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A Pharmacokinetics Study of Favipiravir in Patients With Severe Influenza

Primary Purpose

Influenza, Human, Critical Illness, Influenza

Status

Completed

Phase

Phase 2

Locations

China

Study Type

Interventional

Intervention

Favipiravir

Oseltamivir 75Mg Capsule

About this trial

This is an interventional treatment trial for Influenza, Human focused on measuring Favipiravir, Influenza, Human, Critical Illness, Pharmacokinetics

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:
1. Agree not to donate sperm during the study and for 7 days following the last dose of study drug, and
2. 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

Sites / Locations

China-Japan Friendship Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Favipiravir+oseltamivir

Arm Description

Favipiravir+oseltamivir will be given twice daily for a 10-day period.

Outcomes

Primary Outcome Measures

Proportion of patients with minimum plasma of Favipiravir trough concentration above the MEC (20μg/ml) at all measured time points after the second dose.

Secondary Outcome Measures

Maximum plasma concentration observed over the treatment period (Cmax )

Minimum plasma concentration observed over the treatment period (Cmin)

Average pre-dose plasma concentration (Trough)

Proportion of patients whose favipiravir plasma concentration at least one time exceeds MEC in study days

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.

Duration (days) of mechanical ventilation

Duration (days) of extracorporeal membrane oxygenation

Duration (days) of supplemental oxygenation

Duration (days) of hospitalization

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

The time (days) to negative RT-PCR for influenza from upper and/or lower respiratory tract samples (capped at day 10)

The proportion of patients with drug related adverse events

The proportion of patients with genetic and phenotypic markers of resistance to favipiravir and/or oseltamivir

Full Information

NCT ID

NCT03394209

First Posted

December 25, 2017

Last Updated

May 14, 2019

Sponsor

Capital Medical University

Collaborators

Beijing Institute of Pharmacology and Toxicology, University of Oxford, Centers for Disease Control and Prevention, China

1. Study Identification

Unique Protocol Identification Number

NCT03394209

Brief Title

A Pharmacokinetics Study of Favipiravir in Patients With Severe Influenza

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2019

Overall Recruitment Status

Completed

Study Start Date

February 6, 2018 (Actual)

Primary Completion Date

February 20, 2019 (Actual)

Study Completion Date

March 27, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Capital Medical University

Collaborators

Beijing Institute of Pharmacology and Toxicology, University of Oxford, Centers for Disease Control and Prevention, China

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Influenza, Human, Critical Illness, Influenza

Keywords

Favipiravir, Influenza, Human, Critical Illness, Pharmacokinetics

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

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)

Allocation

N/A

Enrollment

34 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Favipiravir+oseltamivir

Arm Type

Experimental

Arm Description

Favipiravir+oseltamivir will be given twice daily for a 10-day period.

Intervention Type

Drug

Intervention Name(s)

Favipiravir

Other Intervention Name(s)

T-705

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Oseltamivir 75Mg Capsule

Intervention Description

oseltamivir will be administered at 75mg twice daily orally for 10 days

Primary Outcome Measure Information:

Title

Proportion of patients with minimum plasma of Favipiravir trough concentration above the MEC (20μg/ml) at all measured time points after the second dose.

Time Frame