Early Convalescent Plasma for High-Risk Outpatients with Covid-19

Abstract

Background: Early administration of convalescent plasma obtained from blood donors who have recovered from coronavirus disease 2019 (Covid-19) may prevent disease progression in acutely ill, high-risk patients with Covid-19.

Methods: In this randomized, multicenter, single-blind trial, we assigned patients who were being treated in an emergency department for Covid-19 symptoms to receive either one unit of convalescent plasma with a high titer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or placebo. All the patients were either 50 years of age or older or had one or more risk factors for disease progression. In addition, all the patients presented to the emergency department within 7 days after symptom onset and were in stable condition for outpatient management. The primary outcome was disease progression within 15 days after randomization, which was a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization. Secondary outcomes included the worst severity of illness on an 8-category ordinal scale, hospital-free days within 30 days after randomization, and death from any cause.

Results: A total of 511 patients were enrolled in the trial (257 in the convalescent-plasma group and 254 in the placebo group). The median age of the patients was 54 years; the median symptom duration was 4 days. In the donor plasma samples, the median titer of SARS-CoV-2 neutralizing antibodies was 1:641. Disease progression occurred in 77 patients (30.0%) in the convalescent-plasma group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, -6.0 to 9.8; posterior probability of superiority of convalescent plasma, 0.68). Five patients in the plasma group and 1 patient in the placebo group died. Outcomes regarding worst illness severity and hospital-free days were similar in the two groups.

Conclusions: The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression. (SIREN-C3PO ClinicalTrials.gov number, NCT04355767.).

Figure 1. Enrollment, Randomization, and Analysis Populations.

Patients who presented to the emergency department (ED) because they had symptoms of coronavirus disease 2019 (Covid-19) were assessed for eligibility. After evaluating the patients, ED personnel determined whether they were good candidates for outpatient management. Patients may have had more than one reason for exclusion from the trial. The intention-to-treat population included all the patients who had undergone randomization. The per-protocol population excluded patients who had undergone randomization but had not received the assigned trial product, had an identified eligibility violation, or had a disease-progression event before the initiation of treatment. In the placebo group, one of the patients who was excluded from the per-protocol analysis did not receive placebo and was later found not to have met the trial eligibility criteria.

Figure 2. Primary Outcome, According to Subgroup.

Shown are data from the post hoc subgroup analysis comparing the primary outcome of disease-progression events at 15 days in the intention-to-treat population between the patients in the convalescent-plasma group and those in the placebo group. Data are shown as the absolute risk difference and 95% credible interval, as calculated by Bayesian analysis; these data have been carried to 2 decimal places to clarify small differences between groups. The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters. COPD denotes chronic obstructive pulmonary disease.

Figure 3. Worst Scores for Covid-19 Severity at 30 Days.

Shown is the distribution of scores for worst-illness severity within 30 days after randomization (a secondary efficacy outcome), according to the 8-category ordinal scale used by the World Health Organization. Moving from lighter to darker shading represents increasing scores on the severity scale. Data for this outcome were missing for seven patients in the convalescent-plasma group and for six in the placebo group.