Table 4. Completed randomized controlled... | American Society of Hematology

Table 4.

Completed randomized controlled trials of CP and hyperimmune globulin therapy

Study	Country	Intervention(s)	Randomized per arm	Number analyzed	Patient population	Primary outcome	Neutralizing antibody titer	Viral variants considered in analyses^*
Prophylaxis
No completed studies
Outpatients (asymptomatic)
No completed studies
Outpatients (mild disease)
Libster et al⁸ NCT04479163	Argentina	250 mL CP on day 1	80	160	Age >74 or 65 to 74 and comorbidity Confirmed SARS-CoV-2 Mild illness, not requiring hospitalization ≤48 h from symptom onset	Development of severe disease—defined as RR ≥30 breaths/min or oxygen saturations <93% on air	Anti–S IgG SARS-CoV-2 (COVIDAR IgG) minimum titer 1:1000	No Recruited June-October 2020
Libster et al⁸ NCT04479163	Argentina	Saline (Placebo)	80	160			Anti–S IgG SARS-CoV-2 (COVIDAR IgG) minimum titer 1:1000	No Recruited June-October 2020
Inpatients (moderate disease (WHO 4 or 5)
Agarwal et al²⁵ CTRI/2020/04/024775	India	Two doses 200 mL CP, 24 h apart, preferably different donors	235	464	Adult Confirmed SARS-CoV-2 SpO₂ ≤93% and RR >24/min or PaO₂/FiO₂ 200-300 Excluded Critically ill (PaO₂/FiO₂ <200 or shock requiring vasopressors)	Composite all- cause mortality or progression to severe disease (PaO₂/FiO₂ <100) within day 28	NAb not used to select plasma, tested at end of study—63% of donors had NAb titer >1:20 with median titer 1:40	No Recruited April-July 2020
Agarwal et al²⁵ CTRI/2020/04/024775	India	Standard care	229	464				No Recruited April-July 2020
Simonovich et al²⁶ NCT04383535	Argentina	10-15 mL/kg Mini-pools (5-10 donors)	228	333	Adult Confirmed SARS-CoV-2, requiring hospitalization, pneumonia, plus SpO₂ <93% or PaO₂/FiO₂ <300 Excluded MV or NIV	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	Anti–S IgG SARS-CoV-2 (COVIDAR IgG) Median titer of 1:3200 (IQR, 1:800 to 1:3200)	No Recruited May-August 2020
Simonovich et al²⁶ NCT04383535	Argentina	Saline (placebo)	105	333				No Recruited May-August 2020
Avendaño-Solà et al^†27 NCT04345523	Spain	250-300 mL CCP on day 1	38	81	Adult Confirmed SARS-CoV-2 Radiological changes or clinical features plus SpO₂ <94%, <12-day symptom onset Excluded MV, high-flow O₂	Proportion of patients in category 5, 6, or 7 of 7-category COVID-19 ordinal scale at day 15	NAb not available to select plasma, all donation on subsequent testing had VMNT-ID50 > 1:80	No Recruited April-July 2020
Avendaño-Solà et al^†27 NCT04345523	Spain	Standard care	43	81				No Recruited April-July 2020
AlQahtani et al²⁸ NCT04356534	Bahrain	Two doses 200 mL CCP, 24 h apart	20	40	Age ≥21 Confirmed SARS-CoV-2 Pneumonia, plus SpO₂ <92% or PaO₂/FiO₂ <300 Excluded MV or MOF	Requirement for ventilation (NIV or MV)	NR	No Recruited April-June 2020
AlQahtani et al²⁸ NCT04356534	Bahrain	Standard care	20	40		Requirement for ventilation (NIV or MV)	NR	No Recruited April-June 2020
Inpatients (moderate or severe disease—WHO 4 to 7)
RECOVERY 2021²⁹ NCT04381936	United Kingdom	Two doses 275 mL CCP, 24 h apart	5795	11 558	Any age Suspected or confirmed COVID-19 Median 9 days symptom onset >90% requiring oxygen therapy (WHO score ≥5)	Clinical—all-cause mortality day 28	Minimum Euroimmun 6	Partially Used surrogate of randomized before/after December 2020 for WT/alpha variant Recruited May 2020 to January 2021
RECOVERY 2021²⁹ NCT04381936	United Kingdom	Standard care	5763	11 558		Clinical—all-cause mortality day 28	Minimum Euroimmun 6
CONCOR-1^†30 NCT04348656	Brazil, Canada, United States	500 mL CCP	614	921	Adult Confirmed SARS-CoV-2 Requiring oxygen therapy (WHO score ≥5) Excluded Symptoms >12 days MV	Intubation or death by day 30	Viral neutralizing antibodies titer >1:160 or antibodies against the RBD of the SARS-CoV-2 spike protein titer >1:100	No Recruited May 2020 to January 2021
CONCOR-1^†30 NCT04348656	Brazil, Canada, United States	Standard care	307	921		Intubation or death by day 30		No Recruited May 2020 to January 2021
O'Donnell et al³¹ NCT04359810	Brazil, United States	200-250 mL CCP	150	223	Adult Confirmed SARS-CoV-2 Requiring oxygen therapy (WHO score ≥5)	Clinical status at day 28 following randomization (7-point ordinal scale based on WHO)	Anti–SARS-CoV-2 antispike IgG antibody titer ≥1:400	No Recruited April-November 2020
O'Donnell et al³¹ NCT04359810	Brazil, United States	200-250 mL nonimmune plasma	73	223			Anti–SARS-CoV-2 antispike IgG antibody titer ≥1:400	No Recruited April-November 2020
CAPSID^†32 NCT04433910	Germany	CCP (250-325 mL) on days 1, 3, and 5	53	105	Age 18-75 years Confirmed SARS-CoV-2 RR >30 or requiring oxygen therapy (WHO score ≥5)	Composite end point of survival and no longer fulfilling criteria of severe COVID-19 (day 21)	Median PRNT50 neutralization titer 1:160 (IQR, 1:80 to 1:320)	No Recruited August-December 2020
CAPSID^†32 NCT04433910	Germany	Standard care, crossover to CCP at day 14 if not improved	52	105				No Recruited August-December 2020
Gharbharan et al³³ NCT04342182	The Netherlands	300 mL CCP on day 1	43	86	Adult Confirmed SARS-CoV-2 within 96 h Excluded Patients on MV >96 h	Mortality until discharge or maximum of 60 days	Minimum of PRNT50 titer of ≥1:80	No Recruited April-June 2020
Gharbharan et al³³ NCT04342182	The Netherlands	Standard care	43	86		Mortality until discharge or maximum of 60 days	Minimum of PRNT50 titer of ≥1:80	No Recruited April-June 2020
Ray et al^†34 CTRI/2020/05/025209	India	Two doses 200 mL CCP, 24 h apart	40	80	Adult Confirmed SARS-CoV-2 RR >30, SpO₂ <90%, PaO₂/FiO₂ <300 Excluded pregnant, MV	All-cause mortality at 30 days	Euroimmun ≥1.5
Ray et al^†34 CTRI/2020/05/025209	India	Standard care	40	80		All-cause mortality at 30 days	Euroimmun ≥1.5
Bennett-Guerrero et al³⁵ NCT04344535	United States	480 mL (2 units) CCP	59	74	Adult Confirmed SARS-CoV-2 Excluded Pregnant/breastfeeding	Number of days patient remained ventilator free (up to 28 days)	Ideally >1:320, but meeting minimum titer per FDA	No Recruited April-August 2020
Bennett-Guerrero et al³⁵ NCT04344535	United States	480 mL (2 units) nonimmune plasma	15	74	Adult Confirmed SARS-CoV-2 Excluded Pregnant/breastfeeding		Ideally >1:320, but meeting minimum titer per FDA	No Recruited April-August 2020
Pouladzadeh et al³⁶ IRCT20200310046736N1	Iran	500 mL CCP	30	60	Confirmed SARS-CoV-2 WHO score >4 Excluded Pregnant/breastfeeding Comorbidities (eg, heart, liver, kidney disease) Smokers	Improvement in the levels of cytokine storm indices	NR	No Recruited March-May 2020
Pouladzadeh et al³⁶ IRCT20200310046736N1	Iran	Standard care	30	60		Improvement in the levels of cytokine storm indices	NR	No Recruited March-May 2020
Hamdy Salman and Ail Mohamed³⁷ NCT04530370	Egypt	250 mL CP on day 1	15	30	Adult Confirmed SARS-CoV-2 2 or more of RR ≥24, SpO₂ ≤93%, PaO₂/FiO₂ <300, pulmonary infiltrates Excluded MOF, septic shock	At least 50% improvement of the severity of illness at any time during 5-day study period	NAb not used to select plasma	No Recruited June-August 2020
Hamdy Salman and Ail Mohamed³⁷ NCT04530370	Egypt	Saline (placebo)	15	30			NAb not used to select plasma	No Recruited June-August 2020
Bajpai et al^†38 NCT04346446	India	Two doses 250 mL CCP, 24 h apart	14	29	Age 18-65 years Confirmed SARS-CoV-2 Pneumonia, plus SpO₂ <93% or PaO₂/FiO₂ <300 Excluded Comorbidities (kidney, heart or liver disease, COPD)	Proportion of patients remaining free of mechanical ventilation day 7	Variable	No Recruited April-May 2020
Bajpai et al^†38 NCT04346446	India	Nonimmune plasma	15	29			Variable	No Recruited April-May 2020
Inpatients (severe disease—WHO 6 to 7)
REMAP-CAP^†39 NCT02735707	Australia, Canada, United Kingdom, United States	Two doses 275 mL CCP, 24 h apart	1084	2000	Adult Confirmed SARS-CoV-2 ≤48 h since admission to ICU	Organ support–free days at day 21	Minimum Euroimmun 6	No Recruited May 2020 to January 2021
REMAP-CAP^†39 NCT02735707	Australia, Canada, United Kingdom, United States	Standard care	916	2000	Adult Confirmed SARS-CoV-2 ≤48 h since admission to ICU	Organ support–free days at day 21	Minimum Euroimmun 6	No Recruited May 2020 to January 2021
Gonzalez et al^†40 NCT04381858	Mexico	Two doses 200 mL CCP, 24 h apart	130	90	Adult (16-90 years) Suspected or confirmed COVID-19 Severe respiratory failure	Duration of hospitalization All-cause mortality day 28	NAb not used to select plasma	No Recruited May-October 2020
Gonzalez et al^†40 NCT04381858	Mexico	IVIg 0.3 g/kg daily for 5 days	60	90		Duration of hospitalization All-cause mortality day 28	NAb not used to select plasma	No Recruited May-October 2020
Li et al⁴¹ ChiCTR2000029757	China	4-13 mL/kg of CP	52	103	Confirmed SARS-CoV-2 Excluded high-titer S-RBD–specific IgG (≥1:640)	Time to clinical improvement (patient discharge or reduction 2 points on 6-point disease severity scale)	Minimum of S-RBD–specific IgG of 1:640 (approximately equivalent to NAb of 1:40)	No Recruited February-April 2020
Li et al⁴¹ ChiCTR2000029757	China	Standard care	51	103				No Recruited February-April 2020

Study	Country	Intervention(s)	Randomized per arm	Number analyzed	Patient population	Primary outcome	Neutralizing antibody titer	Viral variants considered in analyses^*
Prophylaxis
No completed studies
Outpatients (asymptomatic)
No completed studies
Outpatients (mild disease)
Libster et al⁸ NCT04479163	Argentina	250 mL CP on day 1	80	160	Age >74 or 65 to 74 and comorbidity Confirmed SARS-CoV-2 Mild illness, not requiring hospitalization ≤48 h from symptom onset	Development of severe disease—defined as RR ≥30 breaths/min or oxygen saturations <93% on air	Anti–S IgG SARS-CoV-2 (COVIDAR IgG) minimum titer 1:1000	No Recruited June-October 2020
Libster et al⁸ NCT04479163	Argentina	Saline (Placebo)	80	160			Anti–S IgG SARS-CoV-2 (COVIDAR IgG) minimum titer 1:1000	No Recruited June-October 2020
Inpatients (moderate disease (WHO 4 or 5)
Agarwal et al²⁵ CTRI/2020/04/024775	India	Two doses 200 mL CP, 24 h apart, preferably different donors	235	464	Adult Confirmed SARS-CoV-2 SpO₂ ≤93% and RR >24/min or PaO₂/FiO₂ 200-300 Excluded Critically ill (PaO₂/FiO₂ <200 or shock requiring vasopressors)	Composite all- cause mortality or progression to severe disease (PaO₂/FiO₂ <100) within day 28	NAb not used to select plasma, tested at end of study—63% of donors had NAb titer >1:20 with median titer 1:40	No Recruited April-July 2020
Agarwal et al²⁵ CTRI/2020/04/024775	India	Standard care	229	464				No Recruited April-July 2020
Simonovich et al²⁶ NCT04383535	Argentina	10-15 mL/kg Mini-pools (5-10 donors)	228	333	Adult Confirmed SARS-CoV-2, requiring hospitalization, pneumonia, plus SpO₂ <93% or PaO₂/FiO₂ <300 Excluded MV or NIV	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	Anti–S IgG SARS-CoV-2 (COVIDAR IgG) Median titer of 1:3200 (IQR, 1:800 to 1:3200)	No Recruited May-August 2020
Simonovich et al²⁶ NCT04383535	Argentina	Saline (placebo)	105	333				No Recruited May-August 2020
Avendaño-Solà et al^†27 NCT04345523	Spain	250-300 mL CCP on day 1	38	81	Adult Confirmed SARS-CoV-2 Radiological changes or clinical features plus SpO₂ <94%, <12-day symptom onset Excluded MV, high-flow O₂	Proportion of patients in category 5, 6, or 7 of 7-category COVID-19 ordinal scale at day 15	NAb not available to select plasma, all donation on subsequent testing had VMNT-ID50 > 1:80	No Recruited April-July 2020
Avendaño-Solà et al^†27 NCT04345523	Spain	Standard care	43	81				No Recruited April-July 2020
AlQahtani et al²⁸ NCT04356534	Bahrain	Two doses 200 mL CCP, 24 h apart	20	40	Age ≥21 Confirmed SARS-CoV-2 Pneumonia, plus SpO₂ <92% or PaO₂/FiO₂ <300 Excluded MV or MOF	Requirement for ventilation (NIV or MV)	NR	No Recruited April-June 2020
AlQahtani et al²⁸ NCT04356534	Bahrain	Standard care	20	40		Requirement for ventilation (NIV or MV)	NR	No Recruited April-June 2020
Inpatients (moderate or severe disease—WHO 4 to 7)
RECOVERY 2021²⁹ NCT04381936	United Kingdom	Two doses 275 mL CCP, 24 h apart	5795	11 558	Any age Suspected or confirmed COVID-19 Median 9 days symptom onset >90% requiring oxygen therapy (WHO score ≥5)	Clinical—all-cause mortality day 28	Minimum Euroimmun 6	Partially Used surrogate of randomized before/after December 2020 for WT/alpha variant Recruited May 2020 to January 2021
RECOVERY 2021²⁹ NCT04381936	United Kingdom	Standard care	5763	11 558		Clinical—all-cause mortality day 28	Minimum Euroimmun 6
CONCOR-1^†30 NCT04348656	Brazil, Canada, United States	500 mL CCP	614	921	Adult Confirmed SARS-CoV-2 Requiring oxygen therapy (WHO score ≥5) Excluded Symptoms >12 days MV	Intubation or death by day 30	Viral neutralizing antibodies titer >1:160 or antibodies against the RBD of the SARS-CoV-2 spike protein titer >1:100	No Recruited May 2020 to January 2021
CONCOR-1^†30 NCT04348656	Brazil, Canada, United States	Standard care	307	921		Intubation or death by day 30		No Recruited May 2020 to January 2021
O'Donnell et al³¹ NCT04359810	Brazil, United States	200-250 mL CCP	150	223	Adult Confirmed SARS-CoV-2 Requiring oxygen therapy (WHO score ≥5)	Clinical status at day 28 following randomization (7-point ordinal scale based on WHO)	Anti–SARS-CoV-2 antispike IgG antibody titer ≥1:400	No Recruited April-November 2020
O'Donnell et al³¹ NCT04359810	Brazil, United States	200-250 mL nonimmune plasma	73	223			Anti–SARS-CoV-2 antispike IgG antibody titer ≥1:400	No Recruited April-November 2020
CAPSID^†32 NCT04433910	Germany	CCP (250-325 mL) on days 1, 3, and 5	53	105	Age 18-75 years Confirmed SARS-CoV-2 RR >30 or requiring oxygen therapy (WHO score ≥5)	Composite end point of survival and no longer fulfilling criteria of severe COVID-19 (day 21)	Median PRNT50 neutralization titer 1:160 (IQR, 1:80 to 1:320)	No Recruited August-December 2020
CAPSID^†32 NCT04433910	Germany	Standard care, crossover to CCP at day 14 if not improved	52	105				No Recruited August-December 2020
Gharbharan et al³³ NCT04342182	The Netherlands	300 mL CCP on day 1	43	86	Adult Confirmed SARS-CoV-2 within 96 h Excluded Patients on MV >96 h	Mortality until discharge or maximum of 60 days	Minimum of PRNT50 titer of ≥1:80	No Recruited April-June 2020
Gharbharan et al³³ NCT04342182	The Netherlands	Standard care	43	86		Mortality until discharge or maximum of 60 days	Minimum of PRNT50 titer of ≥1:80	No Recruited April-June 2020
Ray et al^†34 CTRI/2020/05/025209	India	Two doses 200 mL CCP, 24 h apart	40	80	Adult Confirmed SARS-CoV-2 RR >30, SpO₂ <90%, PaO₂/FiO₂ <300 Excluded pregnant, MV	All-cause mortality at 30 days	Euroimmun ≥1.5
Ray et al^†34 CTRI/2020/05/025209	India	Standard care	40	80		All-cause mortality at 30 days	Euroimmun ≥1.5
Bennett-Guerrero et al³⁵ NCT04344535	United States	480 mL (2 units) CCP	59	74	Adult Confirmed SARS-CoV-2 Excluded Pregnant/breastfeeding	Number of days patient remained ventilator free (up to 28 days)	Ideally >1:320, but meeting minimum titer per FDA	No Recruited April-August 2020
Bennett-Guerrero et al³⁵ NCT04344535	United States	480 mL (2 units) nonimmune plasma	15	74	Adult Confirmed SARS-CoV-2 Excluded Pregnant/breastfeeding		Ideally >1:320, but meeting minimum titer per FDA	No Recruited April-August 2020
Pouladzadeh et al³⁶ IRCT20200310046736N1	Iran	500 mL CCP	30	60	Confirmed SARS-CoV-2 WHO score >4 Excluded Pregnant/breastfeeding Comorbidities (eg, heart, liver, kidney disease) Smokers	Improvement in the levels of cytokine storm indices	NR	No Recruited March-May 2020
Pouladzadeh et al³⁶ IRCT20200310046736N1	Iran	Standard care	30	60		Improvement in the levels of cytokine storm indices	NR	No Recruited March-May 2020
Hamdy Salman and Ail Mohamed³⁷ NCT04530370	Egypt	250 mL CP on day 1	15	30	Adult Confirmed SARS-CoV-2 2 or more of RR ≥24, SpO₂ ≤93%, PaO₂/FiO₂ <300, pulmonary infiltrates Excluded MOF, septic shock	At least 50% improvement of the severity of illness at any time during 5-day study period	NAb not used to select plasma	No Recruited June-August 2020
Hamdy Salman and Ail Mohamed³⁷ NCT04530370	Egypt	Saline (placebo)	15	30			NAb not used to select plasma	No Recruited June-August 2020
Bajpai et al^†38 NCT04346446	India	Two doses 250 mL CCP, 24 h apart	14	29	Age 18-65 years Confirmed SARS-CoV-2 Pneumonia, plus SpO₂ <93% or PaO₂/FiO₂ <300 Excluded Comorbidities (kidney, heart or liver disease, COPD)	Proportion of patients remaining free of mechanical ventilation day 7	Variable	No Recruited April-May 2020
Bajpai et al^†38 NCT04346446	India	Nonimmune plasma	15	29			Variable	No Recruited April-May 2020
Inpatients (severe disease—WHO 6 to 7)
REMAP-CAP^†39 NCT02735707	Australia, Canada, United Kingdom, United States	Two doses 275 mL CCP, 24 h apart	1084	2000	Adult Confirmed SARS-CoV-2 ≤48 h since admission to ICU	Organ support–free days at day 21	Minimum Euroimmun 6	No Recruited May 2020 to January 2021
REMAP-CAP^†39 NCT02735707	Australia, Canada, United Kingdom, United States	Standard care	916	2000	Adult Confirmed SARS-CoV-2 ≤48 h since admission to ICU	Organ support–free days at day 21	Minimum Euroimmun 6	No Recruited May 2020 to January 2021
Gonzalez et al^†40 NCT04381858	Mexico	Two doses 200 mL CCP, 24 h apart	130	90	Adult (16-90 years) Suspected or confirmed COVID-19 Severe respiratory failure	Duration of hospitalization All-cause mortality day 28	NAb not used to select plasma	No Recruited May-October 2020
Gonzalez et al^†40 NCT04381858	Mexico	IVIg 0.3 g/kg daily for 5 days	60	90		Duration of hospitalization All-cause mortality day 28	NAb not used to select plasma	No Recruited May-October 2020
Li et al⁴¹ ChiCTR2000029757	China	4-13 mL/kg of CP	52	103	Confirmed SARS-CoV-2 Excluded high-titer S-RBD–specific IgG (≥1:640)	Time to clinical improvement (patient discharge or reduction 2 points on 6-point disease severity scale)	Minimum of S-RBD–specific IgG of 1:640 (approximately equivalent to NAb of 1:40)	No Recruited February-April 2020
Li et al⁴¹ ChiCTR2000029757	China	Standard care	51	103				No Recruited February-April 2020

Was the type of virus (e.g., alpha, beta, gamma, delta, etc.) detected at baseline taken into consideration as a subgroup analysis?

^†

Pre–peer review.

CCP, COVID-19 convalescent plasma; COPD, chronic obstructive pulmonary disease; FDA, Food and Drug Administration; FiO₂, fraction of inspired oxygen; ICU, intensive care unit; IQR, interquartile range; IVIg, intravenous immunoglobulin; MOF, multiorgan failure; MV, mechanical ventilation; NAb, neutralizing antibody; NIV, non-invasive ventilation; PaO₂, partial pressure of oxygen; PRNT50, 50% reduction in plaque count using the plaque reduction neutralization test; RR, respiratory rate; SpO₂, oxygen saturation; VMNT, virus microneutralization test; WT, wild type.

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