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

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

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.

Study Overview

• Status: Completed
• Conditions: Influenza
• Intervention / Treatment: Drug: Baloxavir Marboxil; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 363
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rates of the 6-Point Ordinal Scale at Day 7	The ordinal scale categories are: Category 1) Discharged (or "ready for discharge") Category 2) Non-ICU hospital ward (or "ready for hospital ward") not requiring supplemental oxygen/non-invasive ventilation Category 3) Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen/non-invasive ventilation Category 4) ICU without mechanical (invasive) ventilation (or "ready for ICU admission") Category 5) Mechanical (invasive) ventilation Category 6) Death	Day 7
Time to Clinical Response	Time to Clinical Response is based on temperature ranges, oxygen saturation, respiratory status, heart rate, and hospitalization status.	Up to Day 35
Percentage of Participants on Mechanical Ventilation		Up to Day 35
Duration of Mechanical Ventilation		Up to Day 35
Percentage of Participants Requiring ICU Stay		Up to Day 35
Duration of ICU Stay		Up to Day 35
Time to Clinical Failure	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	Up to Day 35
Time to Hospital Discharge		Up to Day 35
Percentage of Participants With Post-Treatment Influenza-Related Complications	Influenza-related complications included pneumonia, myositis or rhabdomyolysis, encephalitis or encephalopathy, myocarditis and/or pericarditis, otitis media, sinusitis, exacerbation of COPD/asthma, sepsis, acute lung injury or acute respiratory distress syndrome.	Up to Day 35
Mortality Rate at Day 7		Up to Day 7
Mortality Rate at Day 28		Up to Day 28
Time to NEWS2 of ≤ 2 Maintained for 24 Hours	A score of 0 (Range 0 - 3) indicates normal health conditions.	Up to Day 35
Time to Cessation of Viral Shedding by Virus Titer	Time to cessation of viral shedding by virus titer is defined as the time, in hours, between the initiation of study treatment and first time when the influenza virus titer is below the limit of detection (0.75 log10 TCID50/mL)	Screening (baseline) and on Days 2, 3, 4, 5, 7, and 10
Change From Baseline in Influenza Virus Titer at Each Timepoint	Influenza virus titer is the quantity of influenza virus in a given volume within the samples obtained from nasal swabs. If influenza virus titer was less than the lower limit of quantification, the virus titer was imputed as 0.749 (log10TCID50/mL). A lower value indicates lower viral titer.	Days 2, 3, 4, 5, 7, and 10
Percentage of Participants With Positive Influenza Virus Titer at Each Timepoint	Influenza virus titer is the quantity of influenza virus in a given volume within the samples obtained from nasal swabs. If influenza virus titer was less than the lower limit of quantification, the virus titer was imputed as 0.749 (log10 TCID50/mL). A lower value indicates lower viral titer.	Days 2, 3, 4, 5, 7, and 10
Area Under the Curve in Virus Titer		Days 1, 2, 3, 4, 5, 7, and 10
Time to Cessation of Viral Shedding by RT-PCR	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)	Screening (baseline) and on Days 2, 3, 4, 5, 7, and 10
Change From Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint	If the amount of virus RNA was less than the lower limit of quantification, the amount of virus RNA was imputed as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL)	Days 2, 3, 4, 5, 7, and 10
Percentage of Participants Positive by RT-PCR at Each Timepoint	If the amount of virus RNA was less than the lower limit of quantification, the amount of virus RNA was imputed as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL)	Days 2, 3, 4, 5, 7, and 10
Area Under the Curve in the Amount of Virus RNA (RT-PCR)		Days 1, 2, 3, 4, 5, 7, and 10
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	Up to Day 35
Percentage of Participants With AEs and SAEs Leading to Discontinuation From Treatment	Discontinuation from study treatment.	Up to Day 35
Percentage of Participants With Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN	ALT = alanine aminotransferase AST = aspartate transaminase	Up to Day 35
Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points		Day 1, 2, 4, 5, 7 and 8
Area Under the Concentration to Time Curve From Time 0 to 72 Hours (AUC0-72) of Baloxavir		0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8
Maximum Plasma Concentration (Cmax) of Baloxavir		0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8
Apparent Half-Life (T1/2) of Baloxavir		0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8
Concentration at 24 Hours (C24) of Baloxavir		0, 0.5, 2, 4, 10, 24, 72 hours from dose on Day 1 and on Day 4, and Day 7, Day 8

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Stannard HL, Mifsud EJ, Wildum S, Brown SK, Koszalka P, Shishido T, Kojima S, Omoto S, Baba K, Kuhlbusch K, Hurt AC, Barr IG. Assessing the fitness of a dual-antiviral drug resistant human influenza virus in the ferret model. Commun Biol. 2022 Sep 28;5(1):1026. doi: 10.1038/s42003-022-04005-4.
• Kumar D, Ison MG, Mira JP, Welte T, Hwan Ha J, Hui DS, Zhong N, Saito T, Katugampola L, Collinson N, Williams S, Wildum S, Ackrill A, Clinch B, Lee N. Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trial. Lancet Infect Dis. 2022 May;22(5):718-730. doi: 10.1016/S1473-3099(21)00469-2. Epub 2022 Jan 24.
• Young B, Tan TT, Leo YS. The place for remdesivir in COVID-19 treatment. Lancet Infect Dis. 2021 Jan;21(1):20-21. doi: 10.1016/S1473-3099(20)30911-7. Epub 2020 Nov 26. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2019
• Primary Completion (Actual): March 16, 2020
• Study Completion (Actual): March 16, 2020

Study Registration Dates

• First Submitted: September 24, 2018
• First Submitted That Met QC Criteria: September 24, 2018
• First Posted (Actual): September 25, 2018

Study Record Updates

• Last Update Posted (Actual): January 6, 2021
• Last Update Submitted That Met QC Criteria: December 14, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Baloxavir
• Other Study ID Numbers: CP40617; 2018-001416-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No