Clinical Trial: Efficacy of Favipiravir Against Ebola (JIKI)

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Efficacy of Favipiravir in Reducing Mortality in Individuals With Ebola Virus Disease in Guinea

Brief Summary:

There is no specific treatment for Ebola Virus Disease (EVD). Current EVD care are supportive, and includes intravenous or oral rehydration, nutrition, pain killers, treatment of coinfections with antibacterial and antimalarial drugs, and blood transfusion when appropriate. Despite these interventions, mortality remains high since the ongoing Ebola outbreak in West Africa was declared in April.

Potential anti-Ebola specific interventions include convalescent plasma, monoclonal and polyclonal antibodies, small inhibitory RNA (siRNA), synthetic adenosine analogues or RNA polymerase inhibitors. All these interventions are considered investigational due to lack of data in humans with EVD.

In this study, the investigators chose to study the efficacy of favipiravir because this drug:

  • showed anti-Ebola efficacy in immunodeficient murine models;
  • has been studied in thousands of adult humans participating in anti-influenza trials, with good tolerance; it has been approved for treating novel or resistant influenza infections in Japan;
  • is immediately available;
  • can be used orally, and can be easily given in both adults and children because pills can be crushed and mixed in food or liquids;
  • has recently been used in Europe for treating several patients with EVD; the French drug safety agency (ANSM) has reviewed published data as well as data provided by the firm (Toyama Chemical Co., Ltd), and approved its compassionate use in EVD.

Here the investigators propose to assess the efficacy of high-dosed favipiravir in reducing mortality in humans with EVD.

Detailed Summary:

Hypotheses:

  1. The efficacy of antivirals in patients with EVD should correlate negatively with time since first symptoms. Thus, in this proof of concept trial, the main analysis will be done in adult patients with early symptoms in whom the efficacy is expected to be the highest;
  2. Favipiravir for EVD should be given at higher doses than that previously tested in studies in human with influenza. For this trial, the dose was calculated based on pharmacokinetics simulations, to rapidly reach plasma concentrations associated with anti-EBOV activity.
  3. A third assumption was made, given recent pre-trial data showing first a strong link between baseline viral load and mortality and second a higher mortality in children below 6 years: the efficacy of antivirals in patients with EVD should correlate negatively with viral load at start of treatment and with young age. Thus a secondary objective is the efficacy of favipiravir in adult patients and children >6 years with moderate baseline viral load (i.e. cycle threshold [Ct] ≥20 measured by RT-PCR) in whom the efficacy is expected to be the highest.

A comparative trial of favipiravir against a standard package of care (with or without placebo) has been deemed not appropriate because of: i) the highly sensitive social and political context; ii) the need to collect rapidly basic phase II evidence on the efficacy of high dosed favipiravir on EVD before choosing the best intervention(s) to be tested in phase III (favipiravir alone or in combination with other drugs; other therapeutic options including convalescent plasma).

Therefore, the investigators propose a non-comparative, proof-of-concept, phase II trial in patients with
Sponsor: Institut National de la Santé Et de la Recherche Médicale, France

Current Primary Outcome: Mortality [ Time Frame: Day-14 ]

Day-0 is the day of the first dose of favipiravir


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Evolution of EBOV plasma RNA and infectious loads [ Time Frame: routine care venepuncture (Day-0; end of symptoms (EOS)+72h and EOS+96h if EOS >Day-9; or Day-12 and Day-13 if EOS <Day-9); (ii) additional trial venepuncture at: Day-2, Day-4 and Day-30 in group A1; Day-2 and Day-30 in group A2 ]
  • Occurrence of grade 3 or 4 clinical or biological adverse events (Common Terminology Criteria for Adverse Events, CTAE, v3.0) [ Time Frame: participants will be followed for the duration of hospital stay up to Day-14 ]
  • Evolution of viral micro-diversity of EBOV (including potential resistance mutations) [ Time Frame: routine care venepuncture (Day-0; end of symptoms (EOS)+72h and EOS+96h if EOS >Day-9; or Day-12 and Day-13 if EOS <Day-9); (ii) additional trial venepuncture at: Day-2, Day-4 and Day-30 in group A1; Day-2 and Day-30 in group A2 ]
  • Plasma trough concentrations of favipiravir [ Time Frame: routine care venepuncture (Day-0; end of symptoms (EOS)+72h and EOS+96h if EOS >Day-9; or Day-12 and Day-13 if EOS <Day-9); (ii) additional trial venepuncture at: Day-2, Day-4 and Day-30 in group A1; Day-2 and Day-30 in group A2 ]
  • Criteria for cure [ Time Frame: Day-30 ]

    Composite criteria for cure are the following:

    • 4 days without fever or significant symptoms AND;
    • able to feed and walk independently AND;
    • two consecutive negative qualitative PCR.
  • Mortality [ Time Frame: Day-14 according to the second group definition (AC1, AC2, YC) ]
    Day-0 is the day of the first dose of favipiravir


Original Secondary Outcome:

  • Evolution of EBOV plasma RNA and infectious loads [ Time Frame: routine care venepuncture (Day-0; end of symptoms (EOS)+72h and EOS+96h if EOS >Day-9; or Day-12 and Day-13 if EOS <Day-9); (ii) additional trial venepuncture at: Day-2, Day-4 and Day-30 in group A1; Day-2 and Day-30 in group A2 ]
  • Occurrence of grade 3 or 4 clinical or biological adverse events (Common Terminology Criteria for Adverse Events, CTAE, v3.0) [ Time Frame: participants will be followed for the duration of hospital stay up to Day-14 ]
  • Evolution of viral micro-diversity of EBOV (including potential resistance mutations) [ Time Frame: routine care venepuncture (Day-0; end of symptoms (EOS)+72h and EOS+96h if EOS >Day-9; or Day-12 and Day-13 if EOS <Day-9); (ii) additional trial venepuncture at: Day-2, Day-4 and Day-30 in group A1; Day-2 and Day-30 in group A2 ]
  • Plasma trough concentrations of favipiravir [ Time Frame: routine care venepuncture (Day-0; end of symptoms (EOS)+72h and EOS+96h if EOS >Day-9; or Day-12 and Day-13 if EOS <Day-9); (ii) additional trial venepuncture at: Day-2, Day-4 and Day-30 in group A1; Day-2 and Day-30 in group A2 ]
  • Criteria for cure [ Time Frame: Day-30 ]

    Composite criteria for cure are the following:

    • 4 days without fever or significant symptoms AND;
    • able to feed and walk independently AND;
    • two consecutive negative qualitative PCR.


Information By: Institut National de la Santé Et de la Recherche Médicale, France

Dates:
Date Received: December 16, 2014
Date Started: December 2014
Date Completion:
Last Updated: November 14, 2016
Last Verified: March 2015