Severe Acute Respiratory Syndrome Coronavirus 2 Convalescent Plasma Versus Standard Plasma in Coronavirus Disease 2019 Infected Hospitalized Patients in New York: A Double-Blind Randomized Trial

Abstract

Objectives: Four peer-reviewed publications have reported results from randomized controlled trials of convalescent plasma for coronavirus disease 2019 infection; none were conducted in the United States nor used standard plasma as a comparator. To determine if administration of convalescent plasma to patients with coronavirus disease 2019 increases antibodies to severe acute respiratory syndrome coronavirus 2 and improves outcome.

Design: Double-blind randomized controlled trial.

Setting: Hospital in New York.

Patients: Patients with polymerase chain reaction documented coronavirus disease 2019 infection.

Interventions: Patients were randomized (4:1) to receive 2 U of convalescent plasma versus standard plasma. Antibodies to severe acute respiratory syndrome coronavirus 2 were measured in plasma units and in trial recipients.

Measurements and main results: Enrollment was terminated after emergency use authorization was granted for convalescent plasma. Seventy-four patients were randomized. At baseline, mean (sd) Acute Physiology and Chronic Health Evaluation II score (23.4 [5.6] and 22.5 [6.6]), percent of patients intubated (19% and 20%), and median (interquartile range) days from symptom onset to randomization of 9 (6-18) and 9 (6-15), were similar in the convalescent plasma versus standard plasma arms, respectively. Convalescent plasma had high neutralizing activity (median [interquartile range] titer 1:526 [1:359-1:786]) and its administration increased antibodies to severe acute respiratory syndrome coronavirus 2 by 14.4%, whereas standard plasma administration led to an 8.6% decrease (p = 0.005). No difference was observed for ventilator-free days through 28 days (primary study endpoint): median (interquartile range) of 28 (2-28) versus 28 (0-28; p = 0.86) for the convalescent plasma and standard plasma groups, respectively. A greater than or equal to 2 point improvement in the World Health Organization scale was achieved by 20% of subjects in both arms (p = 0.99). All-cause mortality through 90 days was numerically lower in the convalescent plasma versus standard plasma groups (27% vs 33%; p = 0.63) but did not achieve statistical significance. A key prespecified subgroup analysis of time to death in patients who were intubated at baseline was statistically significant; however, sample size numbers were small.

Conclusions: Administration of convalescent plasma to hospitalized patients with coronavirus disease 2019 infection increased antibodies to severe acute respiratory syndrome coronavirus disease 2 but was not associated with improved outcome.

Trial registration: ClinicalTrials.gov NCT04344535.

Figure 1.

Convalescent plasma (CP) neutralizing titer (NT50) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A, The median (interquartile range) NT50 for randomly selected units tested in a plaque neutralization assay using SARS-CoV-2 virus (n = 13). Each dot represents the calculated NT50 value (titer) for an individual plasma sample. The dashed line at 1:80 corresponds with the minimum suggested titer recommended by the Food and Drug Administration for CP. B, The average (sd) number of plaques of SARS-CoV-2 for serial dilutions of CP.

Figure 2.

Antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in plasma recipients. Presence of immunoglobulin M (IgM) (A) and immunoglobulin G (IgG) (B) antibody levels to the nucleocapsid protein (NP) of SARS-CoV-2 in trial participants at baseline. Humans without exposure to SARS-CoV-2 typically exhibit less than 25 reflectance light units, with several hundred reflectance light units indicating a very strong antigen/antibody band. Percent (C) and absolute (D) changes in IgG antibody levels to the NP of SARS-CoV-2 at 1, 7, 14, 21, and 28 d after administration of 2 U of convalescent versus standard plasma (on day 0–baseline). Antibody levels were not measured after hospital discharge/death. IQR = interquartile range.

Figure 3.

Time to all-cause mortality from randomization to 28 and 90 d. The Kaplan-Meier failure estimates of the time from intervention (administration of convalescent plasma or standard plasma) to death through 28 d (A) and 90 d (B) for all randomized subjects and for patients intubated (C) and not intubated (D) at baseline (prespecified subset analyses). The 90-d study window was defined as 90 ± 10 d.