Use of covid-19 convalescent plasma to treat patients admitted to hospital for covid-19 with or without underlying immunodeficiency: open label, randomised clinical trial

Trial design

CORIMUNO-19 is a publicly supported platform, established by Assistance Publique-Hôpitaux de Paris, France, at the beginning of the covid-19 pandemic, dedicated to performing cohort, open label, randomised controlled trials of immune modulatory drugs in patients admitted to hospital with moderate or severe covid-19 disease.17 CORIPLASM (Efficacy of Convalescent Plasma to Treat Covid-19 Patients, a Nested Trial in the CORIMUNO-19 Cohort) was an embedded multicentre, open label, randomised controlled trial in patients with moderate covid-19 pneumonia conducted in French hospitals. Online supplemental appendix II and III have the full trial protocol and statistical analysis plan.

Study population and randomisation

At hospital admission, patients were evaluated for eligibility criteria: adults aged ≥18 years admitted to hospital, positive test result for the SARS-CoV-2 virus by nasopharyngeal polymerase chain reaction or computed tomography scan, or both, before randomisation, onset of symptoms <9 days, illness of mild or moderate severity according to the WHO Clinical Progression Scale (admitted to hospital, mild disease, no oxygen needed; admitted to hospital, moderate disease, oxygen <3 litres needed, online supplemental appendix I), not pregnant, no previous severe grade 3 allergic reaction to plasma transfusion, and no current bacterial infection reported.

ABO compatibility with available covid-19 convalescent plasma was verified before inclusion of patients. Written informed consent was obtained from all patients or their legal representatives at inclusion in CORIMUNO-19. Specific written informed consent was sought from eligible patients before inclusion in the CORIPLASM trial. The independent clinical research organisation compiled the computerised randomisation list, and the patient's randomisation number was accessed through a secure site by a site study team member. Randomisation was performed within two hours of enrolment. Eligible patients were randomised 1:1 to receive convalescent plasma or usual care. Usual care could include the use of dexamethasone, tocilizumab, supportive care, including supplemental oxygen, antiviral agents, and antibiotics. A data and safety monitoring board provided guidance on the trial after inclusion of every 60 patients.

Study product

Convalescent donors were eligible for plasma donation 15 days after the end of symptoms related to covid-19 disease. Apheresis plasma was collected by Etablissement Français du Sang and underwent pathogen reduction (Intercept Blood System, Cerus, Concord, CA) and standard testing according to current regulations in France. Anti-SARS-CoV-2 potency was assessed in each donation, with a requirement for a SARS-CoV-2 seroneutralisation titre ≥40, as described by Gallian et al.18 Antibody content was determined by immunoglobulin G enzyme linked immunosorbent assay (Euroimmun, Bussy-Saint-Martin, France). Covid-19 convalescent plasma with a seroneutralisation titre ≥40, made available for the trial and collected between April and June 2020, gave a mean enzyme linked immunosorbent assay ratio of 6.1 (standard deviation 2.9, range 0.4-13.0). After the first three patients received two units of ABO compatible covid-19 convalescent plasma according to the protocol, all subsequent patients randomised to the convalescent plasma group received four units of convalescent plasma (200-220 mL/unit, 2 units/day over two consecutive days) provided by different donors.

Study endpoints

As in all of the CORIMUNO-19 nested trials, an early primary endpoint was defined as a WHO Clinical Progression Scale score of ≥6 (online supplemental appendix I) on day 4 of randomisation. Higher values on the WHO Clinical Progression Scale indicate a worse outcome. The primary endpoint specific to the CORIPLASM trial was survival without the need for assisted ventilation (including non-invasive ventilation or high flow oxygen) at day 14 of randomisation (WHO Clinical Progression Scale score <6) or additional immunomodulatory treatment, with the exception of corticosteroids included within the standard of care (changes to the protocol, online supplemental file 1). Secondary endpoints were WHO Clinical Progression Scale score on days 4, 7, and 14 after randomisation, overall survival on days 14 and 28 after randomisation (ie, for the periods days 1-14 and days 1-28, respectively), time to discharge, time to end of dependence on oxygen supply, and changes to a series of biological parameters at days 4, 7, and 14 after randomisation.

Predefined subgroup analyses included immunosuppression status (underlying immunodeficiency: yes/no), duration of symptoms before randomisation (≤5 days, >5 days), and use of steroids. Safety data included all clinical and biological adverse events observed during the study follow-up. Immunodeficiency was defined as the presence of at least one of these medical conditions: active malignant neoplasm, lymphoid or myeloid neoplasms, haematopoietic stem cell or solid organ transplantation, or HIV/AIDS and not receiving highly active antiretroviral treatment.

Statistical analysis

The sample size was set at 120 participants (60 per group), with a bayesian interim analysis after 60 participants were randomised. We computed that the trial would have a frequentist power of 97.2% to detect a decrease in event proportions from 0.50 to 0.20, and 73.9% to detect a decrease in event proportions from 0.50 to 0.30. The study statisticians, who were masked to the group assignments, oversaw the interim and final analyses. Interim analysis reports were shared only with members of the data and safety monitoring board and not with the trial investigators. The trial investigators were blinded to all results during the trial.

The treatment effect was mainly expressed as an absolute risk difference for the early primary endpoint, and a hazard ratio for the longer term primary endpoint. Both were analysed in a bayesian framework. A posterior probability of absolute risk difference <0 or hazard ratio <1 but >0.99 at the interim analysis or >0.95 at the final analysis, indicated efficacy. We also computed posterior probabilities of absolute risk difference <−5.5% and hazard ratio <0.85, denoting a moderate or greater effect. At the interim analysis, a posterior probability of moderate or greater impact <0.20 defined a futility boundary. The treatment effect was summarised by the posterior median and equal tail credible intervals.

Because decision rules are one sided, consistent credible intervals would theoretically be one sided 95% credible intervals, but we chose to report two sided 90% credible intervals with the same upper boundary. For the early primary endpoint, the posterior distribution of absolute risk difference was computed analytically, with a beta prior distribution, with parameters one and one for the proportion in each group. An odds ratio adjusted for age and centre (centre being treated as a random effect) was also estimated with a bayesian logistic regression model. For the longer term primary endpoint, the posterior hazard ratio distribution adjusted for age and centre was computed with Markov chain Monte Carlo with normal prior distributions, with mean 0 and variance 10⁶ for the log hazard ratio. Different prior distributions were used as sensitivity analyses.

Secondary outcomes were analysed in a frequentist framework, except for WHO Clinical Progression Scale scores, analysed as an ordinal variable with a bayesian proportional odds model. Analyses of secondary outcomes were also adjusted for age and centre. For time to discharge and time to end of dependence on oxygen supply, we estimated adjusted subdistribution hazard ratios with Fine-Grey models, death being the competing event. Estimating subdistribution hazard ratios was preferred over cause specific hazard ratios because subdistribution hazard ratios have a one-to-one relation with the cumulative incidence (ie, the proportion) of events, and we considered that subdistribution hazard ratios would therefore be more relevant than the ratio of rates at which these events occur in time. We used interaction tests between the treatment group and subgroups to test for treatment effect heterogeneity between the subgroups, with similar regression models as the main adjusted analyses. The statistical analysis plan has full details of the statistical analyses (online supplemental appendix III).

Analyses were done on an intention-to-treat basis. The original protocol specified a modified intention-to-treat analysis excluding patients declining the intervention and those who could not receive the planned plasma treatment because ABO compatible covid-19 convalescent plasma was not available. Because those situations did not occur, no modified intention-to-treat analysis was performed. No correction for multiplicity was done for secondary outcomes, and corresponding results should be regarded as exploratory. Two interim analyses were conducted (online supplemental table S1). Statistical analyses were done with SAS (version 9.4, SAS Institute) and R (version 4.0.5, R Foundation) statistical software.

Patient and public involvement

Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research, because the trial has been designed in an emergency setting. However, according to the French law, the results have been sent to all participants or to their families.

Primary outcomes

Thirteen (22%) patients in the covid-19 convalescent plasma group versus eight (13%) patients in the usual care group had a WHO Clinical Progression Scale score of ≥6 at day 4 (median posterior absolute risk difference 8.0%, 90% credible interval –3.2% to 19.4%; adjusted odds ratio 1.88, 95% credible interval 0.71 to 5.24; table 2, online supplemental table S3, and online supplemental figure S2). The WHO Clinical Progression Scale score on day 4 was analysed as an ordinal outcome in a proportional odds model, giving a median posterior adjusted odds ratio of 1.42 (95% credible interval 0.70 to 2.91), hence showing higher scores in the covid-19 convalescent plasma group, although the difference was not significant. By day 14, patients in the convalescent plasma and usual care groups needed non-invasive or high flow ventilation (n=15 in the convalescent plasma group and n=13 in the usual care group) or additional immunomodulatory treatment in the form of anti-interleukin 6 receptor monoclonal antibody (n=0 in the convalescent plasma group and n=5 in the usual care group), or had died (n=2 in each group). Also, one and five patients died after reaching the primary outcome in the convalescent plasma and usual care groups, respectively. Figure 2 shows the cumulative incidence of assisted ventilation or death. The median posterior adjusted hazard ratio was 1.04 (95% credible interval 0.55 to 1.97), and the posterior probability of a moderate or greater benefit was 0.269 (table 2 and online supplemental table S4). The results were consistent across the range of prior distributions used in the sensitivity analyses (online supplemental figure S3).

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Secondary outcomes

At day 14, three (5%) and eight (13%) patients had died in the covid-19 convalescent plasma and usual care groups, respectively (adjusted hazard ratio 0.40, 95% confidence interval 0.10 to 1.53) (figure 3 and online supplemental table S5). At day 28, nine (12%) and 12 (20%) patients had died in the convalescent plasma and usual care groups, respectively (0.51, 0.20 to 1.32). The distribution of WHO Clinical Progression Scale scores from day 1 to day 14 did not differ significantly within groups, with a posterior odds ratio of 1.04 (95% credible interval 0.37 to 2.86) for the convalescent plasma group compared with the usual care group in a longitudinal ordinal model. The WHO Clinical Progression Scale scores tended to be higher in the convalescent plasma group between days 3 and 5, and then lower at day 14, with lower mortality (figure 4 and online supplemental table S6), although these findings were not significant. At day 14 and day 28, 38 and 48 patients in the convalescent plasma group and 36 and 45 in the usual care group, respectively, were discharged, with an adjusted day 28 subdistribution hazard ratio of 0.99 (95% confidence interval 0.65 to 1.49) adjusted for age and centre (online supplemental table S7). The incidence of not needing oxygen by day 28 was not different between the groups: 76% and 62% by day 14 and 82% and 71% by day 28 in the convalescent plasma and usual care groups, respectively (subdistribution hazard ratio 1.18, 95% confidence interval 0.73 to 1.91) (online supplemental table S7).

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Subgroup analyses

Figure 5 shows the primary outcome at day 14 (need for non-invasive or mechanical ventilation, use of additional immunomodulatory drugs, or death), with no difference in the subgroups. In the 47 patients who had an underlying immunodeficiency, the rate of a WHO Clinical Progression Scale score of ≥6 at day 4 was not significantly different in the covid-19 convalescent plasma group compared with the usual care group (24% v 15%, adjusted odds ratio 1.97, 95% confidence interval 0.53 to 7.39). At day 28, four of 21 patients had died in the convalescent plasma group versus nine of 26 patients in the usual care group (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10) (figure 6). Despite these findings favouring convalescent plasma, we found no evidence of an interaction between immunodeficiency status and treatment (P=0.34): 4/21 patients died in the covid-19 convalescent plasma group versus 9/26 in the usual care group (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10) (figure 6). We found limited mortality in the absence of underlying immunodeficiency (figure 7). Duration of symptoms or use of dexamethasone had no effect on day 28 survival (figure 5). Post hoc analysis of antibody potency in transfused covid-19 convalescent plasma in relation to outcome did not show a significant dose effect (online supplemental table S8).

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Adverse events

Adverse events were reported in 44 (73%) and 36 (60%) patients in the covid-19 convalescent plasma (n=124 events) and usual care (n=103 events) groups, respectively (incidence rate ratio 1.06, 95% confidence interval 0.63 to 1.77; online supplemental table S9). We found serious adverse events in 30 (50%) and 26 (43%) patients in the convalescent plasma (n=46 events) and usual care (n=48 events) groups, respectively (incidence rate ratio 0.84, 95% confidence interval 0.46 to 1.54). We found 10 sepsis related events with usual care (six with convalescent plasma) and four incidences of acute pulmonary oedema with convalescent plasma (none with usual care).

Causes of death were covid-19 related acute respiratory distress syndrome (n=3 in the convalescent plasma group and n=10 in the usual care group), cardiac origin (n=2 convalescent plasma, n=0 usual care), sepsis (n=2 convalescent plasma, n=3 usual care), gastrointestinal (n=0 convalescent plasma, n=1 usual care), vascular (n=1 convalescent plasma, n=0 usual care), and one of unknown origin (convalescent plasma).

Principal findings

In this CORIPLASM trial, we found no difference in early outcomes between the covid-19 convalescent plasma and usual care groups for patients admitted to hospital for covid-19 disease not requiring assisted ventilation. The survival rate at day 14 and day 28 was higher in the convalescent plasma group but this finding was not significant.

The lack of efficacy associated with covid-19 convalescent plasma agrees with the results of most prospective randomised clinical trials of patients admitted to hospital for covid-19 disease.19 Only a small number of randomised studies have reported better survival after treatment with convalescent plasma,20 21 whereas several other trials, notably the large RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial,22 found no evidence of survival benefit with convalescent plasma. Large retrospective studies in the US reported evidence of reduced mortality associated with treatment with covid-19 convalescent plasma in patients admitted to hospital with covid-19.23 24 The reasons for these discrepancies might be related to the characteristics of the convalescent plasma, time to treatment from first symptoms, treatment modalities, and patient characteristics.

Our study included a substantial proportion of patients with underlying immunosuppression. Similar to previous findings,25 we found that these patients with covid-19 have a worse prognosis, as seen in the usual care group. Several studies have suggested that convalescent plasma might be particularly effective in patients who lack an immune response, particularly a humoral response. We reported previously that treatment with covid-19 convalescent plasma was associated with a favourable outcome in patients who were immunosuppressed (mainly B cell haematological malignancies treated with anti-CD-20 monoclonal antibodies).6 Further evidence was provided by two independent exposed and non-exposed studies with propensity score in patients with underlying immunosuppression. Hazard ratios of 0.52 (95% confidence interval 0.29 to 0.92) and 0.50 (0.34 to 0.72) were reported in favour of convalescent plasma treatment, respectively.6 7 This reduction in mortality was similar to patients with immunosuppression randomised to the convalescent plasma group in the CORIPLASM trial.

Comparison with other studies

Most other randomised trials published so far did not report subgroup analyses for patients with underlying immunosuppression. One exception is the REMAP-CAP (Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community Acquired Pneumonia) trial that investigated convalescent plasma in critically ill patients with covid-19.22 Although the overall results of this study did not provide evidence of the efficacy of covid-19 convalescent plasma in these patients, a prespecified subgroup analysis showed a potential benefit of convalescent plasma in patients with immunodeficiency. Another randomised trial performed in patients with a diverse range of clinical conditions reported a significant effect of covid-19 convalescent plasma on clinical improvement and survival in the subgroup of 56 individuals with cancer.26 Finally, a meta-analysis incorporating the CORIPLASM trial has confirmed the potential benefit of covid-19 convalescent plasma in individuals with immunosuppression with mild-to-moderate covid-19 disease, based on greater statistical power because of the large number of individuals with immunosuppression included in the meta-analysis (1487 from randomised trials, 265 from case series, and 368 from cohorts).27

An antibody dose effect has been reported in several randomised studies3 28 as well as in the early access programme in the US.23 In the CORIPLASM trial, 800-880 mL of covid-19 convalescent plasma were transfused to patients randomised to the convalescent plasma group. In most studies so far, patients most often received 250-500 mL of convalescent plasma, except in the CAPSID (A Clinical Trial of Convalescent Plasma Compared to Best Supportive Care for Treatment of Patients With Severe Covid-19) trial where patients received 700-750 mL of convalescent plasma.24 28 The CAPSID trial reported a significant antibody dose effect for several outcomes, including survival at day 28. By contrast, the CORIPLASM protocol recommended four covid-19 convalescent plasma units provided by different donors for each patient, which resulted in less variation in mean antibody content in transfused convalescent plasma from patient to patient. This difference in transfusion practice might explain why we did not see an antibody dose effect in our study. Furthermore, convalescent plasma for the CORIPLASM study was collected early in the covid-19 crisis when vaccination was not available and before the occurrence of relevant SARS-CoV-2 variants.

Several studies have shown that plasma provided by convalescent donors who were vaccinated strongly increased anti-SARS-CoV-2 antibody titres and seroneutralisation ratios and also increased cross reactivity with a broader spectrum for variants to which the donor had not been exposed.12 29 High titre plasma from these convalescent donors who were vaccinated might have increased clinical efficacy. Early intervention with covid-19 convalescent plasma has been associated with improved outcome.3 4 Patients in our study had a median duration of symptoms of seven days at the time of inclusion, a short time period compared with most trials of patients admitted to hospital. Prespecified subgroup analyses, however, did not favour increased efficacy of convalescent plasma associated with a shorter time since onset of symptoms. The high number of patients with underlying immunosuppression, for whom seroconversion is not expected early on, might have contributed to this finding. Also, and as found in other covid-19 trials, early admission to hospital might be associated with more severe disease.8 22

Patients in the covid-19 convalescent plasma group tended to have worsening pulmonary clinical conditions than patients in the usual care group early after transfusion. The occurrence of early transient pulmonary worsening after transfusion of convalescent plasma has also been reported elsewhere,30 and might be related to antibody dependent enhancement involving immune complex mediated inflammatory immunopathology in infected tissues.31 Also, an antibody dependent Fc receptor mediated infection of tissues macrophages (and circulating monocytes) might result in a massive inflammatory response, as recently reported,32 which could also contribute to pulmonary worsening after transfusion of convalescent plasma.

These early outcomes are seldom reported in clinical studies, and distinguishing early pulmonary worsening from transfusion associated circulatory overload, transfusion related acute lung injury, or overall disease worsening, possibly started before transfusion, can be challenging. The transfusion of four units of plasma might have contributed to circulatory overload in some patients. Further spacing of administration of convalescent plasma (ie, 1 unit/day over four days) could reduce this risk. Early worsening did not prevent subsequent improvement and increased survival as early as day 14 after randomisation, although this effect was not significant. Antibody mediated SARS-CoV-2 uptake by monocytes and macrophages triggering inflammatory cell death and inhibition of viral replication might be a mechanism for subsequent improvement in disease.33

Limitations of this study

Our study had some limitations. The relatively small size of the trial limited the ability to appropriately assess outcomes, such as patient mortality, but we did access treatment with covid-19 convalescent plasma in immunosuppressed patients. Also, information on patient serostatus at inclusion was often not available. Although the mean antibody ratio in transfused convalescent plasma in our study was well above the US Food and Drug Administration threshold for high titre convalescent plasma (Euroimmun anti-SARS-CoV-2 immunoglobin G ratio >3.5),34 transfusion of higher titre plasma from convalescent donors who were vaccinated might improve efficacy.3 12 23 26

The emergence of the omicron variant of the SARS-CoV-2 virus with its BA.1-BA.5 subvariants has highlighted the risks associated with immune resistant SARS-CoV-2 and loss of efficacy of available monoclonal antibodies.11 Whereas several months are necessary to produce one or more new monoclonal antibodies more suited to changes in circulating viral strains, convalescent plasma, particularly from donors who are vaccinated, has shown increased resilience to immune resistant SARS-CoV-2 variants,12 30 increased scalability because of the existing collection infrastructure, as well as increased adaptability. The time between the onset of a covid-19 variant and the availability of convalescent plasma from donors infected with the variant disease is about four weeks.

Conclusions

The results of the CORIPLASM trial, along with recent data from other trials and cohort studies, support further evaluation and consequent use of convalescent plasma in patients who are immunocompromised for whom treatment options are limited. Recent guidelines from the Association for the Advancement of Blood and Biotherapies suggest transfusion of covid-19 convalescent plasma in addition to standard of care for patients admitted to hospital with covid-19 and pre-existing immunosuppression.34