Convalescent plasma for COVID-19 in hospitalised patients: an open-label, randomised clinical trial

Abstract

Background: The effects of convalescent plasma (CP) therapy in hospitalised patients with coronavirus disease 2019 (COVID-19) remain uncertain. This study investigates the effect of CP on clinical improvement in these patients.

Methods: This is an investigator-initiated, randomised, parallel arm, open-label, superiority clinical trial. Patients were randomly (1:1) assigned to two infusions of CP plus standard of care (SOC) or SOC alone. The primary outcome was the proportion of patients with clinical improvement 28 days after enrolment.

Results: A total of 160 (80 in each arm) patients (66.3% critically ill, 33.7% severely ill) completed the trial. The median (interquartile range (IQR)) age was 60.5 (48-68) years; 58.1% were male and the median (IQR) time from symptom onset to randomisation was 10 (8-12) days. Neutralising antibody titres >1:80 were present in 133 (83.1%) patients at baseline. The proportion of patients with clinical improvement on day 28 was 61.3% in the CP+SOC group and 65.0% in the SOC group (difference -3.7%, 95% CI -18.8-11.3%). The results were similar in the severe and critically ill subgroups. There was no significant difference between CP+SOC and SOC groups in pre-specified secondary outcomes, including 28-day mortality, days alive and free of respiratory support and duration of invasive ventilatory support. Inflammatory and other laboratory marker values on days 3, 7 and 14 were similar between groups.

Conclusions: CP+SOC did not result in a higher proportion of clinical improvement on day 28 in hospitalised patients with COVID-19 compared to SOC alone.

FIGURE 1

Flow diagram of patients in the clinical trial. COVID-19: coronavirus disease 2019; SOC: standard of care; CP: convalescent plasma; ICU: intensive care unit. ^#: not meeting inclusion criteria: >14 days of symptoms (n=88); negative severe acute respiratory syndrome coronavirus 2 reverse transcriptase PCR (n=38); previous use of immunosuppressants (n=30); no need for oxygen support (n=5); age <18 years (n=2). ^¶: screened patients were sequentially approached until a maximum of four subjects were enrolled daily due to limited capacity from the research team to collect blood samples and infuse convalescent plasma within advocated time interval. Eligible patients exceeding this limit were approached the next day or were excluded from the study if no longer compliant with inclusion criteria.

FIGURE 2

Distribution of neutralising antibody titres in convalescent plasma and standard-of-care (control) groups at randomisation and on day 3. Each colour indicates the proportion of patients with a given neutralising antibody titre. Titres of 1:10 or 1:20 were grouped in the 1:20 category. At randomisation, n=80 (convalescent plasma) and n=78 (control); on day 3, n=78 (convalescent plasma) and n=76 (control).

FIGURE 3

Inflammatory markers at randomisation, and on days 3, 7 and 14. a) D-dimer; b) C-reactive protein; c) tumour necrosis factor (TNF)-α; d) interleukin-6. The box plot inner horizontal lines indicate median; boxes, interquartile range (25th and 75th percentiles); whiskers extend to the most extreme observed values with 1.5 times the interquartile range of the nearer quartile, and dots represent observed values outside that range. The numbers of patients evaluated at each time point in both convalescent plasma and control groups are at the bottom of the figure.