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  • Periodic Reporting for period 2 - REACTION (Evaluation of the efficacy and of the antiviral activity of T-705 (favipiravir) duringEbola virus infection in non-human primates humans)
H2020

REACTION Report Summary

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

Periodic Reporting for period 2 - REACTION (Evaluation of the efficacy and of the antiviral activity of T-705 (favipiravir) duringEbola virus infection in non-human primates humans)

Reporting period: 2015-11-01 to 2016-10-31

Summary of the context and overall objectives of the project

The Ebola outbreak in West Africa was the largest and deadliest the world has ever seen. This public health crisis shifted into a complex emergency. The Ebola crisis required both an immediate response to treat patients and prevent further spread of the epidemic, as well as long term commitment in the complex sociocultural context.

The main objective of the REACTION! project is to provide rapid evidence of favipiravir (FAV) anti-Ebola efficacy in reducing mortality and Ebola viral load in humans with Ebola Virus Disease (EVD). In Work Package (WP) 1, efficacy of T-705 (favipiravir) in reducing mortality and decreasing Ebola plasma viral load at early stage of infection in a pilot non-randomized phase IIb sequential trial was assessed. Furthermore, a specific goal of REACTION! is to ensure that effective clinical care regimens are taken up safely and to engage the community and local health care workers in trials (WP2).
Next to the clinical trial, we are evaluating antiviral activity of FAV in non-human primates (NHP) at different doses and different time points in natural history of the disease (WP3).
In WP4 data from the JIKI trial of WP1 and the in vivo experiments (WP3) will be analyzed to provide a better quantitative understanding of the determinants of the viral response to treatment.
WP5 ensures effective dissemination and communication of results and WP6 focuses on management of the project.

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

Work carried out by REACTION! has ensured successful realization of specific objectives. You can find the published articles on our website (http://www.reaction-ebola.eu/).

JIKI Trial
A paper describing experimental treatment with FAV for EVD (Sissoko et al. - PLOS Medicine 2016) was successfully published. Among main findings were that:
1. Monotherapy with FAV is not effective in patients with Ct values<20, and merits further study in patients with Ct values of ≥20;
2. High-dose FAV is well tolerated and higher doses could be tested.

A Ct value, or cycle threshold value, is a measurement to determine the amount of nucleic acid in the sample by Polymerase chain reaction (PCR), thus inversely representing amount of virus; the higher the Ct value, the less virus in the sample.

An important question, raised by the scientific community after publication, was the level of concentrations of FAV achieved in patients of the JIKI trial. In absence of a control group and of clear and strong signal on mortality reduction, these data were indeed urgently needed to better evaluate efficacy of FAV and how it could be potentially used in further outbreaks. Because drug concentration measurements require more time that other tests, we published trial results without reporting drug concentrations and those were analyzed after.
Our main findings, are the following:
1. At day 2, concentrations were lower but close to targeted values;
2. At day 4 concentrations largely dropped which was not anticipated;
3. There was no significant relationship between FAV concentrations and EBOV viral kinetics or survival.

Our conclusion is that these results suggest FAV concentrations were likely not sufficient to strongly inhibit the viral replication in many patients. Consistent to our initial conclusion we also think that these results warrant further dose-finding studies in healthy volunteers to assess the concentrations and the tolerance that could be achieved with higher doses of FAV.

The trial has provided a lot of experience in quickly setting up and running a trial in unusual circumstances. The community and non-governmental organizations were involved and together research was integrated into care to improve healthcare.

Social Mobilization
Efforts were pursued to realize social mobilization and community engagement during the JIKI trial by developing strategies to mobilize community for vaccine trials. Research on how to support this was initiated during JIKI and was prolonged in the following Prevac trial. Our research has provided significant insights in how the community responds to initiation of a trial.
Results from this research performed are:
1. Conduct of research improves care;
2. The community shows a need for recognition by caregivers;
3. It seems that survivors and caregivers are being ostracized by their communities;
4. Variability in how researchers compensate participation trials creates a market and inequities;
5. There generally is good acceptability of vaccine trials;
6. We developed a community mobilization strategy.

NHP
For optimal use of FAV as drug during future outbreaks studies for tolerance, dose-finding and efficacy are held in NHP infected with EBV. The partners of WP3/4 have performed important experiments to refine the pharmacokinetic (PK) model that is usable in Mauritian macaques, a species of NHP. A model for the drug PK in uninfected NHP and a report on the effect of FAV in mice have been published.

A first step of experiments was finalized last year to confirm the antiviral activity of the drug. Follow-up experiments to verify the efficacy of FAV in EVD-infected NHP and to use adapted doses of FAV to test an optimized treatment protocol were initiated and planned. Additionally partners collect sets of samples of NHP to determine genetic diversity, viremia, PK, clinical biochemistry and haematology.

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)

JIKI Trial
Even though the results of the FAV clinical trial were negative, FAV was shown not to be effective, still it was very important to show the effect of FAV on the viral replication in patients with a Ct≥20 or a viral load below 108 genome copies/ml. Also very important is that the JIKI trial, performed in an emergency situation, was unrandomized and provided immediate care to patients with EVD; it realized improved care for Ebola patients through the clinical trial, and improved broader scientific literacy.

In future studies, further trials should be powered, to show that monotherapy with FAV decreases mortality by at least 30%. It may also be of interest to evaluate higher doses than used in the JIKI trial. Use of FAV in a combination therapy will also be tested.

Directly after JIKI-trial other initiatives were started to continue research on treatment of EVD in patients. Additionally the trial team contributes actively to the epidemiologic investigations of the last clusters of EVD beyond the epidemic in Guinea.

NHP
The experiments in NHP have provided insights in the drug activity and efficacy in EBV-diseased NHP and in the viral characteristics and diversity. The studies performed with adapted doses of Favipiravir will provide us with the knowledge to create an optimized treatment protocol of FAV, particularly in case of a future outbreak of EVD.

Synergistic drug interactions
WP4 partners are involved in the analysis of mice infected with the Lassa virus and treated with FAV and ribavirin (RIB). These data were collected and published. We used the data as a model to understand the effect of RIB in the treatment of haemorrhagic fever, shown to be synergistic with FAV (Westover et al. - Antiviral Research 2016). Results suggest that RIB does not act directly on viral replication, but rather limits the liver inflammation in a dose-dependent manner. It is this liver inflammation-limiting effect that, in combination with FAV acting as a genuine antiviral, may improve survival in mice. Results obtained will be used to evaluate by simulation the benefit of RIB in NHPs and possibly humans.

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