Nuanced findings for a large experimental treatment trial for Ebola virus disease

While not conclusive, valuable research generated through researching an experimental treatment for Ebola virus disease in Guinea during the recent Ebola outbreak will support future research into treating Ebola virus disease, according to Prof. Denis Malvy from INSERM, France and a large team of international researchers in a new Research Article published in this week's PLOS Medicine.

Ebola virus disease is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the recent Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for Ebola virus disease research that included favipiravir, an antiviral developed for the treatment of severe influenza. To test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak and to collect preliminary data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with Ebola virus disease, a multinational team of researchers conducted a study in Guinea called JIKI (meaning "Hope" in the Malinke language). Because of the exceptional circumstances of the recent Ebola outbreak the study was a historically controlled multicenter non-randomized trial, in which all 126 participants received favipiravir along with standardized care.

The results of the study indicate that monotherapy with favipiravir is unlikely to be effective in patients with very high viremia (Ebola virus in the blood) and merits further investigation in patients with intermediate to high viremia. This conclusion is based on two findings, namely, the observed mortality rates and the dynamics of Ebola virus RNA measured in the blood of patients on treatment. In patients with very high viremia, mortality was 7% higher than expected based on historical Ebola cases and Ebola virus measurements did not decrease. This suggests that any future trial is unlikely to demonstrate any benefit of favipiravir in these patients. In patients with lower viremia, mortality was 33% lower than expected based on historical controls and viremia decreased rapidly on treatment but the study was not able to attribute this decrease to favipiravir. The trial was non-randomized and the 95% confidence interval of mortality overlapped with what was expected from historical Ebola patients. Therefore, this finding does not prove that favipiravir was effective in these patients but only suggests that the question remains open and gives some indication on how to better address it.

The authors conclude, "[i]n the midst of an Ebola outbreak, researchers may be faced with elements that make them feel that randomizing patients to receive either standard care or standard care plus an experimental drug is not ethically acceptable. In these rare circumstances, it can be decided to not run a trial and to wait for more favorable conditions, or to run a non-randomized trial. In this pilot experience, we did the latter. Our conclusions are nuanced. On the one hand, we cannot conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, cannot be as firm as they would have been if we could have used randomization. On the other hand, we learned a lot about how to quickly set up and run a trial in such unusual circumstances and in close relationship with the community and non-governmental organizations, we integrated research into care so that it improved care, we rapidly generated and shared with the scientific community intermediate data that were useful for designing Ebola research, and we gathered evidence that will allow researchers to base further trials on strong preliminary assumptions."

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The JIKI trial was supported by grants from the French National Agency for AIDS and viral hepatitis research (ANRS, Paris, France), the French Institute for Health Research (Inserm, Paris, France) and the European Union (Horizon 2020 programme, grant N° 666092 REACTION and N° 666100 EVIDENT; European Commission's Directorate-General for International Cooperation and Development, service contract IFS/2011/272-372). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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.

Sissoko D, Laouenan C, Folkesson E, M'Lebing A-B, Beavogui A-H, Baize S, et al. (2016) Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea. PLoS Med 13(3): e1001967. doi:10.1371/journal.pmed.1001967

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

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Denis Malvy
INSERM U1219
CHU de Bordeaux
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