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  • Periodic Report Summary 6 - EUROHYP-1 (European multicentre, randomised, phase III clinical trial of hypothermia plus best medical treatment versus best medical treatment alone for acute ischaemic stroke)

Periodic Report Summary 6 - EUROHYP-1 (European multicentre, randomised, phase III clinical trial of hypothermia plus best medical treatment versus best medical treatment alone for acute ischaemic stroke)

Project Context and Objectives:
The social and economic burdens of stroke are enormous. Stroke is the second cause of death in the European Union (EU), with over 500,000 deaths each year. Taking the EU27, Croatia, Iceland, Norway, and Switzerland together, Eurostat estimates, based on hospital discharge reports, a staggering 1.9 million strokes per year, with an estimated 1.33 million new strokes and 0.57 million recurrent events. Considering that the large majority of stroke patients (80 to 85%) have ischaemic events - these represent about 1.52 million ischaemic strokes every year in Europe. Therefore, most of the stroke burden is because of ischaemic stroke, and for this reason EuroHYP-1 focuses on ischaemic stroke in order to answer this most pressing need.
Project Objectives:
(1) Generate robust evidence (Class I) about the therapeutic effects of mild hypothermia (34-35°C) in patients with acute ischaemic stroke. The objective is to perform a trial with the highest quality standards in terms of trial design and conduct. This objective will be achieved via the completion of a trial which has been conceived based on the direct involvement and advice of the leading European stroke scientists and the support by pan-European stroke organisations (for example the European Stroke Organisation - ESO).
(2) Share and disseminate effectively the data generated with the clinical study in order to inform evidence-based recommendations about the effect (benefit, futility, or harm) of mild hypothermia (34-35°C) for patients with acute ischaemic stroke started within 6 hours of onset.
(3) In case of positive results, support the adoption of the new treatment in all European Member States, as well as other regions in the world through a focused effort to influence guideline development and clinical best-practice dissemination. This effort aims at changing current clinical practice and will be conducted in close collaboration with the European and National Stroke Associations, forums that regularly organize Medical Education Events.
(4) Embedded into the randomized clinical trial design are supplementary studies that will identify patient characteristics: gender and age, imaging or biochemical characteristics - predicting benefit, futility or harm of mild hypothermia (34-35° C).
(5) Through the use of a state-of-the-art imaging platform, to test the hypotheses that the protective effect of cooling is accompanied by a reduction in infarct size, reduced brain swelling, and a reduced incidence of haematoma formation in patients who have also received thrombolysis.
(6) To validate with undisputed, robust clinical evidence several leading theorems linked to the beneficial effect of cooling, by analysis of brain damage and inflammation-related biomarkers. Importantly, these biomarkers will be provided and studied in close collaboration with innovation-oriented SMEs from Europe.
(7) To determine the health-economic impact of therapeutic cooling. Specifically, economic analysis will assess the hypothesis that therapeutic cooling - in spite of the higher initial, acute-care costs - reduces expenditure in the rehabilitation and long-term care and alleviates the burden on health care systems and families.
(8) The incorporation of cooling technologies produced and developed by research-oriented European SMEs. Accordingly, the objective is to create an innovation platform, enabling the further improvement in the area of cooling technologies.
Project Results:
By the end of year six of the project the EuroHyp-1 consortium achieved several important results. Regulatory approval has been obtained in thirteen countries: Belgium, Denmark, Finland, France, Germany, Italy, Ireland, Lithuania, Poland, Spain, Sweden, Turkey and UK. 26 sites in seven countries are open for patient recruitment. A total of 98 patients have been recruited by the end of February 2017.
Despite several important achievements, a source of disappointment remained the slow recruitment of patients into the trial. This is due in large part to the complexity of having the trial approved by national competent authorities and local Research Ethics Committees in all 15 countries participating, because to our knowledge this is the first academic trial that is considered both a drug and a device trial by the national competent authority of the country of the study sponsor (Germany).
Reasons for slow recruitment in study sites that have already been approved are mainly related to the large number of exclusion criteria and to the complexity and length of the treatment delivery, which makes patient enrolment and trial treatment much more time consuming than originally anticipated.
During year 5, we have implemented a range of corrective actions to facilitate regulatory approval of countries and study sites and – in addition to these – a protocol amendment (version 5.0) has been submitted and approved in order to reduce the complexity of the trial and thereby to increase patient enrolment, without compromising its clinical relevance and scientific validity.
At the end of year 5 of EuroHYP-1 we submitted a proposal to the Directorate General of Research (European Commission), to increase the reimbursement per included patient to meet the actual costs of the therapeutic cooling intervention. This will ensure that the costs of the participating sites will be reimbursed, in line with the standard funding rules applicable in FP7 programs.
As an additional measure - in an effort made to accelerate enrolment and to guarantee the delivery of the data on the most important outcome measures required for the assessment of therapeutic cooling - two sub-studies have been proposed to be suspended: the biomarker and ultrasound work streams, aiming to collect biologic samples and ultrasound readings.
In Year 6 the consortium concluded the negotiations associated to the extension of the grant period until 31 July 2018 and implemented the measures agreed, which were aiming to accelerate recruitment. Notably, there was a large Investigator Training Meeting organized in October 2017 in which the best recruiting EuroHYP-1 centres shared their experience linked to the successful delivery of therapeutic hypothermia and the organization of stroke care in their units, incorporating therapeutic cooling in their research practice. In addition, the progress with hypothermia research in stroke has been reviewed, and also beyond, including other therapeutic uses as well - for ex. cardiac arrest. Numerous presentations were introduced about the experience with therapeutic cooling in EuroHYP-1 and the ways in which the quality of treatment delivery can be improved. The training contributed to the improved performance of the trial, which led to the recruitment of 98 patients by end February 2017.
Potential Impact:
Given a total recruitment of 98 patients, it is possible (but unlikely) that the results, when available, will give a definitive answer as to any beneficial or detrimental effects of therapeutic hypothermia in stroke. However, in combination with previously published findings the total number of patients included in randomised controlled trials is now 471, and so our planned meta-analyses of these data will give reasonably precise estimates of potential harms and benefits, and the effectiveness of different approaches to cooling, to guide future research and practice.
Further, while there were many regulatory and organisational challenges encountered during the trial, it is clear that one impediment to faster recruitment was the logistical challenge in delivering hypothermia in a usual-care setting, experienced by some but not all centres. Qualitative research of the drivers for these differences will allow a deeper understanding of the challenges in developing less burdensome approaches to delivering hypothermia in future stroke trials.
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