PREPARE – Platform foR European Preparedness Against (Re-)emerging Epidemics|
Type of funding scheme:
Collaborative Project (large-scale integrating project)
Work programme topics addressed:
HEALTH.2013.2.3.3-1: Clinical management of patients in severe epidemics. FP7-HEALTH-2013-INNOVATION-1.
Name of coordinating person:
Prof. Dr. Herman Goossens
Representatives of CAPNETZ network:
Prof. Dr. Tobias Welte, Hannover Medical School
Prof. Dr. Mathias Pletz, Jena University Hospital
Prof. Dr. Gernot Rohde, Maastricht UMC+
Infectious diseases (ID) rank high among the greatest threats to human wellbeing and prosperity. Global trends such as globalisation, migration, tourism, intensive farming and changing climate enhance the likelihood of severe ID outbreaks occurring. The movements of people and goods is accelerating and exposed individuals can travel anywhere in the world in less than the incubation period of most dangerous pathogens; during this time, current technology cannot allow their detection. ID outbreaks therefore usually emerge unexpectedly and can – in the absence of timely containment – develop into epidemics or even pandemics, characterised by a rapid and sharp increase of the number of infected patients. Analysis of emerging ID events between 1940 and 2004 shows that Europe is a global hotspot for emerging ID events, along with the north-eastern United States, Japan, Asia and south-eastern Australia. As IDs will continue to emerge and re-emerge, leading to unpredictable epidemics and difficult challenges to public health, extensive pandemic and epidemic preparedness systems are needed to protect health and socio-economics in the EU.
Much progress has been made in the design and development of appropriate
structures and procedures for rapid and adequate ID outbreak public
health response measures by national and international health
authorities. Likewise, preclinical research responses to severe ID
threats and outbreaks by the scientific research community (e.g.,
epidemiological, microbiological, immunological and genetic research)
has also made important progress during the last decade in terms of the
ability to respond rapidly to ID outbreaks.
This is in sharp contrast
to the clinical research response, which is often delayed, isolated and
fragmented, having - as a consequence - little to no impact on
improving patient outcomes and developing high-quality evidence to
inform clinical management strategies.
PREPARE’s mission is to
address this gap by establishing a EUROPEAN CLINICAL RESEARCH FRAMEWORK
FOR HARMONISED LARGE-SCALE CLINICAL RESEARCH STUDIES ON INFECTIOUS
DISEASES, PREPARED TO RAPIDLY RESPOND TO ANY SEVERE ID OUTBREAK,
PROVIDING REAL-TIME EVIDENCE FOR CLINICAL MANAGEMENT OF PATIENTS AND FOR
INFORMING PUBLIC HEALTH RESPONSES.
Work Package 5
Title: PRACTICE 1c: European adaptive randomised controlled trial to improve survival in hospitalised patients with Severe Acute Respiratory Infection (SARI)
To inform evidence-based guidelines for optimal ICU management of patients with SARI, before and during EID outbreaks
- To select the most suitable interventions for evaluation in adult patients with SARI admitted to ICU;
- To finalise the design of a perpetual European adaptive RCT to improve survival in patients with SARI suited to rapidly adapt interventions and clinical syndromes (i.e. non-SARI) at the time of epidemics;
- To determine the effectiveness of different interventions in critically ill adult patients with SARI in reducing day-60 mortality when compared to standard care;
- To determine the effectiveness of different interventions in critically ill adult patients with SARI in reducing, when compared to standard care, hospital mortality, ICU length of stay, hospital length of stay, 30-day and 60-day organ failure free days and ventilation free days.
Description of work and role of participants
This is a perpetual (during course of PREPARE) European adaptive RCT evaluating the effectiveness of several (up to four) interventions in reducing day-60 mortality in adult patients admitted to ICU with SARI. Each intervention will be compared to standard care using a Bayesian approach for statistical analysis. We will use Response-Adaptive Randomisation (RAR) with futility and superiority thresholds that will help with search efficiency across a space of several different arms. This implies that the effectiveness of interventions will be compared to standard care (but not to other interventions) after two predefined numbers of recruitment, using predefined levels of critical improvement. Only if both levels of critical improvement are met, full patient recruitment will be continued. Interventions not reaching these predefined critical improvement levels will be discontinued. In all, we will recruit 2,000-4,000 patients, in about 100-200 ICUs, in 10-15 countries.
Candidate clinical sites (ICUs) sites will among others be selected from
the CAPNETZ network.
We will define inclusion and
exclusion criteria. The study will be performed in adult intensive care
units (ICU) and will have 2,000-4,000 patients enrolled. The targeted
patient population are subjects > 16 yr, admitted to ICU with fever
(>38.5°C) or hypothermia (<35.5°C), cough or sore throat, needing
invasive mechanical ventilation, with lung infiltrates on chest X-ray
and with either Pa02/ Fi02 ratio <300 or with septic shock. Depending
on the research question, the RCT may need generic exclusion criteria
such as known allergy to the study drug, pregnancy (if risk/benefit
ratio is unfavourable), imminent death, predicted life-expectancy less
than 60 days or declined consent. The microbiological aetiology will be
determined upon clinical samples obtained as part of standard care
procedures. Throat swabs and sputum samples will be obtained and stored
for further use.