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Platform foR European Preparedness Against (Re-)emerging Epidemics

Periodic Report Summary 6 - 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:
WP1 has mapped and identified EARL barriers and cultural barriers in Europe in several reports that have been periodically updated. The team developed an “EARL database solution” by working with the PREPARE data management WP (WP8). This work involves tracking key performance indicators for PREPARE clinical studies and has been extended through collaborations with the COMBACTE hospital network. WP1 has also developed a range of tools to capture EARL experience in the PREPARE clinical work packages including data capture tools for contracting, ethics and other regulatory approvals and a ‘lessons log’ for capturing recruitment experience.

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 season 5 on 1st Oct 2018 recruiting 393 patients in 7 primary care and 22 secondary care sites (total of 1.524 to date, largely exceeding the landmark of 1.000 recruitments). ARBO recruited 227 patients in season 4 (May-Oct 2019) in 22 sites, bringing the total inclusion to 930. PED is recruiting in 19 sites in its fourth season with 848 patients included to date (128 SLS, 381 ARI, 339 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 final trial report was published on the EU Clinical Trials register on the 26th July 2019.
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 6, even though it is still suffering from inevitable delays caused by contracting, GDPR legislation, and other (changes in) trial-related regulations. An amended version of the CORE protocol was approved. In addition, a new version of the corticosteroid domain (adding a new arm), the antibiotic and macrolide domains and a new domain to investigate the use of oseltamivir in severe CAP patients were approved and initiated. The eCRF has been extensively revised to align this with the other regions of the REMAP-CAP study. One eligibility CRF is currently in use globally and has a modular build to facilitate new domains and interventions entering the trial. Trial management procedures have been aligned globally and frequent meetings at all levels (PM, DSWGs, EU RMC and ITSC) ensure global collaboration. 140 patients were included in 26 centres in Ireland, Netherlands, Spain, Portugal, UK, Germany, Belgium, Croatia, Romania and Hungary. To facilitate recruitment and increase site performance, we continue to work with 3 subnetworks in Europe. Representing institutions of the NET-GER (Jena University) and NET-UKD (ICNARC) were included as partner in the PREPARE consortium.
WP6 performed viral diagnostic analyses for the PREPARE PEDS-Mermaids Acute respiratory tract infection (ARI) and sepsis like illness (SLS) study (WP3). A manuscript describing the PEDS-Mermaids ARI has been submitted for publication.
To date, blood gene expression profiles have been generated from acute and convalescent specimens of 835 MERMAIDS participants (338 primary care, 497 hospitalized), representing the largest study of this kind to date. Analyses are ongoing which, in addition to gaining insight into disease pathogenesis of several respiratory pathogens across different comorbidities, are aimed at novel prognostic and diagnostic markers of acute respiratory infections.
Detailed analyses using specimens and data from the PREPARE influenza challenge study in human volunteers have generated insights into influenza pathophysiology.
As PREPARE switched into COVID-19 outbreak mode, WP6 started to build a COVID-19 literature mining and question answering portal, which is applied as part of a multipartner COVID-19 Disease Map collaboration.
WP7 continuously prepared and sent sampling kits to all sites in ALIC4E and ARI. The samples for the ARBO MERMAIDS were processed with priority in view of the increasing West Nile activity in Europe. To validate protein microarray to use it for PED-MERMAIDS, serum samples collected at the Erasmus MC from children were tested using a protein microarray containing 38 different recombinant proteins of influenza virus hemagglutinin (HA1-part), and 10 different recombinant proteins of the spike protein of Corona virus. 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 2019.
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 for the MERMAID ARBO study was kept in production to enable further patient inclusions into the study and perform data entry within the eCRF. The subject inclusions and data entry for the MERMAID PED and MERMAID ARI studies were closed during period 6, the eCRFs for both studies have been kept in a stand-by mode. The eCRF for the WP5 REMAP-CAP was adapted according to version 3.0 of the protocol and has been aligned with the Australian eCRF (Spiral).
WP9 organised and delivered a PREPARE symposium at European Respiratory Society Congress Madrid on 29 September 2019, targeted at broad spectrum of stakeholders. PREPARE co-organised the Fourth Arbovirus course together with ESCMID (held in Ljubljana on 19-21 March 2019. 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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