Table 4c. COVID-19 Convalescent Plasma: Selected Clinical Trial Data

Last Updated: March 6, 2023

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

Table 4c. COVID-19 Convalescent Plasma: Selected Clinical Trial Data
Methods	Results	Limitations and Interpretation
REMAP-CAP: Multinational, Open-Label RCT of High-Titer CCP in Hospitalized Patients With Critical COVID-19 in Australia, Canada, the United Kingdom, and the United States¹
Key Inclusion Criterion Admitted to ICU while receiving respiratory support (HFNC oxygen, NIV, MV, ECMO) and/or vasopressor or inotrope support Key Exclusion Criteria CCP contraindicated Death imminent Interventions High-titer CCP (550 mL +/- 150 mL) within 48 hours of randomization (n = 1,084) Usual care (n = 916) Primary Endpoint Number of organ support-free days by Day 21 Key Secondary Endpoints In-hospital mortality Mortality by Day 28 and Day 90 Number of respiratory support-free days ICU LOS	Participant Characteristics Mean age 61 years; 68% men 32% on MV 29% SARS-CoV-2 antibody negative at baseline 94% received corticosteroids, 45% received RDV, 39% received IL-6 inhibitors Primary Outcome Median number of organ support-free days by Day 21: 0 days in CCP arm vs. 3 days in usual care arm (OR 0.97; 95% CrI, 0.82–1.14) Secondary Outcomes No difference between arms in: In-hospital mortality: 37% in CCP arm vs. 38% in usual care arm Mortality by Day 28 or Day 90 Median number of respiratory support-free days: 0 days in CCP arm vs. 2 days in usual care arm Median ICU LOS: 21 days in CCP arm vs. 17 days in usual care arm	Key Limitations Open-label study Not all patients in CCP arm received CCP (86% received CCP as per protocol and 95% received some CCP). Interpretation There was no benefit of CCP in hospitalized patients with critical COVID-19.
CONCOR-1: Multinational, Open-Label RCT of CCP for Hospitalized Patients With COVID-19 in Canada, the United States, and Brazil²
Key Inclusion Criteria Receipt of supplemental oxygen Within 12 days of respiratory symptom onset Key Exclusion Criterion Imminent or current intubation Interventions 1–2 units of CCP (approximately 500 mL) from 1–2 donors (n = 625) SOC (n = 313) Primary Endpoint Intubation or death by Day 30 Key Secondary Endpoints Time to intubation or death by Day 30 Mortality by Day 30 ICU LOS by Day 30 Need for renal dialysis by Day 30 Frequency of SAEs by Day 30	Participant Characteristics Mean age 68 years; 59% men 84% receiving systemic corticosteroids at enrollment Primary Outcome Intubation or death by Day 30: 32% in CCP arm vs. 28% in SOC arm (relative risk 1.16; 95% CI, 0.94–1.43, P = 0.18) Secondary Outcomes By Day 30, no difference between arms in: Time to intubation or death Mortality: 23% in CCP arm vs. 21% in SOC arm Mean ICU LOS: 4.3 days in CCP arm vs. 3.7 days in SOC arm Need for renal dialysis: 1.6% in CCP arm vs. 2.0% in SOC arm Frequency of SAEs by Day 30: 33% in CCP arm vs. 26% in SOC arm	Key Limitations Open-label study Trial stopped at 78% of planned enrollment after meeting prespecified futility criteria for early termination. Interpretation There was no benefit of CCP in oxygen-dependent, hospitalized patients with COVID-19 who were within 12 days of symptom onset.
RECOVERY: Open-Label RCT of High-Titer CCP in Hospitalized Patients in the United Kingdom³
Key Inclusion Criterion Clinically suspected or laboratory-confirmed SARS-CoV-2 infection Key Exclusion Criterion CCP contraindicated Interventions 2 units of high-titer CCP (approximately 275 mL per unit) with IgG against SARS-CoV-2 spike protein and sample to cutoff ratio ≥6.0. First unit administered ASAP after randomization, second unit administered ≥12 hours later (n = 5,795) Usual care (n = 5,763) Primary Endpoint All-cause mortality by Day 28 Key Secondary Endpoints Time to hospital discharge by Day 28 Among patients not receiving MV, progression to MV or death by Day 28	Participant Characteristics Mean age 64 years; 64% men 5% on MV 92% received corticosteroids Primary Outcomes No difference between arms in: All-cause mortality by Day 28: 24% in each arm Mortality in patients without detectable SARS-CoV-2 antibodies: 32% in CCP arm vs. 34% in usual care arm Secondary Outcomes No difference between arms in: Proportion discharged by Day 28: 66% in both arms Proportion who progressed to MV or death by Day 28: 29% in CCP arm vs. 29% in usual care arm	Key Limitation Open-label study Interpretation There was no benefit of CCP in hospitalized patients with COVID-19.
RECOVER: Open-Label RCT of High-Titer CCP in Hospitalized Patients With Severe COVID-19 in 4 Risk Groups in Germany⁴
Key Inclusion Criteria PCR-confirmed SARS-CoV-2 infection Hospitalized with SpO₂ ≤94% on room air or PaO₂/FiO₂ <300 mm Hg ≥1 of the following criteria: Hematologic cancer and/or receipt of active cancer therapy in past 24 months for any cancer Chronic immunosuppression due to medications and/or underlying disease Aged >50 to ≤75 years with ALC <0.8 x 10⁹ cells/L and/or D-dimer >1 μg/mL Aged >75 years without other listed criteria Key Exclusion Criterion Requiring MV or NIV Interventions 2 units (238–337 mL) of high-titer CCP (≥1:80) or vaccinated donor plasma from 2 donors on Days 1 and 2 (n = 68) SOC (n = 66) Primary Endpoint Time to 2-point improvement on a 7-point OS or hospital discharge Key Secondary Endpoints 28-day, 56-day, and 84-day overall survival rate	Participant Characteristics 136 participants were enrolled between September 2020 and January 2022. Mean age 69 years; 68% men; 97% White Participants were enrolled from 4 mutually exclusive patient groups: Patients with cancer (n = 56) Patients with immunosuppression who did not have cancer (n = 16, including 12 solid organ transplant recipients) Patients aged >50 to ≤75 years with lymphopenia and/or elevated D-dimer levels (n = 36) Patients aged >75 years without other criteria (n = 26) 11% were fully vaccinated 8% received small-molecule antiviral drugs (12% in plasma arm vs. 5% in SOC arm); 37% received anti-inflammatory drugs (40% in plasma arm vs. 33% in SOC arm) 60% received supplemental oxygen via nasal cannula; 21% received HFNC oxygen or NIV Median 7 days between symptom onset and randomization Primary Outcome Median time to 2-point improvement on OS or hospital discharge: 13 days in plasma arm vs. 18 days in SOC arm (HR 1.29; 95% CI, 0.86–1.93; P = 0.205) Median time to improvement or hospital discharge among patients with cancer: 13 days in plasma arm vs. 31 days in SOC arm (HR 2.50; 95% CI, 1.34–4.79; P = 0.003) Key Secondary Outcomes No difference between arms in overall survival; 27 patients (19.9%) died (HR for survival 0.72; 95% CI, 0.33–1.55; P = 0.403) Fewer patients with cancer died in plasma arm than in SOC arm (HR 0.28; 95% CI, 0.06–0.96; P = 0.042)	Key Limitations Open-label study The live virus neutralizing assay used to select plasma for this trial may not produce the same results as the assays used to qualify high-titer CCP in the current FDA EUA. Small sample size Trial was terminated early because the neutralizing activity of stored plasma against the Omicron variant was not known. Low proportion of vaccinated participants and limited use of current SOC therapies, such as antiviral or immunomodulatory agents Subgroup analyses were not adjusted for multiple comparisons. Interpretation The trial did not demonstrate a benefit of high-titer CCP or vaccinated donor plasma in the overall study population. Results from the predefined subgroup analysis of patients with cancer suggest a potential benefit of CCP or vaccinated donor plasma. However, this analysis was conducted largely before the emergence of the Omicron subvariants, so the results should be interpreted with caution.
CSSC-004: RCT of Early Treatment With High-Titer CCP in Outpatients With COVID-19 in the United States⁵
Key Inclusion Criterion COVID-19 symptoms for <8 days Key Exclusion Criteria Prior or planned COVID-19–related hospitalization Receipt of anti-SARS-CoV-2 mAbs Interventions Approximately 250 mL of CCP with SARS-CoV-2 spike-RBD IgG titer ≥1:320 (n = 592) Non-SARS-CoV-2 plasma (n = 589) Primary Endpoint COVID-19-related hospitalization or all-cause death within 28 days	Participant Characteristics Median age 44 years; 7% aged ≥65 years; 57% women; 79% White 8% with type 2 DM; 2% with CVD; 38% with BMI ≥30 82% unvaccinated Median 6 days between symptom onset and transfusion Primary Outcomes COVID-19-related hospitalization within 28 days: 2.9% in CCP arm vs. 6.3% in control arm (absolute risk reduction 3.4 percentage points; 95% CI, 1.0–5.8; P = 0.005) 53 of 54 hospitalizations occurred in unvaccinated individuals. None occurred in fully vaccinated individuals. All-cause deaths within 28 days: 0 in CCP arm vs. 3 in control arm	Key Limitation Patients were at relatively low risk for disease progression. Interpretation This trial demonstrated a benefit of CCP in unvaccinated outpatients with <8 days of COVID-19 symptoms.
CONV-ERT: RCT of High-Titer, Methylene Blue-Treated CCP as an Early Treatment for Outpatients With COVID-19 in Spain⁶
Key Inclusion Criteria Aged ≥50 years Mild or moderate COVID-19 symptoms for ≤7 days Key Exclusion Criteria Severe COVID-19 symptoms or requirement for hospitalization for any reason Previous SARS-CoV-2 infection Receipt of ≥1 COVID-19 vaccine Interventions 250–300 mL of high-titer, methylene blue-treated CCP (n = 188) 0.9% saline (n = 188) Primary Endpoints Hospitalization within 28 days Mean change in SARS-CoV-2 VL from baseline to Day 7 Key Secondary Endpoints Death by Day 60 Time to complete symptom resolution	Participant Characteristics Mean age 56 years; 54% men 75% with ≥1 risk factor for COVID-19 progression 97% with mild COVID-19 Median 4.4 days of symptoms prior to enrollment Among 369 patients with available baseline serologic testing, 88% negative for both IgG anti-SARS-CoV-2 spike and IgM anti-SARS-CoV-2 S1-RBD Primary Outcomes Hospitalization within 28 days: 12% in CCP arm vs. 11% in placebo arm (relative risk 1.05; 95% CrI, 0.78–1.41) Mean change in SARS-CoV-2 VL: -2.41 log₁₀ copies/mL in CCP arm vs. -2.32 log₁₀ copies/mL in placebo arm Key Secondary Outcomes Death by Day 60: 0 in CCP arm vs. 2 in placebo arm (relative risk 0.20; 95% CI 0.01–4.14) No difference between arms in median time to symptom resolution: 12.0 days for both arms (HR 1.05; 95% CI, 0.85–1.30)	Key Limitations Trial was underpowered because it was terminated early due to rising vaccination rates among the eligible patient population. Methylene blue, which was used for pathogen inactivation in donor plasma, could have potentially impaired Fc-region functionality of Ig and negatively impacted product efficacy and blinding. Interpretation This trial did not demonstrate a benefit of CCP in unvaccinated outpatients with <7 days of COVID-19 symptoms.
Double-Blind RCT of Early High-Titer CCP Therapy to Prevent Severe COVID-19 in Nonhospitalized Older Adults in Argentina⁷
Key Inclusion Criteria Aged ≥75 years or aged 65–74 years with ≥1 coexisting condition Mild COVID-19 symptoms for <72 hours Key Exclusion Criterion Severe respiratory disease Interventions 250 mL of CCP with IgG against SARS-CoV-2 spike protein >1:1,000 (n = 80) Saline (n = 80) Primary Endpoint Severe respiratory disease, defined as respiratory rate ≥30 breaths/min and/or SpO₂ <93% on room air, by Day 15	Participant Characteristics Mean age 77 years; 38% men Most with comorbidities Primary Outcome Severe respiratory disease by Day 15: 16% in CCP arm vs. 31% in placebo arm (relative risk 0.52; 95% CI, 0.29–0.94; P = 0.03)	Key Limitations Small sample size Early termination because number of COVID-19 cases decreased Interpretation This trial demonstrated a benefit of CCP in older adult outpatients with <72 hours of mild COVID-19 symptoms.
SIREN-C3PO: Multicenter, Single-Blind RCT of High-Titer CCP in Adults With COVID-19 in the United States⁸
Key Inclusion Criteria ED patient with ≤7 days of symptoms PCR-confirmed SARS-CoV-2 infection Aged ≥50 years or aged ≥18 years with ≥1 risk factor for disease progression Key Exclusion Criterion Need for supplemental oxygen Interventions 250 mL of high-titer CCP (median titer 1:641) (n = 257) Saline (n = 254) Primary Endpoint Disease progression, defined as hospital admission, death, or seeking emergency or urgent care within 15 days of randomization Key Secondary Endpoints Severity of illness, as measured by OS All-cause mortality within 30 days Number of hospital-free days by Day 30	Participant Characteristics Median age 54 years; 46% men More patients with immunosuppression in CCP arm than in placebo arm (13% vs. 7%) More patients with ≥3 risk factors in CCP arm than in placebo arm (55% vs. 48%) Primary Outcomes No difference between arms in proportion with disease progression: 30% in CCP arm vs. 32% in placebo arm (risk difference 1.9%; 95% CrI, -6.0% to 9.8%) 25 patients (19 in CCP arm and 6 in placebo arm) required hospitalization during index visit. In a post hoc analysis that excluded these patients, disease progression occurred in 24% in CCP arm vs. 30% in placebo arm (risk difference 5.8%; 95% CrI, -1.9% to 13.6%). Secondary Outcomes All-cause mortality within 30 days: 5 (1.9%) in CCP arm vs. 1 (0.4%) in placebo arm No difference between arms in illness severity or mean number of hospital-free days	Key Limitations In the primary analysis, the number of patients who required hospital admission during the index visit was not balanced across arms. The CCP arm included more patients with multiple risk factors, including immunosuppression. Interpretation The use of high-titer CCP within 1 week of symptom onset did not prevent disease progression in outpatients with COVID-19 who were at high risk of severe disease.
CoV-Early: Double-Blind RCT of CCP in Nonhospitalized High-Risk Adults With COVID-19 in the Netherlands⁹
Key Inclusion Criteria Aged ≥70 years, aged ≥50 years with a comorbidity, or aged ≥18 years and severely immunocompromised Positive SARS-CoV-2 RT-PCR or antigen test result COVID-19 symptoms for ≤7 days Key Exclusion Criteria Life expectancy <28 days History of TRALI IgA deficiency Interventions 300 mL of CCP with minimum PRNT50 titer of 1:160 (n = 207) Non-SARS-CoV-2 plasma collected prior to pandemic (n = 209) Primary Endpoint Improvement based on 5-point OS by Day 28 Secondary Endpoints Percentage of hospital admissions Number of days of symptoms	Participant Characteristics Median age 60 years; 22% women Median 5 days of symptoms Median 1 comorbidity Median SpO₂ 97% at baseline 7.9% SARS-CoV-2 IgG antibody negative at baseline 2.9% fully vaccinated; 5.0% received 1 vaccine Primary Outcome Odds of receiving highest score on 5-point OS by Day 28: OR 0.86; 95% CrI, 0.59–1.22 in CCP arm Secondary Outcomes Percentage of hospital admissions: 10 patients (4.8%) in CCP arm vs. 18 patients (8.6%) in non-SARS-CoV-2 arm (aHR 0.61; 95% CI, 0.28–1.34) Number of days of symptoms: 13 days in CCP arm vs. 12 days in non-CCP arm (P = 0.99)	Key Limitations Study was discontinued after 421 of 690 planned participants were enrolled, resulting in decreased power. The CCP used was selected based on a PRNT50 assay and may not qualify as high-titer CCP per the current FDA EUA. Interpretation This trial did not demonstrate a benefit of CCP in nonhospitalized high-risk patients with COVID-19.
Retrospective Evaluation of CCP Antibody Levels and the Risk of Death From COVID-19 in the United States¹⁰
Key Inclusion Criteria Severe or life-threatening COVID-19 Patients for whom samples of transfused CCP were available for retrospective analysis of antibody titer Interventions High-titer CCP (n = 515), medium-titer CCP (n = 2,006), or low-titer CCP (n = 561), characterized retrospectively Primary Endpoint Mortality by Day 30 after CCP transfusion	Participant Characteristics 31% aged ≥70 years; 61% men; 48% White, 37% Hispanic/Latinx 61% in ICU; 33% on MV 51% received corticosteroids, 31% received RDV Primary Outcomes Mortality by Day 30 after transfusion: 22% in high-titer CCP arm vs. 27% in medium-titer CCP arm vs. 30% in low-titer CCP arm Lower risk of death in high-titer CCP arm than low-titer CCP arm (relative risk 0.75; 95% CI, 0.61–0.93) Lower mortality among patients not receiving MV before CCP transfusion (relative risk 0.66; 95% CI, 0.48–0.91) No difference in mortality between high-titer and low-titer arms among patients on MV before CCP transfusion (relative risk 1.02; 95% CI, 0.78–1.32)	Key Limitation Lack of untreated control arm Interpretation The study data are not sufficient to establish the efficacy or safety of CCP.
Key: ALC = absolute lymphocyte count; ASAP = as soon as possible; BMI = body mass index; CCP = COVID-19 convalescent plasma; CVD = cardiovascular disease; DM = diabetes mellitus; ECMO = extracorporeal membrane oxygenation; ED = emergency department; EUA = Emergency Use Authorization; Fc = fragment crystallizable; FDA = Food and Drug Administration; HFNC = high-flow nasal cannula; ICU = intensive care unit; Ig = immunoglobulin; IL = interleukin; LOS = length of stay; mAb = monoclonal antibody; MV = mechanical ventilation; NIV = noninvasive ventilation; OS = ordinal scale; the Panel = the COVID-19 Treatment Guidelines Panel; PaO₂/FiO₂ = ratio of arterial partial pressure of oxygen to fraction of inspired oxygen; PCR = polymerase chain reaction; PRNT50 = 50% plaque reduction neutralization test; RBD = receptor-binding domain; RCT = randomized controlled trial; RDV = remdesivir; RT-PCR = reverse transcription polymerase chain reaction; SAE = serious adverse event; SOC = standard of care; SpO₂ = oxygen saturation; TRALI = transfusion-related acute lung injury; VL = viral load

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