Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): study protocol for an international, multicentre, randomized, open-label trial

Philippe Bégin, Jeannie Callum, Nancy M Heddle, Richard Cook, Michelle P Zeller, Alan Tinmouth, Dean A Fergusson, Melissa M Cushing, Marshall J Glesby, Michaël Chassé, Dana V Devine, Nancy Robitalle, Renée Bazin, Nadine Shehata, Andrés Finzi, Allison McGeer, Damon C Scales, Lisa Schwartz, Alexis F Turgeon, Ryan Zarychanski, Nick Daneman, Richard Carl, Luiz Amorim, Caroline Gabe, Martin Ellis, Bruce S Sachais, Kent Cadogan Loftsgard, Erin Jamula, Julie Carruthers, Joanne Duncan, Kayla Lucier, Na Li, Yang Liu, Chantal Armali, Amie Kron, Dimpy Modi, Marie-Christine Auclair, Sabrina Cerro, Meda Avram, Donald M Arnold, Philippe Bégin, Jeannie Callum, Nancy M Heddle, Richard Cook, Michelle P Zeller, Alan Tinmouth, Dean A Fergusson, Melissa M Cushing, Marshall J Glesby, Michaël Chassé, Dana V Devine, Nancy Robitalle, Renée Bazin, Nadine Shehata, Andrés Finzi, Allison McGeer, Damon C Scales, Lisa Schwartz, Alexis F Turgeon, Ryan Zarychanski, Nick Daneman, Richard Carl, Luiz Amorim, Caroline Gabe, Martin Ellis, Bruce S Sachais, Kent Cadogan Loftsgard, Erin Jamula, Julie Carruthers, Joanne Duncan, Kayla Lucier, Na Li, Yang Liu, Chantal Armali, Amie Kron, Dimpy Modi, Marie-Christine Auclair, Sabrina Cerro, Meda Avram, Donald M Arnold

Abstract

Background: Convalescent plasma has been used for numerous viral diseases including influenza, severe acute respiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use is weak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 community acquired pneumonia. We have undertaken a randomized controlled trial to assess the efficacy and safety of COVID-19 convalescent plasma (CCP) in patients with SARS-CoV-2 infection.

Methods: CONCOR-1 is an open-label, multicentre, randomized trial. Inclusion criteria include the following: patients > 16 years, admitted to hospital with COVID-19 infection, receiving supplemental oxygen for respiratory complications of COVID-19, and availability of blood group compatible CCP. Exclusion criteria are : onset of respiratory symptoms more than 12 days prior to randomization, intubated or imminent plan for intubation, and previous severe reactions to plasma. Consenting patients are randomized 2:1 to receive either approximately 500 mL of CCP or standard of care. CCP is collected from donors who have recovered from COVID-19 and who have detectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at day 30. Secondary outcomes include ventilator-free days, length of stay in intensive care or hospital, transfusion reactions, serious adverse events, and reduction in SARS-CoV-2 viral load. Exploratory analyses include patients who received CCP containing high titre antibodies. A sample size of 1200 patients gives 80% power to detect a 25% relative risk reduction assuming a 30% baseline risk of intubation or death at 30 days (two-sided test; α = 0.05). An interim analysis and sample size re-estimation will be done by an unblinded independent biostatistician after primary outcome data are available for 50% of the target recruitment (n = 600).

Discussion: This trial will determine whether CCP will reduce intubation or death non-intubated adults with COVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titres and neutralization assays for donor qualification.

Trial registration: Clinicaltrials.gov NCT04348656 . Registered on 16 April 2020.

Keywords: COVID-19; Convalescent plasma; Coronavirus; Randomized controlled trial; SARS-CoV-2.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Trial overview
Fig. 2
Fig. 2
Possible mechanisms of action of passively transferred antibodies in COVID-19. These include viral neutralization, complement-mediated antibody-dependent virolysis, antibody-dependent enhancement of immune response, antibody-mediated presentation of antigen, and antibody-dependent cell cytotoxicity. Of these, only viral neutralization is measured by neutralization assays currently used to qualify convalescent plasma
Fig. 3
Fig. 3
Flow chart for AE and SAE reporting in the trial
Fig. 4
Fig. 4
Organizational chart for the CONCOR-1 trial
Fig. 5
Fig. 5
Expected distribution of transfused plasma potency. The distribution of mean antibody titre in transfused convalescent plasma units was projected by performing a simulation in which plasma units from different donors were paired randomly. The simulation is based on the titres of 1150 plasma units currently in inventory at one of the blood suppliers (Héma-Québec). Titers were originally established with an in-house ELISA but have been translated in equivalent d/co units from the ORTHO VITRIOS IgG assay

References

    1. Worldometers. COVID-19 Coronovirus Pandemic. . Accessed 18 May 2020.
    1. Casadevall A, Pirofski L. The convalescent sera option for containing COVID-19. J Clin Invest. 2020;130(4):1545–1548. doi: 10.1172/JCI138003.
    1. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, Wang F, Li D, Yang M, Xing L, Wei J, Xiao H, Yang Y, Qu J, Qing L, Chen L, Xu Z, Peng L, Li Y, Zheng H, Chen F, Huang K, Jiang Y, Liu D, Zhang Z, Liu Y, Liu L. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020;323(16):1582–1589. doi: 10.1001/jama.2020.4783.
    1. Cheng Y, Wong R, Soo YOY, Wong WS, Lee CK, Ng MHL, Chan P, Wong KC, Leung CB, Cheng G. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44–46. doi: 10.1007/s10096-004-1271-9.
    1. Hung IFN, To KKW. Lee CK, Lee KL, Chan K, Yan WW, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52(4):447–456. doi: 10.1093/cid/ciq106.
    1. Beigel JH, Aga E, Elie-Turenne MC, Cho J, Tebas P, Clark CL, Metcalf JP, Ozment C, Raviprakash K, Beeler J, Holley HP Jr, War1ner S, Chorley C, Lane HC, Hughes MD, Davey RT Jr, Beigel JH, Aga E, Elie-Turenne MC, Cho J, Tebas P, Clark CL, Metcalf JP, Ozment C, Raviprakash K, Beeler J, Holley HP Jr, Warner S, Chorley C, Lane HC, Hughes MD, Davey RT, Barron M, Bastani A, Bauer P, Borkowsky W, Cairns C, Deville J, Elie MC, Fichtenbaum C, Finberg R, Jain M, Kaufman D, Lin M, Lin J, Maves R, Morrow L, Nguyen MH, Park P, Polk C, Randolph A, Rao S, Rubinson L, Schofield C, Shoham S, Stalets E, Stapleton RD. Anti-influenza immune plasma for the treatment of patients with severe influenza A: a randomised, double-blind, phase 3 trial. Lancet Respir Med. 2019;7(11):941–50. 10.1016/S2213-2600(19)30199-7.
    1. Sahr F, Ansumana R, Massaquoi TA, Idriss BR, Sesay FR, Lamin JM, Baker S, Nicol S, Conton B, Johnson W, Abiri OT, Kargbo O, Kamara P, Goba A, Russell JB, Gevao SM. Evaluation of convalescent whole blood for treating Ebola virus disease in Freetown, Sierra Leone. J Inf Secur. 2017;74(3):302–309. doi: 10.1016/j.jinf.2016.11.009.
    1. Van Griensven J, Edwards T, De Lamballerie X, Semple MG, Gallian P, Baize S, et al. Evaluation of convalescent plasma for Ebola virus disease in Guinea. N Engl J Med. 2016;374(1):33–42. doi: 10.1056/NEJMoa1511812.
    1. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, Makki S, Rooney KD, Convalescent Plasma Study Group. Nguyen-van-Tam JS, Beck CR. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis. 2015;211(1):80–90. doi: 10.1093/infdis/jiu396.
    1. Devasenapathy N, Ye Z, Loeb M, Fang F, Najafabadi B, Xiao Y, et al. Indirect evidence on efficacy and safety of convalescent plasma in severe COVID-19 patients: systematic review and meta-analysis. CMAJ. 2020;192(27):E745–E755. doi: 10.1503/cmaj.200642.
    1. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M, Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, Peng Y, Hu Y, Lin L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, Gong Q, Zhang W, Zheng X, Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, Zhang X, Yang X. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci. 2020;117(17):9490–9496. doi: 10.1073/pnas.2004168117.
    1. Zhang B, Liu S, Tan T, Huang W, Dong Y, Chen L, Chen Q, Zhang L, Zhong Q, Zhang X, Zou Y, Zhang S. Treatment with convalescent plasma for critically ill patients with SARS-CoV-2 infection. Chest. 2020;158(1):e9–13. doi: 10.1016/j.chest.2020.03.039.
    1. 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 COVID-19 patients. J Infect Dis. 2020;222(1):38–43. doi: 10.1093/infdis/jiaa228.
    1. Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, Kong Y, Ren L, Wei Q, Mei H, Hu C, Tao C, Yang R, Wang J, Yu Y, Guo Y, Wu X, Xu Z, Zeng L, Xiong N, Chen L, Wang J, Man N, Liu Y, Xu H, Deng E, Zhang X, Li C, Wang C, Su S, Zhang L, Wang J, Wu Y, Liu Z. 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):460–470. doi: 10.1001/jama.2020.10044.
    1. Gharbharan A, Jordans CCE, GeurtsvanKessel C, den Hollander JG, Karim F, Mollema FPN, et al. Convalescent plasma for COVID-19. A randomized clinical trial. medRxiv. 2020; 10.1101/2020.07.01.20139857.
    1. Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T. Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID trial) BMJ. 2020;371:m3939. doi: 10.1136/bmj.m3939.
    1. Tanne JH. Covid-19: FDA approves use of convalescent plasma to treat critically ill patients. BMJ. 2020;368:m1256. doi: 10.1136/bmj.m1256.
    1. Joyner MJ, Senefeld JW, Klassen SA, Mills JR, Johnson PW, Theel ES, et al. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three month experience. medRxiv. 2020; 10.1101/2020.08.12.20169359.
    1. Joyner MJ, Wright RS, Fairweather D, Senefeld JW, Bruno KA, Klassen SA, Carter RE, Klompas AM, Wiggins CC, Shepherd JRA, Rea RF, Whelan ER, Clayburn AJ, Spiegel MR, Johnson PW, Lesser ER, Baker SE, Larson KF, Ripoll JG, Andersen KJ, Hodge DO, Kunze KL, Buras MR, Vogt MNP, Herasevich V, Dennis JJ, Regimbal RJ, Bauer PR, Blair JE, van Buskirk CM, Winters JL, Stubbs JR, Paneth NS, Verdun NC, Marks P, Casadevall A. Early safety indicators of COVID-19 convalescent plasma in 5000 patients. J Clin Invest. 2020;130(9):4791–4797. doi: 10.1172/JCI140200.
    1. Joyner MJ, Bruno KA, Klassen SA, Kunze KL, Johnson PW, Lesser ER, Wiggins CC, Senefeld JW, Klompas AM, Hodge DO, Shepherd JRA, Rea RF, Whelan ER, Clayburn AJ, Spiegel MR, Baker SE, Larson KF, Ripoll JG, Andersen KJ, Buras MR, Vogt MNP, Herasevich V, Dennis JJ, Regimbal RJ, Bauer PR, Blair JE, van Buskirk CM, Winters JL, Stubbs JR, van Helmond N, Butterfield BP, Sexton MA, Diaz Soto JC, Paneth NS, Verdun NC, Marks P, Casadevall A, Fairweather DL, Carter RE, Wright RS. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clin Proc. 2020;95(9):1888–1897. doi: 10.1016/j.mayocp.2020.06.028.
    1. Liu L, Wei Q, Lin Q, Fang J, Wang H, Kwok H, Tang H, Nishiura K, Peng J, Tan Z, Wu T, Cheung KW, Chan KH, Alvarez X, Qin C, Lackner A, Perlman S, Yuen KY, Chen Z. Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. JCI Insight. 2019;4(4):e123158. doi: 10.1172/jci.insight.123158.
    1. Yeh K, Chiueh T, Siu LK, Lin J, Chan PKS, Peng M, et al. Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital. J Antimicrob Chemother. 2005;56(5):919–922. doi: 10.1093/jac/dki346.
    1. Beigel JH, Tebas P, Elie-Turenne MC, Bajwa E, Bell TE, Cairns CB, Shoham S, Deville JG, Feucht E, Feinberg J, Luke T, Raviprakash K, Danko J, O'Neil D, Metcalf JA, King K, Burgess TH, Aga E, Lane HC, Hughes MD, Davey RT, Tebas P, Quinn J, Jiang Y, Elie-Turenne MC, Hoelle R, Iovine N, Wills RS, Pata S, Huggins M, Manukian B, Bajwa E, Holland C, Brait K, Hunt T, Stowell C, Slater A, Bell TE, Townsends M, Cairns CB, Quackenbush EB, Park YA, Jordan PG, Blanchet C, Chronowski K, Alvarez K, Shoham S, Ostrander D, Woessner T, Thoman S, Deville JG, Lin J, Ziman A, Shankar K, Feucht E, Blok T, Batts D, Beck B, Massey G, Bradley C, Feinberg J, Carey P, Baer J, Whitehead EM, Kohrs S, Giulitto R, Schofield C, Fairchok M, Chambers S, Baker C, RN, Parker M, Harshbarger M, Nguyen MH, Carey ME, Paronish J, Cornell F, Cramer J, Pakstis DL, Ison MG, Wunderink R, Glesby M, Ham K, Hughes V, Cushing M, Goss C, Grenade J, Park PK, Napolitano LM, Raghavendran K, Hyzy RC, Davenport R, Brierley K, Downs T, Gong MN, Uehlinger J, Lin M, Fritsche J, Green T, McLeod B, Patel D, Bavaro MF, Deiss R, Brandt C, Cammarata S, Kremp A, Hollis-Perry K, Lalani T, Banks S, Johnson J, Maguire J, McNiff J, Rigg LE, Ganesan A, Barahona I, Danko J, Spencer S, Stagliano D, Burgess T, Talmor D, Mohammed M, Banner-Goodspeed V, Salata R, Finberg R, Wang J, Longtine K, Longtine J, O'Neil M, Bauer PR, Gajic O, Weist SM, Sevransky J, Brown M, Roback J, Oropello J, Twohig B, Jhang J, Seethala R, Chen WH, Fontaine M, Saharia K, Husson J, DeBiasi R, Wilson JL, Criss VR, Voell J, Leitman S, Atkins JW, Patel H, Paige T, Cantilena C, Siegel D, DeMuth F, Fletcher CH, Pelletier JPR, Alnuaimat H, Pourde M. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study. Lancet Respir Med. 2017;5(6):500–511. doi: 10.1016/S2213-2600(17)30174-1.
    1. Davey RT, Fernández-Cruz E, Markowitz N, Pett S, Babiker AG, Wentworth D, et al. Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial. Lancet Respir Med. 2019;7(11):951–963. doi: 10.1016/S2213-2600(19)30253-X.
    1. World Health Organization. Clinical management Clinical management: Living guidance COVID-19. . Accessed 10 Mar 2021.
    1. Medical Dictionary for Regulatory Activities. Welcome to MedDRA. . Accessed 12 Jun 2020.
    1. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Accessed 12 Jun 2020.
    1. International Society of Blood Transfusion Working Party on Haemovigilance. Proposed Standard Definitions for Surveillance of Non Infectious Adverse Transfusion Reactions. . Accessed 12 Jun 2020.
    1. Cook D, Lauzier F, Rocha MG, Sayles MJ, Finfer S. Serious adverse events in academic critical care research. CMAJ. 2008;178(9):1181–1184. doi: 10.1503/cmaj.071366.
    1. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L) Qual Life Res. 2011;20(10):1727–1736. doi: 10.1007/s11136-011-9903-x.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–381. doi: 10.1016/j.jbi.2008.08.010.
    1. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O’Neal L, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019;95:103208. doi: 10.1016/j.jbi.2019.103208.
    1. Public Health Agency of Canada. Coronavirus Disease 2019 (COVID-19). . Accessed 09 May 2020.
    1. Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, and the Northwell COVID-19 Research Consortium. Barnaby DP, Becker LB, Chelico JD, Cohen SL, Cookingham J, Coppa K, Diefenbach MA, Dominello AJ, Duer-Hefele J, Falzon L, Gitlin J, Hajizadeh N, Harvin TG, Hirschwerk DA, Kim EJ, Kozel ZM, Marrast LM, Mogavero JN, Osorio GA, Qiu M, Zanos TP. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323(20):2052–2059. doi: 10.1001/jama.2020.6775.
    1. Lan K, DeMets D. Discrete sequential boundaries for clinical trials. Biometrika. 1983;70(3):659–663. doi: 10.2307/2336502.
    1. O’Brien P, Fleming T. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549–556. doi: 10.2307/2530245.
    1. Liu STH, Lin HM, Baine I, Wajnberg A, Gumprecht JP, Rahman F, Rodriguez D, Tandon P, Bassily-Marcus A, Bander J, Sanky C, Dupper A, Zheng A, Nguyen FT, Amanat F, Stadlbauer D, Altman DR, Chen BK, Krammer F, Mendu DR, Firpo-Betancourt A, Levin MA, Bagiella E, Casadevall A, Cordon-Cardo C, Jhang JS, Arinsburg SA, Reich DL, Aberg JA, Bouvier NM. Convalescent plasma treatment of severe COVID-19: a propensity score–matched control study. Nat Med. 2020;26(11):1708–1713. doi: 10.1038/s41591-020-1088-9.
    1. Food and Drug Administration. Investigational COVID-19 Convalescent Plasma Guidance for Industry. . Accessed 12 Jun 2020.
    1. Korber B, Fischer WM, Gnanakaran S, Yoon H, Theiler J, Abfalterer W, Hengartner N, Giorgi EE, Bhattacharya T, Foley B, Hastie KM, Parker MD, Partridge DG, Evans CM, Freeman TM, de Silva TI, McDanal C, Perez LG, Tang H, Moon-Walker A, Whelan SP, LaBranche CC, Saphire EO, Montefiori DC, Angyal A, Brown RL, Carrilero L, Green LR, Groves DC, Johnson KJ, Keeley AJ, Lindsey BB, Parsons PJ, Raza M, Rowland-Jones S, Smith N, Tucker RM, Wang D, Wyles MD. Tracking changes in SARS-CoV-2 spike: evidence that D614G increases infectivity of the COVID-19 virus. Cell. 2020;182(4):812–827. doi: 10.1016/j.cell.2020.06.043.
    1. Ahmed SM, Palermo AGS. Community engagement in research: frameworks for education and peer review. Am J Public Health. 2010;100(8):1380–1387. doi: 10.2105/AJPH.2009.178137.
    1. World Health Organisation. RCCE Action Plan Guidance Covid-19 preparedness & response. . Accessed 12 Jun 2020.
    1. Holzer JK, Ellis L, Merritt MW. Why we need community engagement in medical research. J Investig Med. 2014;62(6):851–855. doi: 10.1097/JIM.0000000000000097.

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