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Efficacy of Favipiravir Against Ebola (JIKI) (JIKI)

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ClinicalTrials.gov Identifier: NCT02329054
Recruitment Status : Completed
First Posted : December 31, 2014
Last Update Posted : November 15, 2016
Sponsor:
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France

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.

In the present trial "JIKI" (means "Hope" in "Kissi" language), investigators, sponsor, scientific advisory board and safety monitoring board will be coordinated in a very reactive way, so that any new fact can be discussed rapidly and the research plan can be adapted accordingly (change in drug dosage; use of drug combination; combination with another strategy such as passive immunization with convalescent plasma, etc.).


Condition or disease Intervention/treatment Phase
Ebola Virus Disease Drug: Favipiravir Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 126 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy of Favipiravir in Reducing Mortality in Individuals With Ebola Virus Disease in Guinea
Study Start Date : December 2014
Actual Primary Completion Date : May 2015
Actual Study Completion Date : September 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ebola

Arm Intervention/treatment
Experimental: Favipiravir
Favipiravir (oral administration, 200 mg light yellow, round-shaped, coated divisible tablets that can be crushed and mixed with liquid)
Drug: Favipiravir

Group A1: Day-0 (inclusion), h0: 2400 mg; h8: 2400 mg; h16: 1200 mg. Day-1 to Day-9: 1200 mg bid.

Group A2: Day-0 (inclusion), h0: 2400 mg; h8: 2400 mg; h16: 1200 mg. Day-1 to Day-9: 1200 mg bid.

Group C: daily dosages will be adapted to their body weight.

Other Name: AVIGAN




Primary Outcome Measures :
  1. Mortality [ Time Frame: Day-14 ]
    Day-0 is the day of the first dose of favipiravir


Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. 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 ]
  4. 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 ]
  5. 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.

  6. 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



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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • age >1 year and weighting ≥10kg,
  • EVD confirmed by a positive qualitative PCR test,
  • signed informed consent (signed by the parents/adults guardians in case of minor patient).

Non inclusion-criteria:

  • pregnancy*,
  • inability to take the drug (encephalopathy, severe vomiting). * Emergency use of favipiravir in pregnant women outside of the trial is envisaged and under evaluation.

In this protocol, the investigators will refer to the following groups according to age and duration of symptoms**:

  • Group A1: adults with time between first symptoms and first dose of favipiravir ≤72h;
  • Group A2: adults with time between first symptoms and first dose of favipiravir >72h;
  • Group C: all children >1 year and weighting ≥10kg. Time of first symptom refers to the time of the beginning of any symptom considered to be related to EVD. **Symptoms to be considered will be: acute onset of fever, severe headache, myalgia, extreme fatigue, vomiting, diarrhoea, abdominal pain, or unexplained hemorrhage.

The division in groups is a matter of analysis, and will not be perceptible by the patients during the trial process. Patients in the three groups will receive the same treatment and will be followed under the same procedures, with only two exceptions: the number of additional blood sample collections will be lower in group A2 and C (n=2) than in group A1 (n=3) and daily dosages will be adapted to the body weight in group C.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02329054


Locations
Guinea
The caregivers treatment center
Conakry, Guinea
MSF Ebola treatment centre
Gueckedou, Guinea
French Red Cross Ebola care center
Macenta, Guinea
ALIMA Ebola care center
Nzerekore, Guinea
Sponsors and Collaborators
Institut National de la Santé Et de la Recherche Médicale, France
Investigators
Principal Investigator: Denis Malvy, Professor CHU de Bordeaux & INSERM, Université de Bordeaux, France

Publications of Results:
Sissoko D, Laouenan C, Folkesson E, M'Lebing AB, Beavogui AH, Baize S, Camara AM, Maes P, Shepherd S, Danel C, Carazo S, Conde MN, Gala JL, Colin G, Savini H, Bore JA, Le Marcis F, Koundouno FR, Petitjean F, Lamah MC, Diederich S, Tounkara A, Poelart G, Berbain E, Dindart JM, Duraffour S, Lefevre A, Leno T, Peyrouset O, Irenge L, Bangoura N, Palich R, Hinzmann J, Kraus A, Barry TS, Berette S, Bongono A, Camara MS, Munoz VC, Doumbouya L, Harouna S, Kighoma PM, Koundouno FR, Lolamou R, Loua CM, Massala V, Moumouni K, Provost C, Samake N, Sekou C, Soumah A, Arnould I, Komano MS, Gustin L, Berutto C, Camara D, Camara FS, Colpaert J, Delamou L, Jansson L, Kourouma E, Loua M, Malme K, Manfrin E, Maomou A, Milinouno A, Ombelet S, Sidiboun AY, Verreckt I, Yombouno P, Bocquin A, Carbonnelle C, Carmoi T, Frange P, Mely S, Nguyen VK, Pannetier D, Taburet AM, Treluyer JM, Kolie J, Moh R, Gonzalez MC, Kuisma E, Liedigk B, Ngabo D, Rudolf M, Thom R, Kerber R, Gabriel M, Di Caro A, Wölfel R, Badir J, Bentahir M, Deccache Y, Dumont C, Durant JF, El Bakkouri K, Uwamahoro MG, Smits B, Toufik N, Van Cauwenberghe S, Ezzedine K, D'Ortenzio E, Pizarro L, Etienne A, Guedj J, Fizet A, de Sainte Fare EB, Murgue B, Tran-Minh T, Rapp C, Piguet P, Poncin M, Draguez B, Duverger TA, Barbe S, Baret G, Defourny I, Carroll M, Raoul H, Augier A, Eholie SP, Yazdanpanah Y, Levy-Marchal C, Antierrens A, Van Herp M, Günther S, de Lamballerie X, Keïta S, Mentre F, Anglaret X, Malvy D; JIKI Study Group. Correction: Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea. PLoS Med. 2016 Apr 5;13(4):e1002009. doi: 10.1371/journal.pmed.1002009. eCollection 2016 Apr.

Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Sissoko D, Laouenan C, Folkesson E, M'Lebing AB, Beavogui AH, Baize S, Camara AM, Maes P, Shepherd S, Danel C, Carazo S, Conde MN, Gala JL, Colin G, Savini H, Bore JA, Le Marcis F, Koundouno FR, Petitjean F, Lamah MC, Diederich S, Tounkara A, Poelart G, Berbain E, Dindart JM, Duraffour S, Lefevre A, Leno T, Peyrouset O, Irenge L, Bangoura N, Palich R, Hinzmann J, Kraus A, Barry TS, Berette S, Bongono A, Camara MS, Chanfreau Munoz V, Doumbouya L, Souley Harouna, Kighoma PM, Koundouno FR, Réné Lolamou, Loua CM, Massala V, Moumouni K, Provost C, Samake N, Sekou C, Soumah A, Arnould I, Komano MS, Gustin L, Berutto C, Camara D, Camara FS, Colpaert J, Delamou L, Jansson L, Kourouma E, Loua M, Malme K, Manfrin E, Maomou A, Milinouno A, Ombelet S, Sidiboun AY, Verreckt I, Yombouno P, Bocquin A, Carbonnelle C, Carmoi T, Frange P, Mely S, Nguyen VK, Pannetier D, Taburet AM, Treluyer JM, Kolie J, Moh R, Gonzalez MC, Kuisma E, Liedigk B, Ngabo D, Rudolf M, Thom R, Kerber R, Gabriel M, Di Caro A, Wölfel R, Badir J, Bentahir M, Deccache Y, Dumont C, Durant JF, El Bakkouri K, Gasasira Uwamahoro M, Smits B, Toufik N, Van Cauwenberghe S, Ezzedine K, D'Ortenzio E, Pizarro L, Etienne A, Guedj J, Fizet A, Barte de Sainte Fare E, Murgue B, Tran-Minh T, Rapp C, Piguet P, Poncin M, Draguez B, Allaford Duverger T, Barbe S, Baret G, Defourny I, Carroll M, Raoul H, Augier A, Eholie SP, Yazdanpanah Y, Levy-Marchal C, Antierrens A, Van Herp M, Günther S, de Lamballerie X, Keïta S, Mentre F, Anglaret X, Malvy D; JIKI Study Group. Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea. PLoS Med. 2016 Mar 1;13(3):e1001967. doi: 10.1371/journal.pmed.1001967. eCollection 2016 Mar. Erratum in: PLoS Med. 2016 Jun;13(6):e1002066. PLoS Med. 2016 Apr;13(4):e1002009. Dortenzio, Eric [corrected to D’Ortenzio, Eric].

Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier: NCT02329054     History of Changes
Other Study ID Numbers: C14-63
First Posted: December 31, 2014    Key Record Dates
Last Update Posted: November 15, 2016
Last Verified: March 2015

Keywords provided by Institut National de la Santé Et de la Recherche Médicale, France:
Ebola Virus Disease
Antivirals
Mortality
Viral load
Proof-of-concept
Phase II trial
Guinea
Adults
Children

Additional relevant MeSH terms:
Hemorrhagic Fever, Ebola
Virus Diseases
Hemorrhagic Fevers, Viral
RNA Virus Infections
Filoviridae Infections
Mononegavirales Infections