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Abstract
Introduction COVID-19 convalescent plasma (CCP) is a possible treatment option for COVID-19. A comprehensive number of clinical trials on CCP efficacy have already been conducted. However, many aspects of CCP treatment still require investigations: in particular (1) Optimisation of the CCP product, (2) Identification of the patient population in need and most likely to benefit from this treatment approach, (3) Timing of administration and (4) CCP efficacy across viral variants in vivo. We aimed to test whether high-titre CCP, administered early, is efficacious in preventing hospitalisation or death in high-risk patients.
Methods and analysis COVIC-19 is a multicentre, randomised, open-label, adaptive superiority phase III trial comparing CCP with very high neutralising antibody titre administered within 7 days of symptom onset plus standard of care versus standard of care alone. We will enrol patients in two cohorts of vulnerable patients [(1) elderly 70+ years, or younger with comorbidities; (2) immunocompromised patients]. Up to 1020 participants will be enrolled in each cohort (at least 340 with a sample size re-estimation after reaching 102 patients). The primary endpoint is the proportion of participants with (1) Hospitalisation due to progressive COVID-19, or (2) Who died by day 28 after randomisation. Principal analysis will follow the intention-to-treat principle.
Ethics and dissemination Ethical approval has been granted by the University of Ulm ethics committee (#41/22) (lead ethics committee for Germany), Comité de protection des personnes Sud-Est I (CPP Sud-Est I) (#2022-A01307-36) (ethics committee for France), and ErasmusMC ethics committee (#MEC-2022-0365) (ethics committee for the Netherlands). Signed informed consent will be obtained from all included patients. The findings will be published in peer-reviewed journals and presented at relevant stakeholder conferences and meetings.
Trial registration Clinical Trials.gov (NCT05271929), EudraCT (2021-006621-22)
- COVID-19
- INFECTIOUS DISEASES
- Clinical trials
- Respiratory infections
- Blood bank & transfusion medicine
Data availability statement
No data are available.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Strengths and limitations of this study
The trial evaluates the efficacy of plasma from convalescent, vaccinated donors with very high antibody titres against COVID-19 in outpatients with the omicron SARS-CoV-2 variant.
The design of the study is pragmatic, with broad inclusion criteria, and a comparison with the current standard of care.
The adaptive design accounts for uncertainty in the frequency of the primary outcome.
The trial addresses the needs of underserved vulnerable patients.
The open-label design is a limitation of the study.
Introduction
The SARS-CoV-2 pandemic has caused more than 6.5 million deaths worldwide. Mortality has been 40% or more for hospitalised patients from clinically vulnerable groups.1–4 Clinically vulnerable patients, such as those with congenital immunodeficiency or patients who are immunocompromised due to underlying disease and/or immunosuppressive therapy, are at high risk of progression to severe COVID-19. These patients are also likely to develop persistent SARS-CoV-2 infection and may shed infectious SARS-CoV-2 particles for a prolonged time.5 6 Furthermore, immunosuppressed or immunodeficient patients are less likely to mount an effective immune response to SARS-CoV-2 vaccination.7 Consequently, treatment is urgently needed to prevent COVID-19 disease progression and hospitalisation in this population. To date, antiviral treatments are available, but their use is limited due to adverse events (AE), drug interactions and availability. Besides, the emergence of virus variants means that the newly developed anti-SARS-CoV-2 monoclonal antibodies (MoAb) may not sufficiently neutralise SARS-CoV-2.8
The use of COVID-19 convalescent plasma (CCP) has been considered a possible treatment strategy: early CCP could reduce morbidity and mortality from COVID-19, avoiding complications such as secondary bacterial infections, and the need for hospitalisation.9–13 In addition, CCP may benefit patients in whom SARS-CoV-2 vaccination may not elicit effective immune responses, such as the elderly, those with immunodeficiencies or those whose immune system is weakened due to an underlying disease or immunosuppressive therapy.11
Also, CCP administration in early COVID-19 may reduce long-term COVID-19 symptoms and improve quality of life. Other benefits could include a reduced strain on limited healthcare resources by reducing the number of COVID-19 hospitalisations and increasing resources for other urgent care in hospitals.
Many clinical trials on CCP have been conducted; however, data on efficacy has been heterogeneous. A recent systematic review and meta-analysis concluded that CCP was not significantly associated with a decrease in all-cause mortality or with any other benefit for other clinical outcomes compared with placebo or standard of care in unselected hospitalised patients with moderate to severe COVID-19. The overall certainty of evidence was high but the reported outcomes were variable in different groups of patients.11
These heterogeneous results could be explained by various aspects of the study design, methodology and patient characteristics. The volume of transfused CCP was low in some of the trials (≤400 mL), only a few studies defined a minimum anti-SARS-CoV-2 titre or the content of antibodies in CCP units was poorly characterised or only measured post hoc in some of the trials. The assays used for measuring anti-SARS-CoV-2 antibody concentrations and neutralisation titres varied substantially. Besides, most of these trials were initiated in spring 2020 when availability and information on comparability of antibody tests were limited.
In the planning period of the ‘first generation’ of clinical trials it was assumed that enrolled patients would be SARS-CoV-2 antibody-negative and that the passive transfer of CCP would convert patients from an antibody-negative to a positive status. It became apparent that a substantial proportion of patients in trials which enrolled hospitalised patients had already mounted a humoral immune response by the time of inclusion in the CCP trials.9 14–18 Among hospitalised patients who lacked SARS-CoV-2 antibodies at baseline, CCP decreased the need for mechanical ventilation or mortality compared with standard of care or placebo.9 11 14 19–21
The majority of trials allowed the inclusion of patients in stages 4–7 of the WHO 8-point Ordinal Severity Scale and a common feature in most of the trials published so far is the inclusion of hospitalised patients only.9 14–18 20–35 Only a few trials enrolled outpatients.9 12 13 36 37 In the Fundación INFANT COVID-19 Randomised Clinical Trial from Argentina, the administration of CCP less than 3 days after the onset of symptoms of COVID-19 in vulnerable patients reduced the risk of disease worsening compared with a control group by about 50% (16% after CCP vs 31% in the control group).38 A subgroup analysis by the concentration of SARS-CoV-2 Spike IgG titres in the transfused CCP units demonstrated that a significant reduction of progression to severe respiratory disease was observed in recipients of CCP with a titre at or above the median.38 A dose effect was observed also in other trials.16 38–41 Another large randomised study in the USA also demonstrated a reduced hospitalisation rate in patients with COVID-19 treated early with CCP.14
Based on the lessons learnt from past CCP trials, the COVIC-19 Clinical Trial combines several features, which distinguish it from previous CCP trials and constitute an innovative optimised treatment approach:
Immunotherapy with plasma containing very high concentrations of neutralising SARS-CoV-2 antibodies elicited by a combination of SARS-CoV-2 infection and vaccination;
Administration of CCP very early after onset of symptoms (within 7 days);
Viral sequencing and cross-neutralisation analyses in the patient population to study potential implications of viral evolution and immune escape.
Objectives
The COVIC-19 Trial is assessing whether administration of high-titre CCP in people with mild COVID-19 aged 70+ years, or under 70 years with comorbidities or immunosuppression, reduces the risk of hospitalisation or death within 28 days. Additional objectives are to demonstrate whether CCP benefits clinically vulnerable patients (including long-term complications) and to provide a framework for the administration of CCP for outpatient care. Moreover, COVIC-19 will monitor the virological response to CCP by measuring SARS-CoV-2 RNA levels, anti-SARS-CoV-2 antibody titres, and the emergence of virus variants by whole-genome sequencing and virus isolation.
Demonstrating the effectiveness of CCP in the outpatient settings may inform future lockdown policy and influence healthcare resource planning. Importantly, at the onset of a pandemic, or in case of the emergence of a variant resistant to all available MoAB, CCP may be the only passive immunotherapy approach widely available.
Methods and analysis
Design
COVIC-19 is a multicentre international, randomised, open-label adaptive superiority phase III trial to evaluate the efficacy and safety of high-titre CCP in the early treatment of SARS-CoV-2 infected patients who are at risk of progression to severe COVID-19. It is conducted in a harmonised approach in Germany, the Netherlands, France and the UK. COVIC-19 will evaluate the efficacy of CCP collected from donors with high-titre neutralising SARS-CoV-2 antibodies plus standard care in reducing the risk of hospitalisation in people with early COVID-19 compared with standard care alone.
The study will randomise adult patients with COVID-19 into one of two arms (1:1): standard of care or CCP with very high neutralising antibody titre in addition to standard of care. Randomisation will be stratified by centre and by cohort. Patients will be included in two cohorts of vulnerable patients. Cohort 1 consists of unvaccinated elderly patients ≥70 years and cohort 2 comprises immunosuppressed patients (figure 1). All subjects will undergo a series of efficacy and safety assessments, including laboratory assays (at baseline, days 3, 14, 28, 90 and 180).
Trial design schematic. PRNT, Plaque reduction neutralisation test.
Nasopharyngeal swabs or oral samples will be obtained at day 1 (baseline/pretreatment), and at days 3, 14, 28 and 180 (and monthly in case of positivity till clearance) for cohort 2 and on the day of hospitalisation (if applicable).
Blood samples will be obtained at day 1 (baseline), 14 and 28 and on the day of hospitalisation (if applicable).
Trial participants
The main eligibility criteria for the two patient cohorts are: men or women currently displaying symptoms of COVID-19 but not requiring admission to hospital for COVID-19 disease or oxygen support; SARS-CoV-2 RNA detected in a specimen within 7 days of onset of symptoms. Specific criteria for each cohort are: (1) Elderly and high COVID-age population: patients, aged 70 years or older, or under 70 years with significant comorbidities resulting in a COVID-age of 70 years or more according to the Association of Local Authority Medical Advisors (ALAMA) risk calculator, and (2) High-risk immunocompromised population: patients with primary (B, T, combined) or acquired (lymphoid or myeloid malignancies, solid tumour with ongoing chemotherapy, allogenic haematopoietic stem cell transplantation, organ transplantation, immunosuppressive treatments, AIDS, etc), immunodeficiencies or patients without detectable seroconversion ≥3 weeks after complete vaccination schedule with an approved vaccine. Patients eligible for either cohort will be included in the immunocompromised cohort.
The main exclusion criteria are: age <18 years (except in the UK); history of documented SARS-CoV-2 infection in the last 90 days prior to enrolment; unauthorised prior or concurrent treatment for COVID-19 (currently MoAb and nirmatrelvir-ritonavir/Paxlovid are authorised in the trial); patients for whom transfusion will not be completed within 7 days of symptom onset; and prior SARS-CoV-2 vaccination (only for cohort 1).
Interventions
Convalescent plasma
The intervention consists of two plasma units provided by COVID-19 convalescent donors, fully compliant with national regulations. The intervention will be administered in addition to the standard of care at the time of randomisation. The first unit of ABO compatible convalescent plasma (200–350 mL per unit) will be infused intravenously as soon as possible after randomisation and the second on the same day or the next day according to anticipated patient tolerance. Plasma has been obtained by apheresis from donors who have recovered from COVID-19 infection (at least 14 days after recovery) and have been vaccinated (at least 3 weeks after first dose of vaccine). As far as availability allows, the plasma units should have been donated by two different convalescent donors. Plasma should contain a minimum neutralising antibody titre of 1:640 against delta (B1.617.2), omicron or any future SARS-CoV-2 variant, or an anti-SARS-CoV-2 antibody concentration ≥4.000 binding antibody units/mL (BAU/mL) measured by the QuantiVac anti-SARS-CoV-2 IgG ELISA (Euroimmun) or ≥20.000U/mL measured by the anti-SARS-CoV-2 Elecsys test (Roche).
Standard of care
The standard of care for COVID-19 is evolving rapidly. We will take specific measures to ensure that the standard of care used in participating patients remains comparable in both arms over the inclusion period. Whenever necessary, the trial steering committee will provide updated guidelines regarding the standard of care and will strongly recommend that participating centres observe them. These recommendations may consider the local availability of COVID-19-specific medications such as MoAb.
Currently, the following COVID-19 medications are authorised for use as standard of care in patients enrolled in the study as pre-exposure prophylaxis, postexposure prophylaxis, as well as early treatment: MoAb (including casirivimab/imdevimab, regdanvimab, sotrovimab and tixagevimab/cilgavimab) and antiviral drugs (molnupiravir, nirmatrelvir/ritonavir and remdesivir).
Randomisation
Patients will be enrolled by their treating physician in the participating centres. Eligible patients will be allocated using a central web-based randomisation service (CleanWeb, Telemedicine Technologies, Boulogne Billancourt, France). The randomisation service will allocate the treatment based on a prespecified randomisation list generated by the data manager. Separate randomisation lists will be used for each patient population. Randomisation will be performed at a 1:1 ratio, blocked (with randomly varying block sizes of two and four) and stratified by centre.
Outcomes
The primary endpoint is the proportion of participants with (1) At least one overnight stay in hospital for progressive COVID-19 symptoms, or (2) Who died, by day 28 after randomisation. COVID-19 related hospitalisations will be adjudicated using a three-member panel. Each member will independently come to a decision on whether the hospitalisation or decision to extend a hospitalisation was or was not related to COVID-19 using as much information that could be provided such as hospital discharge forms but remain blinded to the randomisation group. Classification of whether the hospitalisation was due to COVID-19 will be by majority decision of the panel.
Secondary outcome measures include core outcomes from the meta-core outcome set (COS) for hospitalised patients (http://www.comet-initiative.org/Studies/Details/1538), and the WHO progression scale.42 There is no COS for patients with COVID-19 managed in the community. Viral outcome measures will enable assessment of mechanism.
Efficacy secondary endpoints are: proportion of participants with hospitalisation for progressive COVID-19 symptoms, or death by day 14 after randomisation; proportion of participants with hospitalisation for progressive COVID-19 symptoms requiring O2 support (requirement based on O2 saturation level on room air ≤93% and/or respiratory rate >30), or death by days 14 and 28 after randomisation; all-cause mortality by days 28, 90 and 180 after randomisation; proportion of patients with supplemental oxygen by days 14 and 28 after randomisation; proportion of patients with non-invasive ventilation by days 14 and 28 after randomisation; proportion of patients with intubation and mechanical ventilation by days 14 and 28 after randomisation; change in 10-point WHO Clinical Progression Scale Score by days 14 and 28 after randomisation; duration of hospital admission censored at 28 days after randomisation (for participants reaching primary endpoint); proportion of patients with admission to Intensive Therapy Unit (ITU)by days 14 and 28 after randomisation; duration of ITU admission censored at 28 days after randomisation; proportion of patients with long COVID-19 symptoms and time to recovery assessed by questionnaire at days 28 and 180 postrandomisation; health-related quality of life assessed using the EQ-5D-5L at days 28 and 180 after randomisation
Safety outcomes are: number of serious AE at 72 hours after randomisation (Grade 3/4 AE and AE unexpected for their nature, onset, evolution, severity or frequency); number of participants with arterial and venous thromboembolic events at days 28, 90 and 180 after randomisation.
Exploratory endpoints are: change in SARS-CoV-2 RNA level (PCR, cycle threshold value) in oral or nose/throat swab samples at days 3, 14, 28 and 180 after randomisation (cohort 2 only); change in anti-SARS-CoV-2 spike antibody levels in blood at days 14 and 28 after randomisation; SARS-CoV-2 whole-genome sequence analysis in oral or nose/throat swab samples at days 1 and 28 after randomisation; proportion and clinical characteristics of patients with cultivable virus at day 28, hospitalisation and day 180; virus sequence variation and cultivability over time, overall and in individuals receiving versus not receiving CCP.
Data collection
For all participating centres, patient characteristics and outcome data will be obtained from the patient records and collected via CleanWeb e-Case Report Form (e-CRF). CleanWeb is Good Clinical Practice (GDP), International Council for Harmonisation (ICH), General Data Protection Regulation (GDPR) and 21 CFR part 11 (Food and Drug Administration) compliant. All data collection and management will be performed in accordance with the European Union’s GDPR. A unique de-identified number will identify all patients, and no patient identifiers will be kept with clinical data. Data can only be accessed by the site investigator and supporting staff. In each country, the country’s final data set will be available to the principal investigator. The research data will be stored at the coordinating centre for 2 years after the last publication of the research results or, without publication, after the final research report is signed.
Sample size
Libster et al observed a 31% risk of severe COVID-19 disease in the control group of their study in an elderly high-risk population with a similar intervention of convalescent plasma.12 The relative risk of severe COVID-19 in treated patients was 0.52 (95% CI 0.29 to 0.94). We estimate that the risk of severe COVID-19 in the elderly population will be 30% and that our intervention will reduce the risk of hospitalisation by 50%. Sample size calculations based on a Z-test, a two-tailed α of 0.05, a 1-β of 0.90, and a relative risk of 0.5 require 316 patients per cohort (632 in the trial). The sample size is increased to 340 (680 total) to account for missing data/loss to follow-up.
The SARS-CoV-2 pandemic is a constantly evolving situation and with the appearance of new variants, there is considerable uncertainty as to the real risk of severe COVID-19 in the population. There is little data regarding the risk of severe COVID-19 in the immunocompromised population. Moreover, the effect observed by Libster et al may be overly optimistic by chance and may be different in our trial. If the effect is overestimated, the trial may not achieve the desired power. Thus, we will include a sample size re-estimation during the course of the trial as a form of adaptive design. For each cohort, sample size re-estimation will be planned using the method proposed by Mehta and Pocock.43 Specifically, an interim analysis will be conducted when 30% of the patients have reached the primary endpoint. The conditional power for detecting the difference in primary outcome between the two arms in the final analysis will then be estimated. If the conditional power is between 50% and 90%, the sample size will be increased in order to achieve 90% power to detect the effect observed at the interim analysis with a maximum sample size of 1020 per cohort. Otherwise, the trial will continue using the planned sample size.
Recruitment schedule
Enrolment in the study is ongoing in Germany, the Netherlands and France. The first participant was enrolled in Germany on 11 April 2022, at Charité Hospital in Berlin. We anticipate the recruitment period will last 2 years for an estimated study completion date of 30 June 2024.
Statistical methods
The analyses will be performed according to the intention-to-treat (ITT) principle. The ITT population (by patient cohort) will be used for all efficacy analyses. A modified ITT population excluding patients who were randomised in error will be considered.
A detailed statistical analysis plan will be developed by the investigators while still blind to any analyses of aggregated data on study outcomes by treatment allocation.
Although conducted as a single trial separate randomisation lists for each cohort, the findings in each cohort are considered as separate trials and will be analysed separately.
All outcomes will be analysed in superiority (two-sided) analyses using simple hypothesis tests. As sensitivity analyses, generalised linear models will be used to account for stratification on the centre. No correction for multiplicity and no hierarchical testing procedures are planned in analysing secondary outcomes. These analyses will therefore be considered as exploratory in nature.
Primary endpoint analysis
The primary outcome will be analysed using a two-sided Z-test to compare proportions of events in the randomisation groups. The risk difference will be provided with its 95% CI. As a sensitivity analysis accounting for stratification on the centre, the endpoint will be analysed using a generalised linear mixed model (with logit link) with a random centre effect. Adjustment for major prognostic factors will be considered depending on the evolution of medical knowledge on the prognosis of patients infected by SARS-CoV-2.
Chen et al have shown that if one increases the sample size only when the interim result is promising, the type 1 error is not inflated by use of the conventional Wald statistic.44 The significance level of the primary analysis will therefore remain at 0.05.
Secondary endpoints analysis
Binary outcomes will be analysed using Z-tests or Fisher’s exact tests. When appropriate, risk differences will also be provided with their 95% CIs. As a sensitivity analysis, generalised linear mixed models (with logit link) with a random centre effect will be performed. Time-to-event outcomes will be analysed using log-rank tests with sensitivity analyses based on Cox regression models with a random centre effect (results will be expressed as HRs with 95% CIs). Finally, quantitative outcomes will be analysed using Student’s t-tests or Mann-Whitney tests, as appropriate. Sensitivity analyses will consist of mixed linear regression with a random centre effect (results will be expressed as mean differences with 95% CIs).
Subgroup analyses
Exploratory analyses of the primary endpoint and other safety and efficacy endpoints will be conducted in subgroups of subjects including but not limited to SARS-CoV-2 variant identified at inclusion, SARS-CoV-2 vaccinal status at inclusion, anti-SARS-CoV-2 MoAb received, and the cumulative dose of antibody received. The interactions between experimental treatment and vaccinal status as well as the dose of antibody received will be explored and tested.
Data safety and monitoring
An independent data safety and monitoring board will review annual safety reports of patient baseline characteristics, serious AE and safety outcomes including all-cause mortality. No formal stopping rules were implemented.
Study management
A steering committee has been established with the overall responsibility for the design, execution and analysis of the trial. The coordinating centre is located at the clinical investigation centre, Centre Hospitalier Universitaire (CHU) de Besançon, Besançon, France. Personnel at the coordinating centre include the study principal investigator for France, study coordinators, biostatisticians and data managers. The coordinating centre is responsible for international coordination of the trial, centralised data collection and analysis. In each participating country a coordinating centre is responsible for day-to-day management of the trial. The study coordinator is responsible for checking protocol adherence weekly and address trial-related issues that may arise during the study.
Patient and public involvement
Representatives of a patients and public involvement group of immunosuppressed patients were involved in the early stages of study design in the UK. The study protocol was also presented to patient representatives involved in the Support-e project.
Ethics and dissemination
Approval has been obtained from research ethics board of all involved institutions (University of Ulm ethics committee decision #41/22 on 12 April 2022; Comité de protection des personnes Sud-Est I #2022-A01307-36 on 11 July 2022; ErasmusMC ethics committee decision #MEC-2022–0365 on 2 August 2022). The amendments to the protocol are described in table 1. Protocol V.2.2 is the one described here. No patient will be recruited before institutional approval is obtained. Signed informed consent will be obtained from all included patients (see online supplemental material).
Supplemental material
Protocol amendments
From the early development of the trial, we have involved experts in the care of patients with COVID-19 as well as blood establishment stakeholders, specialists in the organisation and research of transfusion (haematologists, transfusion specialists, healthcare researchers, epidemiologists, blood organisation decision makers and senior scientists). This diversity of expertise will ensure that the objectives, methods, and results analysis and interpretation answer pertinent questions for clinicians and patients.
For clinicians and researchers, traditional dissemination will be used, including publication in relevant peer-reviewed medical journals and presentations at local, national and international conferences and meetings. We will work closely with the stakeholders of the blood establishments involved and the different clinical specialties to provide reports for the specific needs of their organisations/disciplines. We plan to reach out to these organisations to present our results, and the team members will be readily available for further discussions, meetings or presentations to answer their specific needs and questions.
Discussion
The ongoing trial is the first to include convalescent plasma with very high antibody titres from convalescent and vaccinated donors. Antibody titres in CCP may vary significantly and higher titres may address previous inconsistencies in CCP efficacy observed in prior studies. We also took specific steps to standardise the CCP titres across antibody assays to improve antibody dose standardisation.
High-titre CCP may represent a therapeutic modality superior to MoAb, in that it stems from a polyclonal immune response which covers a broader range of viral epitopes and may prevent the selection of immune resistance. CCP can also readily be adapted to emerging viral variants since collection can occur as early as 4 weeks after symptom resolution in a donor.
Promising results from non-randomised studies45–47 or subgroup analyses of randomised trials11 19 48 49 and recent meta-analyses11 50 show that immunocompromised patients may benefit from the use of CCP in COVID-19. COVIC-19 is the first randomised study to specifically address this population. Long-term viral persistence has been observed in immunocompromised patients and is associated with SARS-CoV-2 immune evasion. COVIC-19 will also provide data regarding the emergence of resistant variants in immunocompromised patients treated with CCP and other treatments.
We acknowledge that patients in the unvaccinated, elderly or high COVID-age cohort are currently unlikely to participate in COVIC-19. The trial was conceived at a time where the likelihood of variants resistant to treatment was of concern (and may still be). However, the risk of resistant variants is still very much present. The open-label design is also a limitation of the study.
Overall, COVIC-19 will provide needed robust evidence regarding the use of CCP in COVID-19 in currently underserved segments of the population.
Data availability statement
No data are available.
Ethics statements
Patient consent for publication
Acknowledgments
The authors wish to thank all trial personnel involved in participating centres and in the blood establishments, and the plasma donors who make the study possible.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
MD and SH are joint first authors.
Contributors LE, DJR, DB, HS, PT, conceived the study. LE, DJR, DB, HS, PT, ET, MD initiated the study design and CV, GB, CEV, HH, AD, SK, ESc, BJAR, TA, ESe helped with implementation. HS and BJAR are grant holders. MD provided expertise in clinical trial design and will conduct the primary statistical analysis. MD, SH and HS wrote the initial manuscript. All authors contributed to refinement of the study protocol and approved the final manuscript
Funding This work is supported by the Support-e project, a project funded by the European Union’s Horizon 2020 research and innovation programme (grant number 101015756, www.support-e.eu), the German Bundesministerium für Bildung und Forschung (BMBF, Projektträger VDE/VDI grant number 16LW0108), and ZonMw, the Netherlands Organisation for Health Research and Development (grant number 10430062010001). The funding sources had no role in the design of the study and will not have any role during its conduct, analysis, interpretation of findings or decision to submit results.
Competing interests PT is an employee of Établissement Français du Sang, the blood establishment responsible for blood collection, qualification and supply in France. HS, SH, SK, TA and ES are employees of the German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen (or its affiliates), the establishment responsible for blood collection, qualification and supply in Baden-Württemberg and Hesse, Germany. CEV, is an employee of Sanquin, the establishment responsible for blood collection, qualification and supply in the Netherlands. The authors declare no other competing interests.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Not commissioned; peer reviewed for ethical and funding approval prior to submission.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.