key: cord-0741889-lqoyxbln
authors: Murphy, MF; Estcourt, L; Grant-Casey, J; Dzik, S
title: International Survey of Trials of Convalescent Plasma to Treat COVID-19 Infection
date: 2020-06-27
journal: Transfus Med Rev
DOI: 10.1016/j.tmrv.2020.06.003
sha: 7f8b3dcc1c88805753dce8700771cfaeebbbe1a6
doc_id: 741889
cord_uid: lqoyxbln

Abstract The collection and clinical use of COVID-19 convalescent plasma (CCP) as a therapy for COVID-19 infection is under development and early use in many centers worldwide. We conducted an international survey of centers undertaking studies of CCP to provide understanding of the common themes and differences between them. 64 studies in 22. countries were identified from clinical trial registries and personal contacts of the authors. 20 of the 64 centers (31%) from 12 of 22 countries (55%) responded to the survey. Of the 20 studies, 11 were randomized controlled trials (RCTs) and 9 were case series. Only 4 of the RCTs plan to recruit 400 patients or more, and only 3 RCTs were blinded. The majority of studies will study the effect of CCP on sick patients requiring hospitalization and those requiring critical care, and none is examining the role of CCP in non-infected at-risk individuals. A wide variety of primary and secondary outcomes are being used. The donor eligibility criteria among the studies are very similar, and the use of plasmapheresis for the collection of CCP is almost universal. The planned dose of CCP ranges from as little as 200mL to well over 1 liter, but is 400-800 mL or 4 mL/kg or greater in all the RCTs. There is considerable variability in donor antibody testing with no consistency regarding the cut-off for antibody titer for acceptance as CCP or the use of pathogen-inactivation. Our survey provides an understanding of the similarities and differences among the studies of CCP, and that by virtue of their design some studies may be more informative than others.

There are huge efforts to find effective therapies for COVID-19 infection. Numerous trials are in progress; indeed, more than 1000 studies addressing various aspects of COVID-19 were found to be registered on ClinicalTrials.gov on 15 th May 2020, including more than 600 interventional studies and randomized clinical trials (RCTs). 1 The collection and clinical use of COVID-19 convalescent plasma (CCP) is under development and early use in many centers and countries. Those implementing CCP are likely to prepare and administer it in different ways. This variation is not surprising given the urgency of the situation, and the limited evidence base for the safety and effectiveness of convalescent plasma against the several infectious agents against which it has been used. 2, 3 There are several key questions surrounding the use of CCP as a therapeutic. These include antibody testing and donor selection, methods of collection and storage, dose and duration of treatment, lot to lot variability, adverse effects, selection of the patients most likely to benefit, and measurement of efficacy. A number of publications have already addressed some of these issues and a few have provided either recommendations [3] [4] [5] [6] [7] [8] or preliminary results 9 . Links to some websites providing information and/or recommendations about CCP are provided in Appendix 1.

Before being offered for routine use, this new intervention should be rigorously tested in clinical trials designed to define both safety and efficacy. This leads to questions about the design and conduct of these trials so that valid data are provided for analysis as quickly as possible. If CCP is found to be safe and effective, the lessons learned from the trials about the optimal methods for preparing and administering CCP will need to be implemented as a matter of urgency.

We report the results of an international survey of centers undertaking early studies of CCP to provide an understanding of the common themes and differences between them in the preparation and investigation of CCP and that by virtue of their design some studies may be more informative than others.

J o u r n a l P r e -p r o o f 4

A survey tool was developed to collect information from centers planning to collect and administer CCP to patients with COVID-19 infection. The centers were identified on 1 st May 2020 from a search of Clinicaltrials.gov, the Chinese Clinical Trial Registry (ChiCTR) and personal contacts of the authors. The survey tool was written in English and designed to gather information on the whole process of the collection and administration of CCP from the identification of suitable donors including antibody testing, through the collection and storage of the product, the identification of patients suitable for its administration and details of the design of clinical trials. We did not ask about the planned completion dates of the studies so it is not known when the results will be available.

The survey was sent electronically to the study contacts for 64 studies in 22 countries shown in Figure 1 and listed in Appendix 2 with a request to complete and return it within 7 days.

We received responses from 20/64 (31%) studies from 12/22 (55%) countries, and they provide the data for this report.

The first survey questions were about the design of the studies. Of the 20 studies, 11 were randomized controlled trials (RCTs) and 9 were case series (Table 1A) . There was blinding of the investigators to the intervention in 3/11 RCTs where standard plasma was used as a comparator, and no blinding in the other 8. Among the RCTs, there was huge variation in the number of study sites (range 1-250), and this was even more marked in the non-RCTs (range 1-1300+). There was also considerable variation in the number of patients receiving CCP in both the RCTs (range 40-5,000) and in the case series (6-10,000).

The comparison intervention to CCP was standard plasma in 3/11 RCTs, and no plasma in the others (although not stated in one study) ( Table 1B ). The clinical stages of illness targeted by the different trials is shown in Figure 2 . Most RCTs (9/11) included symptomatic, infected but not critically ill patients; 6 RCTs included critically ill patients; and 2 included asymptomatic infected patients. In contrast, all but one of the case series included critically ill patients. None of the studies focused on non-infected at risk individuals. Children were included as study participants in 3 of the RCTs. All studies required a positive PCR test of the recipient except for one of the studies in Iran (Iran-1) and the study in France. The collection of possible adverse effects was similar for all studies, although only 4 studies specifically included antibody dependent enhancement of infection (ADE).

There was considerable variability in the primary and secondary outcomes for the studies (Table 2) . Figure 3 provides a summary of the primary outcomes with the most frequent being clinical change and mortality. The primary outcomes for the 3 largest RCTs were a composite of intubation or death at day 30 (USA-6), ventilation-free days (Canada-1) and mortality at 28 days (UK-2).

The donor eligibility criteria for the collection of CCP were very similar amongst the studies (Table 3 ). In 15/16 studies where this information was provided, the respondents indicated the requirement for a prior positive polymerase chain reaction (PCR) assay for SARS-COV2.

The time required from recovery of symptoms of COVID-19 infection before collection of CCP varied from 14 to 28 days. Nearly all studies indicated that female donors would be tested for HLA or HLA and HNA antibodies to minimize the risk of transfusion-related acute lung injury (TRALI). Plasmapheresis was selected as the method of collection of CCP by nearly all investigators.

The dose of plasma was 400-800mL or 4mL/kg or greater in all 10 RCTs and in 6/8 of the case series providing this information (Table 4 ). Protocols called for CCP to be stored in the frozen state prior to thawing before administration in all 16 studies that provided this information apart from one study (Germany-1). 6 studies including only 2 of the RCTs indicated that the CCP would be pathogen-inactivated.

Responses were received to questions about donor antibody testing from 15/20 of survey participants (Table 5 ). 11/15 of all studies and 8/11 of the RCTs indicated that antibody testing would be carried out before the administration of CCP, and the remainder after its administration. 11/15 of all studies and 6/11 of the RCTs indicated that testing would include neutralizing antibodies sometimes with additional testing for non-neutralizing antibodies.

Only 8 studies provided information about cut-off levels or titers of antibodies used to qualify donors.

The COVID-19 pandemic represents a major threat to global health and has caused enormous strain on healthcare systems worldwide. One of the major research challenges is to develop trials to determine the effectiveness of any promising therapies, and one of these treatment options is CCP. A systematic review has shown that convalescent plasma (CP) may have clinical benefit for people with acute viral diseases such as influenza and severe acute respiratory syndrome (SARS) 10 , but its effectiveness in patients with COVID-19 is as yet uncertain. 8 One reason for this is that many outbreaks are regional and short-lived not providing sufficient time to collect and carefully study the safety and efficacy of CP. The current COVID-19 pandemic may not be bound by such limitations and there is likely to be sufficient time to collect CCP to treat newly infected patients. The logical first research questions are to determine the safety and effectiveness of CCP; and not surprisingly, numerous studies have been established to do this worldwide. We have undertaken an international survey of centers who have instituted studies of CCP to provide an understanding of the similarities and differences between them.

We identified 64 CCP studies in 22 countries by searching trial registries and through personal contacts. This probably represents an unprecedented upsurge in studies of any single topic in transfusion medicine. We recognise that we may not have identified all CCP studies, and that further studies will have been initiated since we began the survey. We The responses raise concerns about their ability to determine the effectiveness of CCP across the clinical spectrum of COVID-19 infected patients. These concerns include the lack of randomisation in 11/20 studies and small sample size in 10/20. Only 4 of the RCTs plan to recruit 400 patients or more so that the majority of studies are unlikely to have sufficient power to detect significant changes in key outcomes. A substantial proportion of survey respondents noted that mortality would be a primary outcome. Current estimates would suggest that the mortality rate of among hospitalized patients is approximately 15%, and in order to detect a 10% relative reduction in death rate (from 15% to 13.5%) with 80% power and alpha = 0.05 would require a study with over 15,000 participants. Furthermore The COVID-19 pandemic provides the first opportunity in history to rigorously define the role of convalescent plasma in a critically important viral respiratory disease.

The authors have no conflicts to declare. 

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