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REACTION Report Summary

Project ID: 666092
Funded under: H2020-EU.3.1.

Periodic Reporting for period 1 - REACTION (Evaluation of the efficacy and of the antiviral activity of T-705 (favipiravir) duringEbola virus infection in non-human primates humans)

Reporting period: 2014-11-01 to 2015-10-31

Summary of the context and overall objectives of the project

The ongoing Ebola outbreak in West Africa is the largest and deadliest the world has ever seen. In September 2014, the number of EBOV cases exceeded the total of all cases from previous known outbreaks. Further, this public health crisis shifted into a complex emergency, with significant, social, economic, humanitarian, political and security dimensions. The current crisis requires both an immediate response to treat patients and prevent the further spread of the epidemic, as well as long term commitment in the complex sociocultural context. REACTION! will address both needs.

The main objective of the REACTION! project is to provide rapid evidence of Favipiravir anti-Ebola efficacy in reducing mortality and Ebola viral load in humans with EVD. Furthermore, the study is divided into six WPs that address six different sub-objectives.
In WP1, we will assess the efficacy of T -705 in reducing mortality and decreasing Ebola plasma viral load in 60 adults at early stage of infection in a pilot non-randomized phase IIb sequential trial. Furthermore, a specific goal of the project is to ensure that effective clinical care regimens are taken up safely (WP2). Parallel to the clinical trial, we will evaluate the antiviral activity of T-705 in NHPs at different doses and different time points in the natural history of the disease (WP3). In WP4, analysis of the data from WP1 (humans) and WP3 (nonhuman primates) will be performed to provide a better quantitative understanding of the determinants of the viral response to treatment. WP5 ensures efficient and effective dissemination and communication of the results to stakeholders and promote further uptake of the results, as well as stimulate exploitation of the results. WP6 will focus on project management of the REACTION! project.

State of play
Between December 2014 and April 2015, 126 patients were included in order to test the efficacy of favipiravir effectiveness against Ebola. The recruitment has terminated by 30th of May 2015. The trial took place in four Ebola Treatment Units in Guinea: Gueckedou (managed by MSF), Macenta (managed by the French Red Cross), Conakry (coastal Guinea) and Nzérékoré (managed by the Alliance for International Medical Action, ALIMA). The effective clinical care in the current emergency situation was ensured and evaluated. Out of 126 participants 111 were analyzed. Analysis of the participants is being conducted and the PK results should be available in October 2015, after which they will be published.

Animal experiments are in progress in the Cynomolgus Non Human Primate model and include 3 major items:
(1) in depth characterisation and validation of the model;
(2) Favipiravir Pharmaco-Kinetics modeling and experiments in non-infected animals;
(3) Favipiravir treatment in Ebola virus infected animals.

• The dosage used in this study has been published in The Lancet.
• Commissioner Moedas welcomes encouraging results - 24 February 2015

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

"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 WHO released a short list of drugs suitable for EVD research. Favipiravir was one of these. Within WP1 we conducted a proof-of-concept trial (JIKI) in four Ebola treatment centers in Guinea (Fig 1), in which all patients received favipiravir along with standardized care. Between December 2014 and April 2015, 126 patients were included, of whom 111 were analyzed (adults and adolescents ≥13 years, n=99; young children ≤6 years, n=12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value ≥20 (Group ACt≥20) and 44 a Ct value<20 (Group ACt<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% in group-ACt≥20 (95%CI 11.6; 32.4) and 91% (95%CI 78.8; 91.1) in Group ACt<20. Both mortality 95%CI included the pre-defined target value (30% and 85%). Baseline serum creatinine was ≥110μmol/L in 48% of patients in Group ACt≥20 (≥300μmol/L in 14%), and in 90% of patients in Group ACt<20 (≥300μmol/L in 44%). In Group ACt≥20 17% of patients with baseline creatinine ≥110μmol/L died, vs. 97% in Group ACt<20. Figure 1 shows the dynamics of Ct values (Fig. 1A) and RNA viral loads (Fig 1B) in patients who survived (blue dots) and in those who died (red dots). In patients who survived, the mean decrease in viral load was 0.33 log10copies/mL per day of follow-up. Favipiravir was well tolerated.
These findings show that:
(i) emergency trials are feasible in the context of a deadly contagious disease outbreak. This was achieved as a result of good collaboration between investigators, health authorities, NGOs, community leaders and patients;
(ii) Future drug trials in EVD should systematically stratify analyses by level of viremia;
(iii) High-dose favipiravir is well tolerated by patients with EVD, and higher doses could be tested.
(iv) Finally, these findings do not prove that favipiravir is effective in EVD, but suggest that the question remains open and give indication on how to better address it in the future.

WP2 ensured and evaluated the effective clinical care in the current emergency situation. This resulted in several outcomes and observations:
I. The ETU "treatment camp" model displays significant variation according to epidemic phase and location/organizational culture; nonetheless, significant cross-cutting issues remain as to the overall acceptability of the "camp" model. What might be more appropriate alternatives to the camp model? Might they have been considered earlier, and why weren't they?
II. Considerable effort is required to translate the deployment of technologies to enforce hygiene, infection control and treatment into effective results in local contexts. The use of technologies –including the protocols and standardizing practices inherent in clinical trials – usually result in remarkable results; yet at times these technologies generate uncertainty, ambiguity and at times outright fear. How are technologies put into practice, and with what result? Might there be strategies to “domesticate” technologies so that they translate into durable and positive effects?
III. Government, international and NGO anxieties about ""reticence"" and other forms of resistance to Ebola control interventions mirror those of communities about the interventions themselves; rumours can become self-validating depending on how they are managed by authorities. What can be understood at level of collective affect (beyond that of individual experience) to better grasp the force of rumours, attend to the anxieties they reflect, and how to effectively dispel them?
IV. At times the response has tended to overt or implied use of force, as signaled by the criminalization of resistance and quasi-military aspects in the organization of interventions in the face of real and imagined violent resistance; striking also are the forms of distancing at play in the language and practices of the response. The dimensions of force, space and distancing point to deeper political histories of violence and struggles over state legitimacy. How will the epidemic alter the constellation of political and international legitimacy in Guinea even as it fades over time?

The main results achieved at month 12 for WP3: evaluation of the antiviral activity of T-705 in NHPs
I. favipiravir efficacy and PK modeling stuat month 12 include:dies based on previous experiments in cellulo and in mice;
II. PK results in non-infected cynomolgus macaques under a regimen of 2 anesthesia per day with favipiravir provided intravenously BID (initial and revisited experimental protocols);
III. validation of an inactivation protocol allowing the dosage of favipiravir in the plasma of infected animals/human patients;
IV. implementation of HPLC dosage of favipiravir from infected samples in accordance with ""MOT"" biosafety regulation;
V. experimental series testing the EBOV infection model in untreated macaques using various inoculum doses administered by the intramuscular route;
VI. first round of prophylactic treatment of macaques infected with EBOV using favipiravir IV BID;
VII. design of a second round of prophylactic treatment of macaques infected with EBOV using favipiravir IV BID;
VIII. complete genomic characterization of EBOV genomes at day 5, 7 and 9 p.i. in infected untreated and treated macaques, including analysis of minor variants at 1% level.

Within WP4, goal is to characterize the interaction between the host, the pathogen and the drug during infection of Ebola virus (EBOV) and treatment with nucleotide analog favipiravir. This approach is applied to gradually bigger in vivo models, from mice to NHPs and humans eventually. So far, our work has been focusing on the pharmacological- and antiviral properties of favipiravir against Ebola virus infection in animals in order to guide the experimentations of favipiravir in NHPs in the BSL4.
We provided the first characterization of the viral dynamics, using data generated by our Hamburg partners. In brief, we showed that favipiravir needed about 2 days to achieve its maximal effectiveness. This may explain why mice receiving favipiravir 8 days post infection did not show any dramatic change in viremia and died within 1-2 days, and reinforce the hypothesis that favipiravir, in order to be effective, will need to be administrated as early as possible. This work has been published in Antiviral Research.
We then focused on the preparation of the NHPs experiments. Based on the data provided by Toyama we developed a pharmacokinetic model for favipiravir administrated IV at 60-150 mg/kg BID. This model has been amended to take into account breed effect and the fact that the NHPs infected with EBOV at BSL4 have a different background than those used by Toyama. Further this model was expanded to be characterized the drug exposure with higher doses of 150-180 mg/kg BID, never tested by Toyama. A scientific paper will be submitted soon.
In parallel we analyzed the viral kinetics in NHPs untreated and treated with 100 mg/kg favipiravir. We provided an exposure-relationship of favipiravir and EBOV. By combining these data with PK model built above, we guided the search for a relevant dosing regimen in NHPs. We predicted that doses of 150 or 180mg/kg BID administrated in prophylaxis should lead to a > 3 log reduction in viremia at peak. These doses will be tested in the next round of experiments which will start next month.

Since the beginning of the action to the end of this period the beneficiaries within WP5 have put in place several tools and measures:
I. The website of the project has been created, put online and updated with the last publications and events:

II. A leaflet of the project has been designed in September 2015, distributed to all members of the consortium and is used during meetings and conferences to promote the project and its objectives;

III. A movie is being realized under the supervision of INSERM and directed by VOIE 93
FILMS: ‘JIKI: l’histoire d’un espoir’. This movie of 4 to 5 minutes with a focus on:
• Documenting preclinical trial through illustrations of INSERM research units in Lyon and Bordeaux;
• Treatment centers of Macenta and N'Zerekore;
• Awareness of the populations on the treatment;
• Scientific assessment to conclude on the first lessons to learn for the fight against outbreak of the disease.

IV. New scientific documents have been published:
• The Lancet journal: France Mentré, Anne-Marie Taburet, Jeremie Guedj, Xavier Anglaret, Sakoba Keïta, Xavier de Lamballerie, and others. The Lancet Infectious Diseases, Vol. 15, No. 2, p150–151 “Dose regimen of favipiravir for Ebola virus disease”.
• The Lancet journal: Naïm Bouazza, Jean-Marc Treluyer, Frantz Foissac, France Mentré, Anne-Marie Taburet, Jérémie Guedj, and others. The Lancet, Vol. 385, No. 9968, p603–604. Published in issue: February 14, 2015 “Favipiravir for children with Ebola”.
• PLOS Medicine (paper submitted) Daouda Sissoko and others. A proof-of-concept trial of favipiravir in Guinea (the JIKI trial): lessons learned for research on treatment of Ebola virus disease.

V. The progress of the project and the preliminary results have been presented at international and national conferences:
• During the annual Conference on Retroviruses and Opportunistic Infections (CROI) 2015 that was held from February 23 to February 26 was the occasion to present the abstract: Favipiravir in Patients with Ebola Virus Disease: Early Results of the JIKI trial in Guinea
• During the Conference “Targeting Ebola 2015” of Institut Pasteur that was held in Paris the 28-29 of May, 2015: presentation of the JIKI clinical trials.
• During the 24th Meeting of the Population Approach Group in Europe, Hersonissos, Greece (June 2nd-5th 2015) - Mentré F, Anne-Marie Taburet, Jeremie Guedj, Naïm Bouazza, Jean-Marc Treluyer, Xavier Anglaret, Sakoba Keïta, Xavier de Lamballerie, Pierre Frange, Denis Malvy. Estimating an effective dose for a repurposed drug to treat Ebola: the case of favipiravir.
• During the Symposium sponsored by the Directorate General for Research and Innovation of the European Commission ‘'Research for an unexpected epidemic: The EU response against Ebola in Philadelphia during the ASTMH 64th Annual Meeting October 25-29, 2015.

VI. Concerning the communication activities during the JIKI trial in the 4 sites where it was implemented (Macenta, Guéckédou, Conakry and Nzérékoré ) from November 2014 to April 2015 the REACTION partners developed messages adapted to each groups: patients, health workers and the local community.

Finally, project management and progression is as anticipated for WP6. At this moment there are no major deviations from the original project tasks, planning and/or consortium affecting the overall project outcome.
A modification in the consortium has been reported to the European Commission, it concerns the transfer of one participating researcher partner (Prof. Nguyen from Universiteit van Amsterdam, The Netherlands) to another institute (Graduate Institute Geneva, Switzerland).
The REACTION! Annual Consortium Meeting was held on October 15th 2015 in Amsterdam, the Netherlands.
Finally, the REACTION! Scientific Advisory Board was contacted and a teleconference between the Scientific Advisory Board and project coordinator was held on November 19th 2015 to discuss project progression and exchange expertise/advice."

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

"The JIKI trial was the first to evaluate a specific anti-EVD treatment, and is, to our knowledge, the largest that has been performed in EVD to date. This trial presented many challenges from inception to the final analysis which have been met pragmatically. The results of the study, as well as the challenges that were encountered, provide useful information for future clinical research in EVD.
Potential impact: The EVD outbreak in West Africa seems to be subsiding, without any effective treatment having yet been demonstrated. In future outbreaks, it will be important to integrate clinical research into standard care. All patients with EVD should be eligible for large trials of experimental treatments. Further studies will be unlikely to show that monotherapy with favipiravir decreases mortality in patients with very high viral load. In contrast, in patients with a Ct≥20 or a viral load below 108 genome copies/ml, future research on favipiravir monotherapy would be merited. Further trials should be powered to show that monotherapy with favipiravir decreases mortality by at least 30%. It may also be of interest to evaluate higher doses than those we used in the JIKI trial. Alternatively, association of favipiravir with another medication in a combination therapy could also be considered.

Predictions that the epidemic might now already be over now appear optimistic despite favourable epidemiological tendencies. In WP2 we the what might be the reasons for recurrent outbreaks? Are they likely to persist? How will the "end" of the epidemic be established? Which aspects of the response will persist even after the end of the epidemic, in order to be prepared for future outbreaks?

For WP4 eventually a review on the PK/PD properties of the anti-EBOV drugs has been written and is currently in revision (2nd round) in Clinical Pharmacokinetics. A paper describing the modeling approach used to characterize favipiravir given intravenously in NHPs is in preparation.

The communication of the results of the JIKI trial (publications and presentation in the framework of international conferences) allows the consortium to present the objectives of the project that aims to verify the effectiveness of the Favipiravir and improve its effectiveness (dose regimen and administration route)."

Related information

Record Number: 190316 / Last updated on: 2016-11-14
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