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

Last Updated: December 1, 2022

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 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

  • Organ support-free days by Day 21 (ordinal outcome)

Key Secondary Endpoints

  • In-hospital mortality
  • Mortality by Day 28 and Day 90
  • 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 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 COVID-19 patients 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

  • Approximately 275 mL per unit of CCP with IgG against SARS-CoV-2 spike protein, with sample to cutoff ratio ≥6.0; administered as 2 units of high-titer CCP (first unit ASAP after randomization, second unit ≥12 hours later the next day) (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:
    • Mortality: 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.
CSSC-004: RCT of Early Treatment With High-Titer CCP in Outpatients With COVID-19 in the United States4

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 time from symptom onset to transfusion: 6 days

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 Spain5 

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: 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 Argentina6

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 States7 

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 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 the 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 slightly 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 Netherlands8

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
  • ≤7 days of symptoms

Key Exclusion Criteria

  • Life expectancy <28 days
  • History of transfusion-related acute lung injury
  • IgA deficiency

Interventions

  • 300 mL 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 being at 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: 4.8% (10 patients) in CCP arm vs. 8.6% (18 patients) in non-SARS-CoV-2 arm (aHR 0.61; 95% CI, 0.28–1.34)
  • Number of days of symptoms: no difference between arms (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 per the current FDA EUA for CCP.

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 States9

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 at 30 days 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 at 30 days 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)
  • Among patients on MV before CCP transfusion, no difference in mortality between high-titer and low-titer arms (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.

References

  1. Writing Committee for the REMAP-CAP Investigators, Estcourt LJ, Turgeon AF, et al. Effect of convalescent plasma on organ support-free days in critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2021;326(17):1690-1702. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34606578.
  2. Bégin P, Callum J, Jamula E, et al. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial. Nat Med. 2021;27(11):2012-2024. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34504336.
  3. RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet. 2021;397(10289):2049-2059. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34000257.
  4. Sullivan DJ, Gebo KA, Shoham S, et al. Early outpatient treatment for COVID-19 with convalescent plasma. N Engl J Med. 2022;386(18):1700-1711. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35353960.
  5. Alemany A, Millat-Martinez P, Corbacho-Monné M, et al. High-titre methylene blue-treated convalescent plasma as an early treatment for outpatients with COVID-19: a randomised, placebo-controlled trial. Lancet Respir Med. 2022;10(3):278-288. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35150610.
  6. Libster R, Pérez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe COVID-19 in older adults. N Engl J Med. 2021;384(7):610-618. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33406353.
  7. Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early convalescent plasma for high-risk outpatients with COVID-19. N Engl J Med. 2021;385(21):1951-1960. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34407339.
  8. Gharbharan A, Jordans C, Zwaginga L, et al. Outpatient convalescent plasma therapy for high-risk patients with early COVID-19: a randomized placebo-controlled trial. Clin Microbiol Infect. 2022;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36007870.
  9. Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent plasma antibody levels and the risk of death from COVID-19. N Engl J Med. 2021;384(11):1015-1027. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33523609.