key: cord-0824988-vx3n87bc
authors: Millat-Martinez, P.; Gharbharan, A.; Alemany, A.; Rokx, C.; GeurtsvanKessel, C.; Papageourgiou, G.; van Geloven, N.; Jordans, C.; Groeneveld, G.; Swaneveld, F.; van der Schoot, E.; Corbacho-Monne, M.; Ouchi, D.; Ferreira, F. P.; Malchair, P.; Videla, S.; Garcia, V. G.; Ruiz-Comellas, A.; Ramirez-Morros, A.; Codina, J. R.; Simon, R. A.; Grifols, J.-R.; Blanco, J.; Blanco, I.; Ara, J.; Bassat, Q.; Clotet, B.; Baro, B.; Troxel, A.; Zwaginga, J. J.; Mitja, O.; Rijnders, B.
title: Convalescent plasma for outpatients with early COVID-19
date: 2021-12-02
journal: nan
DOI: 10.1101/2021.11.30.21266810
sha: 707f5199496e610f55dacb0c48ab3ae73956df06
doc_id: 824988
cord_uid: vx3n87bc

Background: Convalescent plasma (CP) for hospitalized patients with COVID-19 has not demonstrated clear benefits. However, data on outpatients with early symptoms are scarce. We aimed to assess whether treatment with CP administered during the first 7 days of symptoms reduced the disease progression or risk of hospitalization of outpatients. Methods: Two double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when <20% of their predefined sample size had been recruited. A Bayesian adaptive individual patient data meta-analysis was implemented. Analyses were done with Bayesian proportional odds and logistic models, where odds ratios (OR)<1.0 indicate a favorable outcome for CP. Fourteen study sites across the Netherlands and Catalonia in Spain participated in the trial. The two studies included outpatients aged [≥]50 years and diagnosed with COVID-19 and symptomatic for [≤]7days. The intervention consisted of one unit (200-300mL) of CP with a predefined minimum level of antibodies. The two primary endpoints were (a) a 5-point disease severity scale (fully recovered by day 7 or not, hospital or ICU admission and death) and (b) a composite of hospitalization or death. Results: Of 797 patients included, 390 received CP and 392 placebo. At baseline, they had a median age of 58 years, 1 comorbidity, symptoms for 5 days and 93% tested negative for SARS-CoV-2 S-protein IgG antibodies. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The OR of CP for an improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311). The OR for hospitalization or death was 0.919 (CI 0.592-1.416). The effect of CP on hospital admission or death was largest in patients with [≤]5 days of symptoms (OR 0.658, 95% CI 0.394-1.085). CP did not decrease the time to full symptom resolution (p=0.62). Conclusion: Treatment with CP of outpatients in the first 7 days of symptoms did not improve the outcome of COVID-19. The possible beneficial effect in patients with [≤]5 days of symptoms requires further study. Registration: NCT04621123 and NCT04589949 on https://www.clinicaltrials.gov

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All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint

The unprecedented pace and amount of research on the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the availability of mortality-reducing therapies within a year after the start of the coronavirus disease 2019 (COVID-19) pandemic (1) (2) (3) . For non-hospitalized COVID-19 patients, only anti-SARS-CoV-2 monoclonal antibodies have emerged as a treatment that reduces hospital admission but only when given in the first week of illness. However, they are typically unavailable to middle and low-income countries (4-7).

Convalescent plasma (CP) from COVID-19 recovered patients contains polyclonal anti-SARS-CoV-2 antibodies, can be collected in large quantities at relatively low costs and was used as a therapeutic strategy in previous viral outbreaks (8, 9) . So far, randomized trials were unable to generate convincing evidence in support of CP for hospitalized patients with COVID-19 (10) (11) (12) (13) (14) (15) (16) (17) (18) . However, because an autologous SARS-CoV-2 antibody response typically precedes hospital admission, CP is more likely to be beneficial when it is administered very early after symptom onset (19) . Indeed, the only evidence from a randomized trial in favor of CP for COVID-19 comes from a small study in which elderly outpatients received CP in the first 72 hours after symptom onset (20). In a more recent trial, CP did not reduce the risk of disease progression of COVID-19 in patients with early disease (≤7 days).

However, in this trial, patients were recruited at emergency rooms and were, therefore, more likely to manifest severe symptoms (21) . This approach resulted in a trial profile of patients with moderate or late-stage disease, opposed to what was intended in the design. Hence, whether early treatment with CP improves the outcome of outpatients with COVID-19 remains an important question.

As soon as effective vaccines against COVID-19 became available in high-income countries, they were prioritized for individuals at higher risk for a poorer COVID-19 outcome. Because studies on CP for outpatients with COVID-19 focus on these high-risk populations as well, a high vaccination uptake will reduce the number of COVID-19 patients eligible for these studies. More importantly, the risk for a severe outcome will be small when patients become infected despite vaccination. Therefore, we anticipated that vaccination would slow down recruitment, reduce the number of events in the All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint recruited patients and result in individual studies being underpowered. In light of the uncertainty for achieving recruitment goals, real-time pooling of individual patient data from ongoing clinical trials was proposed as a tool for providing timely data to respond to the public health crisis (22) . With this in mind, we initiated the COntinuous Monitoring of Pooled International trials of convaLEscent plasma for COVID-19 patients at home Consortium (COMPILEhome), which provided a platform to pool individual patient data continuously and in real-time from randomized clinical trials (RCTs) on CP for outpatients with COVID-19 (22) . The COMPILE was conceived very early in the CCP initiative, anticipating the downstream challenges pertaining to enrollment and study power. This COMPILEhome consortium merged the data from 2 double-blind RCTs, the CoV-Early (NCT04589949) and the COnVert (NCT04621123) studies, to assess the effectiveness of high-titer CP for COVID-19 outpatients.

Beginning in November 2020, we systematically searched for RCTs recruiting outpatients that compared treatment with CP with a blinded or unblinded control arm in the European (https://www.clinicaltrialsregister.eu/) and American (www.clinicaltrials.gov) trial register. Search terms were convalescent plasma, COVID-19, phase 2 or phase 3, adult, and recruiting or not recruiting. Studies were selected if they were RCTs on outpatients, if their inclusion criteria were confined to patients who had symptoms less than 7 days, and if they had a planned sample size of at least 100 participants of age 50 or older. Investigators of qualifying trials were contacted and informed about COMPILEhome and invited to collaborate in the study.

The full COMPILEhome protocol is available as an online supplement. The study was designed as a Bayesian adaptive individual patient data meta-analysis of ongoing clinical trials. Prior to the start of pooling, the study teams agreed upon a minimal set of data required to analyze the primary and secondary endpoints was agreed upon by the study teams. Each trial provided updated data every 6 weeks.

The pooled data were monitored by 2 unblinded statisticians and a data and safety monitoring board All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint (DSMB) every 6 weeks using a pre-established stopping guideline for efficacy. At each interim analysis, a posterior distribution of the treatment effect was estimated.

Although the exact inclusion and exclusion criteria could vary across the trials, all the subjects had to fulfill the following criteria; 1) Participant of a trial that joined the COMPILEhome consortium, 2)

Confirmed COVID-19 diagnosis by a diagnostic PCR or antigen test, 3) Neither hospitalized nor at the emergency room department of a hospital before or at the time of randomization, 4) Symptomatic with illness onset ≤7 days at the time of screening for the study, and 5) Age 50 or older. Trials had to be approved by the institutional review boards, and competent authorities of the countries involved, and all patients gave written informed consent.

To qualify for COMPILEhome, participants randomly assigned to the experimental group had to receive an infusion of ABO-compatible CP with high antibody titers as determined via a semiquantitative antibody test against the spike protein or a virus neutralization assay. Only trials in which the participants were masked for the intervention were included.

Two primary efficacy outcome variables were selected. The first primary endpoint incorporated the speed of recovery and the progression of COVID-19 that would lead to hospital or intensive care unit (ICU) admission or death. It was defined as the highest score on a 5-point ordinal disease severity scale in the 28 days after randomization. A patient was scored 1 if he/she was fully recovered within seven days after transfusion, 2 when continued symptoms attributable to COVID-19 were present on day seven, 3 when admission to a hospital was required at any point, 4 when invasive ventilation was required at any point, and 5 when the patient had died at any moment. The second primary endpoint was the occurrence of hospitalization or death within 28 days.

Secondary endpoints were time to full symptom resolution (assessed by the blinded study team during a telephone contact on day 7, day 14, and day 28) and the safety of CP in outpatients with All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint COVID-19. Pre-planned subgroup analyses assessed the efficacy of the 2 primary outcomes in the following subgroups: 1) days since disease onset (1-5 or >5days), 2) level of neutralizing antibody anti-SARS-CoV-2 titers in transfused plasma and 3) Negative serum anti-SARS-CoV-2 IgG status (Trimeric Spike antibody test, Liaison, Diasorin, Saluggia, Italy).

The first primary endpoint was analyzed with a Bayesian proportional odds model with normally distributed priors. The model included a main treatment effect shared among the trials (using a skeptical standard deviation of 0.4), main trial effects (using standard deviation 0.5 for the prior distribution), and trial by treatment interactions (using a standard deviation of 0.14 for the prior distribution). The following covariates were included with a standard deviation of 0.5 for the prior distribution: age, sex, number of comorbidities (0-9), oxygen saturation at baseline (in %), immunocompromised state (Y/N) and duration of time (in days) since COVID-19 symptom onset (Appendix Table 1 ). The second primary endpoint was analyzed with a Bayesian logistic model with a similar specification.

The use of the Bayesian framework and stopping rules enables continuous monitoring of the accrued data, and allowed for real-time decisions without penalties for multiple data looks associated with the classic frequentist approach. The results of each interim analysis were reported to the unblinded DSMB. The process and pre-specified thresholds for efficacy are described in detail in the protocol.

The full statistical analysis plan is available as an online supplement.

The number of studies and patients included in COMPILEhome was not restricted and there was no pre-determined minimum or maximum sample size. The monitoring was planned to continue until the DSMB determined that there was sufficient evidence to recommend stopping the study. This situation could be achieved when the predefined stopping thresholds signaled efficacy or when the included studies had finished enrollment or any future recruitment was very unlikely to change the conclusion.

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint

The search for trials resulted in 35 identified studies, thirty-one of which did not meet the selection criteria of the consortium (Appendix Figure 1 ). Of the four remaining studies, one study team opted to abstain from pooling data while another never responded to repeated emails and calls, resulting in two trials included in the pooled analysis: The COnV-ert study (NCT04621123) and the CoV-Early study (NCT04589949). The COnV-ert study received approval from the Table 2 and the study protocols.

The two trials used a different assay to measure the titer of SARS-CoV-2 neutralizing antibodies.

Therefore, a panel of 15 plasma samples was provided for comparison by the Support-E consortium, aimed at harmonizing CP evaluation in Europe (23) . These results confirmed the linearity of both assays and allowed conversion of all neutralizing antibody titers into international units (IU/mL). The median neutralizing antibody titer in the plasma units was 1:386 (IQR 1:233-1:707) IU/mL, which is twice the median titer we previously observed in Dutch CP donors. (19) More details are described in the online supplementary data, in Appendix Table 1 and Appendix All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint Table 2 and in the individual study protocols.

Between November 2020 and July 2021, the CoV-Early and COnV-ert study teams contacted approximately 4450 outpatients with a positive SARS-CoV-2 PCR or an antigen test. The majority of exclusions occurred for one of the following reasons: few remaining or clearly improving symptoms, no comorbidities, >7 days of symptoms, unable to come to study site or declined to participate. The online supplement provides more information about the recruitment procedures of each trial.

The rapid uptake of COVID-19 vaccination in Europe, which significantly affected recruitment rate in both studies (Appendix Figure 2 ) and the authorization of specific anti-SARS-CoV-2 monoclonal antibodies for high-risk outpatients resulted in early trial termination (COnV-ert on 8th of June and CoV-Early on 13th of July 2021) following recommendations of their DSMBs. By that time, 797 participants had been enrolled and 782 of them had received the allocated intervention and could be pooled for the analysis (Figure 1 ).

Patients included in the analysis had a median age of 58 years (IQR 53-64), a median of 5 days (IQR 4-6) from symptom onset, and a median of 1 comorbidity (IQR 0-2). According to the baseline assessment, 688 patients (93%) had a negative result for serum IgG anti SARS-CoV-2 S-protein, and 21 had completed their COVID-19 vaccination. 14 participants had received one of 2 doses of a mRNA vaccine at the time of inclusion. Baseline characteristics were comparable between both study arms (Table 1) . Table 2 perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint 20 probability of benefit. The results of all covariates included in the primary analysis can be found in the online supplement (Appendix Figure 5 and 6 ).

No differences between CP and control patients regarding time to complete resolution of COVID-19 symptoms was seen (log-rank p=0.62, Figure 2 ). The effect size of CP on the binary outcome of hospital admission or death was larger in patients with ≤5 days of symptoms (OR 0.658, 95% CI 0.394-1.085) compared to those with >5 days (1.427, 95% CI 0.789-2.580) and comparable results (OR 0.720 95% CI 0.486-1.064) were observed for the ordinal outcome (Appendix Figure 7 and 8) .

Finally, the OR for patients who received CP with neutralizing antibody titers above or below the median titer were identical (Appendix Figure 9 ). Also, no notable difference was observed when patients with IgG anti-SARS-CoV-2 antibodies detected at baseline were excluded (OR 0.880 95% CI 0.590-1.310 for the binary outcome, 0.892 95% CI 0.643-1.236 for ordinal outcome, Appendix Figures   7 and 8) .

The intervention was well-tolerated. 89 serious adverse events (SAE) were reported, 4 were considered related to the plasma transfusion (3 in the control arm). Three patients could leave the hospital <24 hours after transfusion while the fourth was hospitalized for 5 days one week after the CP transfusion and diagnosed with thrombophlebitis at the infusion site and a pulmonary embolism (Table 3 ).

In this analysis of 782 patients with COVID-19 randomized to high-titer CP or placebo within 7 days of disease onset, treatment with CP did not prevent COVID-19 progression, hospitalization, or other clinical outcomes. Our results agree with those by Korley et al. in patients of the same age and symptom duration but with probably more severe symptoms as they were recruited at emergency rooms in the USA (21) . These findings differ from those of a smaller trial that used CP within 72 hours All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint 21 of symptom onset in much older patients (≥75 years) (20). We explored signs of efficacy in various subgroups most likely to benefit from CP. The only subgroup in our study that we found that could potentially benefit from CP was the subgroup with ≤5 days from the onset of symptoms (OR 0.70, CI 0.47-1.03). The potential effect of CP when administered early after disease onset has been suggested by other authors (24) , and could explain the results reported by Libster et al. study (20) .

However, in our study this was a secondary endpoint and the confidence interval was wide, so confirmation in other studies is needed. Regarding the safety parameters of this strategy, our study shows no major concerns, with only 4 SAEs related to the plasma infusion; these findings are in line with those described in previous studies (25) .

Our study has several strengths. It is the largest of its kind, studying the effect of CP for high-risk outpatients with COVID-19 early after initiation of symptoms. The fact that 93% of all patients were SARS-CoV-2 antibody negative at the time of inclusion confirms that they were recruited in the early stage of the disease. Pooling of the data from both studies was pre-planned and initiated before any interim analyses were performed and when both studies were early in their recruitment. Both teams remained fully blinded as the (interim) analyses were done by an unblinded statistical team that shared the results with the DSMB on a regular basis. We, therefore, consider our results methodologically sound.

Several limitations should be mentioned. Although we only included patients aged ≥50, and most of them also had comorbidities, the hospital admission rate was relatively low at 9.3%. Therefore, the study was not powered to exclude a small overall treatment effect. However, administering CP to infectious and symptomatic outpatients is complex and labor-intensive. Hence, we think that small CCP's clinical role is significantly diminished if unable to establish something greater than "a small effect" because it ceases to be practical. As vaccination uptake progressed in patients aged 50 or older and monoclonal antibody-based therapy with proven effectiveness in high-risk outpatients became available, the recruitment dropped dramatically as of June 2021. This resulted in the recommendation by the individual and COMPILEhome DSMBs that further enrollment was unlikely to All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint change the results, and both studies were discontinued. Regarding the advent of the SARS-CoV-2 variants that may be less susceptible to antibodies induced by the original SARS-CoV-2 virus or the alpha variant, it is reassuring that >95% of the patients in both countries were included at a time when the delta variant was still rare (<5%) (Appendix Figure 3 and 4) . The last limitation of our study (and all studies on CP for COVID-19 so far) is the lack of a proper phase 2 dose-finding study. In a recent study, we administered 600 mL of CP to 25 SARS-CoV-2 antibody-negative B-cell depleted patients diagnosed with COVID-19 (26) . While all seroconverted immediately after transfusion, the median virus neutralization titer only rose to 1:40. This is 4 times lower than the median titer in immunocompetent convalescent COVID-19 patients and up to 100 times lower than titers observed after treatment with monoclonal antibodies (7, 19) . Therefore, we postulate that the range of neutralizing antibody titers present in the 200-300 mL of plasma we used may well have been too low. That underdosing may partially explain our findings is also suggested by a study in which human CP with a neutralizing antibody titer of 1:320 did not prevent disease in hamsters while a titer of 1:2560 did (27) . Hence, we recommend that any future study on CP for COVID-19 should use donors at the upper extreme end of antibody titers (e.g., >1:2560 IU). Although, this was virtually impossible in 2020, this should no longer be difficult now as plasma donors recently vaccinated or boosted with a mRNA SARS-CoV-2 vaccine can be selected.

In conclusion, treatment of COVID-19 with CP in the first 7 days after symptom onset did not improve the outcome. Proper dose-finding studies should be conducted, preferentially in patients with ≤5 days of symptoms before future phase 3 studies on CP are initiated. This study was made possible by a research grant from ZONMW, the Netherlands (10430062010001).

Sanquin Blood Supply provided convalescent plasma free of charge for study sites in the Netherlands.

The trial was sponsored by the Fight AIDS and Infectious Diseases Foundation with funding from the pharmaceutical company Grifols S.A and the crowdfunding campaign YoMeCorono (www.yomecorono.com). The study received support of the Hospital Universitari Germans Trias i Pujol, and Banc de Sang i Teixits de Catalunya (BST). We thank all the plasma donors and the participants in this study and all the effort they made to attend the visits for follow up. We thank Gerard Carot-Sans for providing medical writing support with manuscript preparation and Roser Escrig for her support in the study design and medical writing assistance with the study documentation. We also thank Laia Bertran, Mireia Clua, Jordi Mitjà, Claudia Laporte, Sergi Gavilan, All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

The authors declare that they have no competing interests.

The funders had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

All rights reserved. No reuse allowed without permission.

perpetuity.

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in

The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint *Serious adverse events (SAE) were registered in all patients that signed the informed consent form (n=797) regardless of being transfused or not. † When a patient is hospitalized more than once, each admission is counted separately. ‡

Any transfusion reaction associated with a plasma transfusion that was considered as a SAE || 2 patients with anaphylaxis very soon after discharge that required urgent therapy by paramedics All rights reserved. No reuse allowed without permission.

perpetuity.

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in

The copyright holder for this this version posted December 2, 2021. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint 31 Figure 2 : Time to full symptom resolution up until day 28 (end of follow-up). CP=Convalescent plasma. Log-rank test p=0.62. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint

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The DSMB members for COMPILEhome (Jan Nouwen, Andrea Troxel, Greg Papageorgiou, David Boulware, Josep Puig). All GGD contact tracers who informed potential study candidates. All infectiologists at Erasmus MC who worked even harder during COVID times to let the study team

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 2, 2021. ; https://doi.org/10.1101/2021.11.30.21266810 doi: medRxiv preprint