A multicenter randomized open-label clinical trial for convalescent plasma in patients hospitalized with COVID-19 pneumonia

Abstract

BACKGROUNDPassive immunotherapy with convalescent plasma (CP) is a potential treatment for COVID-19. Evidence from controlled clinical trials is inconclusive.METHODSWe conducted a randomized, open-label, controlled clinical trial at 27 hospitals in Spain. Patients had to be admitted for COVID-19 pneumonia within 7 days from symptom onset and not on mechanical ventilation or high-flow oxygen devices. Patients were randomized 1:1 to treatment with CP in addition to standard of care (SOC) or to the control arm receiving only SOC. The primary endpoint was the proportion of patients in categories 5 (noninvasive ventilation or high-flow oxygen), 6 (invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), or 7 (death) at 14 days. Primary analysis was performed in the intention-to-treat population.RESULTSBetween April 4, 2020, and February 5, 2021, 350 patients were randomly assigned to either CP (n = 179) or SOC (n = 171). At 14 days, proportion of patients in categories 5, 6, or 7 was 11.7% in the CP group versus 16.4% in the control group (P = 0.205). The difference was greater at 28 days, with 8.4% of patients in categories 5-7 in the CP group versus 17.0% in the control group (P = 0.021). The difference in overall survival did not reach statistical significance (HR 0.46, 95% CI 0.19-1.14, log-rank P = 0.087).CONCLUSIONCP showed a significant benefit in preventing progression to noninvasive ventilation or high-flow oxygen, invasive mechanical ventilation or ECMO, or death at 28 days. The effect on the predefined primary endpoint at 14 days and the effect on overall survival were not statistically significant.TRIAL REGISTRATIONClinicaltrials.gov, NCT04345523.FUNDINGGovernment of Spain, Instituto de Salud Carlos III.

Keywords: COVID-19; Immunotherapy.

Figure 1. Trial flow diagram.

Figure 2. Patients on noninvasive ventilation or high-flow oxygen, invasive mechanical ventilation or ECMO, or who died, shown at 14 days according to subgroup analysis.

Odds ratio not calculated for subgroups with a zero value. (A) n indicates patients in categories 5–7 (noninvasive ventilation or high flow oxygen devices; invasive mechanical ventilation or ECMO; death) at that time point, whereas N indicates the total number of patients in the group, following the intention-to-treat principle. (B) Periods were established according to official information on waves and actual trial recruitment. First wave: April 4, 2020, to July 9, 2020; second wave: September 7, 2020, to December 5, 2020; third wave: December 10, 2020, to February 5, 2021. (C) Includes patients receiving corticosteroids on the day of randomization or before. (D) Four patients had missing serology values, 146 patients included. (E) Four CP patients did not receive plasma (consent withdrawal, not plasma available) and only results from 175 used plasma units are available.

Figure 3. Patients on noninvasive ventilation or high-flow oxygen, invasive mechanical ventilation or ECMO, or who died, shown at 28 days according to subgroup analysis.

Odds ratio not calculated for subgroups with a zero value. (A) n indicates patients in categories 5–7 (noninvasive ventilation or high-flow oxygen devices; invasive mechanical ventilation or ECMO; death) at that time point, whereas N indicates the total number of patients in the group, following the intention-to-treat principle. (B) Periods were established according to official information on waves and actual trial recruitment. First wave: April 4, 2020, to July 9, 2020; second wave: September 7, 2020, to December 5, 2020; third wave: December 10, 2020, to February 5, 2021. (C) Includes patients receiving corticosteroids on the day of randomization or before. (D) Four patients had missing serology values, 146 patients included. (E) Four CP patients did not receive plasma (consent withdrawal, not plasma available) and only results from 175 used plasma units are available.

Figure 4. Clinical outcomes of patients treated with convalescent plasma as compared with standard of care.

The distribution of the clinical status according to the 7-point ordinal scale is shown at 14 and 28 days. Outcomes at 14 and 28 days after randomization refer to the clinical status at that time, even if the patient was discharged and rehospitalized. In case of discharge before the end of study, patients were scheduled for a visit (either in an outpatient clinic or a phone visit) at 14, 29, and 60 days after randomization. Possible rehospitalizations were actively investigated. Categories 1 and 2 (nonhospitalized) are shown together.

Figure 5. Overall survival by group.