Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Abstract

Importance: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.

Objective: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19.

Design, setting, and participants: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021.

Interventions: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916).

Main outcomes and measures: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events.

Results: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group.

Conclusions and relevance: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days.

Trial registration: ClinicalTrials.gov Identifier: NCT02735707.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Estcourt reported receiving grants from the National Institute for Health Research and European Union Horizon 2020. Dr Turgeon reported receiving grants from the Canadian Institutes of Health Research. Dr McQuilten reported receiving grants from the Australian Medical Research Future Fund. Dr McVerry reported receiving grants from the Pittsburgh Foundation, the Translational Breast Cancer Research Consortium, UPMC Learning While Doing Program, National Heart, Lung, and Blood Institute, and Bayer Pharmaceuticals and receiving personal fees from Boehringer Ingelheim. Dr Annane reported receiving grants from the French Ministry of Health and Solidarity. Dr Arnold reported receiving grants from the Canadian Institutes of Health Research. Ms Beane reported receiving grants and salary support from Wellcome Trust. Ms Bentum-Puijk reported receiving grants from the European Commission and the European Union. Dr L. Berry reported receiving grants from Berry Consultants. Dr Bradbury reported receiving personal fees from Lilly, Bristol Myers Squibb, Pfizer, Bayer, Amgen, Novartis, Janssen, Portola Advisors, and Ablynx. Dr Buxton reported receiving personal fees from the Breast Cancer Research Foundation, Amgen, and Eisai. Dr Callum reported receiving grants from the Canadian Blood Services and Octapharma. Dr Cove reported receiving grants from National University Health System; receiving consulting fees from Medtronic and Baxter; and holding a US patent for removal of carbon dioxide via dialysis. Dr Daly reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Derde reported receiving grants from University Medical Center Utrecht; being a member of the COVID-19 guideline committee of the Surviving Sepsis Campaign/European Society of Intensive Care Medicine and the European Society of Intensive Care Medicine COVID-19 taskforce; and serving as chair of the Dutch intensivists taskforce acute infectious threats. Dr Detry reported receiving grants from the European Union Platform for European Preparedness Against Reemerging Epidemics (PREPARE) consortium, the Australian National Health and Medical Research Council, the Health Research Council of New Zealand, and the UPMC Learning While Doing Program. Dr De Jong reported receiving personal fees from Roche Scientific, Shionogi Scientific, and Janssen. Dr Fitzgerald reported receiving grants from the PREPARE Network and the European Commission. Dr Gordon reported receiving grants from the National Institute for Health Research and receiving personal fees from 30 Respiratory, GlaxoSmithKline, and Bristol Myers Squibb. Dr Gosbell reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Haniffa reported receiving grants from the Wellcome Trust Innovations Project, the Minderoo Foundation, and the UK Research and Innovation African Critical Care Registry Network. Dr Higgins reported receiving grants from the National Health and Medical Research Council, the Minderoo Foundation, and the National Blood Authority. Dr Hills reported receiving grants from the Health Research Council of New Zealand. Dr Hoad reported receiving grants from the Australian Red Cross Lifeblood, which is funded by the Australian government. Dr Horvat reported receiving grants from the National Institute of Child Health and Human Development. Dr Huang reported receiving grants from the Breast Cancer Research Foundation. Dr Lamontagne reported receiving grants from the Canadian Institutes of Health Research. Dr Lawler reported receiving consulting fees from Novartis, Coronna LLC, and Brigham and Women’s Hospital; receiving royalties from McGraw-Hill Publishing; and receiving grants from the Canadian Institutes of Health Research, the LifeArc Foundation, the National Institutes of Health, the Peter Munk Cardiac Centre, the Ted Rogers Centre for Heart Research, the Thistledown Foundation, and the province of Ontario. Dr Lorenzi reported receiving personal fees from Berry Consultants. Dr Marshall reported receiving personal fees from AM-Pharma (data and safety monitoring board chair) and Critical Care Medicine (associate editor). Dr McAuley reported receiving personal fees from Bayer, GlaxoSmithKline, Boehringer Ingelheim, Novartis, Eli Lilly, Vir Biotechnology, Faron Pharmaceuticals, and Sobi; receiving grants from the National Institute for Health Research, Wellcome Trust, Innovate UK, the Medical Research Council, and the Northern Ireland Health and Social Care Research and Development Division; and holding a patent for an anti-inflammatory treatment that was issued to Queen’s University Belfast. Dr McGlothlin reported receiving grants from the PREPARE Network, the European Commission, and the Global Coalition for Adapative Research. Mr Mouncey reported receiving grants from the European Union, the PREPARE Network, the National Institute for Health Research, and European Union Horizon 2020. Dr Nichol reported receiving grants from the Health Research Board of Ireland and Baxter and receiving personal fees from AM-Pharma. Dr Parke reported receiving grants from Fisher and Paykel Healthcare Ltd. Ms Parker reported receiving grants from Monash University. Mr Richardson reported receiving funding from the Welsh government. Dr Rowan reported receiving grants from the European Commission and the National Institute for Health Research. Dr Saunders reported receiving grants from the PREPARE Network, the European Commission, and the Global Coalition for Adapative Research. Dr Serpa Neto reported receiving personal fees from Drager and Endpoint Health. Dr Tinmouth reported receiving grants and personal fees from the Canadian Blood Services. Ms Turner reported receiving grants from the Health Research Council of New Zealand. Dr van de Veerdonk reported receiving personal fees from Gilead, Sobi, and GlaxoSmithKline. Dr Wood reported receiving grants from the Australian Medical Research Future Fund. Dr S. Berry reported being an employee of Berry Consultants with an ownership role. Dr Lewis reported being an employee of Berry Consultants. Dr Menon reported receiving grants from the National Institute for Health Research. Dr McArthur reported receiving grants from the Health Research Council of New Zealand. Dr Zarychanski reported receiving grants from the Canadian Institutes of Health Research, the University of Manitoba, LifeArc, the Thistledown Foundation, Research Manitoba, the CancerCare Manitoba Foundation, the Victoria General Hospital Foundation, the Peter Munk Cardiac Centre, and the Manitoba Medical Services Foundation. Dr Webb reported receiving grants from the National Health and Medical Research Council and the Minderoo Foundation. Dr Shankar-Hari reported receiving grants from the National Institute for Clinical Research. No other disclosures were reported.

Figures

Figure 1.. Screening, Randomization, and Follow-up of Participants in the REMAP-CAP COVID-19 Immunoglobulin Domain Randomized Clinical Trial

aSee Supplement 1 for additional information about the platform trial. bPatients could have met more than 1 ineligibility criterion. A domain refers to a common therapeutic area (eg, antiviral therapy) within which several interventions or intervention dosing strategies could be randomly assigned. cRequired to have high-flow nasal cannula oxygenation, invasive or noninvasive mechanical ventilation, or vasopressor or inotropic infusion. dRandomization started with balanced assignment and then adapted with preferential assignment to those interventions that appeared most favorable until predefined statistical triggers of superiority or futility were met. eAdditional information about delayed convalescent plasma appears in Supplement 2 (eTables 1 and 5 and eFigure 1). fThe results for patients who were not critically ill were partially pooled with critically ill patients in the primary analysis, which provides a more precise estimate of the treatment effect of convalescent plasma. gThe primary analysis of alternative interventions within the immunoglobulin domain is estimated from a model that adjusts for patient factors and for assignment to other interventions.

Figure 2.. Primary Outcome of Organ Support–Free Days Up to Day 21

A, The ordinal scale includes death (in-hospital death, the worst possible outcome) and a score of 0 to 21 (the numbers of days alive without organ support) by trial group as the cumulative proportion (y-axis) for each trial group by day (x-axis), with death listed first. The curves that rise more slowly are more favorable. The difference in the height of the 2 curves at any point represents the difference in the cumulative probability of having a value for days without organ support of less than or equal to that point on the x-axis. B, The color red represents worse values and blue represents better values, the deepest red is death and deepest blue is 21 days. From the primary analysis using a bayesian cumulative logistic model, the median-adjusted odds ratio was 0.97 (95% credible interval, 0.83-1.15) for the convalescent plasma group compared with the no convalescent plasma group, yielding a probability of superiority of 37.8% over the no convalescent plasma group and a probability of futility of 99.4%.

Figure 3.. Primary and Secondary Outcomesa

Additional data are available in Supplement 2 (eTables 5-6). CrI indicates credible interval; ECMO, extracorporeal membrane oxygenation; HR, hazard ratio; ICU, intensive care unit; OR, odds ratio; WHO, World Health Organization. aData for the secondary analyses excluded participants who had been randomized within another domain within the moderate stratum and then randomized to the immunoglobulin domain in the severe stratum (excluded 7 participants). A maximum of 1980 participants were included within the secondary analyses. bAn OR or HR greater than 1 equates to the threshold for superiority to control for the primary outcome. cAn OR or HR less than 1.2 equates to the threshold for futility for the primary outcome. No formal hypothesis tests were performed on the secondary outcomes and summaries of the posterior distributions were provided for descriptive purposes only. dAnalyzed as time-to-event outcomes. The 28-day and 90-day survival outcomes are summarized as the proportion alive at days 28 and 90. The lengths of ICU stay and hospital stay are summarized by the median time to ICU and hospital discharge. eBased on the data collected, a modified version of the original WHO scale was used, combining outcome scores of 0 to 2 into a single category (0 = uninfected, 1 = ambulatory with no limitation of activities, and 2 = ambulatory with limitation of activities). For the convalescent plasma group, the median WHO score was 6 (required intubation and mechanical ventilation) and the IQR range was 3 (hospitalized but did not require oxygen therapy) to 7 (required ventilation plus additional organ support with vasopressors, kidney replacement therapy, or ECMO). For the no convalescent plasma group, the median WHO score was 5 (required noninvasive mechanical ventilation or high-flow oxygen) and the IQR was the combined 0-2 score (uninfected or ambulatory) to 7 (required ventilation plus additional organ support with vasopressors, kidney replacement therapy, or ECMO).

Figure 4.. Prespecified Subgroup Analyses for the Primary Outcome of Organ Support–Free Daysa

CrI indicates credible interval; PCR, polymerase chain reaction. aExcluded participants who had been randomized within another domain within the moderate stratum and then randomized to the immunoglobulin domain in the severe stratum (excluded 7 participants). A maximum of 1980 participants were included within the subgroup analyses and there were known outcomes for organ support–free days for 1972 of these participants. bAn odds ratio greater than 1 equates to the threshold for superiority vs control for the primary outcome. An odds ratio less than 1.2 equates to the threshold of futility for the primary outcome. cFor the number of units administered with SARS-CoV-2 antibody titers of 8 or greater (measured via the Euroimmun assay), the number of participants analyzed equals the total number in the no convalescent plasma (control) group (n = 900) plus the number in the intervention group who received 0, 1, or 2 units of convalescent plasma. dDefined as receiving an immunosuppressive treatment or having an immunosuppressive disease (the full definition appears in the eMethods in Supplement 2).