.16)
Day 1 - 4 hours postdose	95.85 (58.36)
Day 1 - 10 hours postdose	64.47 (39.47)
Day 2 - 24 hours postdose	53.36 (37.42)
Day 4 - Predose	24.26 (15.87)
Day 4 - 30 minutes postdose	49.16 (52.07)
Day 4 - 2 hours postdose	109.66 (95.22)
Day 4 - 4 hours postdose	117.69 (60.54)
Day 4 - 10 hours postdose	94.08 (49.71)
Day 5 - 24 hours postdose	77.98 (42.89)
Day 7 - predose	23.31 (25.87)
Day 8 - 24 hours postdose	105.00 (NA)
Visit 8	28.37 (61.61)

26. Secondary Outcome

Title	Area Under the Concentration to Time Curve From Time 0 to 72 Hours (AUC0-72) of Baloxavir
Time Frame	0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8

Outcome Measure Data

Analysis Population Description

Participants who provided informed consent to intensive pharmacokinetic (PK) sampling in the Baloxavir Marboxil arm.

Arm/Group Title	Baloxavir Marboxil
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	8
Day 1	2820 (70.5)
Day 4	3170 (53.5)

27. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Baloxavir
Time Frame	0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8

Outcome Measure Data

Analysis Population Description

Participants who provided informed consent to intensive PK sampling in the Baloxavir Marboxil arm.

Arm/Group Title	Baloxavir Marboxil
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	8
Day 1	86.3 (64.6)
Day 4	123 (51.7)

28. Secondary Outcome

Title	Apparent Half-Life (T1/2) of Baloxavir
Time Frame	0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8

Outcome Measure Data

Analysis Population Description

Participants who provided informed consent to intensive PK sampling and had a sufficient number of samples available for analysis

Arm/Group Title	Baloxavir Marboxil
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	8
Day 1	18.9 (NA)
Day 4	23.4 (12.8)

29. Secondary Outcome

Title	Concentration at 24 Hours (C24) of Baloxavir
Time Frame	0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8

Outcome Measure Data

Analysis Population Description

Participants who provided informed consent to intensive PK sampling in the Baloxavir Marboxil arm

Arm/Group Title	Baloxavir Marboxil
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Measure Participants	8
Day 1	43.9 (74.4)
Day 4	67.1 (66.8)
Day 7	105 (NA)

Adverse Events

Time Frame	Randomization up to Day 35
Arm/Group Title	Baloxavir Marboxil		Placebo
Arm/Group Description	Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with standard of care (SOC) NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.		Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
All Cause Mortality
	Baloxavir Marboxil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/239 (1.7%)		7/124 (5.6%)
Serious Adverse Events
	Baloxavir Marboxil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/239 (12.1%)		19/124 (15.3%)
Blood and lymphatic system disorders
Febrile neutropenia	1/239 (0.4%)	1	0/124 (0%)	0
Cardiac disorders
Acute myocardial infarction	1/239 (0.4%)	1	0/124 (0%)	0
Atrial fibrillation	1/239 (0.4%)	1	0/124 (0%)	0
Bradycardia	1/239 (0.4%)	1	0/124 (0%)	0
Cardiac failure	1/239 (0.4%)	1	1/124 (0.8%)	1
Congestive cardiomyopathy	0/239 (0%)	0	1/124 (0.8%)	1
Myocardial ischaemia	1/239 (0.4%)	1	0/124 (0%)	0
Supraventricular tachycardia	1/239 (0.4%)	1	0/124 (0%)	0
Gastrointestinal disorders
Constipation	0/239 (0%)	0	1/124 (0.8%)	1
Rectal haemorrhage	0/239 (0%)	0	1/124 (0.8%)	1
Small intestinal obstruction	0/239 (0%)	0	1/124 (0.8%)	1
General disorders
Multiple organ dysfunction syndrome	2/239 (0.8%)	2	0/124 (0%)	0
Immune system disorders
Graft versus host disease	0/239 (0%)	0	1/124 (0.8%)	1
Infections and infestations
Asymptomatic bacteriuria	1/239 (0.4%)	1	0/124 (0%)	0
Bronchitis	1/239 (0.4%)	1	0/124 (0%)	0
Cellulitis	0/239 (0%)	0	1/124 (0.8%)	1
Clostridium difficile colitis	1/239 (0.4%)	1	0/124 (0%)	0
Device related infection	0/239 (0%)	0	1/124 (0.8%)	1
Endocarditis	1/239 (0.4%)	1	0/124 (0%)	0
Lower respiratory tract infection viral	1/239 (0.4%)	1	0/124 (0%)	0
Pneumonia	7/239 (2.9%)	7	5/124 (4%)	5
Pneumonia bacterial	2/239 (0.8%)	2	1/124 (0.8%)	1
Pneumonia viral	1/239 (0.4%)	1	0/124 (0%)	0
Sepsis	0/239 (0%)	0	1/124 (0.8%)	1
Septic shock	1/239 (0.4%)	1	0/124 (0%)	0
Superinfection viral	1/239 (0.4%)	1	0/124 (0%)	0
Injury, poisoning and procedural complications
Ankle fracture	1/239 (0.4%)	1	0/124 (0%)	0
Fall	0/239 (0%)	0	1/124 (0.8%)	1
Spinal compression fracture	0/239 (0%)	0	1/124 (0.8%)	1
Investigations
Hepatic enzyme increased	0/239 (0%)	0	1/124 (0.8%)	1
Metabolism and nutrition disorders
Gout	0/239 (0%)	0	1/124 (0.8%)	1
Nervous system disorders
Cerebral artery embolism	1/239 (0.4%)	1	0/124 (0%)	0
Encephalopathy	0/239 (0%)	0	1/124 (0.8%)	1
Product Issues
Device malfunction	1/239 (0.4%)	1	0/124 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/239 (0%)	0	1/124 (0.8%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	2/239 (0.8%)	2	1/124 (0.8%)	1
Asthma	1/239 (0.4%)	1	0/124 (0%)	0
Bronchospasm	1/239 (0.4%)	2	0/124 (0%)	0
Chronic obstructive pulmonary disease	3/239 (1.3%)	4	0/124 (0%)	0
Dyspnoea	1/239 (0.4%)	1	0/124 (0%)	0
Interstitial lung disease	0/239 (0%)	0	2/124 (1.6%)	2
Respiratory failure	1/239 (0.4%)	1	1/124 (0.8%)	1
Vascular disorders
Aortic aneurysm rupture	1/239 (0.4%)	1	0/124 (0%)	0
Hypotension	1/239 (0.4%)	1	0/124 (0%)	0
Orthostatic hypotension	0/239 (0%)	0	1/124 (0.8%)	1
Peripheral ischaemia	1/239 (0.4%)	1	0/124 (0%)	0
Other (Not Including Serious) Adverse Events
	Baloxavir Marboxil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/239 (18.4%)		27/124 (21.8%)
Gastrointestinal disorders
Constipation	10/239 (4.2%)	10	6/124 (4.8%)	6
Diarrhoea	8/239 (3.3%)	8	6/124 (4.8%)	7
Nausea	7/239 (2.9%)	9	4/124 (3.2%)	4
Infections and infestations
Pneumonia	5/239 (2.1%)	6	4/124 (3.2%)	4
Investigations
Hepatic enzyme increased	6/239 (2.5%)	7	5/124 (4%)	5
Metabolism and nutrition disorders
Hypokalaemia	9/239 (3.8%)	9	5/124 (4%)	5
Nervous system disorders
Headache	9/239 (3.8%)	11	2/124 (1.6%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.