Objective
CCP remains an unproven treatment for COVID-19. CONCOR-1 (CONvalescent Plasma for Hospitalized Adults with Acute COVID-19 Respiratory Illness) is a multicenter, open-label superiority trial designed to answer whether CCP, collected from individuals who have recovered from COVID-19 infection that contains anti-SARS-CoV-2 antibodies, decreases the risk of intubation or death at day 30 in hospitalized adult patients with acute COVID-19 respiratory illness compared to standard of care. We hypothesize that CCP will reduce the risk of intubation and death at day 30, and improve other outcomes including the need for critical care support, duration of hospitalization and quality of life. Results of serological testing on the CCP will be correlated with patient outcomes.
Trial Design
CONCOR-1 is a parallel arm, multicenter, open-label, superiority randomized controlled trial comparing CCP to standard of care (Figure 1). Centres in Canada, the United States of America (USA), Brazil, and Israel will be invited to participate. Eligible patients will be randomized using a 2:1 allocation to receive either CCP or standard of care. The protocol was approved by all Research Ethics Boards at participating sites, the blood collection facilities, Health Canada (Control # 238201) and the United States Food and Drug Administration (IND 22075). Approval will be obtained from Brazilian and Israeli authorities prior to trial commencement in these countries.
Study Setting
The trial will take place at approximately 80 academic and community hospitals in Canada, USA, Brazil and Israel. A complete list of active study sites can be found in the trial record at clinicaltrials.gov.
Eligible patients
Patients will be eligbile for the trial if: 1) age > 16 years; 2) hospitalized with confirmed SARS-CoV-2 infection; 3) receiving supplemental oxygen for COVID-19 respiratory illness; 4) ABO-compatible CCP is available. Exclusion criteria are: 1) onset of respiratory signs or symptoms >12 days before randomization; 2) currently intubated or a plan is in place for intubation; 3) a plan is in place for no active treatment; or 4) contraindication to plasma transfusion (e.g. history of anaphylaxis, refusal of blood products). These criteria are meant to capture patients who are early in the disease course and at risk of worsening respiratory illness. Co-enrolment in other interventional trials is permitted, with the exception of other CCP trials. We will collect data on all co-interventions and co-enrolment.
Recruitment
Sites will work with their local infectious disease team to determine a strategy for identifying admitted patients who test positive for COVID-19 and to communicate these results to the research team. Infectious disease physicians were identified to act as site co-investigators wherever possible to facilitate this process. Sites will submit screening data on a weekly basis to the methods centre, which will include reasons for screen failures. Screening logs will be reviewed regularly by the trial Executive Committee to identify common exclusions and strategies to optimize recruitment.
Informed Consent
Informed consent will be obtained from each participant by authorized study personnel prior to any study procedures taking place. Informed consent may be written or verbal. Obtaining verbal informed consent remotely is permitted to avoid exposing research staff to COVID-19, and may be facilitated by telephone or video-assisted consent tools. Where required by the local research ethics board, written informed consent will be obtained from the patient or legally authorized representative who provided verbal consent, once safe to do so. Participants will also provide consent for use of blood samples for study testing as described in the protocol and for publication of the results using aggregate data. No additional biobanking will be done.
Randomization
Allocation sequence generation will be performed by an independent biostatistician using a computer generated algorithm and stratified by center and age (<60 and ≥ 60 years). Age is included as a stratum variable due to known increased mortality with age. The randomization sequence will be generated using a secure, concealed, computer-generated system and blocked with random block sizes to ensure concealment. The allocation sequence will be maintained securely within the electronic data capture software system and accessible only to the independent, unblinded statistician. Participants will be randomized by authorized study personnel at each site who will assign participants to interventions using a centralized website. Access to this website is restricted to trained study individuals via a unique username and password.
Intervention
The experimental intervention is a single dose of approximately 500 mL of CCP. Apheresis CCP will be collected by Canadian Blood Services (CBS), Héma-Québec (HQ), the New York Blood Center (NYBC), Hemorio (Brazil) and Magen David Adom (Israel). CCP donors must meet all donor eligibility criteria for routine apheresis plasma donation plus: 1) confirmed COVID-19 infection by nasal swab or by antibody testing; 2) complete resolution of symptoms for at least 14 days; 3) male donors, or female with no pregnancy history or with a negative HLA antibody test result; and 4) ≥ 6 days since last plasma donation. CCP will be compatible for ABO blood group, or have evidence of low anti-A or anti-B titres (<1:50). CCP will be transfused by nursing staff as a single dose of approximately 500mL from one donor, or two doses of 250mL from one or two donors, administered within 24 hours of randomization. The 500 mL dose of CCP will be infused over 4 hours and patients will be monitored closely for adverse events during the infusion. This dose of CCP is consistent with previous CCP studies [3,5,22].
The detection of anti-SARS-CoV-2 antibodies in donor plasma will be done either by ELISA or cyclic enhanced immunofluorescence assay with a minimum titer of 1:100, or by neutralization assay with a minimum titer of 1:160. As there are no scientific data to support one qualifying antibody test over another, the blood suppliers were permitted to select the qualifying titer and methodology independently based on availability. The FDA has recommended the use of minimal titer of neutralizing antibodies of 1:160 (or 1:80 when no compatible units are available), recognizing that these thresholds lack validation and other biomarkers may be important (e.g. antibody-dependent cell cytotoxicity, complement-mediated virolysis or antibody-dependent presentation of antigens) (Figure 2) [6,23,24]. At the end of the trial, all CPP units will be tested for neutralizing antibodies to correlate with clinical outcomes. Information collected on CCP donors includes donor age, date of onset and severity of COVID-19 symptoms, and SARS-CoV-2 antibody titers.
The control arm of the trial is standard of care. An open-label design was justified since the primary outcomes (intubation or death) are objective in nature. In addition, masking procedures such as plasma bag covers and additional labeling of plasma units would impose significant challenges to blood bank personnel during the pandemic, which would have made the trial infeasible in many centres. The use of standard plasma as the control was not felt to be justified because of the potential harm with no anticipated benefit. The 2:1 allocation is anticipated to maximize acceptability by patients and local investigators and will improve power for sub-analyses of antibody titer.
Modifications to the intervention are not expected. Adherence to this one-time intervention will be monitored and is expected to be high; strategies to improve adherence will be developed if needed. The CCP infusion will be stopped if an adverse event occurs that is deemed to be related to the CCP or at the patient’s request. Discontinuation practices align with local clinical policies regarding management of transfusion reactions. Participants will receive routine clinical follow up care as required for any harm caused by the trial.
All participants will receive treatment as per local standard practice. In the rare event that a trial participant requires standard plasma for a non-study reason, local transfusion medicine labs will provide plasma with the longest storage duration (plasma is routinely stored for up to one year) to reduce of contamination with anti-SARS-CoV-2 antibodies. All blood products received during the trial will be documented.
Outcomes
The primary outcome is a composite of intubation or death at day 30. The primary outcome was chosen due to its clinical relevance and objective assessment. Secondary outcomes are: time to intubation or death, ventilator-free days, in-hospital death by day 90, time to in-hospital death, death by day 30, ICU length of stay, hospital length of stay, need for extracorporeal membrane oxygenation (ECMO), need for renal replacement therapy, myocarditis, patient reported outcome as measured by EQ-5D-5L, incremental cost per quality adjusted year, CCP transfusion related adverse events and serious adverse events. Viral load from blood samples collected before and 48 hours after randomization will be measured to determine the impact of CCP on viral clearance.
Adverse Event Reporting and Harms
All transfusion-associated adverse events and adverse events with a severity of grade 3 or higher will be captured. Adverse events will be classified using the Medical Dictionary for Regulatory Activities (MedDRA) [25] and graded by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria [26]. Terminology and grading from the International Society on Blood Transfusion will also be recorded for transfusion-associated adverse events [27].
Events Requiring Expedited Reporting
Suspected unexpected serious adverse reactions (SUSAR) must be reported to the sponsor within 24 hours. These are events that have a reasonable causal relationship to the CCP transfusion, are considered unexpected, and meet any of the following criteria for a serious adverse event:
- Results in death;
- Is life-threatening; this means that the subject is at risk of death at the time of the event; it does not mean that the event hypothetically might have caused death if it was more severe;
- Requires hospitalization (overnight or longer) or prolongation of existing hospitalization or invasive procedure;
- Results in persistent or significant disability or incapacity;
- Results in congenital anomaly or birth defect;
- Is not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or require intervention to prevent one of the above outcomes
Any incidences of TRALI or TACO must be reported to the sponsor within 24 hours.
Other unexpected serious adverse events which are not related to CCP must be reported within 96 hours, if they meet reporting criteria. Due to the critical nature of illness of the study population, a revised definition of a reportable SAE was developed for use in this trial based off of guidelines used in critical care trials [28]. Therefore, the following events are not considered reportable SAEs for the purposes of the trial: AEs that are part of the natural history of the primary disease process or expected complications of critical illness; AEs expected 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 event reporting.
Participant Timeline
Patients admitted to hospital with a positive COVID-19 test result are assessed for eligibility. Eligible patients who have consented will be randomized as soon as possible (day of randomization is considered day 1). The assessment schedule for study patients is summarized in Table 1.
Table 1. Schedule of patient assessments
|
|
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Follow up
|
Visit
|
Screening
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Baseline (D1)
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D2 – D30(1)
(or until discharge)
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D30(2)
(if patients discharged)(10)
|
Time Window (days)
|
|
|
|
+/- 3 days
|
Informed Consent/Assent
|
X
|
|
|
|
Verify Eligibility Criteria
|
X
|
|
|
|
Randomization
|
|
X
|
|
|
CCP Administration (3)
|
|
X
|
|
|
Demographics
|
|
X
|
|
|
Co-morbidities
|
|
X
|
|
|
COVID-19 History(4)
|
|
X
|
|
|
Height and Weight
|
|
X
|
|
|
Vital Signs
|
|
X
|
|
|
SpO2
|
|
X
|
X
|
|
FiO2
|
|
X
|
X
|
|
COVID treatments
|
|
X
|
X
|
X
|
Hospitalization Daily Assessment (5)
|
|
X
|
X
|
|
Results of blood tests (done as per clinical need)
|
|
X
|
X(6)
|
|
EQ-5D(7)
|
|
X
|
|
X
|
Vital Status (dead/ alive)
|
|
|
X
|
X
|
Adverse Event Review
|
|
X
|
X
|
X
|
Discharge status (8)
|
|
|
|
X
|
Mechanical Ventilation since discharge
|
|
|
|
X
|
Viral load, cytokines and anti-CoV-2 titers(9)
|
|
X
|
X
|
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(1) Only collected if still hospitalized
(2) Phone call if subject is already discharged from the hospital
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(3) Only for subject randomized to the CCP treatment
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(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 1-7, 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, longterm 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
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(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 hospital between Day 30 and Day 90 or is still in hospital at Day 90.
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Blinding
CONCOR-1 is an open-label trial. The use of objective outcomes of death and intubation will mitigate bias as a result of the open-label design. The statistician performing the final analysis will remain blinded throughout the trial. Blinded safety reports will be generated at regular intervals for the Executive Committee, Independent Data Safety Monitoring Committee (IDSMC), and Steering Committee.
Data Collection
Baseline, daily physiologic and laboratory data, and outcome data will be collected from randomization to day 30 (Table 1). Data are entered into an electronic data capture system (EDC) by site personnel. The only required blood samples for the trial are the ABO blood group for determination of CCP compatibility and two samples for testing of viral load and antibody levels. The latter two samples are obtained from either discards from routinely collected blood samples or from samples collected specifically for this purpose. Other laboratory values are captured if ordered as part of routine patient care. All laboratory tests have been validated and undergo routine quality control as part of the clinical laboratories’ quality management program. Quality of life assessment is performed using the 5-level EQ-5D instrument at baseline and at day 30 [29]. Data capture from electronic clinical charts and data entry are performed remotely wherever possible to mitigate infection risk to research personnel. Standardized training is provided to all site staff performing data collection and entry prior to site activation in the form of training videos, with proof of completion required to obtain a training certificate. An Operations Manual is provided to sites with detailed instructions for data collection and use of the forms within the EDC.
Participant retention and complete follow-up is not anticipated to be problematic as beyond day 1 (CCP infusion) and a follow-up contact at day 30, participants are not required to perform any additional trial specific activities. The trial was designed in this way to reduce burden on participants and promote retention. Participants who discontinue or deviate from the study protocol will still have all study data collected, unless they withdraw consent for study participation.
Data Management
The CONCOR-1 database and randomization platform utilizes the REDCap (Research Electronic Data Capture) software, located on a secure authenticated server at the CONCOR-1 methods centre, McMaster University Medical Centre, Hamilton, Ontario, Canada [30,31]. REDCap is a secure, web-based software platform designed to support data capture for research studies. Study patient data may be initially collected on paper CRFs (Additional File 1) and consent and eligibility confirmed before being entered into the eCRF. Upwards of 60 hospitals (or hospital groups) may participate, each able to input and access their own site data. The responsibilities of the sites for collection and inputting of data, timeliness and responding to data queries are outlined in the Operations Manual. A comprehensive description of the longitudinal design of the trial, site eCRF training, electronic query/resolution workflow for ongoing quality review, (based on documented data cleaning rules and validation rules), and access to data are all documented in the CONCOR-1 Data Management Plan. All paper CRFs are found in the REDCap database file repository folder for easy download by sites, along with a link to all trial procedures and protocols.
Sample size estimation
We estimate that 1200 patients will be required to achieve 80% power to detect a relative risk reduction of 25% with CCP (2-tailed test at level α =0.05 and 2:1 allocation), assuming a 30% baseline risk of intubation or death at Day 30 with standard of care. This standard of care event rate estimate was derived from Canadian data where the risk of ICU admission among hospitalized patients was 23% [32], and data from New York City where up to 41.5% of hospitalized patients required mechanical ventilation [33]. Because of uncertainty of baseline event rate, a sample size re-estimation will take place when the primary outcome is available for 50% of the target sample. Sample size will be adjusted upwards if the observed event rate suggests that the trial is underpowered for the test based on the primary outcome.
Statistical analysis plan
The statistical analysis plan is provided in Additional File 2. A single interim analysis is planned when data on the primary outcome are available for 50% of the target sample. The Lan-DeMets spending function [34] analog of the O’Brien-Fleming stopping rule [35] will be used to monitor the primary endpoint to guide the IDSMC. Conditional power will be presented for futility analysis as additional information for the IDSMC. A recommendation for premature trial termination may be made if there is reasonable cause, including but not limited to: 1) a concern regarding an unacceptable risk to subjects, 2) results of the interim analysis demonstrating superiority, 3) results of the interim analysis for the revised sample size making the resultant trial infeasible 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) data that are not sufficiently complete and/or are not evaluable, 7) regulatory authorities recommend termination of the trial, or, 8) novel scientific data on the efficacy or safety of CCP becomes available raising concerns about the safety of CCP.
The primary outcome will be analyzed using a 2-sided Wald test of the null hypothesis that probability of intubation or death at day 30 is the same among individuals receiving CCP or standard of care with a relative risk and an associated 95% confidence interval presented. A secondary analysis of time to event responses will be modeled using cause-specific Cox regression models accommodating censoring at the time of study withdrawal or upon the occurrence of competing events.
For secondary outcomes the restricted mean number of ventilator free days will be compared using a nonparametric analysis. The survival status at day 30 and day 90 will be compared based on a comparison of binomial proportions, and the proportion of patients needing ECMO, needing renal replacement therapy, and/or with myocarditis will be compared between the two arms. Subgroup analyses will include:
- Co-enrolment in other therapeutic trials
- Age (> 60)
- Sex
- Ethinicity
- 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 hours vs. > 72 hours)
- ABO blood type of recipient
We expect to have complete data on individuals for the primary and secondary outcomes and we will make all efforts to minimize loss-to-follow up. If an individual withdraws from the trial early, their time to event outcomes will be censored at the time of withdrawal. For binary outcomes where data are missing, the first analysis will be based on a completed cases (modified intention to treat) sample. A second analysis will deal with potential bias from using a complete case analysis by imputing missing data via imputation models fitted to the data from individuals providing complete information. Major protocol deviations and violations will be entered in the EDC in real time and monitored monthly throughout the trial by a subgroup of individuals from the Executive Committee and corrective action taken whenever possible. The Statistical Analysis Plan provides details related to handling of missing data and non-adherence to the protocol.
Confidentiality
No identifying information will be collected until patients have consented to trial participation. If allowed by local ethics boards, screening logs may contain patient initials but this information remains at the study site. For enrolled participants, case report forms (both paper and electronic) are identified by a unique study identification number. The study key containing the study identification number and patient identifiers will be securely stored at each study site. Any source documentation required to be sent off-site will be de-identified prior to transmission. Sites will store all study records securely, with access restricted to authorized individuals, for the duration of the trial and required retention period.
Data Monitoring
The IDSMC is comprised of six individuals with expertise in biostatistics, transfusion medicine, infectious disease, and clinical research methodology (see IDSMC charter- Additional File 3). The first official meeting will take place when the day 30 follow-up is completed for the first 20 randomized patients. Report formats will be reviewed and approved by the IDSMC. After the initial meeting, the IDSMC will meet when complete data is available for every 100 patients enrolled to review operational and safety data (see Adverse Events section). The IDSMC will also receive monthly safety reports. The IDSMC will report to the study sponsor and the study Executive Committee, which includes the co-principal investigators.
The interim analysis is described in the Statistical Analysis Plan section. The results of the interim analysis will be unblinded for the independent biostatistician performing the analysis and the members of the IDSMC. All other study personnel and investigators will remain blinded to the results of the interim analysis. The primary purpose of the interim analysis is for sample size re-estimation. An O'Brien- Fleming stopping rule [35] will be used at that time, but treated as a guideline, so there is minimal impact on the threshold for statistical significance for the final significance test of the primary outcome. The IDSMC can make recommendations related to stopping for efficacy, futility and or safety but the steering committee will be responsible for making the final decision.
Auditing
An independent third-party auditor will be used to facilitate site activation, verify accuracy of data entered into the electronic case report form, and oversee GCP compliance on behalf of the sponsor. A detailed auditing plan will be developed to describe the procedures and frequency of audits and the documents to be reviewed. Visits may be performed remotely as required by pandemic restrictions, or may take place on-site. In the event of a remote auditing visit, de-identified source documentation will be provided to the auditors. Audit reports will be provided to the sponsor after each visit. Visits will be performed after the first patient has been enrolled at a site, and regularly thereafter once a certain number of patients have subsequently been enrolled.
Trial Management
Methods Centre and Coordinating Centers
The methods centre for the trial is the McMaster Centre for Transfusion Research, McMaster University. The methods centre will work directly with the blood suppliers to ensure the effective operations of all aspects of the trial. The methods centre is responsible for regulatory requirements, data management, and data analysis; and oversees the working groups for CCP distribution and communications, as well as regulatory affairs, site activation, and blood banks outside Québec. The logistics centre (University of Toronto, QUEST research team) is responsible for developing study procedures, site blood bank and clinical team training modules, site support, and site recruitment outside Québec. The Québec coordinating center (Ste-Justine, Université de Montréal) is responsible for site recruitment, training and activation, regulatory affairs, and blood banks in Québec, as well as serological analyses. The New York coordinating center (Weill Cornell Medicine) will work with NYBC (supplier of CCP) and is responsible for regulatory requirements in the USA and for the coordination of the three New York hospital sites. Hemorio and Meir Medical Centre will act as co-ordinating centres in Brazil and Israel, respectively, and will work closely with CPP suppliers in those countries. Each co-ordinating centre includes physicians with transfusion medicine and/or immunological expertise, methodologists, experienced research coordinators and research and administrative support staff (Figure 4).
Trial oversight
The Steering Committee (SC) has the overall responsibility for the design, execution, analysis interpretation and publication of results of the trial. The SC includes the broad range of clinical expertise from hematology, immunology, virology, critical care, research methodology, transfusion medicine required for the conduct of this large-scale RCT, blood supplier representatives, and a patient advisor.
SC Members, Affiliations and Areas of Expertise:
- Dr Donald Arnold; Department of Medicine, McMaster University; Hamilton, Ontario, Canada (hematology; transfusion medicine)
- Dr Philippe Bégin; Department of Pediatrics, CHU Sainte-Justine; Department of Medicine, CHUM, Université de Montréal; Montréal, Québec, Canada (immunology)
- Dr Jeannie Callum; Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre; Department of Laboratory Medicine 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 and Actuarial Science, University of Waterloo; Waterloo, Ontario, Canada (statistics; clinical trial design and analysis)
- 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 Research Institute; Canadian Blood Services, Ottawa, Ontario, Canada (hematology, transfusion medicine)
- Dr Dean Fergusson; Ottawa Hospital Research Institute; Department of Medicine, University of Ottawa; Canadian Blood Services (clinical trial methodology, knowledge translation, transfusion medicine)
- Dr Melissa Cushing; Transfusion Medicine and Cellular Therapy, NewYork-Presbyterian; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine; New York City and Ithaca, New York, USA (transfusion medicine)
- Dr Michaël Chassé; Department of Medicine (Critical Care), University of Montreal Health Centre (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, British Columbia, Canada (transfusion medicine)
- Dr Nancy Robitaille; Héma-Québec; Department of Pediatrics, CHU Sainte-Justine, Université de Montréal; Montréal, Québec, Canada (transfusion medicine, hematology)
- 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 of Health Policy Management and Evaluation, University of Toronto; Division of Hematology, Mount Sinai Hospital; Canadian Blood Services, Toronto; Toronto, Ontario, Canada (transfusion medicine)
- Dr Damon Scales; Department of Critical Care Medicine, 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 Laboratory Medicine and Pathobiology and Dalla Lana School of Public Health, University of Toronto; Toronto, Ontario, Canada (infectious disease)
- Dr Alexis Turgeon; Department of Anesthesiology and Critical Care Medicine, Division of Critical Care Medicine, Faculty of Medicine, Université Laval; CHU de Québec – Université Laval Research Centre, Population Health and Optimal Health Practices Research Unit, Trauma - Emergency - Critical Care Medicine, Université Laval; Québec City, Québec, Canada (critical care)
- Dr Lisa Schwartz; Department of Health Research Methods, Evidence & Impact, McMaster University; Hamilton, Ontario, Canada (bioethics)
- Dr Ryan Zarychanski; Department of Internal Medicine, University of Manitoba; Winnipeg, Manitoba, Canada (hematology, critical care)
- Dr Nick Daneman; Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto; Toronto, Ontario, Canada (infectious disease, health policy)
- Mr Richard Carl (patient representative)
Executive Committee
The Executive Committee (EC) oversees the day to day operations of the trial including monitoring trial progress, approving inter-institutional agreements, data management and quality assurance. Members include: Dr Donald Arnold, Dr Philippe Bégin, Dr Jeannie Callum, Prof Nancy Heddle, Dr Alan Tinmouth, Dr Michelle Zeller, Dr Marshall Glesby, Dr Melissa Cushing, and Dr Richard Cook. Ad hoc members 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 and the USA. These individuals have expertise in transfusion medicine, infectious disease, cardiology, clinical trials, methodology, epidemiology and biostatistics. An independent biostatistician will provide regular reports to the IDSMC. The IDSMC will monitor the safety and protection of human subjects participating in the trial; the proper conduct of the trial; and the ongoing scientific integrity, validity, and clinical and scientific relevance. The IDSMC will provide recommendations about continuing, modifying, and/or stopping the trial based on considerations of treatment outcomes, patient safety, and trial futility as appropriate.
Communications
As the structure of the CONCOR-1 trial evolved, an organizational chart (Figure 4) was created to optimize flow of information to all relevant groups. Any protocol amendment will first require approval by the relevant national regulatory bodies then the methods centre will be responsible for communicating protocol amendments to the study sites (in the form of new versions of the protocol and a summary of changes document) and collecting copies of the necessary local approvals prior to implementation.
Access to Data
Study data may be made available to other investigators upon request. Such requests must first be approved by the Steering Committee.
Dissemination Plans
The principal investigators will be responsible for publication of the data (manuscripts, abstracts and posters, etc) and are committed to publish and disseminate the study results in a timely manner without excessive restriction, regardless of whether the initial study hypothesis is confirmed or not. Investigators will not publish any data without approval from the Steering Committee. Medical writers will not be used. Authorship eligibility will comply with the International Committee of Medical Journal Editors criteria. The CONCOR-1 protocol has already been shared with US and European coalitions to allow investigators to collaborate on a core protocol and to share data. Results will be disseminated to patients and the public through the CONCOR-1 website (https://concor1.ca/), the media and to various community groups identified by the study’s Community Advisory Committee members. Site investigators will also play a role in distributing results to patients and colleagues.
Ancillary and post-trial care
There is no specific ancillary or post-trial care related to the trial; however, patients will continue to receive standard of care for their underlying condition as per clinical practice. Insurance to cover the cost of compensation for participants who suffer harm from trial participation is available for Canadian and American participants.