FAQ – preliminary results
Do the first results of the Ebola-Tx trial mean that we are now 100% sure that convalescent plasma is not effective against Ebola?
We can only conclude that the way plasma was used in this study did not have a large effect on mortality. Whether other ways of using plasma could lead to a clear effect on mortality needs further study.
In the Ebola-Tx trial, plasma was given following the WHO guidelines: one single administration of 2 x 250 ml of plasma from two distinct “random” donors, without knowing the exact amount of Ebola virus neutralising antibodies in the plasma.
The results show that use of convalescent plasma in this manner did not lead to a 20% reduction in mortality, which was considered a clinically relevant outcome for the trial. However, we currently do not know how many donors might have had low levels of neutralising antibodies. Samples of the donor plasma were recently shipped to France to measure these antibodies in a high biosafety laboratory in Lyon. The objective is to find out whether plasma with a high level of antibodies was more effective. This would indicate that plasma collection should aim to recruit donors with a high antibody concentration, or that the plasma should be administered in a more concentrated form. The latter can be done via the production of hyperimmune globulines, which is a purified and concentrated product of plasma. We also will have to study whether plasma needs to be given in larger volumes or on several occasions, instead of one single administration, to be effective.
What are the next steps for the Ebola-Tx research consortium?
The consortium will first and foremost complete the current study by analysing the amount of virus neutralising antibodies present in the donor plasma (see above) and correlating it with patients who received the donor plasma. This will take place in the first six months of 2016.
Could it be that plasma works only for some patients?
There may be an indication that convalescent plasma has a greater effect in sub-groups such as pregnant women and children. However, the Ebola-Tx trial is not powered or able to draw any conclusions in this regard, because of the small number of patients in these sub-groups.
Why was the concentration of antibodies in the plasma not determined before administration?
WHO guidance (2014) stipulates that convalescent plasma can be administered without knowing the concentration of neutralising antibodies, for various reasons.
First, these reference tests need to be done in specialised, high biosafety laboratories which do not exist in West-Africa. Hence, awaiting the results from these tests would have caused long delays.
Basic antibody tests, which can be done in West-Africa, give even less indications regarding the minimal concentration of antibodies needed to select plasma for treatment. What we do know, however, is that there is a very poor correlation between the level of antibodies these basic tests detect and the level of neutralising antibodies. For instance, a donor can have a high level of antibodies in these tests, but there could be very few of these that neutralise the virus. And the opposite can be true as well.
Second, it is also not well known yet what concentration is required to be effective. Hence, even when the level of neutralising antibodies would be known, we cannot immediately define what the necessary minimal concentration would be. More scientific evidence needs to be gathered to answer this question.
Fewer patients were recruited in the trial than originally foreseen. Does this influence the study results?
Ebola-Tx is the largest ever trial on convalescent plasma as therapeutic treatment for Ebola, recruiting 102 patients. The study protocol originally foresaw 130 patients. Patient enrolment was stopped early July 2015 when the independent Data Safety Monitoring board, who monitors and guides the study, thought it was the right moment to stop recruitment. Their advice was motivated by the slowing down of the outbreak in Conakry in May and June 2015. The trial was still correctly powered to detect an overall absolute difference of 20% in day 14 survival as pre-defined in the study protocol thanks to a large number of control patients.
What does that mean, a non-randomised trial with historical control group?
All patients enrolled in the study (from February 2015) received convalescent plasma. Their results were compared with patients admitted to the same Ebola treatment centre in Conakry prior to the start of the study (before February 2015). Randomising would have meant withholding a potentially lifesaving treatment. In the absence of a therapeutic Ebola treatment this was deemed not acceptable in Guinea in the highly volatile setting of the Ebola outbreak.
Why are the preliminary results of the Ebola-Tx trial important?
Many things were learned in this trial. First, the study demonstrates that is feasible to organise this complex study in the middle of an Ebola outbreak. It was possible to introduce plasma collection in Guinea, administer it to Ebola patients, and have Ebola survivors coming forward to donate plasma. We also learned that plasma administration was safe and that there were few side effects. Even though the lack of observed improvement in survival is indeed disappointing, scientific progress is not only about positive findings.
Ebola-Tx delivers the first insights on the use of convalescent plasma against Ebola, which teaches us a lot and opens the way for future research which might lead to treatments that work. Further analysis of this trial might still find an effect of plasma that contains high amounts of antibodies or used in another manner. And even if plasma would ultimately not be found to be effective against Ebola, then it would be important to know this, so future studies can focus on other treatments.
FAQ – start of the study
What will the Ebola-Tx trial try to achieve?
The Ebola-Tx trial evaluates the efficacy of convalescent plasma (CP) therapy, trying to boost the immune system of Ebola patients with antibodies in the blood of recovered Ebola Virus Disease (EVD) patients.
Our first objective is to find out whether this therapy improves patients’ survival chances. At the same time, we are also studying if and how the approach can be scaled up.
Using antibodies contained in the blood of recovered patients is a well-established technique that has been used for several other infectious diseases, tetanus for example. WHO encouraged the organisation of trials for Ebola.
Why hasn’t this approach been tried before?
Outbreaks thus far have always been small and brought under control relatively quickly therefore there has never been the opportunity for a well-designed study of this therapy. During the 1995 outbreak in Kikwit (DRC), for example, ITM researchers and partners in the DRC used whole blood transfusions to treat 8 patients, 7 of which survived.
In the current epidemic two other convalescent plasma studies were set up at the Elwa2 clinic in Monrovia, Liberia (run by Clinical Research Management, Inc.) and in Freetown, Sierra Leone (led by the University of Liverpool). ITM is also involved in the latter study.
How does the trial work in practice?
The design of our study is an emergency, phase 2/3, open-label, non-randomized, clinical trial that will evaluate CP added to standardized supportive care (SC) in patients with confirmed EVD. Historical controls from the current epidemic will serve as comparator group.
We plan to enroll a minimum of 130 patients.
The primary measured outcome is the survival rate 14 days after the start of the treatment.
Who can participate in the trial?
The WHO has asked that research during this Ebola emergency aim to be as inclusive as possible, including children and pregnant women. Recruitment into the trial is therefore based on written consent from the patient or guardian of that patient with no bias related to gender, age, social, economic or cultural issues. Only those that are ineligible based on study criterion (no confirmed Ebola virus disease, history of allergic reaction to blood products, etc.) are not be considered for this study.
How are donors recruited for the trial?
Recovered patients who have been free of Ebola for at least 3 months are recruited through survivors’ groups in Guinea.
Which safety measures are put in place for plasma donation?
All plasma is thoroughly screened for infectious diseases that may be transmitted through transfusions. In addition, the plasma is treated in such a way that any other viruses or bacteria will be killed as well.
What kind of equipment is used for the donation of plasma?
Plasma is produced by a methodology called apheresis. With apheresis machines, the liquid part of the blood is collected and the red blood cells are given back to the patients. This is a well-established procedure routinely done in many countries. The apheresis equipment for the Ebola-Tx project has been donated by the Bill & Melinda Gates Foundation.
How often can a donor donate, and how much plasma will be taken?
According to WHO guidelines recovered Ebola patients can donate plasma once every two weeks
The quantity of plasma depends on the weight and size of the donor and varies between 440 and 640 ml.
Will donors be compensated for participating in the trial?
Donors only receive a travel reimbursement. Yet, in close consultation with survivor groups, the Ebola-Tx study group is supporting the donors to further develop their association and to carry out educational activities in the country.
How much plasma is administered to Ebola patients?
Patients receive two units of 200-250 ml.
How important is the role of Ebola survivors in the project?
Ebola survivors may be stigmatised in their communities. It is important for people to know that survivors are no danger to their loved ones and the community at large. Their participation in the study shows that they are Ebola free and it might even help other Ebola patients recover.
The relationship with the communities is very important. The research consortium includes several representatives from Guinea who have a strong link with their communities. Our anthropologists have worked on a daily basis with survivors, through the Guinean “association des guéris”, to help make sure that they are informed and involved as the study proceeds.