Final Report Summary - EUROHYP-1 (European multicentre, randomised, phase III clinical trial of hypothermia plus best medical treatment versus best medical treatment alone for acute ischaemic stroke)
Executive Summary:
EuroHYP-1 was the largest prospective clinical trial on Therapeutic Hypothermia for stroke patients ever conducted in Europe. With EuroHYP-1 the heterogeneous approaches to therapeutic cooling in awake patients were harmonized within a unique protocol and spread among 63 renowned stroke centres in 13 countries. Leaders in stroke and clinical sciences across Europe were brought together with experts in biostatistics, health economics, regulatory trial conduct and ambitious enterprises - including several European Small-size Enterprises, which developed innovative cooling technologies - to form a network and to generate & investigate the scientific evidence for therapeutic hypothermia in this prospective, randomized, phase III, open label clinical trial with blinded outcome assessment. The first patient was enrolled in November 2013 in Germany. Soon after this, new evidence from
interventional stroke trials with neurothrombectomy compromised the original EuroHYP-1 Clinical Trial Protocol and retarded the inclusion of patients, hence several actions were taken by the consortium in order to restore recruitment. These included an amendment of the Clinical Trial
Protocol in 2015, opening of additional study sites across Europe, as well as the augmentation of cooling-specific training of study personnel. Despite several important achievements, progress with the opening of new sites and recruitment of patients into the trial was slow. This was due in large part to the complexity of having the trial approved in most of the 13 participating countries by up to two national competent authorities: one authority (committee) for devices and a second one for medicines - in addition to local Research Ethics Committees. To our knowledge, EuroHYP-1 was the first academic trial to have been considered both a drug and a device trial by the national competent authority of the country of the study sponsor, Germany in the case of this trial. Nevertheless, slow recruitment persisted in study sites that did receive approval. Reasons were mainly related to the novelty of the intervention, the extensive exclusion criteria and the complexity & duration of the treatment delivery: an intervention taking up to twenty hours, or even longer - which rendered patient enrolment and trial treatment delivery extremely resource intensive. The staffing requirements exceeded expectations and the requirement to continue intensive patient treatment throughout off-service hours and night shifts challenged even the first-class academic stroke units, that typically deliver complex interventions of 2-3 hours only, with a rapid response.
Despite the difficulties experienced with the slow and limited recruitment, EuroHYP-1 delivered a major advancement in understanding not only the difficulties facing this novel intervention - but also the solutions which could be applied to make this treatment more feasible, for a successful delivery by the regular stroke centres. For a detailed description about the scientific advancement achieved and the identification of additional innovation pathways required please see the next sections in this report, in which we described in detail the discoveries made around the requirements which must be fulfilled to enable a successful cooling intervention delivery.
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.
(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.
(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.
(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:
Following a recruitment period of 52 months, in March 2018, recruitment was closed after inclusion of 98 patients. 49 patients were randomised to therapeutic hypothermia versus 49 to standard treatment alone. Four patients were lost to follow-up. The functional outcome after 91 days did not differ between the groups (odds ratio, 1.01; 95% confidence interval [CI], 0.48 to 2.13; p = 0.97). The number of patients with one or more serious adverse events was not different (relative risk, 1.22; 95% CI, 0.65 to 1.94; p = 0.52). Based on the analysis conducted, no safety concerns arise regarding hypothermia from EuroHYP-1.
All CT and MR brain imaging performed on arrival at hospital before randomisation into the trial, and at follow-up 24-48 hours after randomisation and start of treatment, was transferred to the central imaging assessment centre and assessed for infarct volume, and infarct extent, swelling, presence of occluded artery and prestroke features (brain shrinkage, white matter lesions, old infarcts), using validated methods and blind to all clinical details. There was no difference in infarct volume at 24 hours after randomisation between patients allocated to hypothermia and the control group. Biomarker studies conducted based on samples obtained in 54 patients, did not reveal a major effect of hypothermia on the levels of markers for brain barrier dysfunction or cardiac stress. However, levels of several inflammatory and immunity markers such as IL-6, CRP or PCT were elevated after 24 hours in the treatment group. At the same time, the observed reduction of glial fibrillary acid protein (GFAP) levels at 72 hours might constitute an indication of a favourable response in the brain with reduced brain damage in patients treated with hypothermia. The EQ5D scores - including deceased patients with a value of zero - did not show a significant difference (relative risk 1.10 95%CI [-0.2213; 0.1375] p=0.64). When we analysed the information provided on the visual analogue scale, in the treatment arm, (n=39 patients), the mean utility was 0.59 (0.44) compared to 0.43 (0.42) in the control arm (n=42 patients), with a non-significant p value at 0.39.
In addition to the valuable learning and progress achieved with four substudies: imaging, biomarkers, health economics/quality of life, and patient experience/tolerability results, one of the main achievements of the trial was the development and consolidation - based on a consensus formulated by the leading hypothermia experts and centres, not only from Europe but also US - of a set of Shivering Prevention Recommendations.
The EuroHYP-1 Shivering Prevention guidance document was prepared following the tolerability and treatment delivery analysis conducted based on the first 60 patients. This analysis highlighted the need to improve shivering control - one of the challenging aspects of therapeutic cooling delivery which must be perfected in order to enable a successful therapeutic cooling delivery. Following an in-depth analysis of several parameters associated to the treatment delivery and the shivering prevention protocol pursued - plus the best practices of the World leading hypothermia centres (not only for stroke but also cardiac arrest), the EuroHYP-1 Shivering Prevention guidance document has been prepared and disseminated, containing the description of the following strategies: (1) preventive use of the pharmacologic treatments, based on a predefined schedule; (2) no cooling without counter warming; (3) initiation of the cooling with well tolerated, quick interventions; (4) adaptation / increasing of the coolant’s temperature for awake stroke patients; (5) stepwise decrease of the core body temperature to discover the shivering threshold. While all strategies are important, one of the major discovery in this exercise was the identification of the coolant temperature as a potential source of issue regarding the tolerability of the treatment. The baseline value for the coolant temperature is usually 4 °C, which is extremely low for an awake patients - the newly recommended temperature is 12 °C, which can be increased to 18 °C in case shivering appears, despite all other measures taken, for example the preventive use of pharmacologic interventions.
Potential Impact:
Considering that the EuroHYP-1 trial made many scientific advancements - however due to the small sample size did not succeed to answer the question about the effect of hypothermia on the health of the patients - the direct socio-economic impact of the project is limited. At the same time, the indirect impact of the trial has been and remains significant, especially considering the progress made by the European SMEs (small and medium-size enterprises) towards perfecting their cooling technologies and the advancements achieved via the identification of technological solutions which deliver better results in the area of shivering control. The companies which benefited directly or indirectly from the collaboration with the EuroHYP-1 consortium members, are listed here - details about these companies can be found on the websites indicated. Braincool: www.braincool.eu , EMCOOLS www.emcools.au and Quickcool: www.quickcool.se
See attached Pdf for the main dissemination activities and the exploitation of results.
At the end of the 52 months recruitment period, with 98 patients included, the EuroHYP-1 trial was underpowered to demonstrate the impact of therapeutic hypothermia on functional outcomes. However, in itself this answered the question faced by the trial: the therapeutic cooling method used initially for the delivery of the treatment: 24 hours of active cooling, with an insufficient and incomplete shivering prevention strategy, was not optimized sufficiently to allow a successful implementation of the treatment.
At the same time, the definition of the EuroHYP-1 Shivering Prevention Recommendations did solve many of the issues. However, this being rolled out at the beginning of 2017 - this change in the treatment delivery came too late in the trial, to have a major impact on the recruitment and overall success of the clinical study. Therapeutic cooling with the current technologies remains a very complex, resource intensive intervention, which could be alleviated only with major technological innovation, for example a technology which combines automated, instrument-based shivering measurements with the cooling intervention itself. Such technology does not exist yet, however the companies involved in this area are considering the development of such innovative solutions. In order to enable the transfer of hypothermia to clinical use in stroke, important implications from EuroHYP-1 arise for future research: (1) Compatibility of Hypothermia with interventional stroke treatment and thrombectomy is essential - this means that a very careful and detailed patient pathway analysis is needed in the hospital, to identify the best ways towards the integration of the cooling intervention into the process; (2) Prophylactic antibiotic treatment of infection and pneumonia has to be considered; (3) For awake stroke patients, more balanced cooling strategies and thorough, pre-emptive shivering control are warranted to improve feasibility, in line with the Shivering Prevention Recommendations developed by the EuroHYP-1 consortium and collaborating hypothermia experts from Europe and United States; (4) Based on the findings of the EuroHYP-1 trial it seems that the target temperature range for the mild hypothermia treatment is feasible only in the 34.5-35.5 °C range rather than the originally targeted 34-35 °C, which proved to be unfeasible in the EuroHYP-1 trial, since only 31% of the 49 patients randomised to hypothermia achieved cooling to the extent defined in the study protocol and had a body temperature ≤35.0°C for at least 6 hours during the active cooling period. The increasing availability of thrombectomy which offers profound benefits and has proven feasibility - in contrast to therapeutic cooling which has now been shown to have limitations with ,current technologies, indicates that resources and effort should be directed towards the definition of completely new, innovative approaches towards cooling and perhaps a much earlier start of cooling, at the pre-hospital period, starting with a treatment initiation in the emergency ambulance vehicles - assuming a stroke diagnosis could be established already at this time. A very early start of cooling - initiated as soon as a patient is in a medical emergency ambulance vehicle - could be a solution for the overlap with the thrombectomy intervention, since thrombectomy must start immediately, as soon as the patient arrives to the hospital. An early, pre-hospital imitation of cooling could increase the chances for a protective impact on the brain tissues. At the same time, this early initiation would require considerable technological advancements and a change in clinical practice - also associated to the diagnosis of stroke, which should become feasible in emergency ambulance vehicles.
List of Websites:
www.eurohyp1.eu
EuroHYP-1 was the largest prospective clinical trial on Therapeutic Hypothermia for stroke patients ever conducted in Europe. With EuroHYP-1 the heterogeneous approaches to therapeutic cooling in awake patients were harmonized within a unique protocol and spread among 63 renowned stroke centres in 13 countries. Leaders in stroke and clinical sciences across Europe were brought together with experts in biostatistics, health economics, regulatory trial conduct and ambitious enterprises - including several European Small-size Enterprises, which developed innovative cooling technologies - to form a network and to generate & investigate the scientific evidence for therapeutic hypothermia in this prospective, randomized, phase III, open label clinical trial with blinded outcome assessment. The first patient was enrolled in November 2013 in Germany. Soon after this, new evidence from
interventional stroke trials with neurothrombectomy compromised the original EuroHYP-1 Clinical Trial Protocol and retarded the inclusion of patients, hence several actions were taken by the consortium in order to restore recruitment. These included an amendment of the Clinical Trial
Protocol in 2015, opening of additional study sites across Europe, as well as the augmentation of cooling-specific training of study personnel. Despite several important achievements, progress with the opening of new sites and recruitment of patients into the trial was slow. This was due in large part to the complexity of having the trial approved in most of the 13 participating countries by up to two national competent authorities: one authority (committee) for devices and a second one for medicines - in addition to local Research Ethics Committees. To our knowledge, EuroHYP-1 was the first academic trial to have been considered both a drug and a device trial by the national competent authority of the country of the study sponsor, Germany in the case of this trial. Nevertheless, slow recruitment persisted in study sites that did receive approval. Reasons were mainly related to the novelty of the intervention, the extensive exclusion criteria and the complexity & duration of the treatment delivery: an intervention taking up to twenty hours, or even longer - which rendered patient enrolment and trial treatment delivery extremely resource intensive. The staffing requirements exceeded expectations and the requirement to continue intensive patient treatment throughout off-service hours and night shifts challenged even the first-class academic stroke units, that typically deliver complex interventions of 2-3 hours only, with a rapid response.
Despite the difficulties experienced with the slow and limited recruitment, EuroHYP-1 delivered a major advancement in understanding not only the difficulties facing this novel intervention - but also the solutions which could be applied to make this treatment more feasible, for a successful delivery by the regular stroke centres. For a detailed description about the scientific advancement achieved and the identification of additional innovation pathways required please see the next sections in this report, in which we described in detail the discoveries made around the requirements which must be fulfilled to enable a successful cooling intervention delivery.
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.
(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.
(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.
(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:
Following a recruitment period of 52 months, in March 2018, recruitment was closed after inclusion of 98 patients. 49 patients were randomised to therapeutic hypothermia versus 49 to standard treatment alone. Four patients were lost to follow-up. The functional outcome after 91 days did not differ between the groups (odds ratio, 1.01; 95% confidence interval [CI], 0.48 to 2.13; p = 0.97). The number of patients with one or more serious adverse events was not different (relative risk, 1.22; 95% CI, 0.65 to 1.94; p = 0.52). Based on the analysis conducted, no safety concerns arise regarding hypothermia from EuroHYP-1.
All CT and MR brain imaging performed on arrival at hospital before randomisation into the trial, and at follow-up 24-48 hours after randomisation and start of treatment, was transferred to the central imaging assessment centre and assessed for infarct volume, and infarct extent, swelling, presence of occluded artery and prestroke features (brain shrinkage, white matter lesions, old infarcts), using validated methods and blind to all clinical details. There was no difference in infarct volume at 24 hours after randomisation between patients allocated to hypothermia and the control group. Biomarker studies conducted based on samples obtained in 54 patients, did not reveal a major effect of hypothermia on the levels of markers for brain barrier dysfunction or cardiac stress. However, levels of several inflammatory and immunity markers such as IL-6, CRP or PCT were elevated after 24 hours in the treatment group. At the same time, the observed reduction of glial fibrillary acid protein (GFAP) levels at 72 hours might constitute an indication of a favourable response in the brain with reduced brain damage in patients treated with hypothermia. The EQ5D scores - including deceased patients with a value of zero - did not show a significant difference (relative risk 1.10 95%CI [-0.2213; 0.1375] p=0.64). When we analysed the information provided on the visual analogue scale, in the treatment arm, (n=39 patients), the mean utility was 0.59 (0.44) compared to 0.43 (0.42) in the control arm (n=42 patients), with a non-significant p value at 0.39.
In addition to the valuable learning and progress achieved with four substudies: imaging, biomarkers, health economics/quality of life, and patient experience/tolerability results, one of the main achievements of the trial was the development and consolidation - based on a consensus formulated by the leading hypothermia experts and centres, not only from Europe but also US - of a set of Shivering Prevention Recommendations.
The EuroHYP-1 Shivering Prevention guidance document was prepared following the tolerability and treatment delivery analysis conducted based on the first 60 patients. This analysis highlighted the need to improve shivering control - one of the challenging aspects of therapeutic cooling delivery which must be perfected in order to enable a successful therapeutic cooling delivery. Following an in-depth analysis of several parameters associated to the treatment delivery and the shivering prevention protocol pursued - plus the best practices of the World leading hypothermia centres (not only for stroke but also cardiac arrest), the EuroHYP-1 Shivering Prevention guidance document has been prepared and disseminated, containing the description of the following strategies: (1) preventive use of the pharmacologic treatments, based on a predefined schedule; (2) no cooling without counter warming; (3) initiation of the cooling with well tolerated, quick interventions; (4) adaptation / increasing of the coolant’s temperature for awake stroke patients; (5) stepwise decrease of the core body temperature to discover the shivering threshold. While all strategies are important, one of the major discovery in this exercise was the identification of the coolant temperature as a potential source of issue regarding the tolerability of the treatment. The baseline value for the coolant temperature is usually 4 °C, which is extremely low for an awake patients - the newly recommended temperature is 12 °C, which can be increased to 18 °C in case shivering appears, despite all other measures taken, for example the preventive use of pharmacologic interventions.
Potential Impact:
Considering that the EuroHYP-1 trial made many scientific advancements - however due to the small sample size did not succeed to answer the question about the effect of hypothermia on the health of the patients - the direct socio-economic impact of the project is limited. At the same time, the indirect impact of the trial has been and remains significant, especially considering the progress made by the European SMEs (small and medium-size enterprises) towards perfecting their cooling technologies and the advancements achieved via the identification of technological solutions which deliver better results in the area of shivering control. The companies which benefited directly or indirectly from the collaboration with the EuroHYP-1 consortium members, are listed here - details about these companies can be found on the websites indicated. Braincool: www.braincool.eu , EMCOOLS www.emcools.au and Quickcool: www.quickcool.se
See attached Pdf for the main dissemination activities and the exploitation of results.
At the end of the 52 months recruitment period, with 98 patients included, the EuroHYP-1 trial was underpowered to demonstrate the impact of therapeutic hypothermia on functional outcomes. However, in itself this answered the question faced by the trial: the therapeutic cooling method used initially for the delivery of the treatment: 24 hours of active cooling, with an insufficient and incomplete shivering prevention strategy, was not optimized sufficiently to allow a successful implementation of the treatment.
At the same time, the definition of the EuroHYP-1 Shivering Prevention Recommendations did solve many of the issues. However, this being rolled out at the beginning of 2017 - this change in the treatment delivery came too late in the trial, to have a major impact on the recruitment and overall success of the clinical study. Therapeutic cooling with the current technologies remains a very complex, resource intensive intervention, which could be alleviated only with major technological innovation, for example a technology which combines automated, instrument-based shivering measurements with the cooling intervention itself. Such technology does not exist yet, however the companies involved in this area are considering the development of such innovative solutions. In order to enable the transfer of hypothermia to clinical use in stroke, important implications from EuroHYP-1 arise for future research: (1) Compatibility of Hypothermia with interventional stroke treatment and thrombectomy is essential - this means that a very careful and detailed patient pathway analysis is needed in the hospital, to identify the best ways towards the integration of the cooling intervention into the process; (2) Prophylactic antibiotic treatment of infection and pneumonia has to be considered; (3) For awake stroke patients, more balanced cooling strategies and thorough, pre-emptive shivering control are warranted to improve feasibility, in line with the Shivering Prevention Recommendations developed by the EuroHYP-1 consortium and collaborating hypothermia experts from Europe and United States; (4) Based on the findings of the EuroHYP-1 trial it seems that the target temperature range for the mild hypothermia treatment is feasible only in the 34.5-35.5 °C range rather than the originally targeted 34-35 °C, which proved to be unfeasible in the EuroHYP-1 trial, since only 31% of the 49 patients randomised to hypothermia achieved cooling to the extent defined in the study protocol and had a body temperature ≤35.0°C for at least 6 hours during the active cooling period. The increasing availability of thrombectomy which offers profound benefits and has proven feasibility - in contrast to therapeutic cooling which has now been shown to have limitations with ,current technologies, indicates that resources and effort should be directed towards the definition of completely new, innovative approaches towards cooling and perhaps a much earlier start of cooling, at the pre-hospital period, starting with a treatment initiation in the emergency ambulance vehicles - assuming a stroke diagnosis could be established already at this time. A very early start of cooling - initiated as soon as a patient is in a medical emergency ambulance vehicle - could be a solution for the overlap with the thrombectomy intervention, since thrombectomy must start immediately, as soon as the patient arrives to the hospital. An early, pre-hospital imitation of cooling could increase the chances for a protective impact on the brain tissues. At the same time, this early initiation would require considerable technological advancements and a change in clinical practice - also associated to the diagnosis of stroke, which should become feasible in emergency ambulance vehicles.
List of Websites:
www.eurohyp1.eu
