Table 3b. COVID-19 Convalescent Plasma: Selected Clinical Data

Last Updated: April 21, 2021

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for COVID-19 CP. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.

Table 3b. COVID-19 Convalescent Plasma: Selected Clinical Data
Study Design Methods Results Limitations and Interpretation
Convalescent Plasma in Hospitalized Patients With COVID-19 (RECOVERY Trial)1
Open-label, platform RCT evaluating potential treatments, including high-titer CP, in hospitalized patients with COVID-19 in the United Kingdom (n = 11,558)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:
  • Clinically suspected or laboratory-confirmed SARS-CoV-2 infection
  • CP available at study site

Key Exclusion Criteria:

  • CP contraindicated (e.g., known allergy to blood components)

Interventions:

  • One 275 mL (+/- 75 mL) unit of CP immediately and another unit the next day (≥12 hours after the first unit)
    • CP was selected by sample to cut-off IgG SARS-CoV-2 spike protein ratio ≥6.0.
  • Usual care

Primary Endpoint:

  • All-cause mortality at Day 28

Secondary Endpoints:

  • Time to hospital discharge
  • Among patients not receiving IMV at randomization, receipt of IMV or death by Day 28
Number of Participants:
  • ITT analysis: CP (n = 5,795) and usual care (n = 5,763)

Participant Characteristics:

  • Mean age was 63.5 years.
  • 63% of patients in the CP arm and 66% in the usual care arm were men.
  • 5% of patients in each arm were on IMV.
  • At baseline, 52% of the patients in the CP arm and 48% in the usual care arm were SARS-CoV-2 antibody seropositive.
  • 93% of the patients in the CP arm and 92% in the usual care arm received corticosteroids.

Outcomes:

  • No difference in 28-day mortality between the CP arm and the usual care arm (24% vs. 24%; rate ratio 1.00; 95% CI, 0.93–1.07).
  • No difference in the proportion of patients discharged within 28 days (66% in CP arm vs. 67% in usual care arm; rate ratio 0.98; 95% CI, 0.94–1.03; P = 0.50).
  • 28-day mortality rate ratio was consistent across prespecified patient subgroups, including subgroups by SARS-CoV-2 antibody presence at randomization. In particular, among patients without detectable SARS-CoV-2 antibodies, there was no evidence of a mortality difference between those who received CP and those who received usual care (32% vs. 34%; rate ratio 0.94; 95% CI, 0.84–1.06).
  • Among those not receiving IMV at baseline, the percentage of patients who progressed to IMV or died was similar in the CP arm and the usual care arm (28% vs. 29%; rate ratio 0.99; 95% CI, 0.93–1.05; P = 0.79).
  • Severe allergic reactions were rare (occurred in 16 patients in the CP arm and 2 in the usual care arm).
Limitations:
  • The study was not blinded.
  • >90% of participants received corticosteroids. There is uncertainty about the effect of CP in hospitalized patients who do not require supplemental oxygen and for whom corticosteroids are not recommended.

Interpretation:

  • The trial did not demonstrate a benefit of CP in hospitalized patients with COVID-19.
Convalescent Plasma in Hospitalized Adults With COVID-19 (PLACID Trial)2
Multicenter, open-label, Phase 2 RCT in hospitalized adults with severe COVID-19 in India (n = 464) Key Inclusion Criteria:
  • Aged ≥18 years
  • Positive SARS-CoV-2 RT-PCR
  • PaO2/FiO2 = 200–300 mm Hg or respiratory rate >24 breaths/min with SpO2 ≤93% on room air

Key Exclusion Criteria:

  • Critical illness

Interventions:

  • 2 doses of 200 mL CP, transfused 24 hours apart
  • SOC

Primary Endpoint:

  • Composite of progression to severe disease (defined as PaO2/FiO2 <100 mm Hg) any time within 28 days of enrollment or all-cause mortality at 28 days
Number of Participants:
  • CP (n = 235) and SOC (n = 229)

Participant Characteristics:

  • Median age was 52 years.
  • 75% of participants in the CP arm and 77% in the SOC arm were men.
  • Higher prevalence of diabetes in the CP arm (48%) than in SOC arm (38%).

Outcomes:

  • No difference between the arms in the primary outcome of progression to severe disease or death (occurred in 18.7% of participants in CP arm and 17.9% in SOC arm).
  • A post hoc analysis evaluating outcomes among patients without detectable SARS-CoV-2 neutralizing antibody titers at baseline also revealed no benefit of CP.
Limitations:
  • The study was not blinded.
  • SARS-CoV-2 antibody testing was not used to select donated CP units; therefore, many participants may have received CP units with low titers of SARS-CoV-2 neutralizing antibodies.

Interpretation:

  • This trial did not demonstrate a benefit of CP in hospitalized patients with severe COVID-19.
Convalescent Plasma in COVID-19 Severe Pneumonia (PlasmAr Study)3
Double-blind, placebo-controlled, multicenter RCT in hospitalized adults with severe COVID-19 in Argentina (n = 333) Key Inclusion Criteria:
  • Aged ≥18 years
  • Positive SARS-CoV-2 RT-PCR
  • Severe COVID-19

Key Exclusion Criteria:

  • Critical illness

Interventions

2:1 Randomization:
  • Single dose (median volume 500 mL) of CP pooled from 2–5 donors. Only plasma units with a SARS-CoV-2 viral spike-RBD IgG titer ≥1:800 were transfused.
  • Placebo

Primary Endpoint:

  • Change in clinical status 30 days after intervention measured using a 6-point ordinal scale
Number of Participants:
  • CP (n = 228) and placebo (n = 105)

Participant Characteristics:

  • Median age was 62 years.
  • 67.6% of the participants were men.
  • 64.9% of the participants had a coexisting condition at trial entry.
  • Median time from symptom onset to enrollment was 8 days.
  • Of 215 participants tested, 46% had no detectable SARS-CoV-2 antibodies at baseline. Median SARS-CoV-2 antibody titer in both the CP arm and placebo arm was 1:50.

Outcomes:

  • No significant differences between the arms in the distribution of outcomes according to the categories on the 6-point ordinal scale (OR 0.83; 95% CI, 0.52–1.35).
  • 30-day mortality was similar in CP arm (11.0%) and placebo arm (11.4%).
  • Infusion-related AEs were more frequent in the CP arm than in the placebo arm (occurred in 4.8% vs. 1.9% of participants).
Limitations:
  • The majority of participants in both arms received concomitant glucocorticoid treatment, potentially masking subtle differences in clinical outcomes between the study arms.

Interpretation:

  • This trial did not demonstrate a benefit of CP in hospitalized patients with severe COVID-19.
Convalescent Plasma in Adults With Severe COVID-194
Double-blind, Phase 2 RCT in hospitalized adults with severe COVID-19 (n = 223) in the United States (n = 73) and Brazil (n = 150)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:
  • Aged ≥18 years
  • COVID-19 pneumonia
  • SpO2 ≤94% on room air or requirement for supplemental oxygen, IMV, or ECMO
Key Exclusion Criteria:
  • >5 days on IMV or ECMO
  • Severe multiorgan failure

Interventions

2:1 Randomization:
  • Single dose of SARS-CoV-2 CP (approximately 250 mL). Only units with a SARS-CoV-2 viral spike-RBD IgG titer ≥1:400 were transfused.
  • Non-SARS-CoV-2 plasma (normal control plasma)

Primary Endpoint:

  • Clinical status on Day 28, measured using an ordinal scale (initially with 7 categories, but modified to 6).

Secondary Endpoints:

  • Time to clinical improvement
  • In-hospital and 28-day mortality
  • Time to discontinuation of supplemental oxygen
  • Time to hospital discharge
Number of Participants:
  • CP (n = 150) and normal control plasma (n = 73)
  • Enrollment initiated in New York City in April 2020 and in Brazil in August 2020

Participant Characteristics:

  • Median age was 61 years.
  • 66% of the participants were men.
  • Median duration of symptoms prior to randomization was 9 days.
  • 57% of the participants required supplemental oxygen at baseline, 25% required high-flow oxygen or noninvasive ventilation, and 13% required IMV or ECMO.
  • There were some imbalances between the study arms at baseline. The CP arm included more women; the participants were younger and had slightly longer symptom durations.
  • 81% of the participants received corticosteroids.

Outcomes:

  • No difference in clinical status on Day 28 was observed between the CP arm and the control arm (OR 1.5 for being in a better category with CP vs. control plasma; 95% CI, 0.83–2.68; P = 0.18).
  • In-hospital mortality was lower in the CP arm (13%) than in the control arm (25%; HR 0.44; 95% CI, 0.22–0.91; P = 0.034). The treatment difference was not significant after adjustment for age, sex, and duration of symptoms at baseline.
  • In both arms, mortality at 28 days was the same as in-hospital mortality.
  • Time to oxygen discontinuation and time to hospital discharge were similar between the arms.
  • 25.5% of patients in the CP arm vs. 36.1% in the control arm experienced SAEs.
Limitations:
  • The intervention in the control group arm was blood plasma without SARS-CoV-2 antibodies. This ensured blinded administration; however, because the trial was not placebo controlled; it is not possible to identify potential harm due to plasma infusion.
  • Low sample size and number of events
  • There were imbalances in baseline characteristics between the study arms that may have impacted study outcomes. After adjustment for the imbalances, the difference in mortality between the arms was not significant.
  • The treatment difference in the primary outcome (clinical status on Day 28) was not statistically significant; mortality was a secondary outcome.
  • There were no subgroup analyses for mortality.

Interpretation:

  • Although the difference between the CP arm and the non-SARS-CoV-2 antibody plasma arm for the primary outcome of clinical status on Day 28 was not statistically significant, the lower 28-day mortality in the CP arm suggests a potential benefit of CP in hospitalized patients with severe COVID-19.
Early High-Titer Plasma Therapy to Prevent Severe COVID-19 in Older Adults5
Double-blind, placebo-controlled RCT in outpatients with mild COVID-19 in Argentina (n = 160) Key Inclusion Criteria:
  • Aged >75 years or aged 65–74 years with ≥1 coexisting condition
  • Outpatient with <72 hours of mild COVID-19 symptoms
Key Exclusion Criteria:
  • Severe respiratory disease

Interventions:

  • Single 250 mL dose of CP with an IgG titer against SARS-CoV-2 spike protein of >1:1000
  • Placebo

Primary Endpoint:

  • Severe respiratory disease defined as a respiratory rate ≥30 breaths/min and/or SpO2 <93% on room air by Day 15
Number of Participants:
  • ITT analysis: CP (n = 80) and placebo (n = 80)

Participant Characteristics:

  • Mean age was 77 years.
  • Most of the patients had comorbidities.

Outcomes:

  • 13 of 80 patients (16%) in the CP arm and 25 of 80 (31%) in the placebo arm experienced severe respiratory disease by Day 15 (relative risk 0.52; 95% CI, 0.29–0.94; P = 0.026).
  • 2 participants in the CP arm and 5 in the placebo arm died.
  • No solicited AEs were reported.
Limitations:
  • The trial was terminated early because cases of COVID-19 at the study site decreased.
  • The trial included relatively few participants.

Interpretation:

  • This trial demonstrated a benefit of CP in elderly outpatients with <72 hours of mild COVID-19 symptoms.
Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-Threatening COVID-196
Multicenter, open-label, randomized trial in hospitalized adults with severe or life-threatening COVID-19 in China (n = 103) Key Inclusion Criteria:
  • Aged ≥18 years
  • Positive SARS-CoV-2 PCR within 72 hours of randomization
  • Met study definition of severe or life-threatening COVID-19
Key Exclusion Criteria:
  • Baseline RBD-specific IgG antibody ≥1:64
  • Certain sequalae of severe COVID-19 (e.g., severe septic shock, severe heart failure)

Interventions:

  • Single 4–13 mL/kg dose of CP. Only CP units with a SARS-CoV-2 viral spike-RBD-specific IgG titer of ≥1:640 were transfused.
  • SOC

Primary Endpoint:

  • Time to clinical improvement (patient discharge or a reduction of 2 points on a 6-point disease severity scale; 6 points = death, 1 point = hospital discharge) within 28 days.
Number of Participants:
  • CP (n = 52) and SOC (n = 51)

Participant Characteristics:

  • Median age was 70 years.
  • 58.3% of the participants were men.

Outcomes:

  • No significant difference in time to clinical improvement between the CP arm and the control arm (HR 1.40; 95% CI, 0.79–2.49; P = 0.26).
  • No significant difference in mortality between the CP arm (16%) and the control arm (24%; P = 0.30).
Limitations:
  • The study was not blinded.
  • The trial was stopped early because of decreasing numbers of cases of COVID-19 at the study site; therefore, the study lacked sufficient power to detect differences in clinical outcomes.
    • Only 103 of 200 planned participants were randomized to receive treatment.
  • CP was administered late (approximately 1 month) into disease course.

Interpretation:

  • This trial did not demonstrate a benefit of CP in hospitalized patients with severe or life-threatening COVID-19.
Early Versus Deferred Anti-SARS-CoV-2 Convalescent Plasma in Hospitalized Patients With COVID-197
Open-label, single-center, Phase 2 randomized trial in hospitalized adults with COVID-19 in Chile (n = 58) Key Inclusion Criteria:
  • Aged ≥18 years
  • ≤7 days of COVID-19 symptoms
  • High risk of progression to respiratory failure
Key Exclusion Criteria:
  • PaO2/FiO2 <200 mm Hg
  • Mechanical ventilation

Interventions

Immediate CP:
  • Two 400 mL doses of CP with anti-SARS-CoV-2 neutralizing antibody titers ≥1:400, transfused 24 hours apart
Deferred CP:
  • CP transfusion only if PaO2/FiO2 <200 mm Hg, or if participant still required hospitalization for COVID-19 symptoms 7 days after enrollment

Primary Endpoint:

  • Composite of mechanical ventilation, hospitalization >14 days, or in-hospital death
Number of Participants:
  • Immediate CP (n = 28) and deferred CP (n = 30)

Participant Characteristics:

  • Median age was 66 years.
  • 50% of the participants were men.
  • Median interval between symptom onset and randomization was 6 days.
  • 13 of 28 participants (43%) in the deferred CP arm received CP at a median of 3 days after enrollment.

Outcomes:

  • There was no difference between the arms in the percentage of participants who met the primary composite endpoint of death, mechanical ventilation, or >14 days hospitalization (32% in immediate CP arm vs. 33% in deferred CP arm; OR 0.95; 95% CI, 0.32–2.84).
  • 18% of participants in the immediate CP arm vs. 7% in the deferred CP arm died within 30 days (OR 3.0; 95% CI, 0.5–17.2; P = 0.25).
Limitations:
  • The study was not blinded.
  • Small sample size.

Interpretation:

  • This trial did not demonstrate a benefit of immediate vs. deferred administration of CP in hospitalized COVID-19 patients with ≤7 days of COVID-19 symptoms.
Convalescent Plasma for COVID-19 (ConCOVID trial)8
Multicenter, open-label, RCT in hospitalized adults with COVID-19 in the Netherlands (n = 86)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:
  • Aged ≥18 years
  • Clinical disease with positive SARS-CoV-2 RT-PCR within 96 hours of enrollment
Key Exclusion Criteria:
  • Mechanical ventilation for >96 hours

Interventions:

  • One to two 300 mL doses of CP with anti-SARS-CoV-2 neutralizing antibody titers ≥1:80
  • SOC

Primary Endpoint:

  • Day-60 mortality
Number of Participants:
  • CP (n = 43) and SOC (n = 43)

Participant Characteristics:

  • Median age was 63 years.
  • Most of the participants were men.

Outcomes:

  • No differences in mortality (P = 0.95), length of hospital stay (P = 0.68), or disease severity at Day 15 (P = 0.58) were observed between the study arms.
Limitations:
  • The study was not blinded.
  • Trial halted early by the investigators when the baseline SARS-CoV-2 neutralizing antibody titers of participant plasma and CP were found to be comparable, challenging the potential benefit of CP for the study population. Thus, the study lacked sufficient power to detect differences in clinical outcomes between the study arms.
    • Only 86 of 426 planned participants were randomized to receive CP or SOC.

Interpretation:

  • This trial did not demonstrate a benefit of COVID-19 CP in hospitalized patients.
Convalescent Plasma for COVID-19 (ConPlas-19 Study)9
Multicenter, open-label, RCT in hospitalized adults with COVID-19 in Spain (n = 81)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:
  • Aged ≥18 years
Key Exclusion Criteria:
  • Receiving IMV, noninvasive ventilation, or high-flow oxygen

Interventions:

  • Single dose of 250–300 mL of CP plus SOC.
    • All administered units had neutralizing antibodies (VMNT-ID50: all titers >1:80, median titer 1:292, IQR 238–451; pseudovirus neutralizing ID50 assay: median titer 1:327; IQR 168–882)
  • SOC alone

Primary Endpoint:

  • Proportion of patients in ordinal scale categories 5, 6, or 7 at Day 15.
Number of Participants:
  • CP (n = 38) and SOC (n = 43)

Participant Characteristics:

  • Mean age was 59 years.
  • At baseline, 49% of the participants were SARS-CoV-2 antibody positive.

Outcomes:

  • 0 of 38 participants (0%) in the CP arm progressed to ordinal scale categories 5–7 vs. 6 of 43 participants (14.0%) in the SOC arm (P = 0.57, not statistically significant according to the planned analysis; but P = 0.03 using Fisher test as a post hoc sensitivity analysis given small numbers and the by-center heterogenous distribution).
  • 0 of 38 participants (0%) in the CP arm died vs. 4 of 43 (9.3%) in the SOC arm (P = 0.06).
Limitations:
  • The study was not blinded.
  • The trial was stopped early because of decreasing numbers of COVID-19 cases at the study site and, thus, the study lacked sufficient power to detect differences in clinical outcomes.
    • Only 81 of planned 278 participants were enrolled.

Interpretation:

  • Although the results did not reach statistical significance and only a small number of clinical events related to COVID-19 occurred, these results suggest a potential benefit of CP in hospitalized patients who are not receiving high-flow oxygen, noninvasive ventilation, or invasive ventilation.
Clinical and Immunological Benefits of Convalescent Plasma Therapy in Severe COVID-1910
Single-center, open-label, RCT in hospitalized adults with COVID-19 and ARDS in India (n = 80)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:
  • Evidence of ARDS (defined as PaO2/FiO2 100–300 mm Hg)
  • Not on mechanical ventilation
Key Exclusion Criteria:
  • Mechanical ventilation

Interventions:

  • 2 consecutive doses of ABO-matched 200 mL CP, 1 day apart
  • SOC alone

Primary Endpoint:

  • All-cause mortality at Day 30
Number of Participants:
  • CP (n = 40) and SOC (n = 40)

Participant Characteristics:

  • Mean age was 61 years.
  • 71% of the participants were men.
  • No difference in mean number of days of hospitalization at enrollment between the CP arm (4.2 days) and the SOC arm (3.9 days).

Outcomes:

  • 10 of 40 participants (25%) in the CP arm had died by Day 30 vs. 14 of 40 (35%) in the SOC arm.
  • Difference in survival between the arms was not statistically significant (HR 0.6731; 95% CI, 0.3010–1.505).
Limitations:
  • The study was not blinded.
  • The study lacked sufficient power to detect differences in clinical outcomes between the study arms.

Interpretation:

  • This trial did not demonstrate a benefit of CP in hospitalized patients with mild to moderate ARDS who are not receiving mechanical ventilation.
Convalescent Plasma Therapy Versus Standard Therapy in Patients With Severe COVID-1911
Open-label, RCT in hospitalized adults with COVID-19 in Bahrain (n = 40)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:
  • Aged ≥21 years
  • Radiologic evidence of pneumonia
  • Requirement for oxygen therapy for COVID-19
Key Exclusion Criteria:
  • Requirement for IMV, noninvasive ventilation, or high-flow oxygen

Interventions:

  • Two 200 mL transfusions of CP over 24 hours
  • SOC alone

Primary Endpoints:

  • Requirement for IMV or noninvasive ventilation
  • In patients who require ventilation, duration of ventilation
Number of Participants:
  • CP (n = 20) and SOC (n = 20)

Participant Characteristics:

  • Mean age was 53 years in the CP arm and 51 years in the SOC arm.
  • Most of the participants were men (75% in the CP arm and 85% in the SOC arm).

Outcomes:

  • 6 patients in the SOC arm and 4 patients in the CP arm required mechanical ventilation (risk ratio 0.67; 95% CI, 0.22–2.0; P = 0.72).
  • 2 patients in the SOC arm died vs. 1 in the CP arm.
Limitations:
  • The study was not blinded.
  • The study lacked sufficient power to detect differences in clinical outcomes between the study arms.

Interpretation:

  • This trial did not demonstrate a benefit of CP in hospitalized patients who are not receiving high-flow oxygen, noninvasive ventilation, or invasive ventilation.
Convalescent Plasma Antibody Levels and the Risk of Death from COVID-1912
Retrospective, indirect evaluation of a subset of patients from the Mayo Clinic COVID-19 CP EAP (n = 3,082). More than 100,000 patients hospitalized with COVID-19 in the United States received CP through the Mayo Clinic EAP. Key Inclusion Criteria:
  • Aged ≥18 years
  • Severe or life-threatening (critical) COVID-19
  • Analysis limited to patients for whom samples were available for retrospective analysis of CP titer.

Intervention:

  • CP transfusion (no titer specified in real time; high, medium, and low titer CP determined retrospectively)

Primary Endpoint:

  • Mortality 30 days after CP transfusion
Number of Participants:
  • High-titer CP (n = 515), medium-titer CP (n = 2,006), and low-titer CP (n = 561)

Participant Characteristics:

  • 61% of the participants were men.
  • 48% of the participants were White and 37% were Hispanic/Latino.
  • 61% of the participants required ICU-level care prior to infusion.
  • 33% of the participants were on mechanical ventilation.
  • 51% of the participants received corticosteroids; 31% received RDV.

Outcomes:

  • The analysis included 3,082 participants who received a single unit of CP. The participants were among 35,322 participants who had received CP through the EAP by July 4, 2020.
  • Death within 30 days occurred in 115 of 515 patients (22%) in the high-titer group, 549 of 2,006 patients (27%) in the medium-titer group, and 166 of 561 patients (30%) in the low-titer group.
  • Using a relative-risk regression model that assumed all patients who were discharged were alive at Day 30, patients in the high-titer group had a lower relative risk of death within 30 days than patients in the low-titer group (relative risk 0.82; 95% CI, 0.67–1.00).
  • Among patients who received mechanical ventilation before transfusion, there was no difference in the risk of death between those who received high-titer CP and those who received low-titer CP (relative risk 1.02; 95% CI, 0.78–1.32).
  • Mortality was lower among patients who were not receiving mechanical ventilation before transfusion (relative risk 0.66; 95% CI, 0.48–0.91).
Limitations:
  • Lack of untreated control arm limits interpretation of the safety and efficacy data; the possibility that differences in outcomes are attributable to harm from low-titer plasma rather than benefit from high-titer plasma cannot be excluded.
  • Assays to determine the effective antibody titers remain limited, and the antibody titers of currently available CP from COVID-19 survivors are highly variable.
  • Efficacy analysis relied on only a subset of EAP patients who represent a fraction of the patients who received CP through the EAP.
  • Post hoc subgroups were selected by combining several subsetting rules that favored subgroups. This approach tends to overestimate the treatment effect.

Interpretation:

  • Given the lack of an untreated control arm and the limitations listed above, this retrospective analysis is not sufficient to establish the efficacy or safety of CP.