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

Date:
March 1, 2016
Source:
PLOS
Summary:
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 medical researchers.
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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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Journal Reference:

  1. Daouda Sissoko, Cedric Laouenan, Elin Folkesson, Abdoul-Bing M’Lebing, Abdoul-Habib Beavogui, Sylvain Baize, Alseny-Modet Camara, Piet Maes, Susan Shepherd, Christine Danel, Sara Carazo, Mamoudou N. Conde, Jean-Luc Gala, Géraldine Colin, Hélène Savini, Joseph Akoi Bore, Frederic Le Marcis, Fara Raymond Koundouno, Frédéric Petitjean, Marie-Claire Lamah, Sandra Diederich, Alexis Tounkara, Geertrui Poelart, Emmanuel Berbain, Jean-Michel Dindart, Sophie Duraffour, Annabelle Lefevre, Tamba Leno, Olivier Peyrouset, Léonid Irenge, N’Famara Bangoura, Romain Palich, Julia Hinzmann, Annette Kraus, Thierno Sadou Barry, Sakoba Berette, André Bongono, Mohamed Seto Camara, Valérie Chanfreau Munoz, Lanciné Doumbouya, Souley Harouna, Patient Mumbere Kighoma, Fara Roger Koundouno, Réné Lolamou, Cécé Moriba Loua, Vincent Massala, Kinda Moumouni, Célia Provost, Nenefing Samake, Conde Sekou, Abdoulaye Soumah, Isabelle Arnould, Michel Saa Komano, Lina Gustin, Carlotta Berutto, Diarra Camara, Fodé Saydou Camara, Joliene Colpaert, Léontine Delamou, Lena Jansson, Etienne Kourouma, Maurice Loua, Kristian Malme, Emma Manfrin, André Maomou, Adele Milinouno, Sien Ombelet, Aboubacar Youla Sidiboun, Isabelle Verreckt, Pauline Yombouno, Anne Bocquin, Caroline Carbonnelle, Thierry Carmoi, Pierre Frange, Stéphane Mely, Vinh-Kim Nguyen, Delphine Pannetier, Anne-Marie Taburet, Jean-Marc Treluyer, Jacques Kolie, Raoul Moh, Minerva Cervantes Gonzalez, Eeva Kuisma, Britta Liedigk, Didier Ngabo, Martin Rudolf, Ruth Thom, Romy Kerber, Martin Gabriel, Antonino Di Caro, Roman Wölfel, Jamal Badir, Mostafa Bentahir, Yann Deccache, Catherine Dumont, Jean-François Durant, Karim El Bakkouri, Marie Gasasira Uwamahoro, Benjamin Smits, Nora Toufik, Stéphane Van Cauwenberghe, Khaled Ezzedine, Eric Dortenzio, Louis Pizarro, Aurélie Etienne, Jérémie Guedj, Alexandra Fizet, Eric Barte de Sainte Fare, Bernadette Murgue, Tuan Tran-Minh, Christophe Rapp, Pascal Piguet, Marc Poncin, Bertrand Draguez, Thierry Allaford Duverger, Solenne Barbe, Guillaume Baret, Isabelle Defourny, Miles Carroll, Hervé Raoul, Augustin Augier, Serge P. Eholie, Yazdan Yazdanpanah, Claire Levy-Marchal, Annick Antierrens, Michel Van Herp, Stephan Günther, Xavier de Lamballerie, Sakoba Keïta, France Mentre, Xavier Anglaret, Denis Malvy. Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea. PLOS Medicine, 2016; 13 (3): e1001967 DOI: 10.1371/journal.pmed.1001967

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PLOS. "Nuanced findings for a large experimental treatment trial for Ebola virus disease." ScienceDaily. ScienceDaily, 1 March 2016. <www.sciencedaily.com/releases/2016/03/160301144757.htm>.
PLOS. (2016, March 1). Nuanced findings for a large experimental treatment trial for Ebola virus disease. ScienceDaily. Retrieved May 8, 2017 from www.sciencedaily.com/releases/2016/03/160301144757.htm
PLOS. "Nuanced findings for a large experimental treatment trial for Ebola virus disease." ScienceDaily. www.sciencedaily.com/releases/2016/03/160301144757.htm (accessed May 8, 2017).