Global impression of the work performed sincew the beginning of the project
The main objective of the REACTION! project is to provide rapid evidence of FAV anti-Ebola efficacy in reducing mortality and Ebola viral load in humans with EVD. We initiated the JIKI trial, a trial in a response to the emergency in Guinea, aimed to assess the efficacy of FAV in reducing mortality in humans with EVD in Guinea.
The first experiments of WP3 and WP4 provided robust PK/efficacy information to design the therapeutic protocols for this JIKI trial. Over the study-period from December 2014 to April 2015 we recruited more than 100 patients in 4 EVD treatment centers.
During the trial, WP1, in addition to providing medical aid where required, collected data on viral load, mortality, tolerability and procedures related to standard-of-care. Partners of WP2 in turn put effort into increasing overall community acceptability of clinical research in this emergency and described how to turn experiences into practical tools for next outbreaks.
Results of the JIKI trial revealed (1) that FAV has encouraging tolerability. (2) that low Ct values have a high prognostic value and (3) that FAV efficacy cannot yet be concluded upon. It is recommended that baseline Ct values should be used to systematically stratify analyses of drug trial in EVD.
Further it is recommended to further investigate FAV monotherapy in patients with medium to high viremia. The experience of JIKI taught us that clinical research can be integrated into standard care towards evaluation of EVD-specific therapies and it even improves healthcare. Still, we recognize that there is a need for recognition of the community, though in general the local community shows good acceptability of vaccine trials. Still, it was observed that survivors and caregivers in EVD affected regions were ostracized; a huge problem after the Ebola epidemic.
To this end we highly recommend to include a community mobilization strategy in clinical research in emergency situations.
After the JIKI trial ended (April 2015), WP3 and WP4, performed their work by treating EVD-infected and uninfected Non Human Primates (NHP) with inoculum doses FAV to determine effective dose and collected samples for virology, genomics, biochemistry, haematology and PK studies. The work packages worked closely together and achieved the following results (1) a NHP model to analyse virus diversity by NGS in infected untreated NHPs (2) doses in the range of 150-180mg/kg were shown to significantly improve survival time and survival rate, and reduce viral replication in NHP infected by EBOV (3) a PK model relevant for analysing PK of FAV in EVD and other viruses (MARV, ZIKV, LAV, YFV). We recommend to evaluate the tolerance of higher doses FAV in patients.
Our results are published in no less than 25 book chapters/scientific publications. In the years during and following the JIKI-trial, we have disseminated our work at international conferences. Our expertise in clinical trials in emergency situation is called upon in many follow-up emergency trials.
Progress beyond the state of the art
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.
Whilst the results of the FAV clinical trial were shown not to be conclusive, it has been 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. The JIKI trial, performed in an international 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 as well as investigating possible combination therapies.
Other initiatives have been started to continue research on treatment of EVD in patients. Additionally, the trial team has contributed actively to the epidemiologic investigations of the last clusters of EVD beyond the epidemic in Guinea - including the FORCE, PREVAC and PREVAIL II trials.