INSERM. France: Preliminary data from the JIKI clinical trial, which is
testing the efficacy of favipiravir in reducing mortality associated
with Ebola, provide two important pieces of information:
• absence of efficacy in individuals who arrive at treatment
centres with a very high level of viral replication and who already
have serious visceral involvement,
• and encouraging signs of efficacy in individuals arriving
at treatment centres with a high or moderate level of viral replication,
who have not yet developed overly severe visceral lesions.
With this classification into two groups, we have a much
better understanding of Ebola virus disease, and can redefine the role
of antiviral monotherapies in the therapeutic arsenal used against the
disease.
The trial, sponsored by Inserm and funded by the European
Commission from the Horizon 2020 Initiative under the project title
REACTION, is supported by two NGOs, Médecins Sans Frontières/Doctors
Without Borders (MSF) and Alliance for International Medical Action
(ALIMA); two laboratory networks, Belgian First Aid and Support Team
(B-FAST) and European Mobile Laboratory (EMLab); the French Red Cross,
and the French Military Health Service.
These preliminary data are being presented on Wednesday 25
February as a late-breaking abstract at the CROI international
conference (Conference on Retroviruses and Opportunistic Infections) in
Seattle.
Given the high mortality associated with Ebola virus despite
high-quality symptomatic treatment, study of specific innovative
therapeutic agents is essential. Potentially useful drugs against the
virus include favipiravir (T-705), an antiviral drug already tested
against influenza virus in adult humans (and well tolerated). The latter
(no more than other potential treatments) has never been tested in
humans for treating Ebola, but its efficacy has been demonstrated in
vitro and in mice.
As part of the mission given to Aviesan to organise the research as a
matter of urgency, the JIKI clinical trial, a phase II multicentre
noncomparative trial, began in Guinea on 17 December 2014, to test the
ability of favipiravir to reduce mortality in individuals infected by
Ebola virus.
Sponsored by Inserm, and jointly funded by the European Commission,
the JIKI trial is being conducted in partnership with MSF, ALIMA, the
French Red Cross, EMLab, B-Fast and the French Military Health Service,
and is taking place in four Ebola treatment centres in Guékédou (MSF),
Nzérékoré (ALIMA), Macenta (French Red Cross) and Conakry (carers’
treatment centre).
In these centres, adults and children over one year of age with a
positive Ebola PCR test who agree to take part (parental consent in the
case of minors) receive treatment with favipiravir for 10 days along
with basic care. Favipiravir comes in the form of 20 mg tablets (the
tablets can be dissolved in a drink) and is administered according to
the following dose regimen :
- Adults: Day 0: 2,400 mg at H0, 2,400 mg at H8 and 1,200 mg at H16, then 1,200 mg twice a day for 9 days;
- Children: doses adjusted to body weight.
The JIKI trial is being followed by an independent monitoring
committee, which met on 11 December 2014, and on 5 January, 14 January
and 26 January 2015. At this last meeting, the committee authorised the
investigators to publish the interim data, which they judged to contain
messages that should be quickly shared with the international community.
These messages, obtained from the first 80 participants (69 adolescents
or adults, and 11 children) are as follows:
- 42% of participants arrived at the treatment centres with a
strongly positive PCR test (cycle threshold value, CT, < 20),
reflecting a very high viral load . Of these patients, 81% had
refractory renal failure and 93% died. In the three months preceding the
trial, mortality among individuals presenting with the same features
was 85%. Comparison of the trial and pretrial data shows that it is
highly unlikely that favipiravir monotherapy will ultimately be proven
to reduce mortality in this population with advanced disease.
- 58% of participants arrived in the treatment centres with a cycle
threshold (CT) ≥ 20, reflecting a high or moderate viral load. Of these
patients, 42% had renal failure, but only 15% died. In the three months
preceding the trial, mortality among individuals presenting with a CT ≥
20 was 30%. Comparison of the trial and pretrial data therefore leads us
to hope that favipiravir monotherapy may reduce mortality in this
population with less advanced disease.
For the researchers, these preliminary data encourage us:
- to continue the trial while trying to provide favipiravir treatment
as soon as possible after the symptoms appear, so as to treat patients
in whom viral multiplication can be controlled, and who have not yet
developed visceral lesions (especially renal lesions);
- to explore other therapeutic options for patients who come to the treatment centres when their disease is too far advanced.
Yves Levy, the chairman and CEO of Inserm said: “The results of
this non-comparative trial have to be confirmed using a larger number of
patients. However, they open up other therapeutic opportunities in drug
combinations, in particular for the treatment of patients suffering
from more advanced stages of this disease. They also clearly show that
research plays an essential role in tackling such epidemics. I would
also like to stress that without the excellent Guinean-French
cooperation, the pioneering role of the Médecins Sans Frontières (MSF)
in this research, the fruitful partnerships with all NGOs involved, and
the European Commission’s responsiveness, this progress could not have
been accomplished.”
European Commissioner for Research, Science and Innovation Carlos Moedas said: “I
am excited about the encouraging results of one of our EU-funded
projects to tackle Ebola. We have preliminary evidence that the
antiviral drug ‘favipiravir’ may be effective against early Ebola
disease. If these results are confirmed by the ongoing clinical trial,
it will be the first-ever treatment to be deployed against this deadly
disease during the current outbreak. These results show the success of
the European Commission’s quick reaction to the Ebola outbreak to
support urgent research on several potential treatments and vaccines
against Ebola with funding from our Horizon 2020 research programme.
This is an astounding example of what the best brains can achieve with
EU support when there is so much at stake. It shows how EU funding can
lead to discoveries that save people’s lives and which are the result of
rapid EU, international and industry cooperation.”
According to Agustin Augier, Secretary-General of Alima, “Those
positive results will reinforce the confidence between affected
populations and the treatment center. This therapeutic solution, even if
partial, will significatively attract ebola patients to the treatment
center. It is a significative step towards tackling the outbreak in the
villages where it still goes on.”
“MSF is pleased to see that favipiravir seems to have a positive
effect for certain patients suffering from EVD. But it also seems that
the most vulnerable patients, the people that are most likely to die
from the disease, don’t benefit at all from favipiravir. That fact, and
the fact that these are only preliminary results, show that it is really
too soon to start using favipiravir outside a trial environment.
Research into favipiravir, and into other potential treatments for EVD,
must be continued, and MSF is willing to play a role in these clinical
trials,” says Dr. Bertrand Draguez, medical director of MSF.
This project has received funding from the European Union’s Horizon 2020 research and innovation programme