Building a European ‘network of networks’ for stroke clinical research – The European Stroke Organisation Trials Alliance (ESOTA)

Abstract

Promoting research to improve stroke prevention, acute care, and recovery is a key mission of the European Stroke Organisation (ESO). Stroke research networks may increase efficiencies and reduce waste in randomised clinical trials of stroke treatments. Several European countries have established national or regional stroke research networks, or have informal groups or stroke registers which may serve as a foundation for establishing a research network. To increase international collaboration on randomised trials for stroke in Europe, the ESO Trials Network Committee is leading the development of an alliance of national networks, the ESO Trials Alliance (ESOTA). Following initial consultation work in 2017, this paper describes an overview of progress to date in the first year of ESOTA activity. Beginning with five founding networks in England, Ireland, Netherlands, Spain, and Switzerland, ESOTA aims to gradually grow, ultimately including several hundred stroke centres and affiliated investigators working collectively on randomised trials of new stroke treatments.

Keywords

Europe randomised trial treatment stroke

Introduction

Stroke is the world’s second leading cause of death, and a major cause of disability, cognitive decline, and dementia.^1,2 Recurrent stroke and coronary events are important contributors to poor outcome after stroke, affecting 4–6% of stroke survivors each year, despite current preventive treatments.^3,4 In Europe’s ageing populations, the total number of people affected by a new stroke, unless prevention measures are significantly improved, is projected to increase by 34% by 2035,⁵ due to a combination of rising incidence rates in some countries and increasing life-expectancy. The societal challenge of stroke is greatest in Eastern and Central Europe, where lifetime risk of stroke is among the highest compared to other global regions.⁶ Direct healthcare costs of stroke in Europe were an estimated €20 billion in 2015, with a further €25 billion in indirect costs.⁵

Promotion of stroke research in Europe is a key aim of the European Stroke Organisation (ESO).⁷ ESO and the Stroke Alliance for Europe (SAFE) have identified improved acute treatment, prevention, and recovery as strategic priority areas to improve stroke outcome.⁷ Initiatives to increase collaboration among European stroke researchers will advance this goal.

Randomised clinical trials are the fairest tests of treatment and lead to high quality evidence about treatments for stroke prevention, acute stroke, and recovery, which prevent consequences of stroke such as death, disability, cognitive impairment, and dementia. However, conducting investigator-led randomised trials is becoming increasingly complex, due to the need for large sample sizes (to detect small incremental effects on top of existing therapies) and growing complexity of the regulatory and funding environment. Research in stroke and other fields can be wasteful and inefficient, in part because of the increasingly complex context in which it is conducted.^8,9

In some countries, a solution has been to establish structured stroke research networks, which have improved the efficiency of stroke clinical trials.¹⁰ Within Europe, despite a strong track record of collaborative research for individual projects, no structured multi-national alliance of stroke research networks exists. A natural progression is for closer international integration of existing stroke research networks in Europe, similar to developments in other disease areas such as critical care medicine and cancer.¹¹

Other countries have developed more informal collaborations to conduct stroke research but have not yet established a stroke research network. Such countries may benefit from the support of ESO to set up structured stroke research networks, as a step towards integrating with other networks.

For several years the ESO Trials Network Committee has worked to support ESO members who wish to conduct randomised trials. Following consultation with ESO members and the ESO Executive Committee in 2017, a proposal to establish an alliance of stroke research networks in ESO member countries (ESO Trials Alliance [ESOTA]) was widely supported.¹² This report follows the first ESOTA symposium held at the 2018 ESO Conference and describes progress in the first year of ESOTA activity.

ESOTA symposium

The symposium was open to all ESO members and was held in two sessions. During the first session, leading investigators from established national stroke research networks described the current operating models and experience learned from their networks. John Marshall, founding chair of the International Forum for Acute Care Trialists, (InFACT) then described experience with the InFACT global alliance of critical care research networks,¹³ followed by an overview of the model for ESOTA (PK). In the second session, interactive workshops were held with attendees (Web-supplement), focussing on building new trials networks in ESO countries, lessons from InFACT, and next steps to develop ESOTA.

Examples of existing stroke research networks in ESO countries:

Several models of stroke research networks exist in ESO countries (Table 1). Examples include:

1. National Institute for Health Research (NIHR) Clinical Research Network, England

Table 1.

Examples of models of existing stroke research networks in ESO countries.

Network	Model	Funding	Staff	Research focus	Sustainability
NIHR CRN England	Infrastructure within health service. Integrated within generic NIHR CRN. National Coordinating Centre and eight Regional (Local) Research Networks and 11 Hyperacute Research Centres.	Recurring funding from UK government	Funded staff. National and Regional Clinical Leads, Network Managers, Research nurses and related staff in network hospitals	Clinical trials and other studies. Acute, prevention, and recovery	Annual funding from NIHR budget
CONTRAST Netherlands	Academic consortium	Grant, private, and in-kind support	Academic leaders, Part-time central coordinator	Clinical trials and related studies. Mainly acute stroke	Grant renewals by open competition
SCTNI, Ireland	Academic consortium	Grant, private, and in-kind support	Academic leaders, Central coordinator, Nurse manager, Part-time nurses in hospitals	Clinical trials and related studies. Acute, prevention, and recovery	Grant renewals by open competition
SSTC Switzerland	National collaboration linked to national society	No ring-fenced funding. National society supports meetings. Clinical Trial Organisation supports trial activity	No network staff	Clinical trials and other studies. Acute, prevention, and recovery	Sustainable low-cost model
Stroke Project Network, Spain	National collaboration linked to national society	No ring-fenced funding. National society supports meetings.	No network staff	Clinical trials and other studies. Acute, prevention, and recovery	Sustainable low-cost model

NIHR established a number of topic-specific research networks in 2005, including a Stroke Research Network (SRN). The NIHR SRN was managed by a National Co-ordinating Centre (NCC) in Newcastle, UK, with an annual budget of £0.5m, which oversaw the performance of eight Local Research Networks in England and linked with networks in Northern Ireland, Scotland and Wales. Each Local Research Network had a budget of £0.5m annually to support a clinical lead, network manager and hospital-based research staff. Over a 10-year period, SRN achieved UK geographical coverage, developed a network of hyper-acute stroke research centres (now numbering 11) with advanced neuroimaging, interventional neuroradiology, neurosurgery, and extended-hours seven-day per week stroke research staff. In its most successful year (2015–2016), it recruited nearly 15% of hospital-admitted acute stroke patients into randomised trials and studies. Since 2015, stroke has been one of 35 specialties within the generic NIHR Clinical Research Network.

2. Collaboration for New Treatments for Acute Stroke (CONTRAST) Consortium, the Netherlands

The CONTRAST consortium is a nationwide collaboration of clinical and translational scientists from all academic and large clinical centres in the Netherlands focussing on acute stroke treatment. Its mission is to improve the effectiveness and safety of acute treatment for stroke and to expand eligibility for treatment. It aims to find ways to improve microvascular reperfusion in ischaemic stroke, thus improving outcome of patients undergoing reperfusion therapy, to extend the indications for thrombectomy, to develop ambulance-based pre-hospital treatments, and to test new treatments for intracerebral haemorrhage.

Decision-making and progress reviews occur at monthly meetings of the scientific committee, which includes all work-package leaders of the scientific projects. Collaborators and organisational structure are described at www.contrast-consortium.nl. The consortium employs a part-time central coordinator and two research leaders, and uses a central biobank, imaging databank and clinical databases.

Currently, five large clinical trials are ongoing, all targeting acute therapy for ischaemic stroke and intracerebral haemorrhage (Web-appendix). Additional sub-studies in combined data from the biobank, imaging bank and clinical databank are planned, as is a linked network of experimental stroke centres.

Funding is provided by academic grants, private partners and by in-kind contributions of the academic and clinical centres, for a period of five years. New funding will be sought to continue and expand its research programme beyond 2022.

3. Swiss Stroke Trials Collaboration

In 2010, the Swiss Stroke Society founded the Swiss Stroke Trialist’s Collaboration (SSTC), a scientific network of clinical and translational stroke scientists from all Swiss stroke units and centres. SSTC aims to facilitate the planning, set-up and conduct of stroke trials and other stroke-related research in Switzerland, including acute, prevention, and neurorehabilitation studies.

Since 2011, SSTC holds an annual meeting attached to the Swiss Stroke Society conference. Investigators present planned or ongoing research projects and discuss study protocols, project feasibility and potential sites within SSTC. Stroke trialists from other European countries are invited to participate. The conduct of the trials is organised in partnership by the principal investigators and local clinical trial units via the Swiss Clinical Trial Organisation (SCTO), which provides infrastructure for databases, monitoring, regulatory and statistical support. The Swiss Stroke Society supports SSTC by organising the annual meeting and providing a platform for researchers. However, trial planning and conduct is financed by the trial sponsors.

Currently more than 10 stroke trials are planned or ongoing in Switzerland (web-appendix).

4. The Spanish Stroke Project Network

The Stroke Project is a research network founded in 1998 by the Stroke Study Group of the Spanish Society of Neurology to promote multi-centre collaborative studies in cerebrovascular diseases. Around 75 hospitals from all regions around Spain are active members. The Stroke Study Group elects a Coordinator to lead the network every two years. He/she receives study proposals from academic investigators and connects participating research groups. An annual meeting is organised to present updates of ongoing and completed studies. Every year, a grant for a research project is awarded to encourage participation.

Since the network started, more than 30 collaborative, multi-centre studies have been performed, leading to many scientific conference communications and international publications. Thirty-one original articles cited in PubMed have been published, with >900 citations and h-index of 12.

5. The Stroke Clinical Trials Network Ireland (SCTNI)

SCTNI was founded in 2015 funded by awards from the Irish Health Research Board, Irish Heart Foundation and industry. It includes 10 university hospitals, with linked Clinical Research Centres, and five general hospitals. Staff includes two Co-Directors, an Education Leader, two project managers, nurse manager and part-time stroke research nurses. In addition to participating in international trials, SCTNI runs Irish-initiated stroke trials and related studies. Examples include CONVINCE, an investigator-led trial testing colchicine for vascular prevention in 18 countries (mainly European), BIOVASC (advanced plaque and brain imaging to identify high-risk patients with non-cardio-embolic stroke), and StrokeCOG (developing interventions for vascular dementia).

Joining research networks into a multinational alliance. InFACT – an example from critical care medicine

Most randomised trials in critical care medicine are investigator-led and not funded by industry sponsors. The Canadian Critical Care Trials Group (CCCTG) is an academic initiative established in 1989 to promote investigator-initiated trials, education and capacity-building for investigator-led research in critical care medicine in Canada.¹⁴ After a phase of gradual development, its first project was a randomised trial investigating optimal treatments to prevent stress ulceration in critically-ill patients.¹⁵ Now the CCCTG has more than 350 members, 60 active research programmes, and over 300 publications.

Similar research networks were established in Australia/New Zealand, USA, Germany, Scandinavia, Brazil, China, and other countries. The International Forum for Acute Care Trialists (InFACT) was established in 2008 as an alliance of international investigator-led groups in critical care research.^13,16 InFACT aims to support international collaboration in investigator-led trials, promote the importance of investigator-led randomised trials to policy-makers, funders, and patient groups, and to build capacity for future research by supporting new research groups, education and mentoring of young investigators. Currently, InFACT has 35 member organisations from Europe, North America, South America, Asia, Africa, and Australia/New Zealand.

Key features of InFACT include:

Low-cost model: InFACT is not supported by large grants and does not employ permanent staff or manage trials on behalf of investigators.

Member autonomy: Although individual member networks maintain a high level of independence, they collaborate on areas of shared interest through working groups (e.g. on outcome measures, antimicrobial resistance, education/mentoring, global pandemic preparedness).

Building relationships: Informal networking linked to scientific meetings is emphasised to develop collegiate relationships, leading to greater international collaboration.

Flexible approach to shared working:

Four models for collaboration on individual trials within the InFACT alliance were described (Table 2).

Table 2.

Models for collaboration between international research networks on randomised trials in InFACT alliance.

Collaboration model	Structure	Research question	Protocol
Informal	Single research group/ network leads. Other investigators join ‘ad hoc’ depending on interest	One main question	Single protocol, written by lead research network
Harmonised	Several networks run independent trials simultaneously	One main question	Several protocols. Close coordination to prepare harmonised protocols to allow later pooling
Integrated	Several networks come together to run a single large trial	One main question	Single shared protocol, written by representatives of several networks
Platform¹⁶	Several networks come together to run a single large thematic study, incorporating several randomised comparisons	Multiple questions	Single shared protocol, written by representatives of several networks. Over-arching protocol allows multiple randomised comparisons sequentially or simultaneously

Informal: One research group or network leads the development and funding of a trial and writes the protocol. Other networks join on an ad hoc basis, depending on their level of interest.

Harmonised: Several national networks lead distinct trials addressing the same question simultaneously, each with their own protocol. The leadership teams of each trial coordinate closely from the outset to prepare similar protocols with similar eligibility criteria and outcome measures, with a pre-specified plan to pool individual-patient data. In this model, efficiencies can be made with trial conduct. For example, a single Data Monitoring Committee overseeing multiple trials can be established. For example, several InFACT members conducted simultaneous harmonised trials of resuscitation in septic shock, and published an individual patient data meta-analysis of the results.¹⁷

Integrated: Several national networks join together to lead a single large trial. A single protocol is jointly written and ownership of the trial is shared among representatives of each participating network. This approach was taken in the NICE-SUGAR trial of intensity of blood glucose control in critically-ill patients.¹⁸

Platform: Several national networks agree an important research theme of shared interest. Within this theme, an over-arching protocol is written which allows several research questions to be addressed in multiple study arms.¹⁹ Randomised comparisons may be undertaken in several arms, with patients exiting one randomised comparison when they experience an outcome and then entering a new randomised comparison. Adaptive trial design and analysis approaches are taken. Non-randomised data collection to inform epidemiological or other studies may be included in other arms. An example is the REMAP CAP study platform focussing on community-acquired pneumonia.

The ESO Trials Alliance – a ‘network of networks’ for clinical stroke research

The InFACT Alliance model may serve as a useful template of a successful, low-cost alliance for stroke networks in Europe. For context, in a 2017 ESO survey of members and trialists, four main areas were cited as challenges for stroke clinician-scientists¹²: (1) study management and contracts; (2) complex regulations (national, ethics, contracts, insurance); (3) funding; (4) capacity (availability of research staff, training new trialists). Stroke networks may act as catalysts to support investigators to find solutions for these and other challenges.¹⁰

Despite the success of several past and current international collaborations to conduct investigator-led randomised stroke trials, many such trials are still mainly conducted at national level in Europe. Significant potential exists across European countries to further integrate stroke research activities, increasing the efficiency of stroke research and leading to more investigator-led randomised trials. Collectively, Europe is the world’s second largest economy with a population of 507 million inhabitants. In the 2017 ESO survey, 18 countries reported national or regional research networks or groups with a focus on stroke research.¹² Other countries (e.g. Austria, Italy), which did not have research groups, have developed organised stroke registries, which may function as foundations upon which to build research networks.

The ESO Trials Alliance (ESOTA) is a new academic initiative led by the ESO Trials Network Committee on behalf of ESO.²⁰ The goal of ESOTA is to establish a European ‘network of networks’ which will be sustainable as long-term infrastructure to conduct stroke research, with a main focus on investigator-led randomised clinical trials. ESOTA aims to: (1) support European collaboration for stroke research; (2) promote capacity-building for trials research in Europe by educational activities and supporting new stroke research networks; (3) promote stroke trials to funders, policy-makers, and other stakeholders (e.g. patient groups). Importantly, management of trials will not be done by ESOTA but will remain with trial leadership groups as usual. Upon request, ESOTA will provide advice and support to investigators when preparing funding applications for clinical trials in Europe. As an academic collaboration, ESOTA does not have financial resources to directly fund trials and will be supported by existing ESO staff. However, as evidenced by InFACT, this model has a proven track record of success.

Several guiding principles for ESOTA have been agreed with the ESO members and Executive Committee. These are: (1) members of ESOTA are networks (not individuals), and membership is voluntary; (2) the goals and structures of ESOTA will be kept simple and feasible; (3) member independence will be kept for participation in trials; and (4) ESOTA will be highly collaborative, with ownership by the members, avoiding ‘top down’ decision-making. Criteria for membership have been agreed (Table 3).

Table 3.

Criteria for membership of ESO Trials Alliance.

	Membership criteria
1	Members of ESOTA will be national or regional networks whose main purpose is clinical research in stroke/cerebrovascular disease. The focus will be on clinical trials although other categories of research (e.g. epidemiology or imaging research) are not excluded
2	Members should be stroke research networks that are organised and stable. Organised means that there is at least one identified leader who is supported by a representative group/committee. Stable means that the network needs to have conducted more than one trial. Networks which have formed for the conduct of a single trial are encouraged to develop and conduct further trials before considering applying to join
3	Participating networks are strongly encouraged to be linked to a national or regional stroke society

A transparent governance structure has been established. The ESO Trials Network Committee will simultaneously function as the ESOTA Steering Group. Nominated Lead Investigators from member networks will join the Steering Group. New positions of Vice-Chair and Secretary will be created, to assist the Chair in the expanded work programme of the ESOTA. All procedures relating to ESO committees continue to apply, including reporting responsibility to the ESO President, Executive Committee, and Board. Financial governance will be via existing ESO structures. Potential conflicts of interest of Steering Group members will be disclosed on the ESOTA website and at meetings.

ESOTA is expected to add value to the existing activities of national research networks in several ways (Table 4). First, it will act as a structure to connect researchers in ESO countries. A stroke researcher with a new trial idea will rapidly be able to find like-minded collaborators in other countries, via the ESOTA National Leads. Second, ESOTA is expected to increase the feasibility of large academic stroke trials in Europe, as a wider range of research sites will be identified more quickly. Third, ESOTA will promote international European collaboration, with the aim of increasing competitiveness of groups of stroke researchers for EU funding. Fourth, ESOTA will act as a structure to promote knowledge sharing (via training and education sessions, and provision of trial support materials). Fifth, if requested, ESOTA will advise colleagues in ESO countries without research networks on beginning such networks. Sixth, ESOTA will promote measures to support the conduct of stroke trials to key European stakeholders. Seventh, ESOTA will also act as a structure allowing ESO representation on related initiatives, such as the Global Alliance of Independent Networks for Stroke trials (GAINS).²¹

Table 4.

Added value of ESO Trials Alliance beyond existing activities of national stroke research networks.

Added value
1. Linking researchers internationally	New structures to connect international stroke researchers in Europe via network National Leads
2. Repository of research sites	New mechanism to rapidly identify a larger number of sites for investigator-led trials, via cascading information throughout member networks
3. Increased competitiveness for European grant funding	Improved ability to create European multinational stroke consortia, increasing competitiveness for European Union funding
4. Improved knowledge sharing	New structure to pool European expertise in conduct of stroke trials and related research, via education, mentoring, and provision of support materials (e.g. templates for monitoring plans and operations procedures for trial governance committees)
5. Support new national stroke networks to set up	New mechanism for ESO members to access advice to establish new national research networks, as a step towards joining ESOTA
6. Advocacy to promote international stroke research	Enhanced focus on promoting importance of international stroke research to funders in Europe (e.g. European Union)
7. ESO representation on global stroke research initiatives	New mechanism to represent ESO on global research initiatives such as the Global Alliance of International Networks for Stroke research (GAINS)

Following consultation with ESO members, the initial priorities for ESOTA are to establish governance and operating procedures, to complete a three-year strategy document to guide initial development, to include the first member networks, to begin education and advocacy activities, and to identify areas for improved collaboration on existing or new clinical trials. Progress has been made on several of these areas. A strategy document which includes time-lines and milestones is near-completion and will be available on the ESOTA website. The first ESOTA member networks are the NIHR Clinical Research Network, England, Stroke Clinical Trials Network Ireland, Netherlands CONTRAST network, Spanish Neurological Society Stroke Research Group-Stroke Project, and Swiss Stroke Trials Group. By 2021, several further European stroke research networks are expected to join, bringing the membership to 10–11 networks comprising several hundred centres. Participation from Eastern European countries is encouraged and will be supported. A website has been developed (www.eso-trialsalliance.org), and educational meetings are planned for ESOC 2019. With the ESO Executive Committee, ESOTA recently coordinated the ESO response to the consultation phase for the European Union Horizon 2020 funding call, scheduled for 2019. A key priority for 2019 will be to promote initial projects to be undertaken by ESOTA members. Network investigators will be encouraged to participate in ESOTA meetings and to engage with ESOTA via their National Network Leads.

Discussion

ESOTA is intended to establish structures to improve multinational European stroke research collaboration for the long-term. It is expected to develop gradually and in a sustainable manner. Although it has just begun, in its first year several important set-up tasks have been achieved. These include approval of the project by the ESO Executive Committee and Board, establishing governance and membership structures, and identifying founding member networks from five ESO countries. In other early activities, ESO members have been surveyed, and consulted, the ESOTA website has gone ‘live’ and the first ESOTA symposium held at ESOC 2018. As a next step, a priority will be to promote greater collaboration on specific projects among ESOTA members.

The agreed mission of ESOTA is to support collaboration, education, communication, and advocacy relating to stroke research in Europe, with a focus on randomised trials. The experience of the InFACT alliance in critical care medicine provides a useful model to guide the future development of ESOTA. Similar to InFACT, which describes itself as ‘a forum, not a federation’, ESOTA is a voluntary, non-binding partnership of national networks which will foster investigator-led clinical trials in European countries. These networks will retain their freedom to conduct their own trials and research studies, but will also have the option to work with colleagues in many other European centres on studies of shared interest. For a stroke researcher, identifying new collaborators will become much more efficient and powerful. Instead of the current model of asking colleagues in his/her personal network to collaborate, a more structured approach will be introduced, whereby National Leads in each ESOTA country can rapidly cascade a request for collaborators throughout each national network.

Almost 200 hospitals exist within the first five member networks in Spain, Switzerland, Ireland, UK, and Netherlands. Over time, ESOTA aims to gradually grow, adding one or two member networks each year, ultimately comprising several hundred centres and affiliated investigators. The ESOTA alliance has excellent potential as a sustainable collaboration of European stroke researchers to attract EU funding, conduct successful future European stroke trials, and improve outcomes for patients. This will represent a low-cost, efficient ‘win-win-win’ scenario for European patients, researchers, and funders.

Supplemental Material

Supplemental material for Building a European ‘network of networks’ for stroke clinical research – The European Stroke Organisation Trials Alliance (ESOTA)

Supplemental Material for Building a European ‘network of networks’ for stroke clinical research – The European Stroke Organisation Trials Alliance (ESOTA) by Peter Kelly, Rustam A Salman, Anita Arsovska, Diederik WJ Dippel, Urs Fischer, Gary A Ford, Blanca Fuentes, Robin Lemmens, John C Marshall, Paul J Nederkoorn, Thompson Robinson, Christian Weimar, Eivind Berge and on behalf of the ESO Trials Network Committee ESOTA Steering Group in European Stroke Journal

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The ESOTA symposium at ESOC 2018 was supported by the European Stroke Organisation..

Ethical approval

Our institution does not require ethical approval for reporting individual cases or case series.

Informed consent

Informed consent for patient information to be published in this article was not obtained because this was an audit.

Guarantor

PK.

Contributorship

PK wrote the first draft of the manuscript. All authors planned and participated in the ESOTA symposium, reviewed and edited the manuscript and approved the final version of the manuscript

Acknowledgement

We thank Luzia Balmer and Daniela Niederfeld for supporting ESO Trials Network Committee activities.

References

World Health Organization. Cardiovascular diseases fact sheet, http://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds (accessed 30 August 2018).

GBD 2013 Causes of Death and Mortality Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality and causes of death for 240 diseases, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015; 385: 117–171.

Mohan

Wolfe

CDA

Rudd

, et al. Risk and cumulative risk of stroke recurrence: A systematic review and meta-analysis. Stroke 2011; 42: 1489–1494.

Touzé

Varenne

Chatellier

, et al. Risk of myocardial infarction and vascular death after transient ischaemic attack and ischaemic stroke. A systematic review and meta-analysis. Stroke 2005; 36: 2748–2755.

Stroke Alliance for Europe. The Burden of Stroke in Europe report. 2017. ISBN 978-1-5272-0858-2

The GBD 2016 Lifetime Risk of Stroke Collaborators. Global, Regional, and Country-Specific Lifetime Risks of Stroke, 1990 and 2016. N Engl J Med 2018; 379: 2429–2437.

Norrving

Barrick

Davalos

, et al. Action plan for stroke in Europe 2018-2030. Eur Stroke J 2018; 3: 309–2. DOI: 10.1177/2396987318808719.

Berge

Al-Shahi Salman

van der Worp

, et al. Increasing value and reducing waste in stroke research. Lancet Neurol 2017; 16: 399–408.

Macleod

Michie

Roberts

, et al. Biomedical research: increasing value, reducing waste. Lancet 2014; 383: 101–104.

10.

Kernan

Use of recruitment networks in randomised trials. Stroke 2013; 44: S119–S121.

11.

Marshall

JC.

Global collaboration in acute care clinical research: opportunities, challenges, and needs. Crit Care Med 2017; 45: 311–320.

12.

Berge

Ford

Stapf

, et al. Are there opportunities for a closer collaboration on clinical stroke research in Europe? Eur Stroke J 2018; 3: 22–28.

13.

The InFACT H1N1 Collaboration: InFACT: a global critical care clinical research response to severe pandemic H1N1 infection. Lancet 2010; 375: 11–13.

14.

Cook

Guyatt

, Marshallet al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N Engl J Med 1998; 338: 791–797.

15.

Canadian Critical Care Trials Group. https://www.ccctg.ca (accessed 28 October 2018).

16.

PRISM Investigators. Early, goal-directed therapy for septic shock – a patient-level meta-analysis. N Engl J Med 2017; 376: 2223–2234.

17.

NICE-SUGAR Study Investigators: Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360: 1283–1297.

18.

International Forum for Acute Care Trialists. http://www.infactglobal.org (accessed 28 October 2018).

19.

Woodcock

LaVange

LM.

Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med 2017; 377: 62–70.

20.

ESO Trials Alliance (2018). https://www.eso-trialsalliance.org (accessed 28 October 2018).

21.

The International GAINS network. https://www.globalstroketrials.org (accessed 28 October 2018).

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.36 MB