A Pharmacokinetics Study of Favipiravir in Patients With Severe Influenza

NCT03394209 | Completed Phase 2 DMC

• 1 other identifier: FAVI-PK-2017001
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

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

Conditions

Influenza, Human; Critical Illness; Influenza

Keywords

Favipiravir, Influenza, Human, Critical Illness, Pharmacokinetics

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• 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

  28 days from starting intervention

Study Arms (1)

Favipiravir+oseltamivir

EXPERIMENTAL

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

Drug: Favipiravir; Drug: Oseltamivir 75Mg Capsule

Interventions

Favipiravir DRUG

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.

Also known as: T-705

Favipiravir+oseltamivir

Oseltamivir 75Mg Capsule DRUG

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

Favipiravir+oseltamivir

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Capital Medical University: lead
• Beijing Institute of Pharmacology and Toxicology: collaborator
• University of Oxford: collaborator
• Centers for Disease Control and Prevention, China: collaborator

Study Sites (1)

China-Japan Friendship Hospital

Beijing, 100029, China

Location

Related Publications (7)

• Gao HN, Lu HZ, Cao B, Du B, Shang H, Gan JH, Lu SH, Yang YD, Fang Q, Shen YZ, Xi XM, Gu Q, Zhou XM, Qu HP, Yan Z, Li FM, Zhao W, Gao ZC, Wang GF, Ruan LX, Wang WH, Ye J, Cao HF, Li XW, Zhang WH, Fang XC, He J, Liang WF, Xie J, Zeng M, Wu XZ, Li J, Xia Q, Jin ZC, Chen Q, Tang C, Zhang ZY, Hou BM, Feng ZX, Sheng JF, Zhong NS, Li LJ. Clinical findings in 111 cases of influenza A (H7N9) virus infection. N Engl J Med. 2013 Jun 13;368(24):2277-85. doi: 10.1056/NEJMoa1305584. Epub 2013 May 22.

  PMID: 23697469 RESULT

• Zheng S, Tang L, Gao H, Wang Y, Yu F, Cui D, Xie G, Yang X, Zhang W, Ye X, Zhang Z, Wang X, Yu L, Zhang Y, Yang S, Liang W, Chen Y, Li L. Benefit of Early Initiation of Neuraminidase Inhibitor Treatment to Hospitalized Patients With Avian Influenza A(H7N9) Virus. Clin Infect Dis. 2018 Mar 19;66(7):1054-1060. doi: 10.1093/cid/cix930.

  PMID: 29077848 RESULT

• Li H, Yang SG, Gu L, Zhang Y, Yan XX, Liang ZA, Zhang W, Jia HY, Chen W, Liu M, Yu KJ, Xue CX, Hu K, Zou Q, Li LJ, Cao B, Wang C; National Influenza A(H1N1)pdm09 Clinical Investigation Group of China. Effect of low-to-moderate-dose corticosteroids on mortality of hospitalized adolescents and adults with influenza A(H1N1)pdm09 viral pneumonia. Influenza Other Respir Viruses. 2017 Jul;11(4):345-354. doi: 10.1111/irv.12456. Epub 2017 Jun 9.

  PMID: 28464462 RESULT

• Wang X, Jiang H, Wu P, Uyeki TM, Feng L, Lai S, Wang L, Huo X, Xu K, Chen E, Wang X, He J, Kang M, Zhang R, Zhang J, Wu J, Hu S, Zhang H, Liu X, Fu W, Ou J, Wu S, Qin Y, Zhang Z, Shi Y, Zhang J, Artois J, Fang VJ, Zhu H, Guan Y, Gilbert M, Horby PW, Leung GM, Gao GF, Cowling BJ, Yu H. Epidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013-17: an epidemiological study of laboratory-confirmed case series. Lancet Infect Dis. 2017 Aug;17(8):822-832. doi: 10.1016/S1473-3099(17)30323-7. Epub 2017 Jun 2.

  PMID: 28583578 RESULT

• Dunning J, Baillie JK, Cao B, Hayden FG; International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). Antiviral combinations for severe influenza. Lancet Infect Dis. 2014 Dec;14(12):1259-70. doi: 10.1016/S1473-3099(14)70821-7. Epub 2014 Sep 8.

  PMID: 25213733 RESULT

• Kumar A. Early versus late oseltamivir treatment in severely ill patients with 2009 pandemic influenza A (H1N1): speed is life. J Antimicrob Chemother. 2011 May;66(5):959-63. doi: 10.1093/jac/dkr090. Epub 2011 Mar 15.

  PMID: 21406435 RESULT

• Kile JC, Ren R, Liu L, Greene CM, Roguski K, Iuliano AD, Jang Y, Jones J, Thor S, Song Y, Zhou S, Trock SC, Dugan V, Wentworth DE, Levine MZ, Uyeki TM, Katz JM, Jernigan DB, Olsen SJ, Fry AM, Azziz-Baumgartner E, Davis CT. Update: Increase in Human Infections with Novel Asian Lineage Avian Influenza A(H7N9) Viruses During the Fifth Epidemic - China, October 1, 2016-August 7, 2017. MMWR Morb Mortal Wkly Rep. 2017 Sep 8;66(35):928-932. doi: 10.15585/mmwr.mm6635a2.

  PMID: 28880856 RESULT

MeSH Terms

Conditions

Influenza, Human; Critical Illness

Interventions

favipiravir; Oseltamivir

Condition Hierarchy (Ancestors)

Respiratory Tract Infections; Infections; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr.Bin Cao

Model Details: 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

Study Record Dates

• First Submitted: December 25, 2017
• First Posted: January 9, 2018
• Study Start: February 6, 2018
• Primary Completion: February 20, 2019
• Study Completion: March 27, 2019
• Last Updated: May 15, 2019

Record last verified: 2019-05

Locations

CN (1)