A Pharmacokinetics Study of Favipiravir in Patients With Severe Influenza

Study Overview
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Brief Summary
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Title: An adaptive study of the pharmacokinetics of favipiravir in patients with severe influenza Study Design: An open label, single group assignment, adaptive study to evaluate the pharmacokinetics of favipiravir in adult patients with severe influenza. In the first stage, participants will receive favipiravir 1600mg BID on day 1, followed by favipiravir 600mg BID for 9 days. If the proportion of patients with a minimum observed plasma trough concentration above the MEC (20μg/ml) at all measured time points after the second dose is less than 80% then a second patient cohort will be recruited and will receive favipiravir 1800mg BID on day 1, followed by favipiravir 800mg BID for 9 days. Intervention: The 1st stage: 1600mg BID on day 1, followed with 600mg BID for 9 days. Sample size: 15 The 2nd stage: 1800mg BID on day 1, followed with 800mg BID for 9 days. Sample size: 15 Population: Males and females aged 18 years or older admitted to hospital with a positive PCR test for influenza and a PaO2/FiO2≤300mmHg or/and on mechanical ventilation for severe lung infection on admission. Sample size 15 or 30 severe influenza patients Research hypothesis The administration of oral favipiravir at either 1600mg/600mg BID or 1800/800mg BID will result in ≥ 80% patients achieving a minimum observed plasma trough concentration above the MEC (20μg/ml) at all measured time points after the second dose. Phase: Phase 2a, PK, safety and feasibility study. Description of Study Agent: Favipiravir (T-705) a viral RNA-dependent RNA polymerase inhibitor. Study Duration: 1 year Participant Duration: 38 days

Official Title
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An Adaptive Study of the Pharmacokinetics of Favipiravir in Patients With Severe

Conditions
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Influenza, Human, Critical Illness, Influenza

Intervention / Treatment
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* Drug: Favipiravir
* Drug: Oseltamivir 75Mg Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalized males or females with a positive PCR test for influenza virus infection Adults aged ≥18years PaO2/FiO2≤300mmHg or on mechanical ventilation < 10 days since symptom onset Negative pregnancy testing for childbearing age females (under 60 years) Willingness to use contraception for 7 days after end of treatment Informed consent In addition, male subjects must: Agree not to donate sperm during the study and for 7 days following the last dose of study drug, and Agree to adhere strictly to one of the following contraceptive measures from the Screening Visit until 7 days after the last dose of study drug: i. abstain from sexual intercourse or ii. have a female partner using effective means of birth control as noted below or iii. use a condom with spermicide or a second barrier method by female partner. Female subjects a. Of child-bearing potential must agree to adhere strictly to one of the following approved contraceptive measures during the study and for 7 days after the last dose of study drug: i. abstain from sexual intercourse or ii. have a male partner incapable of fathering a child (eg, had a vasectomy at least 6 months with history of negative semen analysis prior Screening or iii. use of one of the following methods, in combination with condom and spermicide use by a male partner: nonhormonal intrauterine device (IUD); diaphragm; or hormonal contraceptives including oral contraceptives, injectable subdermal implants, hormonal IUD, or vaginal ring b. Be unable to bear children defined as one of the following: i. absence of a menstrual period for ≥12 consecutive months with FSH confirmation, ii. be 60 years of age or greater, iii. had surgical removal of uterus or removal of both ovaries, or iv. had undergone tubal ligation >6 weeks prior to Day 1 dosing Exclusion Criteria: Any condition that does not allow for safely following the protocol Patient refusal to accept invasive organ support treatment if needed Pregnant or breastfeeding Any condition resulted to reception of renal replacement therapy AST > 5 times upper of limit or Child Pugh score ≥ C Serum uric acid level > 3 times upper level of normal (430 ummol/L) associated with symptoms of gout Has a history of gout or is under treatment for: gout or hyperuricemia; hereditary xanthinuria; hypouricemia or xanthine calculi of the urinary tract Has a history of hypersensitivity to an anti-viral nucleoside-analog drug targeting a viral RNA polymerase Physician makes a decision that trial involvement is not in patients' best interest. Currently or have been involved in another anti-influenza treatment trial in the last 28 days

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Interventional Model Description: This is a adaptive study, which include two steps. 1st step: 1600mg BID on day 1, followed by 600mg BID for 9 days. Sample size: 15 PK analysis: If the proportion of patients with a minimum observed plasma trough concentration above the MEC (20μg/ml) at all measured time points after the second dose is greater than or equal to 80% then the dose is considered adequate and the study will be completed. If not, then a second patient cohort will be recruited and will receive favipiravir 1800mg BID on day 1, followed by favipiravir 800mg BID for 9 days. Sample size: 15
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Favipiravir+oseltamivir<br>Favipiravir+oseltamivir will be given twice daily for a 10-day period. | Drug: Favipiravir<br>* In first step: favipiravir tablet is orally administered. This drug will be given twice daily for a 10-day period. For the First day, the dosage is 1600 mg twice daily. Starting from the second day, the dosage is 600 mg twice daily. In second step: favipiravir tablet is orally administered. This drug will be given twice daily for a 10-day period. For the First day, the dosage is 1800 mg twice daily. Starting from the second day, the dosage is 800 mg twice daily.<br>* Other names: T-705;Drug: Oseltamivir 75Mg Capsule<br>* oseltamivir will be administered at 75mg twice daily orally for 10 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with minimum plasma of Favipiravir trough concentration above the MEC (20μg/ml) at all measured time points after the second dose. |  | 10 days during the intervention period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration observed over the treatment period (Cmax ) |  | 10 days during the intervention period | 
| Minimum plasma concentration observed over the treatment period (Cmin) |  | 10 days during the intervention period | 
| Average pre-dose plasma concentration (Trough) |  | 10 days during the intervention period | 
| Proportion of patients whose favipiravir plasma concentration at least one time exceeds MEC in study days |  | 10 days during the intervention period | 
| The proportion of patients falling into each category of a five-point ordinal scale on day 10 and day 28 after starting favipiravir | The category of a five-point ordinal scale: death; hospitalised on ECMO and/or mechanical ventilation; hospitalised on supplemental oxygenation; hospitalised not on supplemental oxygenation; discharged. | 28 days from starting intervention | 
| Duration (days) of mechanical ventilation |  | from reception of mechanical ventilation to ventilator weening, an average of 10 days | 
| Duration (days) of extracorporeal membrane oxygenation |  | from starting ECMO to weening, an average of 9 days | 
| Duration (days) of supplemental oxygenation |  | Duration (days) of hospitalization with oxygen therapy，an average of 13 days | 
| Duration (days) of hospitalization |  | Days from admission to discharge，an average of 19 days | 
| The proportion of patients with a negative RT-PCR for influenza from upper and/or lower respiratory tract samples on day 10 after starting treatment |  | Duration of viral shedding,an average of 15 days | 
| The time (days) to negative RT-PCR for influenza from upper and/or lower respiratory tract samples (capped at day 10) |  | Duration of viral shedding,an average of 15 days | 
| The proportion of patients with drug related adverse events |  | 38 days from starting intervention | 
| The proportion of patients with genetic and phenotypic markers of resistance to favipiravir and/or oseltamivir |  | Days from admission to discharge，an average of 19 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Favipiravir, Influenza, Human, Critical Illness, Pharmacokinetics