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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Influenza

Intervention / Treatment
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* Drug: Baloxavir Marboxil
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Baloxavir Marboxil<br>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<br>* 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.<br>|
| Placebo Comparator: Placebo<br>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<br>* Participants will receive matching placebo on Days 1, 4 and 7.<br>|

What is the study measuring?
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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 |