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

Elliott Bennett-Guerrero, MD; Jamie L. Romeiser, PhD; Lillian R. Talbot, BS; Tahmeena Ahmed, MD; Linda J. Mamone, MD; Sunitha M. Singh, MD; Janet C. Hearing, PhD; Huda Salman, MD, PHD; Dishaw D. Holiprosad, BS; Alex T. Freedenberg, BS; Jason A. Carter, PhD; Nicholas J. Browne, BS; Megan E. Cosgrove, PhD; Margaret E. Shevik, BS; Laura M. Generale, BS; Margaret A. Andrew, BSN; Sharon Nachman, MD; Bettina C. Fries, MD

Disclosures

Crit Care Med. 2021;49(7):1015-1025. 

In This Article

Abstract and Introduction

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.

Introduction

The global coronavirus disease 2019 (COVID-19) pandemic has resulted in more than 1.5 million deaths worldwide.[1,2] Historical data, mostly from nonrandomized studies, suggest that convalescent plasma (CP) may be a useful tool in the treatment of some viral illnesses with limited therapeutic alternatives.[3,4] Early in the COVID-19 pandemic, several case series[5–9] and matched cohort studies[10–12] reported encouraging preliminary results for CP. An uncontrolled national expanded access program (EAP) spanning 2,747 U.S. sites with over 85,000 patients transfused[13] reported a favorable safety profile through the first 5,000[14] and subsequent 20,000 patients.[15] More recently, an exploratory analysis of 35,000 hospitalized patients from this uncontrolled EAP reported encouraging but weak relationships between 7-day mortality and both 1) time from diagnosis to treatment and 2) CP immunoglobulin G (IgG) levels.[16] Based in part on these emerging data and the large unmet medical need, the U.S. Food and Drug Administration (FDA) granted an emergency use authorization (EUA) for CP in the treatment of COVID-19 on August 23, 2020.[17]

Notwithstanding the above, to our knowledge, there have been only four peer-reviewed publications reporting the results from randomized controlled trials (RCTs) of CP for COVID-19 infection.[18–20] Three of these trials, which took place in China,[19] India,[18] and Argentina,[20] reported no significant benefit to CP. A second trial from Argentina involving early administration (within 72 hr after symptom onset) of CP showed benefit.[21] Two of these trials were not blinded,[18,19] and none were conducted in the United States, where the deployment of care may be different. In addition, none of these trials used standard plasma (SP) as a control arm, which could affect the results.

Herein, we report the results of a double-blind RCT, comparing CP versus SP, initiated in the New York Metropolitan area during the "spring 2020" COVID-19 surge.

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