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Trials. 2021 May 04;22(1):323
The Author(s)
Bégin, Philippe
Callum, Jeannie
Heddle, Nancy M.
Cook, Richard
Zeller, Michelle P.
Tinmouth, Alan
Fergusson, Dean A.
Cushing, Melissa M.
Glesby, Marshall J.
Chassé, Michaël
Devine, Dana V.
Robitalle, Nancy
Bazin, Renée
Shehata, Nadine
Finzi, Andrés
McGeer, Allison
Scales, Damon C.
Schwartz, Lisa
Turgeon, Alexis F.
Zarychanski, Ryan
Daneman, Nick
Carl, Richard
Amorim, Luiz
Gabe, Caroline
Ellis, Martin
Sachais, Bruce S.
Loftsgard, Kent C.
Jamula, Erin
Carruthers, Julie
Duncan, Joanne
Lucier, Kayla
Li, Na
Liu, Yang
Armali, Chantal
Kron, Amie
Modi, Dimpy
Auclair, Marie-Christine
Cerro, Sabrina
Avram, Meda
Arnold, Donald M.
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.
STUDY PROTOCOL Open AccessConvalescent plasma for adults with acuteCOVID-19 respiratory illness (CONCOR-1):study protocol for an international,multicentre, randomized, open-label trialPhilippe Bégin1,2, Jeannie Callum3,4, Nancy M. Heddle5,6, Richard Cook7, Michelle P. Zeller5,6,10, Alan Tinmouth8,9,10,Dean A. Fergusson11,12,13, Melissa M. Cushing14,15, Marshall J. Glesby16, Michaël Chassé17,18, Dana V. Devine10,19,Nancy Robitalle20,21, Renée Bazin22, Nadine Shehata23,24,25, Andrés Finzi26,27, Allison McGeer28,29,Damon C. Scales30,31, Lisa Schwartz32, Alexis F. Turgeon33,34, Ryan Zarychanski35, Nick Daneman36, Richard Carl5,6,Luiz Amorim37, Caroline Gabe6, Martin Ellis38,39, Bruce S. Sachais15,40, Kent Cadogan Loftsgard6, Erin Jamula6,Julie Carruthers6, Joanne Duncan6, Kayla Lucier6, Na Li6,41,42, Yang Liu6, Chantal Armali3, Amie Kron3, Dimpy Modi3,Marie-Christine Auclair43, Sabrina Cerro43, Meda Avram43 and Donald M. Arnold5,6*AbstractBackground: Convalescent plasma has been used for numerous viral diseases including influenza, severe acuterespiratory syndrome, Middle East respiratory syndrome and Ebola virus; however, evidence to support its use isweak. SARS-CoV-2 is a novel coronavirus responsible for the 2019 global pandemic of COVID-19 communityacquired 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.(Continued on next page)© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.* Correspondence: arnold@mcmaster.ca5Department of Medicine, McMaster University, Hamilton, Ontario, Canada6McMaster Centre for Transfusion Research, McMaster University, Hamilton,Ontario, CanadaFull list of author information is available at the end of the articleBégin et al. Trials (2021) 22:323 https://doi.org/10.1186/s13063-021-05235-3(Continued from previous page)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 respiratorycomplications of COVID-19, and availability of blood group compatible CCP. Exclusion criteria are : onset ofrespiratory symptoms more than 12 days prior to randomization, intubated or imminent plan for intubation, andprevious severe reactions to plasma. Consenting patients are randomized 2:1 to receive either approximately 500mL of CCP or standard of care. CCP is collected from donors who have recovered from COVID-19 and who havedetectable anti-SARS-CoV-2 antibodies quantified serologically. The primary outcome is intubation or death at day30. Secondary outcomes include ventilator-free days, length of stay in intensive care or hospital, transfusionreactions, serious adverse events, and reduction in SARS-CoV-2 viral load. Exploratory analyses include patients whoreceived 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). Aninterim analysis and sample size re-estimation will be done by an unblinded independent biostatistician afterprimary 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 withCOVID-19. The trial will also provide information on the role of and thresholds for SARS-CoV-2 antibody titres andneutralization assays for donor qualification.Trial registration: Clinicaltrials.gov NCT04348656. Registered on 16 April 2020.Keywords: Convalescent plasma, SARS-CoV-2, Coronavirus, COVID-19, Randomized controlled trialBackgroundCOVID-19 is an acute viral illness caused by the novelSARS-CoV-2 coronavirus. With a high number of infec-tions , therapeutic options are urgently needed to miti-gate morbidity and mortality [1]. One potentialtherapeutic option is convalescent plasma collected fromindividuals who have recovered from COVID-19 [2].COVID-19 convalescent plasma (CCP) contains anti-SARS-CoV-2 antibodies, which can neutralize the virus,reduce viral load, and potentially improve clinical out-comes [3].Convalescent plasma has been used during other pan-demics. During the severe acute respiratory syndrome(SARS) epidemic, a non-randomized study from HongKong (n = 80) showed a reduction in mortality with con-valescent plasma compared with historical controls (13%vs. 17% respectively) [4]. For influenza, an observationalstudy (n = 93) of convalescent plasma showed a reduc-tion in mortality, with an odds ratio (OR) of 0.20 [95%confidence interval (CI), 0.06–0.69] [5], and a phase 3randomized trial (n = 200) using hyperimmune plasmadid not show an improvement in clinical status on day 7[6]. In Ebola, improved survival was observed in a non-randomized study of convalescent whole blood [7], butnot with convalescent plasma [8]. A systematic review ofconvalescent plasma for viral pneumonias caused by se-vere influenza or coronavirus infection (SARS-CoV-1 orMiddle East respiratory syndrome (MERS)) included 32non-randomized studies (n = 1327). The conclusionbased on very low-quality evidence was that convales-cent plasma may be associated with a reduction in mor-tality, length of stay, and duration of ventilation and thatwell-designed clinical trials are needed [9]. A recent sys-tematic review that included four randomized controlledtrials (RCTs) and two non-randomized studies of conva-lescent plasma or hyperimmune products showed low-quality evidence for lack of harm and insufficient evi-dence of efficacy [10].Case series of CCP use in patients with COVID-19from China reported positive results with CCP adminis-tered before 22 days of symptom onset [3, 11, 12]. Con-versely, other studies reported no benefit when CCP wasadministered later in the course of disease (> 21 days)[13]. A randomized trial from China (n = 103) reportedno improvement in outcomes with CCP although thedirection of the effect suggested benefit for patients withsevere but not life-threatening disease [14]. AnotherRCT (n = 86) from the Netherlands reported no im-provement with CCP but the trial was stopped earlywhen high titre anti-SARS-CoV2 antibodies were de-tected in patients at baseline [15]. An RCT from India(n = 464) showed no difference in mortality or diseaseprogression, but CCP donors were not screened for anti-body titres [16]. An RCT from Argentina (n= 228)showed no benefit of CCP compared with placebo forimprovement in clinical status by day 30 (**Please insertthis new reference: Siminovich et al PMID: 33232588**),while another plaebo-controlled RCT from Argentina(n= 160) showed a reduction in the development of se-vere respiratory disease when high-titre CCP was givenearly in the disease course (within 72 hours of symptomonset) (*** Please insert this new reference: Libster et alPMID:33406353**) On March 25, 2020, the US FDAlaunched an Expanded Access Program for CCP [17].Bégin et al. Trials (2021) 22:323 Page 2 of 17An observational study of 35,322 patients who receivedCCP under that program suggested that CCP was mosteffective when given early in the disease course and withhigh titre anti-SARS-CoV2 antibodies [18]. A previousreport of 20,000 transfused patients showed few adverseevents with CCP (< 1%) such as allergic reactions,transfusion-associated circulatory overload (TACO),transfusion-related acute lung injury (TRALI), thrombo-embolic events, hypotension, or cardiac events [19, 20].A theoretical risk of CCP is antibody-dependent en-hancement of infection [2, 21].Methods/designObjectiveCCP remains an unproven treatment for COVID-19.CONCOR-1 (CONvalescent Plasma for HospitalizedAdults with Acute COVID-19 Respiratory Illness) is amulticentre, open-label superiority trial designed to an-swer whether CCP, collected from individuals who haverecovered from COVID-19 infection that contains anti-SARS-CoV-2 antibodies, decreases the risk of intubationor death at day 30 in hospitalized adult patients withacute COVID-19 respiratory illness compared to stand-ard of care. We hypothesize that CCP will reduce therisk of intubation and death at day 30 and improve otheroutcomes including the need for critical care support,duration of hospitalization, and quality of life. Results ofserological testing on the CCP will be correlated withpatient outcomes.Trial designCONCOR-1 is a parallel arm, multicentre, open-label,superiority randomized controlled trial comparing CCPto standard of care (Fig. 1). Centres in Canada, theUnited States of America (USA), and Brazil are invitedto participate. Eligible patients are randomized using a2:1 allocation to receive either CCP or standard of care.The protocol was approved by all Research EthicsBoards at participating sites, the blood collection facil-ities, Health Canada (Control # 238201), the UnitedStates Food and Drug Administration (IND 22075), andthe National Research Ethics Commission (ComissãoNacional de Ética em Pesquisa) in Brazil (approval4.305.792). The trial was registered at clinicaltrials.gov(NCT04348656).Study settingThe trial will take place at approximately 80 academicand community hospitals in Canada, USA, and Brazil. Acomplete list of active study sites can be found in thetrial record at clinicaltrials.gov.Eligible patientsPatients are eligible for the trial if (1) age > 16 years; (2)hospitalized with confirmed SARS-CoV-2 infection; (3)receiving supplemental oxygen for COVID-19 respira-tory illness; (4) ABO-compatible CCP is available. Exclu-sion criteria are : (1) onset of respiratory signs orsymptoms > 12 days before randomization; (2) currentlyintubated or a plan is in place for intubation; (3) a planis in place for no active treatment; or (4) contraindica-tion to plasma transfusion (e.g. history of anaphylaxis,refusal of blood products). These criteria are meant tocapture patients who are early in the disease course andat risk of worsening respiratory illness. Co-enrolment inother interventional trials is permitted, with the excep-tion of other CCP trials. We will collect data on all co-interventions and co-enrolment.Fig. 1 Trial overviewBégin et al. Trials (2021) 22:323 Page 3 of 17RecruitmentSites work with their local infectious disease team to de-termine a strategy for identifying admitted patients whotest positive for COVID-19 and to communicate theseresults to the research team. Infectious disease physi-cians act as site co-investigators wherever possible to fa-cilitate this process. Sites submit screening data on aweekly basis to the methods centre, which include rea-sons for screen failures. Screening logs are reviewedregularly by the trial Executive Committee to identifycommon exclusions and strategies to optimizerecruitment.Informed consentInformed consent is obtained from each participant byauthorized study personnel prior to any study proce-dures taking place. Informed consent may be written orverbal. Obtaining verbal informed consent remotely ispermitted to avoid exposing research staff to COVID-19and may be facilitated by telephone or video-assistedconsent tools. Where required by the local research eth-ics board, written informed consent is obtained from thepatient or legally authorized representative who providedverbal consent, once safe to do so. Participants provideconsent for use of blood samples for study testing as de-scribed in the protocol and for publication of the resultsusing aggregate data. No additional biobanking isplanned.RandomizationAllocation sequence generation is performed by an in-dependent biostatistician using a computer-generated al-gorithm and stratified by centre and age (< 60 and ≥ 60years). Age is included as a stratum variable due toknown increased mortality with age. The randomizationsequence is generated using a secure, concealed,computer-generated system and blocked with randomblock sizes to ensure concealment. The allocation se-quence is maintained securely within the electronic datacapture software system and accessible only to the inde-pendent, unblinded statistician. Participants are random-ized by authorized study personnel at each site who willassign participants to interventions using a centralizedwebsite. Access to this website is restricted to trainedstudy individuals via a unique username and password.InterventionThe experimental intervention is a single dose of ap-proximately 500 mL of CCP. Apheresis CCP is will becollected by Canadian Blood Services (CBS), Héma-Qué-bec (HQ), the New York Blood Center (NYBC), andHemorio (Brazil). CCP donors must meet all donor eligi-bility criteria for routine apheresis plasma donation plus(1) confirmed COVID-19 infection by nasal swab or byantibody testing; (2) complete resolution of symptomsfor at least 14 days; (3) male donors, or female with nopregnancy history or with a negative HLA antibody testresult; and (4) ≥ 6 days since last plasma donation. CCPwill be compatible for ABO blood group or have evi-dence of low anti-A or anti-B titres (< 1:50). CCP is etransfused by nursing staff as a single dose of approxi-mately 500mL from one donor, or two doses of 250 mLfrom one or two donors, administered within 24 h ofrandomization. The 500 mL dose of CCP is infused over4 h, and patients are monitored for adverse events dur-ing the infusion. This dose of CCP is consistent withprevious CCP studies [3, 5, 22].Anti-SARS-CoV-2 antibodies in donor plasma is mea-sured by ELISA or cyclic enhanced immunofluores-cence assay with a minimum titre of 1:100, or byneutralization assay with a minimum titre of 1:160. Asthere are no scientific data to support one qualifyingantibody test over another, the blood suppliers were per-mitted to select the qualifying titre and methodology in-dependently based on availability. The FDA hasrecommended the use of minimal titre of neutralizingantibodies of 1:160 (or 1:80 when no compatible unitsare available), recognizing that these thresholds lack val-idation and other biomarkers may be important (e.g.antibody-dependent cell cytotoxicity, complement-mediated virolysis, or antibody-dependent presentationof antigens) (Fig. 2) [6, 23, 24]. At the end of the trial, allCPP units will be tested for neutralizing antibodies tocorrelate with clinical outcomes. Information collectedon CCP donors includes donor age, date of onset and se-verity of COVID-19 symptoms, and SARS-CoV-2 anti-body titres.The control arm of the trial is standard of care.Standard of care treatment was not prescribed in theprotocol. It consistsof supportive care treatments forrespiratory illness, and specific treatments forCOVID-19 available [25]. An open-label design wasjustified since the primary outcomes (intubation ordeath) are objective in nature. In addition, maskingprocedures such as plasma bag covers and additionallabeling of plasma units would have imposed signifi-cant challenges to blood bank personnel during thepandemic, which would have have made the trial in-feasible in many centres. The use of standard plasmaas the control was not felt to be justified because ofthe potential harm with no anticipated benefit. The 2:1 allocation is anticipated to maximize acceptabilityby patients and local investigators and will improvepower for sub-analyses of antibody titre.Modifications to the intervention are not expected.Adherence to this one-time intervention will be moni-tored and is expected to be high; strategies to improveadherence will be developed if needed. The CCPBégin et al. Trials (2021) 22:323 Page 4 of 17infusion should bewill be stopped if an adverse event oc-curs that is deemed to be related to the CCP or at thepatient’s request. Discontinuation practices align withlocal clinical policies regarding management of transfu-sion reactions. Participants will receive routine clinicalfollow-up care as required for any harm caused by thetrial.All participants receive treatment as per local standardpractice. In the rare event that a trial participant requiresstandard plasma for a non-study reason, local transfu-sion medicine labs will provide plasma with the longeststorage duration (plasma is routinely stored for up to1 year) to reduce of contamination with anti-SARS-CoV-2 antibodies. All blood products received duringthe trial will be documented.OutcomesThe primary outcome is a composite of intubation ordeath at day 30. The primary outcome was chosen dueto its clinical relevance and objective assessment. Sec-ondary outcomes are time to intubation or death,ventilator-free days, in-hospital death by day 90, time toin-hospital death, death by day 30, ICU length of stay,hospital length of stay, need for extracorporeal mem-brane oxygenation (ECMO), need for renal replacementtherapy, myocarditis, patient-reported outcome as mea-sured by EQ-5D-5 L, incremental cost per quality ad-justed year, CCP transfusion-related adverse events andserious adverse events. Viral load from blood samplescollected before and 48 h after randomization will bemeasured to determine the impact of CCP on viralclearance.Adverse event reporting and harmsAll transfusion-associated adverse events and adverseevents with a severity of grade 3 or higher are captured.Adverse events are classified using the Medical Diction-ary for Regulatory Activities (MedDRA) [26] and gradedby the Common Terminology Criteria for AdverseEvents (CTCAE) version 4.0 criteria [27]. Terminologyand grading from the International Society on BloodTransfusion are recorded for transfusion-associated ad-verse events [28].Events requiring expedited reportingSuspected unexpected serious adverse reactions (SUSAR) are reported to the sponsor within 24 h. These areevents that have a reasonable causal relationship to theCCP transfusion, are considered unexpected, and meetany of the following criteria for a serious adverse event:Fig. 2 Possible mechanisms of action of passively transferred antibodies in COVID-19. These include viral neutralization, complement-mediatedantibody-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 plasmaBégin et al. Trials (2021) 22:323 Page 5 of 171. Results in death;2. Is life-threatening; this means that the subject is atrisk of death at the time of the event; it does notmean that the event hypothetically might havecaused death if it was more severe;3. Requires hospitalization (overnight or longer) orprolongation of existing hospitalization or invasiveprocedure;4. Results in persistent or significant disability orincapacity;5. Results in congenital anomaly or birth defect;6. Is not be immediately life-threatening or result indeath or hospitalization but may jeopardize the sub-ject or require intervention to prevent one of theabove outcomes.Any TRALI or TACO event is reported to the spon-sor within 24 h.Other unexpected serious adverse events which arenot related to CCP are reported within 96 h, if they meetreporting criteria. Due to the critical nature of illness ofthe study population, a revised definition of a reportableserious adverse event (SAE) was developed for use inthis trial based off of guidelines used in critical care trials[29]. Therefore, the following events are not consideredreportable SAEs for the purposes of the trial: AEs thatare part of the natural history of the primary diseaseprocess or expected complications of critical illness; AEsexpected in the context of a baseline medical condition;and AEs that are already captured as study outcomes.Figure 3 shows the flow diagram for adverse eventreporting.Participant timelinePatients admitted to hospital with a positive COVID-19test result are assessed for eligibility. Eligible patientswho have consented are randomized as soon as possible(day of randomization is considered day 1). The assess-ment schedule for study patients is summarized inTable 1.BlindingCONCOR-1 is an open-label trial. The use of objectiveoutcomes of death and intubation will mitigate bias as aresult of the open-label design. The statistician perform-ing the final analysis will remain blinded throughout thetrial. Blinded safety reports will be generated at regularintervals for the Executive Committee, Independent DataSafety Monitoring Committee (IDSMC), and SteeringCommittee.Data collectionBaseline, daily physiologic and laboratory data, and out-come data are collected from randomization to day 30(Table 1). Data are entered into an electronic data cap-ture system (EDC) by site personnel. The only requiredblood samples for the trial are the ABO blood group fordetermination of CCP compatibility and two samples fortesting of viral load and antibody levels, which are sentto a central laboratory. Other laboratory tests are cap-tured if ordered as part of routine patient care. All la-boratory tests have been validated and undergo routinequality control as part of the clinical laboratories’ qualitymanagement program.Samples from all blood donors are tested for anti-bodies against SARS-CoV2 using quantitative and func-tional assays at centralized laboratories. No additionaltests are planned for this trial.Quality of life assessment is performed using the 5-level EQ-5D instrument at baseline and at day 30 [30].Data capture from electronic clinical charts and dataentry are performed remotely wherever possible to miti-gate infection risk to research personnel. Standardizedtraining is provided to all site staff performing data col-lection and entry prior to site activation in the form oftraining videos, with proof of completion required to ob-tain a training certificate. An Operations Manual is pro-vided to sites with detailed instructions for datacollection and use of the forms within the EDC.Participant retention and complete follow-up is notanticipated to be problematic as beyond day 1 (CCP in-fusion) and a follow-up contact at day 30, participantsare not required to perform any additional trial-specificactivities. The trial was designed to reduce burden onparticipants and promote retention. Participants whodiscontinue or deviate from the study protocol will stillhave all study data collected, unless they withdraw con-sent for study participation.Data managementThe CONCOR-1 database and randomization platformutilizes the REDCap (Research Electronic Data Capture)software, located on a secure authenticated server at theCONCOR-1 methods centre, McMaster University Med-ical Centre, Hamilton, Ontario, Canada [31, 32]. RED-Cap is a secure, web-based software platform designedto support data capture for research studies. Study pa-tient data may be initially collected on paper CRFs (Add-itional file 1) and consent and eligibility confirmedbefore being entered into the eCRF. Upwards of 60 hos-pitals (or hospital groups) may participate, each able toinput and access their own site data. The responsibilitiesof the sites for collection and inputting of data, timeli-ness, and responding to data queries are outlined in theOperations Manual. A comprehensive description of thelongitudinal design of the trial, site eCRF training, elec-tronic query/resolution workflow for ongoing quality re-view (based on documented data cleaning rules andBégin et al. Trials (2021) 22:323 Page 6 of 17validation rules), and access to data are documented inthe CONCOR-1 Data Management Plan. All paper CRFsare found in the REDCap database file repository folderfor easy download by sites, along with a link to all trialprocedures and protocols.Sample size estimationWe estimate that 1200 patients will be required toachieve 80% power to detect a relative risk reduction of25% with CCP (2-tailed test at level α = 0.05 and 2:1 al-location), assuming a 30% baseline risk of intubation ordeath at day 30 with standard of care. This standard ofcare event rate estimate was derived from Canadian datawhere the risk of ICU admission among hospitalized pa-tients was 23% [33], and data from New York City whereup to 41.5% of hospitalized patients required mechanicalventilation [34]. Because of uncertainty of baseline eventrate, a sample size re-estimation is planned for whenthe primary outcome is available for 50% of the targetsample. Sample size can be adjusted upwards if the ob-served event rate suggests that the trial is underpoweredfor the test based on the primary outcome.Statistical analysis planThe statistical analysis plan is provided in Add-itional file 2. A single interim analysis is planned whenFig. 3 Flow chart for AE and SAE reporting in the trialBégin et al. Trials (2021) 22:323 Page 7 of 17data on the primary outcome are available for 50% ofthe target sample. The Lan-DeMets spending function[35] analog of the O’Brien-Fleming stopping rule [36]will be used to monitor the primary endpoint to guidethe IDSMC. Conditional power will be presented for fu-tility analysis as additional information for the IDSMC.A recommendation for premature trial termination maybe made if there is reasonable cause, including but notlimited to (1) a concern regarding an unacceptable riskto subjects, (2) results of the interim analysis demon-strating superiority, (3) results of the interim analysis forthe revised sample size making the resultant trial infeas-ible due to the large number of patients required, (4)evidence from the futility analysis is compelling, (5)overall compliance with the protocol is poor, (6) datathat are not sufficiently complete and/or are notevaluable, (7) regulatory authorities recommend termin-ation of the trial, or (8) novel scientific data on the effi-cacy or safety of CCP becomes available raising concernsabout the safety of CCP.The primary outcome will be analysed using a 2-sided Wald test of the null hypothesis that probabilityof intubation or death at day 30 is the same amongindividuals receiving CCP or standard of care with arelative risk and an associated 95% confidence intervalpresented. A secondary analysis of time to event re-sponses will be modeled using cause-specific Cox re-gression models accommodating censoring at the timeof study withdrawal or upon the occurrence of com-peting events.For secondary outcomes the restricted mean numberof ventilator-free days will be compared using aTable 1 Schedule of patient assessmentsFollow-upVisit Screening Baseline (D1) D2–D30(1)(or until discharge)D30(2)(if patients discharged)(10)Time window (days) +/− 3 daysInformed consent/assent XVerify eligibility criteria XRandomization XCCP administration (3) XDemographics XComorbidities XCOVID-19 history(4) XHeight and weight XVital signs XSpO2 X XFiO2 X XCOVID treatments X X XHospitalization daily assessment (5) X XResults of blood tests (done as per clinical need) X X(6)EQ-5D(7) X XVital status (dead/ alive) X XAdverse event review X X XDischarge status (8) XMechanical ventilation since discharge XViral load, cytokines and anti-CoV-2 titres(9) X X(1) Only collected if still hospitalized(2) Phone call if subject is already discharged from the hospital(3) Only for subject randomized to the CCP treatment(4) Includes date of first symptoms; description of symptoms and date of diagnostic test(5) Mechanical ventilation, ECMO, renal replacement therapy, or myocarditis(6) Daily from day 1 to 7, then day 14 ± 3 days(7) EQ-5D to be collected on day 30 regardless of hospitalization status(8) Discharge or hospital status (admitted, home, local hospital, long-term care facility)(9) To be performed using frozen leftover sample or extra tube collected once at baseline and once during follow-up between D2 and D6(10) For patients still hospitalized at day 30, chart review will be conducted at day 90 to determine whether the patient was discharged or died in hospitalbetween day 30 and day 90 or is still in hospital at day 90Bégin et al. Trials (2021) 22:323 Page 8 of 17nonparametric analysis. The survival status at day 30and day 90 will be compared based on a comparison ofbinomial proportions, and the proportion of patientsneeding ECMO, needing renal replacement therapy,and/or with myocarditis will be compared between thetwo arms. Subgroup analyses will include: Co-enrolment in other therapeutic trials Age (> 60) Sex Ethnicity Obesity Medical comorbidities (diabetes, cardiac, respiratory) Smoking status (> 15 pack year history; never/ever/current smoker) Number of CCP donors (one vs. two) Severity of illness in donors (hospitalized vs. not) Onset of any symptom (> 12 days vs. ≤ 12 days) Timing of administration of CCP from diagnosis (≤72 h vs. > 72 h) ABO blood type of recipient Detectable vs non-detectable viral plasma viral loadat baseline Anti-SARS-CoV-2 seropositivity at baseline Oxygen status at baseline (≤ 2 L vs > 2 L)We expect to have complete data on individuals forthe primary and secondary outcomes and we will makeall efforts to minimize loss to follow-up. If an individualwithdraws from the trial early, their time to event out-comes will be censored at the time of withdrawal. Forbinary outcomes where data are missing, the first ana-lysis will be based on a completed cases (modifiedintention to treat) sample. A second analysis will dealwith potential bias from using a complete case analysisby imputing missing data via imputation models fitted tothe data from individuals providing complete informa-tion. Major protocol deviations and violations will be en-tered in the EDC in real time and monitored monthlythroughout the trial by a subgroup of individuals fromthe Executive Committee and corrective action takenwhenever possible. The Statistical Analysis Plan providesdetails related to handling of missing data and non-adherence to the protocol.ConfidentialityNo identifying information is collected until patientsconsent to trial participation. If allowed by local eth-ics boards, screening logs may contain patient initialsbut this information remains at the study site. For en-rolled participants, case report forms (both paper andelectronic) are identified by a unique study identifica-tion number. The study key containing the studyidentification number and patient identifiers will besecurely stored at each study site. Any source docu-mentation required to be sent off-site will be de-identified prior to transmission. Sites will store allstudy records securely, with access restricted to au-thorized individuals, for the duration of the trial andrequired retention period.Data monitoringThe IDSMC is comprised of six individuals with expert-ise in biostatistics, transfusion medicine, infectious dis-ease, and clinical research methodology (see IDSMCcharter- Additional file 3). The first official meeting isplanned for when the day 30 follow-up is completed forthe first 20 randomized patients. Report formats will bereviewed and approved by the IDSMC. After the initialmeeting, the IDSMC will meet when complete data isavailable for every 100 patients enrolled to review oper-ational and safety data (see “Adverse event reporting andharms” section). The IDSMC will also receive monthlysafety reports. The IDSMC will report to the study spon-sor and the study Executive Committee, which includesthe co-principal investigators.The interim analysis is described in the Statistical Ana-lysis Plan section. The results of the interim analysis willbe unblinded for the independent biostatistician per-forming the analysis and the members of the IDSMC.All other study personnel and investigators will remainblinded to the results of the interim analysis. The pri-mary purpose of the interim analysis is for sample sizere-estimation. An O’Brien-Fleming stopping rule [36]will be used at that time, but treated as a guideline, sothere is minimal impact on the threshold for statisticalsignificance for the final significance test of the primaryoutcome. The IDSMC can make recommendations re-lated to stopping for efficacy, futility, and/or safety, butthe Steering Committee will be responsible for makingthe final decision.AuditingAn independent third-party auditor facilitates site activa-tion, verifies accuracy of data entered into the electroniccase report form, and oversees GCP compliance on be-half of the sponsor. A detailed auditing plan describesthe procedures and frequency of audits and the docu-ments to be reviewed. Visits may be performed remotelyas required by pandemic restrictions, or may take placeon-site. In the event of a remote auditing visit, de-identified source documentation will be provided to theauditors. Audit reports will be provided to the sponsorafter each visit. Visits will be performed after the firstpatient has been enrolled at a site, and regularly there-after once a certain number of patients have subse-quently been enrolled.Bégin et al. Trials (2021) 22:323 Page 9 of 17Trial managementMethods centre and coordinating centresThe methods centre for the trial is the McMaster Centrefor Transfusion Research, McMaster University. Themethods centre will work directly with the blood sup-pliers to ensure the effective operations of all aspects ofthe trial. The methods centre is responsible for regula-tory requirements, data management, and data ana-lysis and oversees the working groups for CCPdistribution and communications, as well as regula-tory affairs, site activation, and blood banks outsideQuébec. The logistics centre (University of Toronto,QUEST research team) is responsible for developingstudy procedures, site blood bank and clinical teamtraining modules, site support, and site recruitmentoutside Québec. The Québec coordinating centre(Ste-Justine, Université de Montréal) is responsible forsite recruitment, training and activation, regulatory af-fairs, and blood banks in Québec, as well as sero-logical analyses. The New York coordinating centre(Weill Cornell Medicine) will work with NYBC (sup-plier of CCP) and is responsible for regulatory re-quirements in the USA and for the coordination ofthe three New York hospital sites. Hemorio will actas the coordinating centre in Brazil and will overseeCCP supply in that country. Each coordinating centreincludes physicians with transfusion medicine and/orimmunological expertise, methodologists, experiencedresearch coordinators, and research and administrativesupport staff (Fig. 4).Trial oversightThe Steering Committee (SC) has the overall responsi-bility for the design, execution, analysis interpretation,and publication of results of the trial. The SC includesthe broad range of clinical expertise from haematology,immunology, virology, critical care, research method-ology, transfusion medicine required for the conduct ofthis large-scale RCT, blood supplier representatives, anda patient advisor.SC members, affiliations, and areas of expertise are asfollows: Dr. Donald Arnold; Department of Medicine,McMaster University; Hamilton, Ontario, Canada(haematology; transfusion medicine) Dr. Philippe Bégin; Department of Pediatrics, CHUSainte-Justine; Department of Medicine, CHUM,Fig. 4 Organizational chart for the CONCOR-1 trialBégin et al. Trials (2021) 22:323 Page 10 of 17Université de Montréal; Montréal, Québec, Canada(immunology) Dr. Jeannie Callum; Department of LaboratoryMedicine and Molecular Diagnostics, SunnybrookHealth Sciences Centre; Department of LaboratoryMedicine and Pathobiology, University of Toronto;Toronto, Ontario, Canada (transfusion medicine) Prof Nancy Heddle; Department of Medicine,McMaster University; Hamilton, Ontario, Canada(transfusion medicine, clinical trial methodology) Dr. Richard Cook; Department of Statistics andActuarial Science, University of Waterloo; Waterloo,Ontario, Canada (statistics; clinical trial design andanalysis) Dr. Michelle Zeller; Canadian Blood Services;Department of Medicine, McMaster University;Hamilton, Ontario, Canada (transfusion medicine) Dr. Alan Tinmouth; Department of Medicine,University of Ottawa; Ottawa Hospital ResearchInstitute; Canadian Blood Services, Ottawa, Ontario,Canada (haematology, transfusion medicine) Dr. Dean Fergusson; Ottawa Hospital ResearchInstitute; Department of Medicine, University ofOttawa; Canadian Blood Services (clinical trialmethodology, knowledge translation, transfusionmedicine) Dr. Melissa Cushing; Transfusion Medicine andCellular Therapy, NewYork-Presbyterian; Depart-ment of Pathology and Laboratory Medicine, WeillCornell Medicine; New York City and Ithaca, NewYork, USA (transfusion medicine) Dr. Michaël Chassé; Department of Medicine(Critical Care), University of Montreal HealthCentre (CHUM); Department of Medicine,University of Montreal; Montréal, Québec, Canada(critical care, clinical trial methodology) Dr. Dana Devine; Canadian Blood Services;Department of Pathology and Laboratory Medicine,University of British Columbia; Vancouver, BritishColumbia, Canada (transfusion medicine) Dr. Nancy Robitaille; Héma-Québec; Department ofPediatrics, CHU Sainte-Justine, Université de Mon-tréal; Montréal, Québec, Canada (transfusion medi-cine, haematology) Dr. Renée Bazin; Medical Affairs and Innovation,Héma-Québec, Québec City, Québec, Canada(transfusion medicine, immunology) Dr. Nadine Shehata; Departments of Medicine,Laboratory Medicine and Pathobiology, Institute ofHealth Policy Management and Evaluation,University of Toronto; Division of Hematology,Mount Sinai Hospital; Canadian Blood Services,Toronto; Toronto, Ontario, Canada (transfusionmedicine) Dr. Damon Scales; Department of Critical CareMedicine, Sunnybrook Health Sciences Centre;Department of Medicine, University of Toronto;Toronto, Ontario, Canada (critical care) Dr. Allison McGeer; Department of Microbiology,Sinai Health System; Department of LaboratoryMedicine and Pathobiology and Dalla Lana Schoolof Public Health, University of Toronto; Toronto,Ontario, Canada (infectious disease) Dr. Alexis Turgeon; Department of Anesthesiologyand Critical Care Medicine, Division of Critical CareMedicine, Faculty of Medicine, Université Laval;CHU de Québec – Université Laval ResearchCentre, Population Health and Optimal HealthPractices Research Unit, Trauma - Emergency -Critical Care Medicine, Université Laval; QuébecCity, Québec, Canada (critical care) Dr. Lisa Schwartz; Department of Health ResearchMethods, Evidence & Impact, McMaster University;Hamilton, Ontario, Canada (bioethics) Dr. Ryan Zarychanski; Department of InternalMedicine, University of Manitoba; Winnipeg,Manitoba, Canada (haematology, critical care) Dr. Nick Daneman; Department of Medicine,Sunnybrook Health Sciences Centre, University ofToronto; Toronto, Ontario, Canada (infectiousdisease, health policy) Dr. Luiz Amorim; Hemorio, Rio de Janeiro, Brazil(transfusion medicine, haematology) Dr. Bruce Sachais; New York Blood CenterEnterprises, New York, NY; Department ofLaboratory Medicine and Pathobiology, WeillCornell Medical College; New York City, New York,USA (transfusion and apheresis medicine) Mr.Richard Carl (patient representative) Mr. Kent Cadogan Loftsgard (community advisor,specialty support to Recruitment Communications)Executive committeeThe Executive Committee (EC) oversees the day to dayoperations of the trial including monitoring trial pro-gress, approving inter-institutional agreements, datamanagement, and quality assurance. Members includethe following: Dr. Donald Arnold, Dr. Philippe Bégin,Dr. Jeannie Callum, Prof Nancy Heddle, Dr. Alan Tin-mouth, Dr. Michelle Zeller, Dr. Marshall Glesby, Dr.Melissa Cushing, and Dr. Richard Cook. Ad hoc mem-bers are Dr. Ryan Zarychanski, Dr. Nancy Robitaille, Dr.Dana Devine, and Dr. Alexis Turgeon.Independent data safety monitoring committee (IDSMC)The IDSMC includes members from both Canada andthe USA. These individuals have expertise in transfusionmedicine, infectious disease, cardiology, clinical trials,Bégin et al. Trials (2021) 22:323 Page 11 of 17methodology, epidemiology, and biostatistics. An inde-pendent biostatistician will provide regular reports tothe IDSMC. The IDSMC will monitor the safety andprotection of human subjects participating in the trial;the proper conduct of the trial; and the ongoing scien-tific integrity, validity, and clinical and scientific rele-vance. The IDSMC will provide recommendations aboutcontinuing, modifying, and/or stopping the trial basedon considerations of treatment outcomes, patient safety,and trial futility as appropriate.CommunicationsAs the structure of the CONCOR-1 trial evolved, anorganizational chart (Fig. 4) was created to optimize flowof information to all relevant groups. Any protocolamendment will first require approval by the relevantnational regulatory bodies, then the methods centre willbe responsible for communicating protocol amendmentsto the study sites (in the form of new versions of theprotocol and a summary of changes document) and col-lecting copies of the necessary local approvals prior toimplementation.Access to dataStudy data may be made available to other investigatorsupon request. Such requests must first be approved bythe Steering Committee.Dissemination plansThe principal investigators will be responsible for publi-cation of the data (manuscripts, abstracts, and posters,etc.) and are committed to publish and disseminate thestudy results in a timely manner without excessive re-striction, regardless of whether the initial study hypoth-esis is confirmed or not. Investigators will not publishany data without approval from the Steering Committee.Medical writers will not be used. Authorship eligibilitywill comply with the International Committee of Med-ical Journal Editors criteria. The CONCOR-1 protocolhas already been shared with US and European coali-tions to allow investigators to collaborate on a coreprotocol and to share data. Results will be disseminatedto patients and the public through the CONCOR-1 web-site (https://concor1.ca/), the media, and to various com-munity groups identified by the study’s CommunityAdvisory Committee members. Site investigators willalso play a role in distributing results to patients andcolleagues.Ancillary and post-trial careThere is no specific ancillary or post-trial care related tothe trial; however, patients will continue to receivestandard of care for their underlying condition as perclinical practice. Insurance to cover the cost ofcompensation for participants who suffer harm fromtrial participation is available for Canadian and Ameri-can participants.DiscussionInitial discussions to establish a Canadian trial of CCPbegan in late March 2020. The first CCP unit was col-lected 1 month later on April 24, 2020. The first patientwas randomized on May 14, 2020. Rapid and intense co-ordination included the assembly of the Steering Com-mittee with the range of required expertise, andcoordination with numerous hospital sites and the bloodsuppliers. The organizational structure for the trialevolved quickly to define the roles of the methodscentre, coordinating centres, and trial-specific workinggroups to allow for broader distribution of the trialworkload to achieve trial launch at a rapid pace.Given the context of the pandemic, there was no op-portunity for a pilot study; nevertheless, we utilized alarge, experienced and diverse Steering Committee toensure as many challenges as possible will be avoidedthough strategic planning. Access to plasma donors wasenhanced through public awareness campaigns, partner-ships with public health, and an increasing number ofrecovered patients. To maximize access to the trial andenhance recruitment, we engaged approximately 50 Can-adian centres, 3 hospitals in New York City (Weill Cor-nell Medicine), and centres in Brazil with a contingencyplan to add more sites if needed. With this extensive re-cruitment plan, we hope to achieve our recruitment tar-get within approximately 18 months. The eligibilitycriteria and outcomes in CONCOR-1 are harmonizedwith CCP trials in other countries. We will make ourprotocol publicly available through consortia in the USAand to allow investigators to share data and ensure com-pleteness if local outbreaks taper off before sites are ableto enroll their target sample size.Modeling supply and demand in an evolving pandemicThe success of the trial depends on both the supply ofCCP from individuals who have recovered fromCOVID-19 and the demand from eligible patients withacute COVID-19 infection. Factors affecting supply in-clude the number of recovered patients with adequateSARS-CoV-2 antibody titres, willingness of donors toprovide CCP, validation of SARS-CoV-2 antibody testing(ELISA and neutralization assays), and turnaround timefor antibody testing. Factors affecting patient recruit-ment are the number of new admissions for COVID-19infections at participating sites, severity of COVID-19 in-fections for admitted patients, and speed of activation ofstudy sites. Many of these factors were not known whenthe protocol was designed, but the investigators andSteering Committee prioritized the development of aBégin et al. Trials (2021) 22:323 Page 12 of 17rigorous protocol that could be implemented quickly.We modeled supply of CCP and demand of COVID-19patients in Quebec based on information available at thetime of protocol development. We partnered with hospi-tals in New York City and Brazil to maximize recruit-ment. In addition, our endpoint is harmonized withother CCP trials internationally.We chose to study hospitalized patients with respira-tory compromise within the first 12 days of respiratorysymptom onset as this patient population appeared toexperience the greatest benefit from convalescent plasma[9]. As passive immunization may be more effective earlyin the course of illness before high enough levels of anti-bodies are formed, patients with onset of respiratorysymptoms more than 12 days from potentialrandomization are not eligible for participation. For pa-tients with more advanced disease (e.g. critically ill re-quiring invasive mechanical ventilation), the benefits ofCCP appear to be less evident [14, 37].The primary outcome is the composite of intubationor death at day 30. Intubation is a clinically relevant out-come because of the high proportion of patients who re-quire intubation (up to 40%) [14], the association withintubation and mortality, and the desire to demonstratea reduction in healthcare utilization. By introducingmortality via the composite outcome, we address situa-tions in which intubation cannot be offered due to pa-tient or physician preference or lack of availability ofventilators. The pattern of intubation practices duringthe pandemic and the availability of ventilators and in-tensive care beds were assessed when the protocol wasdesigned through an informal survey of intensive carephysicians. We recognized that patterns of practice aredynamic and could evolve over the epidemic. Due to theuncertainty around the 30% baseline estimate of theevent rate, we included an adaptive sample size recalcu-lation mid-way through the trial so that the sample sizecan be adjusted if appropriate.Equitable CCP distributionAs part of the CONCOR-1 trial, we have established aplatform for the distribution of CCP to ensure equity ofplasma availability to hospitals and patients throughoutCanada and the NYC sites while balancing optimal pa-tient recruitment. This platform allows research staff toreserve an ABO-compatible unit for an eligible patientand release it back into inventory if the patient is ran-domized to standard of care. We developed a distribu-tion model where CBS provides CCP to hub hospitalsthat distribute to other proximal sites. This CCP distri-bution platform is shared with other CCP trials inCanada for critically ill patients (REMAP-CAP:NCT02735707) and pediatrics (CONCOR-Kids:NCT04377568). The CCP distribution working groupconsists of representatives from all Canadian CCP trials,the blood suppliers, hospital transfusion services, a bio-ethicist, an operations researcher who developed thesoftware application and a full-time research coordinatorwho will monitor CCP inventory daily. For sites in Qué-bec, New York, and Brazil, the blood suppliers will dis-tribute the CCP directly to the participating sites.Agreements between HQ and CBS will facilitate sharingof CCP for less common blood groups (B and AB).The protocol was designed to mitigate risk to researchand clinical staff during the pandemic by including re-mote processes for consent, data collection, and moni-toring that do not rely on in-person contact. Datacollection will be done through a daily review of thehealth record and telephone contact with the clinicalteam as required, and data monitoring will be done byremote access to health records until on-site monitoringis permitted. No additional procedures are required forthe trial except for the CCP transfusion and a screeningABO blood group, which may be routine for all COVID-19 patients in certain study sites. Both study samples(baseline and 48 h after randomization) for viral loadand antibody levels can be collected at the time of a pre-planned blood draw or from sample discards from theclinical laboratories.Co-enrolment in drug trials is permitted. This will re-quire collaboration with other site investigators toharmonize screening and consent procedures and estab-lish trial prioritization. The rate of co-enrolment will beprospectively monitored by the IDSMC and the SC andthe effect of co-enrolment will be evaluated in subgroupanalyses. We anticipate that the rate of co-enrolmentwill be less than 20% since CONCOR-1 will recruit frommany community hospitals where other COVID-19 trialsare not open.SerologyAntibody testing to qualify CCP products is done byELISA, cyclic enhanced immunofluorescence assay, orviral neutralization assays. This strategy is aligned withFDA recommendations on the use of CCP [38] and ac-commodates the differences in the donor qualificationrequirements by the blood suppliers. As a secondaryanalysis, we will explore the relation between clinicaloutcomes and CCP anti-receptor-binding domain (RBD)and neutralizing antibody titres, which will be ultimatelymeasured in all units. A previous non-randomized retro-spective study reported that patient receiving a singleunit of CCP with an anti-SARS-CoV2 titre greater than18.35 s/co had lower mortality rate compared to thosereceiving one CCP unit with a titre lower than 4.6 s/co(Ortho VITROS IgG assay) (unpublished pre-print). Fig-ure 5 shows how these dosages compare in terms of finalamount of anti-SARS-CoV2 antibody transfused basedBégin et al. Trials (2021) 22:323 Page 13 of 17on a simulation based of CCP collected to date for thetrial at the HQ sites, and assuming transfusion of twounits from randomly matched donors. Of note, two iso-lates of SARS-CoV-2 have been identified in Canada andthe USA (wild type and D614G mutant) [39]. TheD614G mutation involves the RBD, and there is debateas to whether this could affect infectivity or specificity ofneutralization. Neutralization assays will therefore beperformed for both isolates to allow comparison. Thesetranslational studies will inform future use of CCP.Community engagementWe established a Community Advisory Committee(CAC) to bring a diversity of perspectives based on rele-vant lived experiences and socio-demographic character-istics of COVID-19 patients, blood donors, andindividuals with specific interests in the pandemic andits impact on the community (e.g. age, sex/gender, edu-cation, socioeconomic status, geographic location andrace). Advisors from marginalized populations affectedby the pandemic will help us understand and advocatefor these groups such as residents of long-term care fa-cilities or family members, individuals of colour, and In-digenous people [40, 41]. Some of the roles of thiscommittee are (1) to maximize the relevance of the re-search for the community; (2) to advise on equitable dis-tribution of CCP; (3) to enhance effective disseminationof study results; and (4) to provide feedback on analysesincluding awareness of the effects of social determinants[41, 42]. The CAC has seven members and plans to meetmonthly.In summary, the CONCOR-1 trial was designed rap-idly as a collaborative effort by a team of experts in clin-ical trials in collaboration with three blood suppliers.This large randomized trial is adequately powered andsufficiently generalizable to address the efficacy andsafety of CCP as potential treatment for COVID-19.Risks to the trialA trial protocol designed to evaluate a new treatmentduring the ongoing pandemic is subject to risks. Forone, enrolment is dependent on disease prevalence; sec-ond, the trial requires an adequate supply of plasmawhich had not been pre-planned; and third, estimates ofevent rate were based on available data at the outset ofthe pandemic and may be unstable. To mitigate theserisks, we have activated the trial in a large number ofcentres throughout Canada including both academic andcommunity hospitals, we have expanded into othercountries, and we are pursuing methods to combine datawith other similar trials without compromising trial in-tegrity. CCP can be shared among the blood suppliers tosupply the trial, and we have engaged with the bloodsuppliers to bolster recruitment of CCP donors. Wehave built-in a sample size re-estimation halfwaythrough the trial.Fig. 5 Expected distribution of transfused plasma potency. The distribution of mean antibody titre in transfused convalescent plasma units wasprojected by performing a simulation in which plasma units from different donors were paired randomly. The simulation is based on the titres of1150 plasma units currently in inventory at one of the blood suppliers (Héma-Québec). Titers were originally established with an in-house ELISAbut have been translated in equivalent d/co units from the ORTHO VITRIOS IgG assayBégin et al. Trials (2021) 22:323 Page 14 of 17Trial statusThe trial has been approved by Health Canada, the FDA,and the National Research Ethics Commission (Comis-são Nacional de Ética em Pesquisa) in Brazil. Researchethics board approvals have been received from all activesites and the blood suppliers. Trial recruitment startedon May 8, 2020. There were 52 active sites (48 inCanada, 3 in New York City, 1 in Brazil; an Israeli sitewas planned but never activated). Over 2000 units ofCCP were collected. On January 29, 2021, the IDSMCreviewed the data from the scheduled interim analysis(n = 614) and recommended that the trial be stopped forfutility. On 29 January 2021, the trial was stopped after940 patients were enrolled. The currently approvedprotocol version is 15 Jan 2021 v8.0.AbbreviationsAE: Adverse event; CAC: Community Advisory Committee; CBS: CanadianBlood Services; CCP: COVID-19 convalescent plasma; CRF: Case report form;CTCAE: Common Terminology Criteria for Adverse Events; EC: ExecutiveCommittee; ECMO: Extracorporeal membrane oxygenation; eCRF: Electroniccase report form; ELISA: Enzyme-linked immunosorbent assay; FDA: Foodand Drug Administration; HQ: Héma-Québec; ICU: Intensive care unit; IDSMC: Independent Data Safety Monitoring Committee; MedDRA: MedicalDictionary for Regulatory Activities; MERS: Middle East respiratory syndrome;NYBC: New York Blood Center; OR: Odds ratio; RBD: Receptor-bindingdomain; RCT: Randomized controlled trial; REDCap: Research Electronic DataCapture; SAE: Serious adverse event; SARS: Severe acute respiratorysyndrome; SC : Steering Committee; SUSAR: Suspected unexpected seriousadverse reaction; TACO: Transfusion-associated circulatory overload;TRALI: Transfusion-related acute lung injurySupplementary InformationSupplementary information accompanies this paper at https://doi.org/10.1186/s13063-021-05235-3.Additional file 1. Paper CRF package Version 4.0, 01 Oct 2020.Additional file 2. Statistical Analysis Plan Version 2.0 19 Mar 2021.Additional file 3. IDSMC Charter version 2.0, 03 Nov 2020.Additional file 4. Clinical Trials Ontario Consent Form Template(English) Version 1.2, 13 Apr 2020 & Consent Form Template (French- forQuebec sites) Version 1.1, 12 Apr 2020.AcknowledgementsThe authors wish to acknowledge the contributions of the followingresearch team members: Methods Centre—Melanie St. John, Shannon Lane,Rebecca Pereira, Emily Sirotich; Logistics Centre—Samia Saeed; QuébecCoordinating Centre—Julie Morin, Marie Saint-Jacques, Maxime Veillette, Ver-onica Martinez; NYC Coordinating Centre—Kathleen Kane, Celine Arar, Dan-ielle Hayden, and Lauren Gripp.Trial SponsorHamilton Health Sciences1200 Main St WHamilton, ON L8N 3Z5Trial Sponsor Representatives(United States Only)Weill Cornell Medical College1300 York AvenueNew York, NY 10065(Brazil only)Fundação Pró-Instituto de Hematologia/Fundarj8 Frei Caneca StreetRio de Janeiro, RJ 20211-030Authors’ contributionsPB, DMA, and JeC conceived the trial. NH, RCo, MPZ, AT, DAF, MMC, MJG,MC, DVD, NR, RB, NS, AF, AM, DCS, LS, AFT, RZ, ND, LA, CG, ME, and RCamade substantial contributions to the concept and design of the trial. Theydrafted and revised the protocol and approved the final version. RCo, DAF,NL, and YL provided statistical expertise and methodological expertise inclinical trial design. EJ, JuC, JD, KL, CA, AK, DM, MCA, SC, and MA revised theprotocol and approved the final version, recruited patients and implementedthe trial. LA, BSS, and KCL, along with others, were members of the SteeringCommittee and provided critical input on study design and execution. KCLwas referred to CONCOR-1 research partnership recruitment by the coordina-tors of the Strategy for Patient- Oriented Research – Primary and IntegratedHealth Care Innovations Network. - https://spor-pihci.com/. DMA, JC, PB, NH,and EJ wrote the manuscript, and it was reviewed and approved by allauthors.FundingFinancial support for this trial is provided by: CIHR – COVID-19 May 2020Rapid Research Funding Opportunity- Operating Grant; Ontario COVID-19Rapid Research Fund; Toronto COVID-19 Action Initiative 2020 (University ofToronto); University Health Network Emergent Access Innovation Fund; Uni-versity Health Academic Health Science Centre Alternative Funding Plan(Sunnybrook Health Sciences Centre); Hamilton Academic Health SciencesOrganization (HAHSO) Alternative Funding Plan Innovation Grant; Ministèrede l’Économie et de l’Innovation (Québec); Saskatchewan Ministry of Health;University of Alberta Hospital Foundation; Sunnybrook Health SciencesCentre Foundation; Fondations CHU Ste-Justine; The Ottawa Hospital Aca-demic Medical Organization; The Ottawa Hospital Foundation COVID-19 Re-search Fund; Sinai Health System Foundation and McMaster University.The sponsor and funders will have no role in the trial design; collection,management, analysis, and interpretation of data; writing of the report; andthe decision to submit the report for publication. The sponsor may reviewany materials intended for publication but the study SC maintains finalauthority over the decision to publish.Availability of data and materialsStudy data may be made available to other investigators upon request. Suchrequests must first be approved by the Steering Committee. Requests shouldbe sent to arnold@mcmaster.ca.DeclarationsEthics approval and consent to participateAll hospital sites had research ethics board approval before trial activation; allparticipants provided informed consent before any study specific procedurestook place. The study was approved by Clinical Trials Ontario (ResearchEthics Board of Record: Sunnybrook Health Sciences Centre), project #2159;the Quebec Ministry of Health and Social Services multicenter ethics review(REB of Record: Comité d’éthique de la recherche du CHU Sainte-Justine),project #MP-21-2020-2863; Comissão Nacional de Ética em Pesquisa, ap-proval 4.305.792; as well as local research ethics boards of participating hos-pitals where applicable.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Author details1Section of Allergy, Immunology and Rheumatology, Department ofPediatrics, CHU Sainte-Justine, Montreal, Quebec, Canada. 2Department ofMedicine, CHUM, Université de Montréal, Montreal, Quebec, Canada.3Department of Laboratory Medicine and Molecular Diagnostics, SunnybrookHealth Sciences Centre, Toronto, Ontario, Canada. 4Department of LaboratoryMedicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.5Department of Medicine, McMaster University, Hamilton, Ontario, Canada.6McMaster Centre for Transfusion Research, McMaster University, Hamilton,Ontario, Canada. 7Department of Statistics and Actuarial Science, Universityof Waterloo, Waterloo, Ontario, Canada. 8Department of Medicine, OttawaHospital, University of Ottawa, Ottawa, Ontario, Canada. 9Ottawa HospitalBégin et al. Trials (2021) 22:323 Page 15 of 17Centre for Transfusion Research, Ottawa Hospital Research Institute, Ottawa,Ontario, Canada. 10Canadian Blood Services, Ottawa, Ontario, Canada.11Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa,Ontario, Canada. 12Department of Medicine, University of Ottawa, Ottawa,Ontario, Canada. 13Adjunct Scientist, Canadian Blood Services, Ottawa,Ontario, Canada. 14Transfusion Medicine and Cellular Therapy,NewYork-Presbyterian, New York, NY, USA. 15Department of Pathology andLaboratory Medicine, Weill Cornell Medicine, New York, NY, USA. 16Divisionof Infectious Diseases, Weill Cornell Medical College, Weill Cornell Medicine,New York, NY, USA. 17Department of Medicine (Critical Care), University ofMontreal Health Centre (CHUM), Montreal, Quebec, Canada. 18Department ofMedicine, University of Montreal, Montreal, Quebec, Canada. 19Department ofPathology and Laboratory Medicine, University of British Columbia, Ottawa,Ontario, Canada. 20Héma-Québec, Saint-Laurent, Montreal, Canada. 21Divisionof Hematology and Oncology, Department of Pediatrics, CHU Sainte-Justine,Université de Montréal, Ottawa, Ontario, Canada. 22Medical Affairs andInnovation, Héma-Québec, Saint-Laurent, Montreal, Canada. 23Departmentsof Medicine, Laboratory Medicine and Pathobiology, Institute of HealthPolicy Management and Evaluation, University of Toronto, Toronto, Ontario,Canada. 24Division of Hematology, Mount Sinai Hospital, Toronto, Ontario,Canada. 25Canadian Blood Services, Toronto, Ontario, Canada. 26Départementde Microbiologie, Infectiologie et Immunologie, Université de Montréal,Montreal, Quebec, Canada. 27CHUM Research Center, Montreal, Quebec,Canada. 28Department of Microbiology, Sinai Health System, Toronto,Ontario, Canada. 29Department of Laboratory Medicine and Pathobiologyand Dalla Lana School of Public Health, University of Toronto, Toronto,Ontario, Canada. 30Department of Critical Care Medicine, Sunnybrook HealthSciences Centre, Toronto, Ontario, Canada. 31Department of Medicine,Interdepartmental Division of Critical Care, University of Toronto, Toronto,Ontario, Canada. 32Department of Health Research Methods, Evidence &Impact, Faculty of Health Sciences, McMaster University, Hamilton, Ontario,Canada. 33Department of Anesthesiology and Critical Care Medicine, Divisionof Critical Care Medicine, Faculty of Medicine, Université Laval, Quebec,Quebec, Canada. 34CHU de Québec – Université Laval Research Centre,Population Health and Optimal Health Practices Research Unit, Trauma -Emergency - Critical Care Medicine, Université Laval, Quebec, Quebec,Canada. 35Department of Internal Medicine, Sections of Hematology/MedicalOncology and Critical Care, University of Manitoba, Winnipeg, Manitoba,Canada. 36Department of Medicine, Division of Infectious Diseases,Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario,Canada. 37Hemorio, Rio de Janeiro, Brazil. 38Hematology Institute and BloodBank, Meir Medical Center, Tel Aviv, Israël. 39Sackler School of Medicine, TelAviv University, Tel Aviv, Israël. 40New York Blood Center Enterprises, NewYork, NY, USA. 41Department of Computing and Software, McMasterUniversity, Hamilton, Ontario, Canada. 42Department of Community HealthSciences, University of Calgary, Hamilton, Ontario, Canada. 43Clinical ResearchDepartment, Centre de recherche du CHU Sainte-Justine, Centre HospitalierUniversitaire Sainte-Justine Centre, Montreal, Canada.Received: 12 January 2021 Accepted: 29 March 2021References1. 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Convalescent plasma for adults with acute COVID-19 respiratory illness (CONCOR-1): study protocol for an international, multicentre, randomized, open-label trial
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