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Platform foR European Preparedness Against (Re-)emerging Epidemics

Periodic Report Summary 3 - 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 nearly reached full speed with the successful launch of its clinical trials. WP1 provided an update on ‘A provider and a user assessment of EARL hurdles for research in Europe’, and a ‘EARL barriers solution’ report building on primary empiric work from the PREPARE observational and intervention studies and incorporating aspects of preparedness planning.
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 2 on 1st Oct 2016 (target of 2000 patients, to date 415 recruited). Analyses of patients from season 1 (Jan-April 2016) suggests that assumptions for sample size calculation were appropriate with respect to expected prevalence of comorbidities and respiratory pathogens. ARBO recruited 162 patients (target 1500) in season 1 (May-Oct 2016) and interim analyses of the collected data are ongoing. PED is recruiting in 11 countries (Sep 2016-Dec 2018) and has currently included 37 patients (target 1000).
The WP4 ALIC4E study on the clinical and cost effectiveness of oseltamivir for influenza like illness (ILI) in primary care is recruiting across 3 flu seasons in 21 networks in 16 European countries. To date 1660 participants are randomized. 50% of patients with ILI in season 1 were positive for the influenza virus when nasal/nasopharyngeal swabs were tested on Idylla.
The WP5 REMAP-CAP study, a Randomized Embedded Multifactorial Adaptive Platform trial to improve survival in patients with severe Community Acquired Pneumonia, was extended to Australia/New Zealand (ANZIC network) and the protocol was revised to have a global core protocol. Expectation is to start enrollment in 2017 in more than 100 ICUs across Europe.
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 15 human volunteers were completed to support understanding of biological processes in naturally infected patients participating in ARI. Transcriptome analyses of ARI and challenge studies samples are ongoing.
WP7 continuously prepared and sent sampling kits to all sites in ALIC4E and ARI. The validation of Idylla was finalised after improvement of the assay based on initial QCMD-panel results. The first ALIC4E samples were successfully analysed both with Idylla and a multiplex PCR. Evaluation studies of pooled RT-PCR serum testing for arboviruses for preanalytics in ARBO have been continued. In response to the Zika virus outbreak, several initiatives have been taken and new sensitive and specific molecular tools have been developed. A micro-array for simultaneous detection of antibodies for a range of arboviruses has been developed.
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). A repository of PREPARE study sites has been created facilitating the rapid implementation of sites in case of future outbreak studies.
WP9 organized several conferences through the societies ERS, WONCA, ESCMID, and ESWI, and provided educational and learning resources through the PREPARE Virtual Learning Centre. A successful Arbovirus external course was organized in Greece (March 2016) for ARBO participants. 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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