Table 2.

Summary of reported RCTs to date

StudyCountryNo./ PlannedStudy designParticipants*Median time from symptom onset to randomizationIntervention†ControlNAb assayNAb titer in donor plasmaPrimary outcome
Li et al22  China 103/200 Open label Laboratory confirmed SARS-CoV-2, severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, requiring MV); excluded patients with high titer S-RBD–specific IgG (≥1:640) 27 d in CP and 30 in control 4-13 mL/kg of CP Standard care S-RBD–specific IgG antibody titer Minimum of S-RBD–specific IgG of 1:640 (approximately equivalent to NAb of 1:40) Time to clinical improvement (patient discharge or reduction 2 points on 6-point disease severity scale) 
Rasheed et al23  Iraq 49/not stated Open label Laboratory confirmed SARS-CoV-2, critically ill with SpO2 <90%, receiving O2 or MV 21 d in CP and 28 in control 400 mL of CP on day 1 Standard care SARS-CoV-2 IgG (semi-quantitative) and IgM (qualitative) 52% “moderately” positive and 48% “strongly” positive Time to recovery from critical illness (clinical improvement permitting discharge from respiratory care unit to ward) 
Agarwal et al24  India 464/464 Open label Laboratory confirmed SARS-CoV-2, moderately ill with either SpO2 ≤93% and RR > 24/min or PaO2/FiO2 200-300; excluded critically ill (PaO2/FiO2 <200 or shock requiring vasopressors) 8 d in CP and 8 in control Two doses 200 mL of CP, 24 h apart, preferably different donors Standard care Micro-neutralization test NAb not used to select plasma, tested at end of study: 63% of donors had NAb titer >1:20 with median titer 1:40 Composite all-cause mortality or progression to severe disease (PaO2/FiO2 <100) within day 28 
Gharbharan et al25  The Netherlands 86/426 Open label Laboratory confirmed SARS-CoV-2 within 96 h; excluded patients on MV >96 h 9 d in CP and 11 in control 300 mL of CP on day 1 Standard care SARS-CoV-2 PRNT Minimum of PRNT50 titer of ≥1:80 Mortality until discharge or maximum of 60 d 
Avendano-Sola26  Spain 81/278 Open label Laboratory confirmed SARS-CoV-2, radiological changes or clinical features plus SpO2 <94%, <12 d onset Excluded: MV, high flow O2 8 d in CP and control 250-300 mL of CP on day 1 Standard care VMNT pseudovirus neutralizing ID50 assay NAb not available to select plasma, all donation on subsequent testing had VMNT-ID50 >1:80 Proportion of patients in category 5, 6, 7 of 7-category COVID-19 ordinal scale at day 15 
Libster et al, NEJM27  Argentina 160/210 Double-blind Laboratory confirmed SARS-CoV-2, mild illness, not requiring hospitalization, age >74 or 65 to 74 and comorbidity, ≤48 h from symptom onset <3 d 250 mL CP on day 1 Saline anti–S IgG SARS-CoV-2 (COVIDAR IgG) Minimum titer 1:1000 Development of severe disease—defined as RR ≥ 30 breaths/min or oxygen saturations <93% on air 
Simonovich et al, NEJM28  Simonovich et al, NEJM 333/333 Double-blind Laboratory confirmed SARS-CoV-2, requiring hospitalization, age ≥18, pneumonia, plus SpO2 <93% or or PaO2/FiO2 <300 Excluded: MV or NIV 8 d in CP and control 10 to 15 mL/kg mini-pools (5 to 10 donors) Saline anti–S IgG SARS-CoV-2 (COVIDAR IgG) IgG median titer of 1:3200 (IQR 1:800 to 1:3200 Clinical status at day 30 ordinal categories

  1. - death

  2. - invasive ventilatory support

  3. - hospitalized with supplemental oxygen requirements

  4. - hospitalized without supplemental oxygen requirements

  5. - discharged without full return of baseline physical function

  6. - discharged with full return of baseline physical function

 
Al Qhatani et al, preprint29  Bahrain 40/40 Open-label Laboratory confirmed SARS-CoV-2, requiring hospitalization, age ≥21, pneumonia, plus SpO2 <92% or PaO2/FiO2 <300Excluded: MV or MOF Not reported Two doses 200 mL CP, 24 h apart Standard care Lansionbio COVID-19 IgM/IgG Not reported Requirement for ventilation 
Bajpai et al, preprint30  India 29/20 Open-label Laboratory confirmed SARS-CoV-2, requiring hospitalization, age 18 to 65, pneumonia, plus SpO2 <93% or PaO2/FiO2 <300 Excluded: comorbidities (kidney, heart or liver disease, COPD) Not reported Two doses 250 mL CP, 24 h apart Nonimmune plasma SARS-CoV-2 Surrogate Virus Neutralization Test (sVNT) Kit (Genscript, USA) Variable Proportion of patients remaining free of mechanical ventilation day 7 
Balcells et al, preprint31  Chile 58/58 Open-label Suspected or confirmed SARS-CoV-2, requiring hospitalization, age ≥18, ≤7 d from symptom onset, CALL score ≥9 points at enrollment Excluded: PaO2/FiO2 <200, pregnant 5 d in CP and 6 days in control Two doses 200 mL CP, 24 h apart Delayed CP if clinical deterioration (PaO2/FiO2 <200 OR hospitalized on day 7) anti-SARS-CoV-2 (S1) IgG titers IgG ≥ 1:400 Composite of mechanical ventilation, hospitalization for >14 d or death during hospitalization 
Hamdy Salman et al, EJA32  Egypt 30/30 Double-blind Laboratory confirmed SARS-CoV-2, requiring hospitalization, age ≥18, 2 or more of RR ≥ 24, SpO2 ≤93%, PaO2/FiO2 <300, pulmonary infiltrates Excluded: MOF, septic shock 30 d in CP and control 250 mL CP on day 1 Saline Neutralizing antibody, Cusabio, ELISA Kit catalog number CSBEL23253HU NAb not used to select plasma At least 50% improvement of the severity of illness at any time during 5 d study period 
Ray et al, preprint33  India 80/80 Open label Laboratory confirmed SARS-CoV-2, requiring hospitalization, age ≥18, RR > 30, SpO2 <90%, PaO2/FiO2 <300 Excluded: pregnant, MV Not reported Two doses 200 mL CP, 24 h apart Standard care anti-SARS-CoV2 spike IgG (Euroimmun) Euroimmun ≥1.5 All-cause mortality at 30 d 
StudyCountryNo./ PlannedStudy designParticipants*Median time from symptom onset to randomizationIntervention†ControlNAb assayNAb titer in donor plasmaPrimary outcome
Li et al22  China 103/200 Open label Laboratory confirmed SARS-CoV-2, severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, requiring MV); excluded patients with high titer S-RBD–specific IgG (≥1:640) 27 d in CP and 30 in control 4-13 mL/kg of CP Standard care S-RBD–specific IgG antibody titer Minimum of S-RBD–specific IgG of 1:640 (approximately equivalent to NAb of 1:40) Time to clinical improvement (patient discharge or reduction 2 points on 6-point disease severity scale) 
Rasheed et al23  Iraq 49/not stated Open label Laboratory confirmed SARS-CoV-2, critically ill with SpO2 <90%, receiving O2 or MV 21 d in CP and 28 in control 400 mL of CP on day 1 Standard care SARS-CoV-2 IgG (semi-quantitative) and IgM (qualitative) 52% “moderately” positive and 48% “strongly” positive Time to recovery from critical illness (clinical improvement permitting discharge from respiratory care unit to ward) 
Agarwal et al24  India 464/464 Open label Laboratory confirmed SARS-CoV-2, moderately ill with either SpO2 ≤93% and RR > 24/min or PaO2/FiO2 200-300; excluded critically ill (PaO2/FiO2 <200 or shock requiring vasopressors) 8 d in CP and 8 in control Two doses 200 mL of CP, 24 h apart, preferably different donors Standard care Micro-neutralization test NAb not used to select plasma, tested at end of study: 63% of donors had NAb titer >1:20 with median titer 1:40 Composite all-cause mortality or progression to severe disease (PaO2/FiO2 <100) within day 28 
Gharbharan et al25  The Netherlands 86/426 Open label Laboratory confirmed SARS-CoV-2 within 96 h; excluded patients on MV >96 h 9 d in CP and 11 in control 300 mL of CP on day 1 Standard care SARS-CoV-2 PRNT Minimum of PRNT50 titer of ≥1:80 Mortality until discharge or maximum of 60 d 
Avendano-Sola26  Spain 81/278 Open label Laboratory confirmed SARS-CoV-2, radiological changes or clinical features plus SpO2 <94%, <12 d onset Excluded: MV, high flow O2 8 d in CP and control 250-300 mL of CP on day 1 Standard care VMNT pseudovirus neutralizing ID50 assay NAb not available to select plasma, all donation on subsequent testing had VMNT-ID50 >1:80 Proportion of patients in category 5, 6, 7 of 7-category COVID-19 ordinal scale at day 15 
Libster et al, NEJM27  Argentina 160/210 Double-blind Laboratory confirmed SARS-CoV-2, mild illness, not requiring hospitalization, age >74 or 65 to 74 and comorbidity, ≤48 h from symptom onset <3 d 250 mL CP on day 1 Saline anti–S IgG SARS-CoV-2 (COVIDAR IgG) Minimum titer 1:1000 Development of severe disease—defined as RR ≥ 30 breaths/min or oxygen saturations <93% on air 
Simonovich et al, NEJM28  Simonovich et al, NEJM 333/333 Double-blind Laboratory confirmed SARS-CoV-2, requiring hospitalization, age ≥18, pneumonia, plus SpO2 <93% or or PaO2/FiO2 <300 Excluded: MV or NIV 8 d in CP and control 10 to 15 mL/kg mini-pools (5 to 10 donors) Saline anti–S IgG SARS-CoV-2 (COVIDAR IgG) IgG median titer of 1:3200 (IQR 1:800 to 1:3200 Clinical status at day 30 ordinal categories

  1. - death

  2. - invasive ventilatory support

  3. - hospitalized with supplemental oxygen requirements

  4. - hospitalized without supplemental oxygen requirements

  5. - discharged without full return of baseline physical function

  6. - discharged with full return of baseline physical function

 
Al Qhatani et al, preprint29  Bahrain 40/40 Open-label Laboratory confirmed SARS-CoV-2, requiring hospitalization, age ≥21, pneumonia, plus SpO2 <92% or PaO2/FiO2 <300Excluded: MV or MOF Not reported Two doses 200 mL CP, 24 h apart Standard care Lansionbio COVID-19 IgM/IgG Not reported Requirement for ventilation 
Bajpai et al, preprint30  India 29/20 Open-label Laboratory confirmed SARS-CoV-2, requiring hospitalization, age 18 to 65, pneumonia, plus SpO2 <93% or PaO2/FiO2 <300 Excluded: comorbidities (kidney, heart or liver disease, COPD) Not reported Two doses 250 mL CP, 24 h apart Nonimmune plasma SARS-CoV-2 Surrogate Virus Neutralization Test (sVNT) Kit (Genscript, USA) Variable Proportion of patients remaining free of mechanical ventilation day 7 
Balcells et al, preprint31  Chile 58/58 Open-label Suspected or confirmed SARS-CoV-2, requiring hospitalization, age ≥18, ≤7 d from symptom onset, CALL score ≥9 points at enrollment Excluded: PaO2/FiO2 <200, pregnant 5 d in CP and 6 days in control Two doses 200 mL CP, 24 h apart Delayed CP if clinical deterioration (PaO2/FiO2 <200 OR hospitalized on day 7) anti-SARS-CoV-2 (S1) IgG titers IgG ≥ 1:400 Composite of mechanical ventilation, hospitalization for >14 d or death during hospitalization 
Hamdy Salman et al, EJA32  Egypt 30/30 Double-blind Laboratory confirmed SARS-CoV-2, requiring hospitalization, age ≥18, 2 or more of RR ≥ 24, SpO2 ≤93%, PaO2/FiO2 <300, pulmonary infiltrates Excluded: MOF, septic shock 30 d in CP and control 250 mL CP on day 1 Saline Neutralizing antibody, Cusabio, ELISA Kit catalog number CSBEL23253HU NAb not used to select plasma At least 50% improvement of the severity of illness at any time during 5 d study period 
Ray et al, preprint33  India 80/80 Open label Laboratory confirmed SARS-CoV-2, requiring hospitalization, age ≥18, RR > 30, SpO2 <90%, PaO2/FiO2 <300 Excluded: pregnant, MV Not reported Two doses 200 mL CP, 24 h apart Standard care anti-SARS-CoV2 spike IgG (Euroimmun) Euroimmun ≥1.5 All-cause mortality at 30 d 

ID50, 50% inhibitory dose; MOF, multiorgan failure; MV, mechanical ventilation; NIV, noninvasive ventilation; PRNT, plaque reduction neutralization test; RR, respiratory rate; S-RBD–specific IgG, S protein–receptor-binding domain-specific IgG; VMNT, virus microneutralization test.

*

Only hospitalized patients have been included in studies reported to date.

†

Comparator was standard of care for all studies.

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