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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 : Completed
First Posted : September 25, 2018
Results First Posted : November 30, 2020
Last Update Posted : January 6, 2021
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)
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 : January 8, 2019
Actual Primary Completion Date : March 16, 2020
Actual Study Completion Date : March 16, 2020

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 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.




Primary Outcome Measures :
  1. Time to Clinical Improvement [ Time Frame: 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 [ Time Frame: 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 [ 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 ]
    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 [ 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 ]
    A score of 0 (Range 0 - 3) indicates normal health conditions.

  13. Time to Cessation of Viral Shedding by Virus Titer [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Days 1, 2, 3, 4, 5, 7, and 10 ]
  17. Time to Cessation of Viral Shedding by RT-PCR [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: Days 1, 2, 3, 4, 5, 7, and 10 ]
  21. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Up to Day 35 ]
    ALT = alanine aminotransferase AST = aspartate transaminase

  24. Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points [ Time Frame: 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 [ 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 ]
  26. 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 ]
  27. 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 ]
  28. 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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 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

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


Locations
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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
  Study Documents (Full-Text)

Documents provided by Hoffmann-La Roche:
Study Protocol  [PDF] May 30, 2019
Statistical Analysis Plan  [PDF] May 7, 2020

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT03684044    
Other Study ID Numbers: CP40617
2018-001416-30 ( EudraCT Number )
First Posted: September 25, 2018    Key Record Dates
Results First Posted: November 30, 2020
Last Update Posted: January 6, 2021
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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).

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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
Baloxavir
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action