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[Preprint]. 2022 Dec 18:2022.12.16.22283585.
doi: 10.1101/2022.12.16.22283585.

COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials

Adam C Levine  1 , Yuriko Fukuta  2 , Moises A Huaman  3 , Jiangda Ou  4 , Barry R Meisenberg  5 , Bela Patel  6 , James H Paxton  7 , Daniel F Hanley  4 , Bart Ja Rijnders  8 , Arvind Gharbharan  8 , Casper Rokx  8 , Jaap Jan Zwaginga  9 , Andrea Alemany  10 , Oriol Mitjà  10   11 , Dan Ouchi  10 , Pere Millat-Martinez  12 , Valerie Durkalski-Mauldin  13 , Frederick K Korley  14 , Larry J Dumont  15 , Clifton W Callaway  16 , Romina Libster  17   18 , Gonzalo Perez Marc  17 , Diego Wappner  17 , Ignacio Esteban  17 , Fernando Polack  17   18 , David J Sullivan  19
Affiliations

COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials

Adam C Levine et al. medRxiv. .

Update in

Abstract

Background: Monoclonal antibody and antiviral treatments for COVID-19 disease remain largely unavailable worldwide, and existing monoclonal antibodies may be less active against circulating omicron variants. Although treatment with COVID-19 convalescent plasma (CCP) is promising, randomized clinical trials (RCTs) among outpatients have shown mixed results.

Methods: We conducted an individual participant data meta-analysis from all outpatient CCP RCTs to assess the overall risk reduction for all-cause hospitalizations by day 28 in all participants who had transfusion initiated. Relevant trials were identified by searching MEDLINE, Embase, MedRxiv, WHO, Cochrane Library, and Web of Science from January 2020 to September 2022.

Results: Five included studies from four countries enrolled and transfused 2,620 adult patients. Comorbidities were present in 1,795 (69%). The anti-Spike or virus neutralizing antibody titer range across all trials was broad. 160 (12.2%) of 1315 control patients were hospitalized, versus 111 (8.5%) of 1305 CCP-treated patients, yielding a 3.7% (95%CI: 1.3%-6.0%; p=.001) ARR and 30.1% RRR for all-cause hospitalization. The effect size was greatest in those with both early transfusion and high titer with a 7.6% ARR (95%CI: 4.0%-11.1%; p=.0001) accompanied by at 51.4% RRR. No significant reduction in hospitalization was seen with treatment > 5 days after symptom onset or in those receiving CCP with antibody titers below the median titer.

Conclusions: Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization. CCP may be most effective when given within 5 days of symptom onset and when antibody titer is higher.

Key points: While the outpatient COVID-19 randomized controlled trial meta-analysis indicated heterogeneity in participant risk factors and convalescent plasma, the combined CCP efficacy for reducing hospitalization was significant, improving with transfusion within 5 days of symptom onset and high antibody neutralization levels.

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Conflict of interest statement

Conflicts of Interest Disclosures: RL report receiving fees for serving as investigators from Pfizer; FP reports receiving fees for serving as a principal investigator from Pfizer, DJS reports AliquantumRx Founder and Board member with stock options (macrolide for malaria), Hemex Health malaria diagnostics consulting and royalties for malaria diagnostic test control standards to Alere- all outside of submitted work. BR reports advisory board membership for Roche and Astra-Zeneca on a COVID-19 therapy and membership of DSMB of a COVID-19 treatment study by Exevir.

Figures

Figure 1.
Figure 1.
PRISMA chart. The MEDLINE, Embase, MedRxiv, Cochrane Library, WHO COVID-19 Research Database, and Web of Science were searched for all RCTs as of 30 September 2022. *WHO COVID-19 global literature on coronavirus disease
Figure 2.
Figure 2.
Forest plot of A) modified Intention to Treat Analysis and B) of modified Intention to Treat Analysis excluding same day hospital admissions Abbreviations. CCP=COVID-19 convalescent plasma; OR=odds ratio; CI=confidence interval
Figure 3.
Figure 3.
Forest plots of transfusion A) within 5 days or B) greater than 5 days Abbreviations. CCP=COVID-19 convalescent plasma; OR=odds ratio; CI=confidence interval
Figure 4.
Figure 4.
Forest plots plasma donor antibody levels A) at or above median titer or B) less than median titer Abbreviations. CCP=COVID-19 convalescent plasma; OR=odds ratio; CI=confidence interval
Figure 5
Figure 5
Forest plots plasma donor antibody levels and early treatment A) at or above median titer AND transfusion within 5 days or B) Total of (Low titer and onset<= 5 days, High titer and onset over 5 days, Low titer and onset over 5 days Abbreviations. CCP=COVID-19 convalescent plasma; OR=odds ratio; CI=confidence interval
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