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Platform foR European Preparedness Against (Re-)emerging Epidemics

Periodic Report Summary 5 - PREPARE (Platform foR European Preparedness Against (Re-)emerging Epidemics)

Project Context and Objectives:
The global health threat posed by infections with epidemic potential grows ever greater. Europe has amongst the best healthcare systems in the world, as well as the world’s supreme researchers in this field. Yet, despite years of global preparations for a potentially devastating influenza pandemic or the next SARS-like outbreak our clinical research response to severe infectious disease (ID) outbreaks is delayed, isolated and fragmented. Recent epidemics have shown that important pathogenesis and clinical management data mostly came from sites that were already undertaking related clinical studies or from established national or regional research networks. As a result, clinical research in response to severe ID outbreaks has relatively little to no impact on improving patient outcomes and developing high-quality evidence to inform clinical management strategies.
These experiences have demonstrated that unless something is done now to change the approach to clinical research in severe infections, the next epidemic will result in a similar missed opportunity to save lives and advance medical knowledge. PREPARE (Platform for European Preparedness Against (Re-)emerging Epidemics) is to address this shortcoming by establishing a European clinical research framework for harmonised large-scale clinical research studies on IDs, prepared to rapidly respond to any severe ID outbreak, providing real-time evidence for clinical management of patients and for informing public health responses.
Covering over 600 primary care sites and over 600 hospital sites in more than 40 European countries and harbouring EU’s leading academic research groups on IDs, PREPARE will transform Europe’s research response to future severe epidemics or pandemics. By establishing a common European clinical research infrastructure, PREPARE will be a one-stop shop for policy-makers, public health agencies, regulators and funders of research into pathogens with pandemic potential. It will achieve this by implementing ‘inter-epidemic’ research programmes covering large scale observational, interventional and adaptive clinical studies in adults and children, patient-oriented studies into the pathogenesis of IDs and development of novel near-patient diagnostics. An important supporting effort of these ‘peace time’ studies will be the development and testing of pre-emptive solutions to ethical, administrative, regulatory, logistical and clinical bottlenecks that prevent rapid clinical research responses in the face of new threats. In addition, together with large European societies ERS, WONCA Europe, ESWI and ESCMID, PREPARE will invest in education and training of the members of the clinical network and external opinion leaders, funders and policy makers, strengthening our collective capacity and streamlining our future response.
The peacetime studies will train PREPARE in mounting a rapid, coordinated deployment of Europe’s elite clinical investigators. As such, PREPARE will be at the basis of establishing a paradigm shift in clinical research in response to severe ID outbreaks.
PREPARE has its roots in the International Severe Acute Respiratory Infection Consortium (ISARIC), and builds on established clinical research networks (GRACE, TRACE, COMBACTE, CAPNETZ, PENTA and SERGAS) and pre-clinical FP7 funded research networks (EMPERIE, ANTIGONE, PREDEMICS, RAPP-ID).
Project Results:
PREPARE has reached full speed with the successful continuation of its clinical trials. WP1 completed the analysis of its cross-sectional survey regarding public views on research participation during a public health emergency, it also completed its analysis of interviews conducted with ALIC4E researchers and patients in Belgium, Sweden and the UK and drafted a report of its findings.
WP2 provided a report on health utilization, clinical management and outcomes based on the systematic review of European clinical management guidelines. WP3 observational MERMAIDS studies, Acute Respiratory Infections (ARI), Arboviral Compatible Febrile Illness (ARBO) and Community Acquired Sepsis-Like Syndrome and Paediatric ARI in infants and children (PED), are currently recruiting: ARI started seasons 3 and 4 on 1st Oct 2017 and on 1st Oct 2018 respectively in a multitude of sites in 8 countries, allowing to achieve the 1000 mark for recruitment (total of 1.384 to date). ARBO recruited 263 patients in season 2 (May-Oct 2017) and 258 patients in 22 sites in season 3 (May-Oct 2018), bringing the total inclusion to 683. PED is recruiting in 19 sites in its third season with 737 patients included to date (117 SLS, 347 ARI, 273 controls).
The WP4 ALIC4E study on the clinical and cost effectiveness of oseltamivir for influenza like illness (ILI) in primary care completed participant recruitment (total inclusion of 3,266 over three flu seasons). It also completed follow up, data entry, data clearing, and much of the analysis of the ALIC4E trial and organized a very successful final meeting in October 2018, attended by representatives of the networks that implemented the study.
The WP5 REMAP-CAP study, a Randomized Embedded Multifactorial Adaptive Platform trial to improve survival in patients with severe Community Acquired Pneumonia, has made remarkable progress in period 5, even though it is still suffering from inevitable delays caused by contracting, GDPR legislation, and other (changes in) trial-related regulations. However, patients were included in multiple centers across the globe, with 5 sites open and recruiting (1 Ireland, 2 Netherlands, 1 Spain, 1 Portugal), 2 sites open for recruitment (Netherlands) and 7 sites fully executed contract but not yet activated.

WP6 developed and validated bioinformatic pipelines for host transcriptome analysis (i.e. primary outcome measure of ARI). A microarray platform for use in ARI was selected and high throughput interactomic pipelines to analyze host-pathogen interactions were developed. Influenza virus challenge studies in 24 human volunteers were completed to support understanding of biological processes in naturally infected patients participating in ARI. Generation of transcriptome data of ARI season 3 patients as well as all patients with confirmed bacterial respiratory infections will be completed by mid 2019. A manuscript describing EBOV-MARV interactomics is in preparation.

WP7 continuously prepared and sent sampling kits to all sites in ALIC4E and ARI (to date, a total of 35,063 kits have been prepared to provide all centres with their requested study materials). 118 season 3 ALIC4E samples were analysed with Idylla. A manuscript concerning the analytical performance of Idylla is being prepared. The samples for the ARBO MERMAIDS were processed with priority in view of the increasing West Nile activity in Europe. UKBonn PI and team moved to Charité – Universitätsmedizin Berlin, Institute for Virology in 2017. The institute at CHARITE is equipped with a brand-new laboratory, which is fully operational since 2018 and no delay in processing of samples were seen in 2018.
The data management systems Research Online for data collection of the trials and the randomization application which enables the adaptive design randomization of ALIC4E and REMAP-CAP are continuously improved (WP8). The eCRF’s for the MERMAID PED, MERMAID ARBO and MERMAID ARI studies were adapted for the subsequent season and kept in production. To enable the use of the Australian randomisation module in combination with the follow-up of the subject with the eCRF in Research Online, a web service is being developed that will integrate both systems.
WP9 organized several conferences through the societies ERS, WONCA and ESCMID, and provided educational and learning resources through the PREPARE Virtual Learning Centre. A high-level strategic plan for the long-term sustainability of PREPARE into the European Clinical Research Alliance on Infectious Diseases (ECRAID) has been developed in collaboration with COMBACTE.

Potential Impact:
PREPARE will create a paradigm shift in clinical management of patients in any severe ID outbreak through a rapid and powerful clinical research response. By addressing key issues such as cooperation among health authorities, clinicians and scientists; involvement of clinicians in alert and response mechanisms; preparedness to rapidly conduct clinical research; and availability of epidemic clinical management tools such as POC diagnostics and treatments with proven effectiveness, PREPARE creates the fundament for highly-effective and coordinated European clinical action aimed at controlling ID outbreaks. This will be an important milestone in the EC vision on integrating European scientific excellence and making Europe better prepared for emerging epidemics, and fully in line with the 15th recommendation made by the IHR review committee which emphasizes the need for a comprehensive clinical research and evaluation programme towards good practice in pandemic preparedness.
PREPARE’s will have an impact on Europe’s operational capacity to rapidly initiate a clinical research response to severe infectious diseases outbreaks through the implementation of solutions to EARL bottlenecks, a stand-by European clinical research network, the availability of evidence based clinical case definitions, protocols and guidelines for clinical studies, a stand-by platform for rapid deployments of large scale pathogenesis studies, and a stand-by European diagnostic and typing platform.

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