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.
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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.
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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 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 Interpretation - There was no benefit of CCP in hospitalized patients with COVID-19.
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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 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.
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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.
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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.
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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.
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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.
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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.
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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.
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