E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Influenza, commonly known as "the flu", is an infectious respiratory disease caused by influenza viruses |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10016790 |
E.1.2 | Term | Flu |
E.1.2 | System Organ Class | 100000004862 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10022001 |
E.1.2 | Term | Influenza (epidemic) |
E.1.2 | System Organ Class | 100000004862 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10022003 |
E.1.2 | Term | Influenza B virus infection |
E.1.2 | System Organ Class | 100000004862 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10022002 |
E.1.2 | Term | Influenza A virus infection |
E.1.2 | System Organ Class | 100000004862 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the clinical efficacy of baloxavir marboxil plus a standard-of-care (SOC) neuraminidase inhibitor (NAI) compared with matching placebo plus a SOC NAI based on time to clinical improvement |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the clinical efficacy of baloxavir marboxil plus a SOC NAI compared with matching placebo plus a SOC NAI based on Response rates of the 6-point ordinal scale at Day 7, Incidence and duration of mechanical ventilation, intensive care unit (ICU) stay, Incidence of post-treatment influenza-related complications, Time to clinical failure, hospital discharge, National Early Warning Score (NEWS) 2 of <= 2 maintained for 24 hours, Mortality rate at Day 7 and 28
• To evaluate the antiviral activity of baloxavir marboxil plus a SOC NAI compared with matching placebo plus a SOC NAI
• To evaluate the polymorphic and treatment-emergent amino acid substitutions in the PA, PB1, PB2, and NA genes and drug susceptibility in patients with evaluable virus
• To evaluate the safety of baloxavir marboxil plus a SOC NAI compared with matching placebo plus a SOC NAI in hospitalized patients with influenza
• To evaluate the single- and multiple dose pharmacokinetics of baloxavir
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Adult patients: Signed informed consent by any patient capable of giving consent, or, where the patient is not capable of giving consent, by his or her legal/authorized representative
- Adolescent patients not able to legally consent: written informed consent for study participation is obtained from patient’s parents or legal guardian, with assent as appropriate by the patient, depending on the patient’s level of understanding and capability to provide assent
- Age >= 12 years at the time of signing the Informed Consent Form/Assent Form
- Ability to comply with the study protocol, in the investigator’s judgment
- Patients 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) A patient with a negative RIDT may be enrolled if influenza is suspected based on local surveillance data or if the patient reports contact with a known case of influenza within the prior 7 days
- The time interval between the onset of symptoms and randomization is within 96 hours
- A score of >= 4 based on the NEWS2
- Patients 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
- For women of childbearing potential: Agreement to remain abstinent (refrain from heterosexual intercourse) 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.
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E.4 | Principal exclusion criteria |
- Patients who have received more than 48 hours of antiviral treatment for influenza prior to screening
- Patients who have received baloxavir marboxil for the current influenza infection
- Known contraindication to neuraminidase inhibitors
- Known hypersensitivity to baloxavir marboxil or the drug product excipients
- Patients hospitalized for exclusively social reasons (e.g., lack of caregivers at home)
- Patients expected to die or be discharged within 48 hours, according to the investigator’s judgement
- Patients weighing <40 kg
- Patients with known severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis
- Patients 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 patient’s safe participation in and completion of the study
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to clinical improvement (defined as time to hospital discharge OR time to NEWS2 of less than or equal to 2 maintained for 24 hours) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Key secondary efficacy:
1. Response rates of the 6-point ordinal scale at Day 7
Secondary efficacy
2. Incidence of mechanical ventilation
3. Duration of mechanical ventilation
4. Incidence of ICU stay
5. Duration of ICU stay
6. Time to clinical failure
7. Time to hospital discharge
8. Incidence of post-treatment influenza-related complications
9. Mortality rate at Day 7
10. Mortality rate at Day 28
11. Time to NEWS2 of <= 2 maintained for 24 hours
Virology
12. Time to cessation of viral shedding by virus titer
13. Time to cessation of viral shedding by RT-PCR
14. Change from baseline in influenza virus titer and in the amount of virus RNA (RT-PCR) at each time point
15. Proportion of patients with positive influenza virus titer and proportion of patients positive by RT-PCR at each time point
16. Area under the concentration-time curve (AUC), in virus titer and in the amount of virus RNA (RT PCR)
17. Polymorphic and treatment-emergent amino acid substitutions in the PA, PB1, PB2, and NA genes
18. Drug susceptibility in patients with evaluable virus
Safety
19. Compare the incidence and severity of adverse event (AE)s and serious AEs
20. Incidence of AEs leading to discontinuation
21. Proportion of patients with any post-treatment ALT and AST above baseline and >3 × ULN, >5 × ULN, >10 × ULN
PK
22. Plasma concentrations of baloxavir (active metabolite) at specified timepoints
23. Baloxavir concentration at pre-dose and at 24 hour after each dose of baloxavir marboxil (C24) (all patients)
24. Total drug exposure (AUC), maximum plasma concentration (Cmax) and Half-life (t1/2) of baloxavir (only for patients undergoing sequential PK sampling) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At Day 7
2-8. Up to Day 35
9. At Day 7
10. At Day 28
11. Up to Day35
12-21. Up to Day 35
22-24. Up to Day 34
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 105 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Belgium |
Brazil |
Bulgaria |
Canada |
Czech Republic |
Estonia |
Finland |
France |
Germany |
Hong Kong |
Hungary |
Israel |
Japan |
Korea, Republic of |
Mexico |
Netherlands |
New Zealand |
Peru |
Romania |
Serbia |
Singapore |
Spain |
Sweden |
Turkey |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the date at which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |