SHS – Sunnybrook Medical Services Alternative Funding Plan Association
SHS-21-001 – CONvalescent Plasma for COVID-19 Research Trial (CONCOR-1 trial)
This trial randomized 940 patients at 72 hospitals in Canada, the United States, and Brazil, between May 2020 and January 2021. From commencing of trial planning to collection of the first donor unit was 5 weeks and to the first patient 7 weeks for this Health Canada and FDA regulated trial. The planned total of 1,200 patients were not enrolled as after a review of the unblinded interim results by the data safety monitoring board (an analysis that included 614 patients), the committee recommended that the CONCOR-1 trial stop enrollment for meeting futility criteria, as it was unlikely to demonstrate a benefit of convalescent plasma even if more patients were enrolled. The study found that convalescent plasma did not reduce the risk of intubation or death (the primary outcome) or other patient-important outcomes (length of stay in intensive care or hospital) compared to patients who received only standard of care treatment for COVID-19 in hospital. However, the donor immunological profile was highly associated with the recipient primary outcome suggesting how donors should be qualified for future trials. Donors with poor functional antibodies in vitro were associated with higher rates of the primary outcome, and donors with highly functional antibodies had improved rates of the primary outcome. Patients receiving convalescent plasma experience more grade 3 and 4 adverse events. In September 2021, the results of the CONCOR-1 trial were published in Nature Medicine (https://doi.org/10.1038/s41591-021-01488-2).
The results indicated that transfusing convalescent plasma with unfavourable antibody profiles could increase the risk of intubation or death (or the converse, highly selected donors could improve outcomes). This is an important new message, because at the beginning of the pandemic there was debate as to whether convalescent plasma could be harmful, and the general message had been that it is would likely be safe and effective. Indeed, in the United States over 600,000 patients were treated outside of clinical trials with convalescent plasma. There was preliminary literature from influenza and other infections suggesting that convalescent plasma could be beneficial if it is administered very early in the disease course (this turned out to not be true based on a recently release trial, called C3PO), or in immune suppressed patients who are unable to make their own antibodies. However, careful selection of convalescent plasma with a favourable antibody profile using multiple testing methods may be beneficial for highly selected recipients. Because of our study, the indiscriminate use of convalescent plasma to treat COVID-19 hospitalized patients is not recommended outside of clinical trials and indeed, use in the United States fell off after its publication. This is an important finding that would not have been determined without performing controlled trials.
We expect to collaborate with study investigators of other clinical trials to understand potential benefits and risks. Our trial data is being integrated into the PRECIOUS study, University of Glasgow, UK). This information from Canada’s largest clinical trial on convalescent plasma and COVID-19 may be analyzed together with the results of similar ongoing studies to provide more precise information and insights that will guide clinical practice and health policy globally. Lastly, the results are being used to inform the design of a novel arm in the REMAP-CAP platform trial enrolling patients with immunodeficiency administered very high titre plasma (>1:640). This platform trial is being submitted to Health Canada in December of 2021 and with planned launch in February 2022 for Canadian hospital sites. Recipient viremia, cytokine and antibody testing on recipients is underway and there will be additional publications forthcoming to understand the role of recipient antibody response and impact of convalescent plasma.
The trial was an international collaboration between patients and their family members, plasma donors, research teams, blood bank staff, study investigators, a community advisory committee, and four blood suppliers (Canadian Blood Services, Héma-Québec, the New York Blood Center, and Hemorio, Brazil’s blood supplier). The CONCOR-1 trial is one of several trials evaluating the effectiveness of CP to treat COVID-19. The CONCOR-1 trial has shown how quickly the transfusion community, along with clinical team members, can rally together to support clinical trials during the pandemic—valuable collaborations that can be drawn on to support future clinical trial work.
Prevention and Treatment
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