Convalescent plasma therapy in COVID-19 critically ill patients during advanced phases of clinical trials and their preliminary results

Lionel Fernel Gamarra Corresponding author: Lionel Fernel Gamarra, Avenida Albert Einstein, 627/701 – Morumbi Zip code: 05652-000 – São Paulo, SP, Brazil. Phone: (55 11) 3747-0243 E-mail: lionelgamarra7@gmail.com

Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.

http://orcid.org/0000-0002-3910-0047

Corresponding author: Lionel Fernel Gamarra, Avenida Albert Einstein, 627/701 – Morumbi Zip code: 05652-000 – São Paulo, SP, Brazil. Phone: (55 11) 3747-0243 E-mail: lionelgamarra7@gmail.com

Authors’ Collaboration

The data extraction, collection, and risk of bias assessment was performed by six authors (Fernando Anselmo de Oliveira, Mariana Penteado Nucci, Gabriel Nery de Albuquerque Rego, Arielly da Hora Alves, Leopoldo Penteado Nucci and , Javier Bustamante Mamani) organized in pairs, independently and randomly reviewed and evaluated the information recorded from the clinical trial protocols and studies identified by the search strategy in the databases mentioned above. Discrepancies in study selection and data extraction between the authors were discussed with two authors (Luciana Cavalheiro Marti and Lionel Fernel Gamarra) and resolved. The final inclusion of studies in this review was agreed among all authors.

Identity number	Phase	Patient features	Intervention by arm	CP dose (day)	Age range (years)	Start date	Completion date	Progress (%)	Recruitment status
NCT02735707⁽¹⁰10. ClinicalTrials.gov. Randomized, embedded, multifactorial adaptive platform trial for community- acquired pneumonia (REMAP-CAP). Bethesda: National Library of Medicine; 2016 [cited 2020 Oct 28]. [First posted Apr 13, 2016; Last update posted Oct 12, 2020]. Available from: https://ClinicalTrials.gov/show/NCT02735707 https://ClinicalTrials.gov/show/NCT02735... ⁾	IV	Severe acute respiratory illness and severe community acquired pneumonia	Corticosteroid versus antibiotics versus macrolide versus Influenza antiviral versus LPV/Rit versus HydChl versus IFN-β1a versus Anak versus Tmab versus Smab versus Vit C versus heparin versus simvastatin versus CP versus ST	1 or 2 units within 48 hours	>18	4/11/16	12/1/23	58	Recruitingz
NCT04391101⁽¹¹11. ClinicalTrials.gov. Convalescent plasma for patients with COVID-19: a pilot study. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 2, 2020; Last update posted Aug 17, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04332380 https://ClinicalTrials.gov/show/NCT04332... ⁾	III	Severe patients treated in ICU	CP associated with ST versus ST	400-500mL	>18	6/1/20	12/1/21	19.2	Not yet recruiting
NCT04372979⁽¹²12. ClinicalTrials.gov. Efficacy of convalescent plasma therapy in the early care of COVID-19 patients (PLASCOSSA). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 4, 2020; Last update posted Oct 26, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04372979 https://ClinicalTrials.gov/show/NCT04372... ⁾	III	Early care of hospitalized patients	CP associated with ST versus SP associated with ST	200-230mL	18-80	5/1/20	5/1/21	37.3	Not yet recruiting
NCT04418518⁽¹³13. ClinicalTrials.gov. A trial of CONvalescent plasma for hospitalized adults with acute COVID-19 respiratory illness (CONCOR-1). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted June 5, 2020; Last update posted July 7, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04418518 https://ClinicalTrials.gov/show/NCT04418... ⁾	III	Early care for patients hospitalized	CP associated with ST versus ST	500mL of single-donor or 2 units of 250mL from 1-2 donations	18-70	6/24/20	12/1/21	15.6	Recruiting
NCT04355767⁽¹⁴14. ClinicalTrials.gov. Convalescent plasma in outpatients with COVID-19 (C3PO). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 21, 2020; Last update posted Sep 29, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04355767 https://ClinicalTrials.gov/show/NCT04355... ⁾	III	Severe/critical hospitalized patients	CP (antibodies titers ≥1:160) versus placebo	CP: 1-unit versus placebo: saline with multivitamin	>18	8/11/20	12/1/22	4.0	Not yet recruiting
NCT04432103⁽¹⁵15. ClinicalTrials.gov. Treatment of severe and critical COVID-19 pneumonia with convalescent plasma. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted June 16, 2020; Last update posted June 17, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04432103 https://ClinicalTrials.gov/show/NCT04432... ⁾	III	Severe/critical hospitalized patients	CP from IgG (severe patients versus critical patients) associated with ST	NR	>19	6/19/20	9/30/20	84.5	Not yet recruiting
NCT04348656⁽¹⁶16. ClinicalTrials.gov. CONvalescent plasma for hospitalized adults with COVID-19 respiratory illness (CONCOR-1). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 16, 2020; Last update posted Oct 20, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04348656 https://ClinicalTrials.gov/show/NCT04348... ⁾	III	Early care for patients hospitalized	CP versus ST	500mL of single-donor or 2 units of 250mL from 1-2 donations	>20	5/14/20	12/31/20	53.2	Recruiting
NCT04425915⁽¹⁷17. ClinicalTrials.gov. Efficacy of convalescent plasma therapy in patients with COVID-19. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted June 11, 2020; Last update posted Sep 3, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04425915 https://ClinicalTrials.gov/show/NCT04425... ⁾	III	Severe/critical hospitalized patients	CP associated with ST versus ST	2 doses of 250mL on consecutive day started by day 3 of symptom onset	>21	6/14/20	5/30/21	26.3	Recruiting
NCT04362176⁽¹⁸18. ClinicalTrials.gov. Passive immunity trial of the nation for COVID-19 (PassItOnII). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 24, 2020; Last update posted Aug 27, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04362176 https://ClinicalTrials.gov/show/NCT04362... ⁾	III	Patients hospitalized or in ICU	Pathogen reduced CP versus placebo	CP: 500mL within 12 hours (day 0) versus placebo: 250mL of Lactate Ringers associated with multivitamins (day 1)	>22	4/24/20	4/1/21	41.8	Recruiting
NCT04381858⁽¹⁹19. ClinicalTrials.gov. Convalescent plasma vs human immunoglobulin to treat COVID-19 pneumonia. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 11, 2020; Last update posted May 12, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04381858 https://ClinicalTrials.gov/show/NCT04381... ⁾	III	Severe respiratory failure with invasive mechanical ventilation	CP (antibodies titers >1:164) versus HIg	CP: 400mL (2 units) versus HIg: 0.3g/kg/day (5 doses)	16-18	5/6/20	9/30/20	89.1	Recruiting
NCT04361253⁽²⁰20. ClinicalTrials.gov. Evaluation of SARS-CoV-2 (COVID-19) antibody-containing plasma therapy (ESCAPE). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 24, 2020; Last update posted May 18, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04361253 https://ClinicalTrials.gov/show/NCT04361... ⁾	III	Patients hospitalized	CP (high-titer) versus SP (FFP or FP 24)	HT-CP: 2 doses of 250mL of single donor within 24 hours; FFP: 2 units of 200-275mL	>1	04/30/20	12/1/21	23.6	Recruiting
NCT04376034⁽²¹21. ClinicalTrials.gov. Convalescent plasma collection and treatment in pediatrics and adults. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 6, 2020; Last update posted May 6, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04376034 https://ClinicalTrials.gov/show/NCT04376... ⁾	III	Mild, moderate and severe/critical severity	CP associated with ST versus ST	Adult: 200 to 250mL; children: 10mL/kg; 2 units severe patients or critical condition	>30 days	4/16/20	3/30/21	43.4	Recruiting
NCT04483960⁽²²22. ClinicalTrials.gov. Australasian COVID-19 trial (ASCOT) [Internet]. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted July 23, 2020; Last update posted July 23, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04483960 https://ClinicalTrials.gov/show/NCT04483... ⁾	III	No severe patients	LPV/Rit versus HydChl versus CP	1 unit on day 1 and day 2	>18	7/21/20	6/12/22	8.0	Recruiting
NCT0434528 9⁽²³23. ClinicalTrials.gov. Efficacy and safety of novel treatment options for adults with COVID-19 pneumonia. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 14, 2020; Last update posted July 31, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04345289 https://ClinicalTrials.gov/show/NCT04345... ⁾	III	Mild, moderate and severe/critical hospitalized patients	CP associated with ST (Smab versus baricitinib versus HydChl) versus ST associated with injective placebo	CP: (twice 300mL) and single dose of 600mL; placebo: (twice 300mL) and single dose of 600mL IV saline oral placebo: three times/day (7 days)	>18	5/1/20	6/15/21	33.2	Recruiting
NCT04342182⁽²⁴24. ClinicalTrials.gov. Convalescent plasma as therapy for Covid-19 severe SARS-CoV-2 disease (CONCOVID Study). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 10, 2020; Last update posted May 18, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04342182 https://ClinicalTrials.gov/show/NCT04342... ⁾	II-III	Hospitalized patients	CP associated with ST versus ST	300mL (according to the Erasmus MC KIS protocol)	>18	4/8/20	7/1/20	100	Recruiting
NCT04388410⁽²⁵25. ClinicalTrials.gov. Safety and efficacy of convalescent plasma transfusion for patients with COVID-19 (EPCOvid-1). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 14, 2020; Last update posted Aug 26, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04388410 https://ClinicalTrials.gov/show/NCT04388... ⁾	II-III	Hospitalized patients with severe disease or at risk for severe disease.	CP versus placebo	CP: 2 units of 200mL within 24-72 hours); placebo: 200mL of saline	>18	8/25/20	12/31/20	15.6	Not yet recruiting
NCT04374526⁽²⁶26. ClinicalTrials.gov. Early transfusIon of convalescent plasma in elderly COVID-19 patients. to prevent disease progression. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 5, 2020; Last update posted Oct 6, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04374526 https://ClinicalTrials.gov/show/NCT04374... ⁾	II-III	Hospitalized patients	CP associated with ST versus ST	200mL/day for 3 days	>65	5/27/20	6/30/21	27.6	Recruiting
NCT04384588⁽²⁷27. ClinicalTrials.gov. COVID19-convalescent plasma for treating patients with active symptomatic COVID 19 infection (FALP-COVID). Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 12, 2020; Last update posted May 12, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04384588 https://ClinicalTrials.gov/show/NCT04384... ⁾	II-III	Oncological and non-oncological patients with severe disease	CP associated with ST versus ST	1 or more units	>15	4/7/20	4/6/21	44.0	Recruiting
NCT04425837⁽²⁸28. ClinicalTrials.gov. Effectiveness and safety of convalescent plasma in patients with high-risk COVID-19. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted June 11, 2020; Last update posted June 11, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04425837 https://ClinicalTrials.gov/show/NCT04425... ⁾	II-III	Hospitalized patients at high risk of severe disease or in ICU	CP (antibodies titers of ≥1:160) associated with ST versus ST	2 doses of 200mL in a day	>18	7/1/20	2/1/21	34.9	Not yet recruiting
NCT04395170⁽²⁹29. ClinicalTrials.gov. Convalescent plasma (PC) and human intravenous anti-COVID-19 immunoglobulin (IV anti COVID-19 IgG) in patients hospitalized for COVID-19. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28] [First posted May 20, 2020; Last update posted July 10, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04395170 https://ClinicalTrials.gov/show/NCT04395... ⁾	II-III	Early care for patients hospitalized	CP associated with ST versus anti-COVID-19 HIg versus ST	CP: 200-250mL (day 1 and 3); 10% IgG solution: 50mL (patient ≥50kg); 1 mL/Kg (patient <50Kg), on days 1 and 3	>18	9/1/20	6/1/21	4.8	Not yet recruiting
NCT04380935⁽³⁰30. ClinicalTrials.gov. Effectiveness and safety of convalescent plasma therapy on COVID-19 patients with acute respiratory distress syndrome. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28] [First posted May 8, 2020; Last update posted Aug 18, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04380935 https://ClinicalTrials.gov/show/NCT04380... ⁾	II-III	Hospitalized patients in ICU (using mechanical ventilation)	CP associated with ST versus ST	NR	>18	5/18/20	10/31/20	71.7	Not yet recruiting
NCT04332835⁽³¹31. ClinicalTrials.gov. Convalescent plasma for patients with COVID-19: a randomized, open label, parallel, controlled clinical study. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted Apr 3, 2020; Last update posted Sep 2, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04332835 https://ClinicalTrials.gov/show/NCT04332... ⁾	II-III	Moderate and severe/critical severity	CP associated with ST versus HyChl associated with ST	250mL on days 1 and 2	18-60	8/8/20	10/31/20	44.0	Not yet recruiting
NCT04385043⁽³²32. ClinicalTrials.gov. Hyperimmune plasma in patients with COVID-19 severe infection. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 12, 2020; Last update posted May 12, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04385043 https://ClinicalTrials.gov/show/NCT04385... ⁾	II-III	Severe/critical hospitalized patients	CP associated with ST versus ST	NR	18-60	5/1/20	5/15/21	35.9	Recruiting
NCT04381936⁽³³33. ClinicalTrials.gov. Randomised evaluation of COVID-19 therapy. Bethesda: National Library of Medicine; 2020 [cited 2020 Oct 28]. [First posted May 11, 2020; Last update posted Sep 29, 2020]. Available from: https://ClinicalTrials.gov/show/NCT04381936 https://ClinicalTrials.gov/show/NCT04381... ⁾	II-III	Hospitalized patients at high-risk of severe disease	LPV/Ritversus corticosteroid versus HyChl versus Azi versus Tmab associated with ST versus CP associated with ST	275mL±75mL on days 1 and 2	all	3/19/20	12/1/31	4.2	Recruiting

References	n/CP sample	Antibody titer	CP dose (mL)	Viral charge (x10 ^/dL)	Previous treatments	Hospitalization (variation)	Adverse events (n)	Mortality rate reduction
Abolghasemi et al.⁽³⁶36. Abolghasemi H, Eshghi P, Cheraghali AM, Imani Fooladi AA, Bolouki Moghaddam F, Imanizadeh S, et al. Clinical efficacy of convalescent plasma for treatment of COVID-19 infections: results of a multicenter clinical study. Transfus Apheresis Sci. 2020;59(5):102875.⁾	189/115 CP versus 74 ST	Plasma antibody titer cut off index >1.1	2x500mL	NI	ST + antiviral (LPV/Rit), HydChl and anti-inflammatory agent	9.54 days CP versus 12.88 days ST CP reduced length of stay by ~26%	~1% CP Transient mild fever and chills following infusion of the plasma (n=1)	14.8% CP versus 24.3% ST ~40%
Li et al.⁽³⁷37. Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: a Randomized Clinical Trial. JAMA. 2020;324(5):460-70. Erratum in: JAMA. 2020;324(5):519.⁾	103/52 CP (23 severe + 29 life-threatening) versus 51 ST (22 severe + 29 life-threatening)	1:350 (6 donors)	4-13mL/kg	Reduction in severe patients: 44.7% (24 hours), 68.1% (48 hours) and 87.2% (72 hours) virus-free Life-threatening patients: 53.8% (24 hours); 73.1 (48 hours) and 84.6% (72 hours) virus-free	Antiviral (41/46; 89.1%); antibacterial (38/46; 82.6%); Chinese herbal medicine (26/46; 56.5%); steroids (21/46 45.7%); antifungal (15/46; 32.6%); HIg (13/46; 28.3%); interferon (12/46; 26.1%)	Severe: 32.00 (26.00-40.00); life-threatening: indeterminate (46.00-indeterminate)	~4% CP Chills and rashes within 2 hours (n=1); shortness of breath, cyanosis and severe dyspnea within 6 hours (n=1)	15.7% CP versus 24.0% ST ~35%
Xia et al.⁽³⁸38. Xia X, Li K, Wu L, Wang Z, Zhu M, Huang B, et al. Improved clinical symptoms and mortality among patients with severe or critical COVID-19 after convalescent plasma transfusion. Blood. 2020;136(6):755-9.⁾	1,568/138	Not significantly higher in rapid responders than in moderate responders	200-1,200mL	20/25 (80%) became virus-free after 14 days	NI	2.4% CP versus 5.1% ST CP reduced admitted to the ICU by ~53%	~2% CP Pruritus or erythema during transfusion (n=3)	2.2% CP versus 4.1% ST ~50%

[1] Corresponding author: Lionel Fernel Gamarra, Avenida Albert Einstein, 627/701 – Morumbi Zip code: 05652-000 – São Paulo, SP, Brazil. Phone: (55 11) 3747-0243 E-mail: lionelgamarra7@gmail.com

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Convalescent plasma therapy in COVID-19 critically ill patients during advanced phases of clinical trials and their preliminary results

ABSTRACT