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PLoS Med. 2016 Mar 1;13(3):e1001967. doi: 10.1371/journal.pmed.1001967. eCollection 2016 Mar.

Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea.

Sissoko D1,2, Laouenan C3,4, Folkesson E5, M'Lebing AB6, Beavogui AH7, Baize S8,9, Camara AM5, Maes P10,11, Shepherd S6, Danel C1,6,12, Carazo S5, Conde MN6, Gala JL13,14,15,16, Colin G1,12,17, Savini H18, Bore JA10,19,20, Le Marcis F21, Koundouno FR10,19,20, Petitjean F6, Lamah MC5, Diederich S10,22, Tounkara A5, Poelart G5, Berbain E5, Dindart JM6, Duraffour S10,11, Lefevre A5, Leno T5, Peyrouset O6, Irenge L13,16, Bangoura N5, Palich R6, Hinzmann J10,23, Kraus A10,24, Barry TS6, Berette S6, Bongono A6, Camara MS6, Chanfreau Munoz V6, Doumbouya L6, Souley Harouna6, Kighoma PM6, Koundouno FR6, Réné Lolamou6, Loua CM6, Massala V6, Moumouni K6, Provost C6, Samake N6, Sekou C6, Soumah A6, Arnould I5, Komano MS5, Gustin L5, Berutto C5, Camara D5, Camara FS5, Colpaert J5, Delamou L5, Jansson L5, Kourouma E5, Loua M5, Malme K5, Manfrin E5, Maomou A5, Milinouno A5, Ombelet S5, Sidiboun AY5, Verreckt I5, Yombouno P5, Bocquin A9, Carbonnelle C9, Carmoi T18, Frange P25, Mely S9, Nguyen VK26, Pannetier D9, Taburet AM27, Treluyer JM25, Kolie J7, Moh R1,12, Gonzalez MC3,4, Kuisma E10,28, Liedigk B10,29, Ngabo D10,28, Rudolf M10,29, Thom R10,28, Kerber R10,29, Gabriel M10,29, Di Caro A10,30, Wölfel R10,31, Badir J13,14, Bentahir M13,16, Deccache Y13,16, Dumont C13,16, Durant JF13,15, El Bakkouri K13,15, Gasasira Uwamahoro M13,15, Smits B13,15, Toufik N13,14, Van Cauwenberghe S13,16, Ezzedine K1, D'Ortenzio E, Pizarro L32, Etienne A3,4, Guedj J3,4, Fizet A8,9, Barte de Sainte Fare E6, Murgue B33, Tran-Minh T17, Rapp C18, Piguet P5, Poncin M5, Draguez B5, Allaford Duverger T6, Barbe S6, Baret G6, Defourny I6, Carroll M10,28,34, Raoul H9, Augier A6, Eholie SP1,12,35, Yazdanpanah Y4, Levy-Marchal C33, Antierrens A5, Van Herp M5, Günther S10,29, de Lamballerie X36, Keïta S37, Mentre F3,4, Anglaret X1,12, Malvy D1,2; JIKI Study Group.

Collaborators (197)

Abdou K, Aletti M, Astruc A, Bachar S, Balamou W, Balandine S, Balde S, Barry M, Beavogui M, Blackwell NA, Bongono JT, Bost CA, Calarco G, Camara D, Camara K, Camara L, Camara N, Camara S, Camara M, Catherine V, Cisse M, Conde M, Cordier PY, Costagliola D, Cotte J, Dampierre H, Delamou PP, Dembadouno F, Demeildre J, Deportere E, Diallo MC, Diawara F, Dieng I, Doble A, Donzo M, Dopavogui AA, Niankoye PD, Doumbouya M, Djibrillou AE, Fadiga M, Feindouno FF, Foissaud V, Gado M, Gaspari D, Gbamaou Z, Gbanamou S, Geopogui GK, Goepogui A, Granier H, Grovogui V, Guilavogui P, Guilavogui M, Haba A, Haba M, Haba P, Hubert V, Iffono K, Salomon Ifono S, Janvier F, Joxe L, Kakule G, Kalissa O, Kamano AT, Kamano FT, Kamano F, Kamano TA, Kamano TM, Kamano FF, Kamano SI, Kamano TM, Kamano TM, Smith SK, Kantambadouno GS, Katembo J, Keita A, Keita MA, Keita N, Keita SS, Keïta S, Koivogui M, Akoi PK, Koho EK, Kolie Y, Niankoye AK, Kondiano TF, Kondiano L, Kondiano EN, Kondiano FM, Kouchiakbe P, Koulemou K, Koulibaly F, Koumassadouno SY, Koumbassadouno FA, Koundouno SF, Koundouno TA, Kourouma M, Kponghomou NL, Kumba S, Labrosse B, Lamah N, Lamah P, Lamah Y, Lamah SW, Lamah JB, Duc GL, Lelano F, Leno ET, Leno E, Leno P, Leno M, N'Bemba Leno C, Lèno FP, Leno B, Lopez C, Loua P, Cece AL, Seny OM, Mahoudeau C, Maikoouva J, Mamadurno TL, Mansare A, Mansare RS, Mansare A, Mara SM, Martineau P, Masson S, Maugey N, Conte CM, Michavila P, Millimono C, Millimono FE, Millimouno SJ, Millimouno SL, David S, Millimouno N, Millimouno FE, Millimouno FM, Montfort C, Mouly N, Moundekeno S, Mundweiller S, Oliano C, Oliano DL, Oliano SM, Ouamouno M, Ouamouno M, Ouendeno TE, Oumou D, Oyengue J, Petrini I, Pommerol E, Dermbaye AR, Rivenc J, Rodrigues R, Rouille V, Sagui E, Sakovogui OO, Samouro S, San HL, Sandouno F, Mathos Sandouno T, Sandouno SM, Sanzan N, Saran T, Sia K, Sidibe R, Sonole S, Dauda DS, Soumaoro I, Sow A, Sow D, Tagbino SE, Tenguiano C, Thea J, Thomas D, Tinkiano MK, Tolno JF, Tolno J, Tolno SE, Tolno S, Touaro N, Touboulic S, Tounkara B, Toure B, Toure N, Toure S, Traore D, Traore F, Traore K, Traore S, Traore S, Trebovic P, Vandamme T, Wammo R, Yaradouno JS, Yatara M, Nouhou OY.

Author information

1
Inserm, UMR 1219, Université de Bordeaux, Bordeaux, France.
2
Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
3
Inserm, IAME, UMR 1137, Université Paris Diderot, Paris, France.
4
Assistance Publique-Hôpitaux de Paris, Hôpital Bichat Claude Bernard, Paris, France.
5
Médecins Sans Frontières Belgique, Brussels, Belgium.
6
ALIMA, Dakar, Senegal.
7
Centre de Recherche en Santé Rurale, Maférinya, Guinea.
8
Institut Pasteur, Centre International de Recherche en Infectiologie, Lyon, France.
9
Inserm, Laboratoire P4 Jean Mérieux, Lyon, France.
10
European Mobile Laboratory Project, Hamburg, Germany.
11
Rega Institute for Medical Research, Leuven, Belgium.
12
Programme PACCI, Abidjan, Côte d'Ivoire.
13
Biological Light Fieldable Laboratory for Emergencies (B-LiFE)/Belgian First Aid and Support (B-FAST), Brussels, Belgium.
14
Cliniques Universitaires Saint-Luc, Brussels, Belgium.
15
Université Catholique de Louvain, Louvain-la-Neuve, Belgium.
16
Belgian Ministry of Defense, Brussels, Belgium.
17
Croix Rouge Française, Paris, France.
18
Service de Santé des Armées, Paris, France.
19
Institut National de Santé Publique, Conakry, Guinea.
20
Laboratoire des Fièvres Hémorragiques en Guinée, Université Gamal Abdel Nasser de Conakry, Conakry, Guinea.
21
Ecole Normale Supérieure, Lyon, France.
22
Friedrich Loeffler Institute-Federal Research Institute for Animal Health, Greifswald, Germany.
23
Robert Koch Institute, Berlin, Germany.
24
Public Health Agency of Sweden, Solna, Sweden.
25
Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, France.
26
Université de Montréal, Montréal, Canada.
27
Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Paris, France.
28
Public Health England, Porton Down, United Kingdom.
29
Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
30
National Institute for Infectious Diseases "L. Spallanzani," Rome, Italy.
31
Bundeswehr Institute of Microbiology, Munich, Germany.
32
Solidarité Thérapeutique et Initiatives pour la Santé (Solthis), Paris, France.
33
Inserm, Paris, France.
34
Southampton General Hospital, University of Southampton, Southampton, United Kingdom.
35
Centre Hospitalier Universitaire de Treichville, Abidjan, Côte d'Ivoire.
36
Université Aix Marseille, Institut de Recherche pour le Développement, École des Hautes Études en Santé Publique, EPV, Marseille, France.
37
Cellule de Coordination Nationale de Lutte contre la Maladie à Virus Ebola, Conakry, Guinea.

Abstract

BACKGROUND:

Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care. Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies.

METHODS AND FINDINGS:

Inclusion criteria were positive Ebola virus reverse transcription PCR (RT-PCR) test, age ≥ 1 y, weight ≥ 10 kg, ability to take oral drugs, and informed consent. All participants received oral favipiravir (day 0: 6,000 mg; day 1 to day 9: 2,400 mg/d). Semi-quantitative Ebola virus RT-PCR (results expressed in "cycle threshold" [Ct]) and biochemistry tests were performed at day 0, day 2, day 4, end of symptoms, day 14, and day 30. Frozen samples were shipped to a reference biosafety level 4 laboratory for RNA viral load measurement using a quantitative reference technique (genome copies/milliliter). Outcomes were mortality, viral load evolution, and adverse events. The analysis was stratified by age and Ct value. A "target value" of mortality was defined a priori for each stratum, to guide the interpretation of interim and final analysis. Between 17 December 2014 and 8 April 2015, 126 patients were included, of whom 111 were analyzed (adults and adolescents, ≥13 y, n = 99; young children, ≤6 y, n = 12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value ≥ 20 (Group A Ct ≥ 20), and 44 had a baseline Ct value < 20 (Group A Ct < 20). Ct values and RNA viral loads were well correlated, with Ct = 20 corresponding to RNA viral load = 7.7 log10 genome copies/ml. Mortality was 20% (95% CI 11.6%-32.4%) in Group A Ct ≥ 20 and 91% (95% CI 78.8%-91.1%) in Group A Ct < 20. Both mortality 95% CIs included the predefined target value (30% and 85%, respectively). Baseline serum creatinine was ≥110 μmol/l in 48% of patients in Group A Ct ≥ 20 (≥300 μmol/l in 14%) and in 90% of patients in Group A Ct < 20 (≥300 μmol/l in 44%). In Group A Ct ≥ 20, 17% of patients with baseline creatinine ≥110 μmol/l died, versus 97% in Group A Ct < 20. In patients who survived, the mean decrease in viral load was 0.33 log10 copies/ml per day of follow-up. RNA viral load values and mortality were not significantly different between adults starting favipiravir within <72 h of symptoms compared to others. Favipiravir was well tolerated.

CONCLUSIONS:

In the context of an outbreak at its peak, with crowded care centers, randomizing patients to receive either standard care or standard care plus an experimental drug was not felt to be appropriate. We did a non-randomized trial. This trial reaches nuanced conclusions. On the one hand, we do not conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, are not as firm as they could have been if we had used randomization. On the other hand, we learned about how to quickly set up and run an Ebola trial, in close relationship with the community and non-governmental organizations; we integrated research into care so that it improved care; and we generated knowledge on EVD that is useful to further research. Our data illustrate the frequency of renal dysfunction and the powerful prognostic value of low Ct values. They suggest that drug trials in EVD should systematically stratify analyses by baseline Ct value, as a surrogate of viral load. They also suggest that favipiravir monotherapy merits further study in patients with medium to high viremia, but not in those with very high viremia.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT02329054.

PMID:
26930627
PMCID:
PMC4773183
DOI:
10.1371/journal.pmed.1001967
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: SB, XdL, HR, and SG received a grant from St Luke International University (Tokyo, Japan) to perform research on favipiravir in non-human primates. YY declared board membership for AbbVie, BMS, Gilead, MSD, Roche, Johnson&Johnson, ViiV Healthcare, Pfizer, and consultancy for AbbVie, BMS, Gilead, MSD, Roche, Johnson&Johnson, ViiV Healthcare, and Pfizer. OP worked for Fab'entech biotechnology from 1st April to 13th November 2015. Between January 2014 and now, SC received a grant from the CHU de Québec research center, which had no relationship with the trial described in the paper. All other authors declared no conflict of interest.

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