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

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ClinicalTrials.gov Identifier: NCT03684044
Recruitment Status : Recruiting
First Posted : September 25, 2018
Last Update Posted : November 13, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 366 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 : January 8, 2019
Estimated Primary Completion Date : March 27, 2021
Estimated Study Completion Date : March 27, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Flu Flu Shot

Arm Intervention/treatment
Experimental: Baloxavir Marboxil

Participants will receive at least two doses of baloxavir marboxil or its matching placebo on Day 1 and 4. A third dose of Baloxavir or its matching 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. SOC NAI will be administered to cover a minimum of treatment exposure from Day 1 to Day 5

Drug: Baloxavir Marboxil

Baloxavir marboxil will be administered as a weight-based dose on Days 1 and 4. A third dose of Baloxavir or its matching placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5

Treatment with a SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) will also be administered in accordance with local clinical practice.


Placebo Comparator: Placebo

Participants will be assigned in a 2:1 ratio to receive baloxavir marboxil or matching placebo.

Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice. SOC NAI will be administered to cover a minimum of treatment exposure from Day 1 to Day 5

Other: Placebo
Participants will receive Baloxavir marboxil or matching placebo in 2:1 ratio. Treatment with a SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) will also be administered in accordance with local clinical practice.




Primary Outcome Measures :
  1. Time to Clinical Improvement [ Time Frame: Up to Day 35 ]

    Time to Clinical Improvement 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 [ Time Frame: Day 7 ]
  2. Time to Clinical Response [ Time Frame: 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 [ Time Frame: Up to Day 35 ]
  4. Duration of Mechanical Ventilation [ Time Frame: Up to Day 35 ]
  5. Percentage of Participants Requiring ICU Stay [ Time Frame: Up to Day 35 ]
  6. Duration of ICU Stay [ Time Frame: Up to Day 35 ]
  7. Time to Clinical Failure [ Time Frame: 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 [ Time Frame: Up to Day 35 ]
  9. Percentage of Participants with Post-Treatment Influenza-Related Complications [ Time Frame: Up to Day 35 ]
  10. Mortality Rate at Day 7 [ Time Frame: Up to Day 7 ]
  11. Mortality Rate at Day 28 [ Time Frame: Up to Day 28 ]
  12. Time to NEWS2 of ≤ 2 maintained for 24 hours [ Time Frame: Up to Day 35 ]
  13. Time to Cessation of Viral Shedding by Virus Titer [ Time Frame: Up to Day 35 ]
  14. Time to Cessation of Viral Shedding by RT-PCR [ Time Frame: Up to Day 35 ]
  15. Change from Baseline in Influenza Virus Titer and in the Amount of Virus RNA (RT-PCR) at Each Timepoint [ Time Frame: Up to Day 35 ]
  16. Percentage of Participants with Positive Influenza Virus Titer and Positive by RT-PCR at Each Timepoint [ Time Frame: Up to Day 35 ]
  17. Area Under the Curve in Virus Titer and in the Amount of Virus RNA (RT-PCR) [ Time Frame: Up to Day 35 ]
  18. Polymorphic and Treatment-Emergent Amino Acid Substitutions in the PA, PB1, PB2, and NA Genes [ Time Frame: Up to Day 35 ]
  19. Drug Susceptibility in Participants with Evaluable Virus [ Time Frame: Up to Day 35 ]
  20. Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Day 35 ]
  21. Percentage of Participants with AEs Leading to Discontinuation [ Time Frame: Up to Day 35 ]
  22. Percentage of Participants with Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN [ Time Frame: Up to Day 35 ]
    ALT = alanine aminotransferase AST = aspartate transaminase

  23. Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points [ Time Frame: Day 1, 2, 4, 5, 7, 8 and Day 11 to Day 30 ]
  24. Area Under the Curve (AUC) of Baloxavir [ Time Frame: Day 1, 2, 4, 5, 7, 8 and Day 11 to Day 30 ]
    Only for participants undergoing sequential PK sampling

  25. Maximum Plasma Concentration (Cmax) of Baloxavir [ Time Frame: Day 1, 2, 4, 5, 7, 8 and Day 11 to Day 30 ]
    Only for participants undergoing sequential PK sampling

  26. Apparent Half-Life (T1/2) of Baloxavir [ Time Frame: Day 1, 2, 4, 5, 7, 8 and Day 11 to Day 30 ]
    Only for patients undergoing sequential PK sampling



Information from the National Library of Medicine

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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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, CNS 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:
  • ALT or 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03684044


Contacts
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Contact: Reference Study ID Number: CP40617 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03684044     History of Changes
Other Study ID Numbers: CP40617
2018-001416-30 ( EudraCT Number )
First Posted: September 25, 2018    Key Record Dates
Last Update Posted: November 13, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Influenza, Human
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Oseltamivir
Zanamivir
Peramivir
Baloxavir
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action