NIHRDataInsights/HRCSData huggingface dataset:
Title: A cluster randomised controlled trial of an occupational therapy intervention for residents with stroke living in UK care-homes
Funder: Department of Health (England)

Abstract: The purpose of the study is to conduct a Phase III RCT to evaluate the effects of a targeted course of occupational therapy (targeted repetitive training of activities of daily living provision of adaptive equipment & minor environmental adaptations and staff training) for people living in a care home with a history of stroke or transient ischaemic attack (TIA) and who are not receiving end of life care. In particular the effects on independence in self care activities of daily living AND Mobility. This will be a pragmatic stage III cluster randomised controlled trial with independent assessment based on a stage II exploratory study. Randomisation will be conducted by the CTU and only revealed to the treating occupational therapist. Homes will be identified randomly; using published care home lists within South and East Birmingham Bangor Devon Portsmouth Nottingham and Preston including all funding models (private charitable not for profit and local authority). The homes will be approached for consent. Individual consent from residents and staff will also be gained. Baseline assessments will be completed prior to randomisation (to reduce possible bias once cluster allocation revealed). Control homes will receive free staff training once the study is completed to improve compliance and loss to follow up in the control group (again to reduce bias). Health technologies being assessed:Active intervention- Occupational therapy delivered by a qualified therapist will includei. Task-related ADL practice with an individualii. Provision of adaptive equipment to an individual. iii Adaptations to the individuals environment such as chair raises and bed levers and small general adaptations to the home such as raised toilet seats and grab rails. iii Care giver training. Individual and group sessions Control-Standard care. The primary outcome will be independence in ADL measured by the Barthel Index. Secondary outcomes will include mobility mood and adverse events. Cognitive status will be assessed at baseline. Staff attitudes will be assessed using the Kogans Old People Scale.Economic evaluation- The EQ5D will be recorded at each time point. The economic evaluation will take from the UK National Health Service perspective and a societal perspective. Outcomes will be measured as quality-adjusted life-years (QALYs).


Research activity codes: 6.7 PHYSICAL
Health categories: STROKE
Title: The Stroke Oxygen Study (SO2S): A multi-centre prospective randomised open blinded-endpoint study to assess whether routine oxygen supplementation (ROS) in the first 72 hours after a stroke improves long-term outcome
Funder: Department of Health (England)

Abstract: Approximately 110000 strokes occur in England every year and it is the third largest cause of mortality. 33000 are significantly disabled making it the single largest cause of adult disability about 50% of stroke survivors are dependent on others for everyday activities. Stroke costs the NHS and the economy approximately £7 billion a year of which £2.8 billion are direct costs £2.4 billion are care costs and £1.8 billion in income loss due to lost productivity and disability.Hypoxia is common early after acute stroke and is associated with worse outcome. About 60% of stroke patients will have at least one episode of hypoxia in the first 48 hours. Even amongst stroke patients who are normoxic on screening during the day 23% develop hypoxia at night. Routine oxygen supplementation could prevent hypoxia and related brain damage. However there is some evidence from preclinical studies that hyperoxia may be neurotoxic and a small clinical study of short-term fixed-dose oxygen supplementation did not show overall benefit.Appropriate management of post stroke hypoxia could prevent deterioration and improve recovery. A survey of British Stroke Physicians shows that there is uncertainty about when and how to treat hypoxia after stroke. European Stroke guidelines and the American Stroke Association suggest maintaining oxygen saturation levels at 92% or above and the UK Royal College of Physicians Guidelines state to keep oxygen saturation at or above 95%. Since there is no evidence from clinical trials to support any of the recommendations it is not surprising that there are differences. This research will provide the clinical data to support the development of evidence-based guidelines and protocols for the prevention and treatment of hypoxia after stroke. This could be incorporated into the recommended minimal procedural data set which underpins care pathways implemented in stroke units as recommended by NICE.


Research activity codes: 6.7 PHYSICAL
Health categories: STROKE
Title: Safety and efficacy of Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke: the TARDIS randomised controlled trial
Funder: Department of Health (England)

Abstract: Design: International collaborative prospective randomised (1:1) open blinded end-point controlled phase III trial of one month of intensive (triple: aspirin [Asp] dipyridamole [Dip] clopidogrel [Clop]) versus guideline [Asp+Dip or Clop alone] antiplatelet therapy in participants with acute ischaemic stroke or TIA. The primary outcome is frequency and severity of stroke/TIA.Setting: 4100 well phenotyped (stroke/TIA; clinical and imaging) participants from UK and overseas hospital-based stroke/TIA services (3500 from main phase and ~600 participants from start up phase). UK participants (1750) will be recruited from NIHR Stroke Research Network sites.Target population: Age>=50. <=48 hours of ictus (30-48 hours if thrombolysed). Non-cardioembolic ischaemic stroke with new motor weakness or dysphasia or hemianopia. TIA with one or more of ABCD2 score >3 crescendo TIA (>1 TIA within 1 week) or on dual antiplatelet therapy. Limb weakness and/or dysphasia must be present for >10 mins if a TIA or at enrolment if a stroke. CT scan to exclude haemorrhage/other pathology if a stroke.Health technology: Open-label IMPs for 30 days: oral Asp (load 300 mg then 75 mg daily) Clop (load 300 mg then 75 mg daily) Dip (modified release 200 mg twice daily). Standard evidence-based vascular and gastro prophylaxis are given as appropriate.Costs/outcomes: The overall hypothesis is that acute triple antiplatelets will reduce early stroke recurrence and its severity and hence resource costs. The primary outcome is stroke/TIA recurrence and its severity. Secondary and safety outcomes include vascular events bleeding and death. Outcome data will also include cognition mood and quality of life. Key costs and outcomes will be collected at each centre and resource utilisation determined locally including length of stay drug cost and discharge disposition. Incremental Cost Effectiveness Ratios and Cost Effectiveness Acceptability Curves will be calculated for both groups.Sample size: Total size =4100 (3500 from HTA main phase ~600 from ongoing BHF start-up phase) assuming alpha=5%; power =90%; distribution of 5-level stroke/TIA ordinal outcome (%): death 0.51 / severe (mRS 2-5) 0.77 / mild (mRS 01) 1.53 / TIA 3.57 / no event 93.62 (total events =262); odds ratio =0.68; treatment crossovers 5%; losses 2%; adjustment for baseline covariates = 20%; and assuming proportionality of odds.Timetable: TARDIS has 50 active UK sites and 479 (stroke 61% TIA 39%) of 350 planned participants in the BHF-funded start-up phase (at 28 of 36 months). To ensure a seamless transition we are now seeking additional sites to make 140+ in total (UK 70+; overseas 70+ from 15 countries).Recruitment: 140 active centres x0.5 participants per month=50 per month x1 year then 70 per month x3.5 years ~3540 participants. The existing approvals from MHRA MREC R&D and SRN cover the whole trial.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: STROKE
Title: High Throughput Science - Genomic and metabolmic analysis of haemorrhagic in the China Kadoorie Biobank
Funder: Medical Research Council

Abstract: Stroke is the second leading cause of death globally, with much less known about its genetic and non-genetic determinants than for other major diseases such as ischaemic heart disease (IHD). In the UK, although intracerebral haemorrhage (ICH) accounts for only 10-15% of stroke cases, it causes more than half of all stroke deaths, and much severe disability. In China, about 30% of incident cases of stroke are due to ICH and almost all suspected cases of stroke will have CT/MRI after admission to hospital, allowing reliable determination of stroke subtypes. Better understanding of genetic and non-genetic risk factors for stroke subtypes is essential for improved prediction and prevention, and the development of new therapies. Twin studies and other family studies indicate a substantial genetic component to stroke risk, but there are to date no reports of well-powered GWAS studies of ICH. We will investigate the genetic contribution to ICH in a case-control study nested within the prospective China Kadoorie Biobank (CKB) study of 0.5 million people, which included extensive data by questionnaires and physical measurements and long-term storage of blood samples. In the CKB follow-up through linkage to death and disease registries and to the nationwide health insurance system on all hospitalised events has accumulated >20,000 first strokes. The GWAS will include 5,000 scan-confirmed incident cases of ICH and 10,000 controls, frequency-matched by area, age, sex, time of enrollment, etc. We will use a 800,000 SNP Affymetrix Axiom® myDesign® array, custom-designed to maximise whole-genome coverage in the Chinese population, enabling imputation of 6-10M SNPs and indels using relevant publically available reference panels. The 10,000 control subjects will also form a set of “common controls” for genotyping studies of other diseases (e.g. ischaemic stroke, IHD). Genome-wide significant associations will be validated by direct genotyping, and up to 100 variants identified as putatively associated with stroke risk (e.g. P<10 6) will be prioritised for replication in additional incident cases from CKB and other cohorts from China and East Asia, together with in silico replication in imputed GWAS data from available ethnically diverse cohorts. In future, we plan to supplement the genetic analysis of these 15,000 subjects with metabolomic measurements on blood plasma based on mass spectrometry and proton nuclear magnetic resonance spectroscopy, and standard blood biomarker assays. Using system biology approaches to combine these ‘-omics’ data with detailed environmental and lifestyle information, we aim ultimately to understand the molecular basis of haemorrhagic stroke.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: STROKE
Title: Initiating End of Life Care in Stroke: clinical decision-making around prognosis
Funder: Marie Curie

Abstract: Background Initiating end-of-life care in an acute stroke context should target those patients and families with greatest need in a timely and acceptable manner. This requires synthesis of information on prognosis, patterns (trajectories) of dying, and patient and family preferences. Within acute stroke, prognostic models are available to identify risks of dying, but variability in dying trajectories makes it difficult for clinicians to know when to commence end-of-life interventions. Aim To investigate the use (at an individual clinician level) of different types of evidence in decisions to initiate end-of-life care within trajectories typical of the acute stroke population. Our objectives are: • To identify trajectories of dying in acute stroke • To investigate patients’ and family members’ experiences of the initiation of end-oflife care within acute stroke • To identify how clinicians draw on different types of prognostic, clinical and other information sources use in making decisions about initiating end-of-life care in acute stroke Methods Two-phase study comprising investigation of dying trajectories in acute stroke (Phase 1), and the use of clinical scenarios to investigate clinical decision-making in the initiation of end-of-life care (Phase 2). The research will be conducted in three acute stroke services in North Wales. In Phase 1, biographical, clinical and service data will be extracted from incident stroke patients’ records over six months. We aim to include 672 patients; 114 may die in the acute stroke phase. Analysis will focus on the investigation of prognostic factors which affect the outcomes associated with different trajectories identified in the data. In addition, semi-structured interviews of a sub-sample of patients, carers or bereaved relatives will uncover associated chronological narratives of experience. Interviews will draw on individually meaningful markers to identify the initiation of end-of-life care (e.g. information provision; withdrawal of interventions), and the way that this impacts upon experiences of care and illness progression. In Phase 2, a think-aloud exercise will be completed by 30 stroke clinicians, examining information used when making clinical decisions about initiating end-of-life care. Case scenarios drawn from Phase 1 will represent the types of patients and decisions that characterise initiating end-of-life care in acute stroke. Clinicians will also be interviewed about wider influences on decision-making. A15848 Dr Chris Burton IN CONFIDENCE MC - Project Award - October 2012 10 Use of results Clinical guidance on the recognition of dying and initiation of end-of-life care in acute stroke will be developed. Understanding clinicians’ decision-making will maximise guidance implementation potential.


Research activity codes: 7.2 END OF LIFE CARE;7.3 MANAGEMENT AND DECISION MAKING
Health categories: STROKE
Title: Performance-based selective training for robot-mediated upper limb motor learning and stroke rehabilitation
Funder: Medical Research Council

Abstract: Stroke is a leading cause of disability, with rising incidence as the western population ages. Stroke morbidity costs the EU economy more than an estimated Euro30b p.a. Over half of stroke survivors suffer from sensory and motor deficits. Upper limb hemiparesis is common, leaving the patients chronically - and sometimes severely - impaired in planning and/or executing movements with their paretic hand (e.g. reaching and grasping), reducing independence and quality of life. Recent research suggests that robot-assisted rehabilitative practice improves upper limb function, but current regimes focus almost exclusively on fixed movement paradigms It is likely that learning and recovery also depend on the selection of practiced movements, varied across individuals, and reflecting their individual abilities. Since current robot-assisted therapy does not involve such movement selection, therapist-assisted rehabilitation is both more patient focussed and more interactive. We suggest, based on pilot data, that individual tailoring of the selection of robot-assisted movements based on patient performance will benefit recovery, and that motor recovery will be most effective when the practice movements are selected from regions of the individual's performance "map" where the change between best and worst performance is most steep (spatially), allowing generalization of training from the best areas into the worst areas. We aim to test (1) that most learning is induced when practice is focused around the steepest local performance gradients; (2) any additional improvement by changing task difficulty across sequential training sessions. We will characterise (3) correlations between the pattern of reaching performance in task space i.e. to test the reliability of the performance map as an index of internal postural parameters; (4) learning-related changes in the parameter space. We will (5) quantify the benefit of performance-based practice to hemiparetic stroke patients.


Research activity codes: 5.7 PHYSICAL;6.7 PHYSICAL
Health categories: STROKE
Title: Early thrombolytic intervention in acute stroke by imaging with Electrical Impedance Tomography
Funder: Medical Research Council

Abstract: Electrical Impedance Tomography (EIT) is a novel medical imaging method in which tomographic images are rapidly produced using rings of electrodes placed around the body. It is safe, portable and inexpensive. The principal applicant's group has demonstrated that EIT can rapidly image functional brain activity in stroke, epilepsy and normal activity in animal models and has developed instrumentation and image reconstruction algorithms which work well in head-shaped tanks. Thrombolytic "clot-busting" treatment is a new treatment for acute stroke which must be given within three hours, but its take-up has been restricted because it is essential to undertake neuroimaging first to exclude a haemorrhage. EIT has the potential to provide an inexpensive portable unit for use in ambulances or GP surgeries which would revolutionise thrombolytic management of stroke by providing imaging at the point of contact. This would be used to sanction administration of thrombolysis immediately by a paramedic or auxiliary health staff. Support is requested for a collaboration between UCL and GE. While there is strong underpinning data to demonstrate proof of principle of the method, modelling and specification studies have indicated there are three tractable technical improvements needed to achieve breakthrough into clinical use. Support is requested for 3.5 post-doctoral research assistants over 2 years for the academic partner to apply innovations established in related fields to image reconstruction algorithms and electrode application to the scalp. GE will provide electronic hardware and commercial development.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: STROKE
Title: TREM-2, inflammation resolution and the transition from brain injury to repair after stroke
Funder: Medical Research Council

Abstract: Inflammation may have both damaging and protective influences during acute and chronic neurodegeneration including after acute cerebral ischaemia/stroke. This duality of inflammation underlines the need to understand how toxic and beneficial inflammation is balanced in the injured brain. In particular, establishing how pro-injurious inflammation can be contained or resolved without compromising the capacity for endogenous or exogenously-triggered brain repair is essential. Our recent data supporting this proposal show that Triggering Receptor Expressed on Myeloid cells-2 (TREM-2) may act as a critical molecular regulator restraining injurious inflammation and supporting repair e.g. we have shown that TREM-2 signalling in microglia and macrophages connects the removal of neurotoxic neutrophils with proliferation of neuronal precursors. However, the role of TREM-2 under the unique conditions of the ischaemic brain has not been studied previously. The overriding aim of this proposal is to test the hypothesis that Triggering Receptor Expressed on Myeloid cells-2 (TREM-2) drives resolution of injurious inflammation and the transition from injury to repair in the brain after acute cerebral ischaemia. We will use a multi-modal approach including an experimental model of stroke, in vitro co-culture systems combining myeloid and neural cells and post-mortem brain tissue from stroke patients. We will exploit and generate novel tools that enable targeted deletion or augmentation of TREM-2 activity. These approaches will be used to determine expression patterns of TREM-2, the effects of TREM-2 on inflammatory cell phenotypes and the impact of TREM-2 deletion or overexpression on inflammatory profile and markers of injury and repair after stroke. We expect our findings will provide a rational basis for developing effective immunomodulatory approaches for the treatment of stroke and other neurological conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: STROKE
Title: A disease model to investigate vascular endothelial function for genetic stroke CADASIL
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephelopathy), caused by NOTCH3 gene mutations, is the most common type of genetic stroke and vascular dementia. It is a systemic arteriopathy with pathological changes mainly restricted to small arteries including: 1) Vascular smooth muscle cell (VSMC) degeneration; 2) Granular osmiophilic material (GOM) deposition in arterial walls; 3) Accumulation of the extracellular domain of Notch3 protein in the basal membrane of arteries; and 4) Cerebral blood flow dysregulation. It has been 15 years since NOTCH3 was found to be the causative gene for CADASIL, but the molecular mechanisms by which the mutant Notch3 results in the pathological changes of arteries are still largely unknown. Despite interesting insights into the disease pathology uncovered using transgenic mouse models and cell based studies, it is still unclear whether NOTCH3 mutations in CADASIL are gain-of-function or loss-of-function mutations. Thus, no specific and effective treatment is available. To clarify the molecular mechanisms of CADASIL, previous efforts have been largely focused on the VSMCs due to the prominent pathological changes in this type of cell. However, impaired endothelial function has been repeatedly observed in arteries of both CADASIL transgenic mice and CADASIL patients. The endothelial dysfunction could be secondary to the SMC damage, which makes the study of the interaction between ECs and VSMCs extremely important in CADASIL. In intact arteries, ECs and SMCs do not function independently and Notch signalling plays a vital role in communication between the two types of cells. We hypothesise that the Notch signalling circuit between ECs and SMCs is disrupted in CADASIL by the NOTCH3 mutations. The recent advance in stem cell biology has made it possible to obtain induced pluripotent stem cells (iPSCs) from somatic cells of patients and un-affected sibling controls to generate patient-specific disease cell models. We plan to use iPSCs to obtain CADASIL patient-specific endothelial cells by targeted differentiation. The endothelial cells will be characterised for their morphology, functions and interaction with CADASIL patient-specific smooth muscle cells. We also plan to generate 3D vessels which carry patient-specific SMCs and ECs for functional analysis of the vessel as a whole. This CADASIL model will be ideal for screening therapeutic options. Findings from the project will not only benefit CADASIL patients, but also contribute to uncovering more information relating to Notch signalling in arterial function which will have a wider impact on the investigation and treatment of EC and VSMC-involved common vascular diseases such as atherosclerosis and hypertension.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: STROKE