Early high antibody titre convalescent plasma for hospitalised COVID-19 patients: DAWn-plasma

Abstract

Background: Several randomised clinical trials have studied convalescent plasma for coronavirus disease 2019 (COVID-19) using different protocols, with different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralising antibody titres, at different time-points and severities of illness.

Methods: In the prospective multicentre DAWn-plasma trial, adult patients hospitalised with COVID-19 were randomised to 4 units of open-label convalescent plasma combined with standard of care (intervention group) or standard of care alone (control group). Plasma from donors with neutralising antibody titres (50% neutralisation titre (NT₅₀)) ≥1/320 was the product of choice for the study.

Results: Between 2 May 2020 and 26 January 2021, 320 patients were randomised to convalescent plasma and 163 patients to the control group according to a 2:1 allocation scheme. A median (interquartile range) volume of 884 (806-906) mL) convalescent plasma was administered and 80.68% of the units came from donors with neutralising antibody titres (NT₅₀) ≥1/320. Median time from onset of symptoms to randomisation was 7 days. The proportion of patients alive and free of mechanical ventilation on day 15 was not different between both groups (convalescent plasma 83.74% (n=267) versus control 84.05% (n=137)) (OR 0.99, 95% CI 0.59-1.66; p=0.9772). The intervention did not change the natural course of antibody titres. The number of serious or severe adverse events was similar in both study arms and transfusion-related side-effects were reported in 19 out of 320 patients in the intervention group (5.94%).

Conclusions: Transfusion of 4 units of convalescent plasma with high neutralising antibody titres early in hospitalised COVID-19 patients did not result in a significant improvement of clinical status or reduced mortality.

FIGURE 1

CONSORT flow diagram: patient enrolment and treatment assignment. DNR: do not resuscitate; FAS: Full Analysis Set; PPS: Per Protocol Set.

FIGURE 2

Kaplan–Meier curve. Proportion of patients remaining free of mechanical ventilation (MV) or death: Full Analysis Set. SOC: standard of care.

FIGURE 3

Pre-specified subgroup analysis for the primary end-point: Full Analysis Set. The odds ratios were obtained by means of a logistic regression that included factors for treatment, study site, study period, subgroup, and interaction between treatment and subgroup. For blood institute, study site was not included in the model due to problems with fitting the model. SOC: standard of care; ICU: intensive care unit; ER: emergency room; NC: not calculated.

FIGURE 4

Outcome according to antibody titre in donor plasma: Full Analysis Set. Association between the number of plasma units with antibody titre ≥1/320 given to patients and outcome (alive without mechanical ventilation (MV) on day 15). The odds ratio reflects the change in odds for being alive with no MV on day 15 when the number of units ≥1/320 increases by 1.

FIGURE 5

Evolution of neutralising antibody titres (50% neutralisation titre (NT₅₀)) in patient sera. Box plots shows median and interquartile range (IQR). Whiskers are drawn at 1.5 IQR. Mean values are indicated by “+”. Circles indicate outlying values. Lines connect individual patient values (squares) between day 0 and 6. SOC: standard of care.

FIGURE 6

Neutralising antibody titre (50% neutralisation titre (NT₅₀)) relation to primary outcome. Number and proportion of patients alive without mechanical ventilation (MV) on day 15 according to NT₅₀ titre levels on a) day 0 and b) day 6, and c) according to the change in titre levels between day 0 and day 6. Results above the bars are shown as n/N, where n=number of patients alive without MV on day 15 in the category and N=total number of patients in the category.

FIGURE 7

Evolution of viral load (baseline versus day 6 since randomisation): Full Analysis Set. Box plots show median and interquartile range (IQR). Whiskers are drawn at 1.5 IQR. Mean values are indicated by “+”. Circles indicate outlying values. Below the limit of quantification values were imputed with half of the minimum observed value. Log₁₀-transformed viral load values at day 6 were compared between groups using a general linear model with factors for treatment, study site and period, and including baseline value as a covariate. The resulting estimate of the treatment difference was 0.23 (95% CI −0.40–0.86).