Use of convalescent plasma in the treatment of critically ill COVID-19 patients: a study protocol

Use of convalescent plasma (CP) has shown promising results during early studies of COVID-19 patients. This study aims to prepare a protocol for the use of CP to treat critically ill COVID-19 patients. This will be a multicentre, double-blinded, controlled randomised trial. Subjects will be randomly assigned to the treatments, and evaluations will be taken at baseline and at intervals according to the protocol. Only those subjects who meet all inclusion criteria will be enrolled in the study. The experimental treatment group will receive CP at volume of 6 mL/kg divided into two doses separated by 24 hours, in addition to the standard treatment for COVID-19. The control group will receive only the standard treatments. The result assessed at the end of this trial will be the primary and secondary endpoints. The primary endpoints (efficacy indicators) will be the discharge from the ICU, discharge from the hospital, days of hospitalisation, days on mechanical ventilation and death. The main secondary endpoints (safety indicators) will be the severe transfusion reactions and transfusion-transmitted diseases. The authors developed the study protocol using standardised criteria for the development of a clinical trial protocol. This study protocol addressed all aspects that are necessary for the standardised implementation of CP for the treatment of COVID-19 patients, including CP collection, administration, evaluation, and follow up.

COVID-19; Convalescent plasma; Study protocol; Efficacy; Safety

[1] Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. New England Journal of Medicine. 2020; 382: 1708–1720.

[2] World Health Organization. Rolling updates on coronavirus disease (COVID-19). 2020. Available at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen (Accessed: 14 January 2021).

[3] Chen L, Xiong J, Bao L, Shi Y. Convalescent plasma as a potential therapy for COVID-19. The Lancet Infectious Diseases. 2020; 20: 398–400.

[4] Li G, Chen X, Xu A. Profile of specific antibodies to the SARS-associated coronavirus. The New England Journal of Medicine. 2003; 349: 508–509.

[5] Long QX, Liu BZ, Deng HJ, Wu GC, Deng K, Chen YK, et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nature Medicine. 2020; 26: 845–848.

[6] FDA. Investigational COVID-19 Convalescent Plasma Emergency INDs. 2020. Available at: https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds (Accessed: 17 January 2021).

[7] Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 Critically Ill Patients with COVID-19 with Convalescent Plasma. Journal of the American Medical Association. 2020; 323: 1582.

[8] Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proceedings of the National Academy of Sciences. 2020; 117: 9490–9496.

[9] Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F, et al. Treatment with convalescent plasma for COVID‐19 patients in Wuhan, China. Journal of Medical Virology. 2020; 92: 1890–1901.

[10] Zhang B, Liu S, Tan T, Huang W, Dong Y, Chen L, et al. Treatment with convalescent plasma for critically ill patients with SARS-CoV-2 infection. Chest. 2020; 158: e9–e13.

[11] Zeng Q, Yu Z, Gou J, Li G, Ma S, Zhang G, et al. Effect of Convalescent Plasma Therapy on Viral Shedding and Survival in Patients with Coronavirus Disease 2019. The Journal of Infectious Diseases. 2020; 222: 38–43.

[12] Joyner M, Wright RS, Fairweather D, Senefeld J, Bruno K, Klassen S, et al. Early safety indicators of COVID-19 convalescent plasma in 5,000 patients. The Journal of Clinical Investigation. 2020. (in press)

[13] Bloch EM, Shoham S, Casadevall A, Sachais BS, Shaz B, Winters JL, et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. Journal of Clinical Investigation. 2020; 130: 2757–2765.

[14] World Health Organization. Blood donor selection: guidelines on assessing donor suitability for blood donation. 2012. Available at: http://apps.who.int/iris/bitstream/10665/76724/1/ 9789241548519_(Accessed: 23 March 2021).

[15] Authors/Organizations. COVID-19 Convalescent Plasma Collection: Donor Eligibility, Processing, Labelling, And Distribution. (AABB protocol). 2020. Available at: http://www.aabb.org/advocacy/regulatory government/Documents/COVID-19-Convalescent-Plasma-Collection.pdf (Accessed: 11 April 2021).

[16] Mayo Clinic. COVID-19 expanded access program. 2020. Available at: https://www.uscovidplasma.org/ (Accessed: 23 April 2021).

[17] European Commission, Safety Directorate-General for Health and Food. An EU programme of COVID-19 convalescent plasma collection and transfusion. Guidance on the collection, testing, processing, storage, distribution and monitored use. 2020. Available at: https://ec.europa.eu/health/sites/default/files/blood_ tissues_organs/docs/guidance_plasma_covid19_en.pdf (Accessed: 25 March 2021).

[18] Lanza F, Seghatchian J. Reflection on passive immunotherapy in those who need most: some novel strategic arguments for obtaining safer therapeutic plasma or autologous antibodies from recovered COVID-19 infected patients. British Journal of Haematology. 2020; 190: e27–e29.

[19] National Guide on Preparation. Use and Quality Assurance of Blood and Blood Components. 2020. Available at: https://www.kanver.org/Upload/Dosya/ulusal_kan_rehberi.pdf (Accessed: 25 March 2021).

[20] Blackall D, Wulff S, Roettger T, Jacobs L, Lacasse A, Patri M, et al. Rapid establishment of a COVID‐19 convalescent plasma program in a regional health care delivery network. Transfusion. 2020; 60: 2203–2209.

[21] US Food and Drug Administration. Recommendations for Investigational COVID-19 Convalescent Plasma. FDA 2020. https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma (Accessed: 17 April 2021).

[22] Eckhardt CM, Cummings MJ, Rajagopalan KN, Borden S, Bitan ZC, Wolf A, et al. Evaluating the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in severely ill adults with COVID-19: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020; 21: 499.

[23] Albalawi M, Zaidi SZA, AlShehry N, AlAskar A, Zaidi ARZ, Abdallah RNM, et al. Safety and Efficacy of Convalescent Plasma to Treat Severe COVID-19: Protocol for the Saudi Collaborative Multicenter Phase II Study. JMIR Research Protocols. 2020; 9: e23543.

[24] Janssen M, Schäkel U, Djuka Fokou C, Krisam J, Stermann J, Kriegsmann K, et al. A Randomized Open label Phase-II Clinical Trial with or without Infusion of Plasma from Subjects after Convalescence of SARS-CoV-2 Infection in High-Risk Patients with Confirmed Severe SARS-CoV-2 Disease (RECOVER): a structured summary of a study protocol for a randomised controlled trial. Trials. 2020; 21: 828.