Periodic Reporting for period 2 - Ebola_Tx (Emergency evaluation of convalescent blood and plasma for Ebola Viral Disease (EVD) in affected West African countries.)
Okres sprawozdawczy: 2015-11-01 do 2016-10-31
CONTEXT
In September 2014, the World Health Organization (WHO) prioritized convalescent whole blood (CWB) and convalescent plasma (CP) transfusion among potential Ebola therapies in the hope they could rapidly be implemented if proven safe and effective. The emergency evaluation of CP to treat EVD in Guinea (Ebola_Tx) Consortium, led by the Institute of Tropical Medicine-Antwerp (ITM-A), brought together a number of partners with complementary expertise to undertake a phase 2/3, open-label, non-randomized, controlled clinical trial to evaluate CP additional to standardized supportive care in confirmed EVD patients in Conakry, Guinea (Clinicaltrials.Gov. NCT02342171).
The project was organized around four work packages (see Figure 1)
OBJECTIVES
The primary objective of the study was to assess if CP combined with supportive care improves the 14 day survival of patients, compared to supportive care alone. An effect of CP would be considered clinically significant if there was an absolute decrease in the case fatality rate of 20% or more, compared to supportive care alone (e.g. from 70% to 50%).
As per WHO guidance, two consecutive transfusions of 200 to 250 ml of ABO-compatible CP was given. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration, as assays to determine this were not unavailable in the affected countries.
In September 2014, the World Health Organization (WHO) prioritized convalescent whole blood (CWB) and convalescent plasma (CP) transfusion among potential Ebola therapies in the hope they could rapidly be implemented if proven safe and effective. The emergency evaluation of CP to treat EVD in Guinea (Ebola_Tx) Consortium, led by the Institute of Tropical Medicine-Antwerp (ITM-A), brought together a number of partners with complementary expertise to undertake a phase 2/3, open-label, non-randomized, controlled clinical trial to evaluate CP additional to standardized supportive care in confirmed EVD patients in Conakry, Guinea (Clinicaltrials.Gov. NCT02342171).
The project was organized around four work packages (see Figure 1)
OBJECTIVES
The primary objective of the study was to assess if CP combined with supportive care improves the 14 day survival of patients, compared to supportive care alone. An effect of CP would be considered clinically significant if there was an absolute decrease in the case fatality rate of 20% or more, compared to supportive care alone (e.g. from 70% to 50%).
As per WHO guidance, two consecutive transfusions of 200 to 250 ml of ABO-compatible CP was given. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration, as assays to determine this were not unavailable in the affected countries.
Safety and feasibility: The Ebola-Tx experience demonstrates that it is possible to organize a complex intervention as a CP trial in the middle of an EVD outbreak. Current data support the acceptability and safety of this intervention. No serious adverse reactions associated with CP administration were documented (Table 1).
Efficacy:
The rationale of the use of CP as EVD treatment is based on the notion that CP contains EVD neutralizing antibodies or other types of antibodies that can block EVD infection. Hence, to fully understand the efficacy of CP, detailed information on how much of these neutralizing and other antibodies were given in the donated CP is required. However, tests to determine this can only be done in high biosafety (BSL4) laboratories, which are not available in the affected West African countries. Shipment of these samples abroad has however proven very complex and time-consuming. Hence, as a public health intervention, CP would be used once available without awaiting these test results.
The first analysis of the trial data looked at the use of unselected CP – meaning the use of CP without knowing the exact amount of anti EVD antibodies present. The use of unselected CP as per WHO guidance (2 units of 200-250 ml) was not associated with the 20% reduction in mortality the trial was designed to detect. There was a small reduction in mortality, with an adjusted absolute risk reduction of 2.6% but the confidence interval excluded a 20% absolute reduction (confidence interval: -13.1 to 8.0) see Table 2 and Abstract 1.
One of the reasons for failing to find a clear effect of unselected CP could have been that the levels of antibodies present in the plasma were low, and to assess this, additional laboratory analyses had to be done in France.
Once the samples were shipped to France and the results of the laboratory analyses were available further statistical analyses on the trial data were done. With this information, we could evaluate how much antibodies each patient had received, and importantly assess whether individuals receiving higher doses would have a greater benefit from CP.
• Key findings are that
- Transfusion of up to 500ml of unselected CP - meaning with unknown quantities of Ebola virus antibodies - was well tolerated but not found to significantly improve survival.
- Higher doses of Ebola virus antibodies were not associated with improved survival
- The level of Ebola virus neutralizing antibodies (among the Ebola virus antibodies) in donor plasma was generally low.
- Higher doses of IgG Ebola virus antibodies (targeting different components of the virus, irrespective of the neutralizing activity) were associated with more pronounced reductions in Ebola viral load.
- In conclusion, while higher doses of IgG Ebola virus antibodies could give stronger reductions in the amount of Ebola virus present in the blood of patients, this did not result in increased survival (see abstract 2).
• Further studies should assess the effectiveness of higher Ebola virus antibody doses
EXPLOITATION AND DISSEMINATION
- Real-time and continuous sharing of information at the national and international level
- Confidential sharing of preliminary findings with WHO, MSF and Guinean authorities
- Confidential sharing of preliminary findings with the WHO Blood Regulatory Network:
- Conference presentations
- Scientific symposia at international conferences:
http://www.professionalabstracts.com/ectmih2015/iplanner/
http://www.ebolatx.eu/event/astmh-64th-annual-meeting
- Project website: www.ebolatx.eu
- Project film (versions of 3 and 11 minutes) (www.ebolatx.eu)
- Extensive media coverage
- Publications
The main trial findings were published in the New England Journal of Medicine (NEJM) http://www.nejm.org/doi/full/10.1056/NEJMoa1511812.
A follow research letter containing information on the amount of antibodies present in the donor plasma and the relation between the dose of antibodies given and the patient outcomes has been published at NEJM. Links to other Ebola-Tx publications can be found on the Ebola-Tx website (www.ebolatx.eu).
Efficacy:
The rationale of the use of CP as EVD treatment is based on the notion that CP contains EVD neutralizing antibodies or other types of antibodies that can block EVD infection. Hence, to fully understand the efficacy of CP, detailed information on how much of these neutralizing and other antibodies were given in the donated CP is required. However, tests to determine this can only be done in high biosafety (BSL4) laboratories, which are not available in the affected West African countries. Shipment of these samples abroad has however proven very complex and time-consuming. Hence, as a public health intervention, CP would be used once available without awaiting these test results.
The first analysis of the trial data looked at the use of unselected CP – meaning the use of CP without knowing the exact amount of anti EVD antibodies present. The use of unselected CP as per WHO guidance (2 units of 200-250 ml) was not associated with the 20% reduction in mortality the trial was designed to detect. There was a small reduction in mortality, with an adjusted absolute risk reduction of 2.6% but the confidence interval excluded a 20% absolute reduction (confidence interval: -13.1 to 8.0) see Table 2 and Abstract 1.
One of the reasons for failing to find a clear effect of unselected CP could have been that the levels of antibodies present in the plasma were low, and to assess this, additional laboratory analyses had to be done in France.
Once the samples were shipped to France and the results of the laboratory analyses were available further statistical analyses on the trial data were done. With this information, we could evaluate how much antibodies each patient had received, and importantly assess whether individuals receiving higher doses would have a greater benefit from CP.
• Key findings are that
- Transfusion of up to 500ml of unselected CP - meaning with unknown quantities of Ebola virus antibodies - was well tolerated but not found to significantly improve survival.
- Higher doses of Ebola virus antibodies were not associated with improved survival
- The level of Ebola virus neutralizing antibodies (among the Ebola virus antibodies) in donor plasma was generally low.
- Higher doses of IgG Ebola virus antibodies (targeting different components of the virus, irrespective of the neutralizing activity) were associated with more pronounced reductions in Ebola viral load.
- In conclusion, while higher doses of IgG Ebola virus antibodies could give stronger reductions in the amount of Ebola virus present in the blood of patients, this did not result in increased survival (see abstract 2).
• Further studies should assess the effectiveness of higher Ebola virus antibody doses
EXPLOITATION AND DISSEMINATION
- Real-time and continuous sharing of information at the national and international level
- Confidential sharing of preliminary findings with WHO, MSF and Guinean authorities
- Confidential sharing of preliminary findings with the WHO Blood Regulatory Network:
- Conference presentations
- Scientific symposia at international conferences:
http://www.professionalabstracts.com/ectmih2015/iplanner/
http://www.ebolatx.eu/event/astmh-64th-annual-meeting
- Project website: www.ebolatx.eu
- Project film (versions of 3 and 11 minutes) (www.ebolatx.eu)
- Extensive media coverage
- Publications
The main trial findings were published in the New England Journal of Medicine (NEJM) http://www.nejm.org/doi/full/10.1056/NEJMoa1511812.
A follow research letter containing information on the amount of antibodies present in the donor plasma and the relation between the dose of antibodies given and the patient outcomes has been published at NEJM. Links to other Ebola-Tx publications can be found on the Ebola-Tx website (www.ebolatx.eu).
The Ebola-Tx experience demonstrates that it is possible to organize a complex intervention as a CP trial in the middle of an EVD outbreak. Current data support the feasibility, acceptability and safety of this intervention. The use of convalescent plasma without knowing the amount of antibodies present did not result in a significant reduction in mortality, and even amongst those patients that received higher antibody doses, mortality was not reduced. These findings have a clear impact on policy and practice as they directly influence the WHO guidance document. Our data clearly show that the use of convalescent plasma as per the WHO guidance document was not effective in reducing mortality. Consequently, other therapeutic options should be prioritized for evaluation in future outbreaks. Before this trial, there were positive anecdotal results from few cases in a previous outbreak in DRC.
At the same time, we also generated data on how efficacy of convalescent plasma could potentially be increased. Higher doses of IgG Ebola virus antibodies gave stronger reductions in the amount of Ebola virus present, and possibly higher or more frequent doses than used in our study – which followed WHO guidance – might be required to achieve even more pronounced reductions in viral load, and potentially an associated reduction in mortality . Further studies in animal models should provide insights on that.
At the same time, we also generated data on how efficacy of convalescent plasma could potentially be increased. Higher doses of IgG Ebola virus antibodies gave stronger reductions in the amount of Ebola virus present, and possibly higher or more frequent doses than used in our study – which followed WHO guidance – might be required to achieve even more pronounced reductions in viral load, and potentially an associated reduction in mortality . Further studies in animal models should provide insights on that.