Studies within a trial priorities to improve the evidence to inform recruitment and retention practice in clinical trials

Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Trials Methodology Research Partnership (MR/S014357/1). The Health Services Research Unit, Institute of Applied Health Sciences (University of Aberdeen), is core-funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. The funders had no involvement in study design, collection, analysis and interpretation of data, reporting or the decision to publish.Peer reviewedPublisher PD

Role, function, and expectations of research funding committees: Perspectives from committee members [version 3; peer review: 1 approved, 2 approved with reservations, 1 not approved]

Research funding committees play an integral role in the research funding process, consisting of a range of skills, knowledge, and expertise (e.g., professional, and public contributors). Although there is some evidence that has explored the efficiency and effectiveness of funding committees in terms of the funding process, there is a lack of published evidence about the purpose, role, and function of funding committees, from the perspective of committee members. A subset of survey data from a cohort of six National Institute for Health and Care Research (NIHR) research programmes, exploring the purpose of a funding committee, and the expectations and role of a funding committee member between October 2020 to December 2021. All committee members were eligible to participate in the survey. Using an inductive approach, 50 completed responses (22.5% response rate) were analysed, focusing on the role of a funding committee member and the functions of a funding committee. Participants highlighted seven key areas for the purpose of a funding committee: prioritising and recommending what research to fund (n=36) and assessment of quality (n=24) being the most common responses. Four areas were considered important to the expectations and role of funding committee members, with reviewing, critically appraising, and discussing applications (n=44); and being fair, objective, and unbiased (n=27) being the most common responses. The findings offer a unique insight into committee members’ expectations about the role, purpose and function of a funding committee and their contribution to the funding recommendation process. There was high agreement that the purpose and role of committees and their members was to offer expert advice to make fair, impartial decisions on which research should be prioritised. Exploring the purpose, role, and function of funding committees has relevance and importance for funding organisations seeking to enhance and optimise the decision-making practice of funding committees

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Understanding the variation of modern endoscopic ultrasound use in patients with oesophageal cancer (VALUE): protocol for a multi-methods study

Objectives Over 9,000 patients are diagnosed with oesophageal cancer annually in the United Kingdom (UK). Decision-making about treatment options is influenced by radiological staging, which may include computed tomography (CT), positron emission tomography (PET), and endoscopic ultrasound (EUS). The use of EUS varies considerably around the UK and, since the introduction of PET-CT, the added value of EUS has been questioned. The VALUE study aims to understand this variation and determine how often and why EUS changes treatment decisions. VALUE will also evaluate patient and clinician experiences and opinions of EUS. Methods This is a prospective, observational study investigating EUS in oesophageal cancer staging. Patients will be recruited at up to eleven sites in the UK, where they will be consented (if eligible) and registered onto iMedidata RAVE. Clinical and demographic data, TNM staging, pre and post EUS treatment decisions, and complications will be collected. We will attempt to sample patients from ethnic minority backgrounds in the study population, as they are underrepresented in research. Up to 30 patients and 30 clinicians will be interviewed to evaluate the use of EUS and experiences of both patient and clinician. The primary endpoint is the proportion of cases that EUS changes treatment decisions. Secondary endpoints include identification of factors that clinicians and patients consider when deciding if EUS should be used, the time from diagnosis to treatment decision before and after EUS, and the reasons why EUS changed management. The study has been registered on Clinicaltrials.gov: blinded. The trial is open to recruitment. Results In total, 180 patients with potentially curable oesophageal cancer who are suitable for EUS will participate. Recruitment is currently planned until September 2025 and study results will be reported after June 2026. Conclusion The VALUE study will enable a better understanding of how and why EUS is used in oesophageal cancer. This research will identify important factors that clinicians and patients consider when deciding EUS use and determine the frequency that EUS changes treatment decisions in the modern staging pathway

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016

© 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Traumatic brain injury (TBI) and spinal cord injury (SCI) are increasingly recognised as global health priorities in view of the preventability of most injuries and the complex and expensive medical care they necessitate. We aimed to measure the incidence, prevalence, and years of life lived with disability (YLDs) for TBI and SCI from all causes of injury in every country, to describe how these measures have changed between 1990 and 2016, and to estimate the proportion of TBI and SCI cases caused by different types of injury. Methods: We used results from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016 to measure the global, regional, and national burden of TBI and SCI by age and sex. We measured the incidence and prevalence of all causes of injury requiring medical care in inpatient and outpatient records, literature studies, and survey data. By use of clinical record data, we estimated the proportion of each cause of injury that required medical care that would result in TBI or SCI being considered as the nature of injury. We used literature studies to establish standardised mortality ratios and applied differential equations to convert incidence to prevalence of long-term disability. Finally, we applied GBD disability weights to calculate YLDs. We used a Bayesian meta-regression tool for epidemiological modelling, used cause-specific mortality rates for non-fatal estimation, and adjusted our results for disability experienced with comorbid conditions. We also analysed results on the basis of the Socio-demographic Index, a compound measure of income per capita, education, and fertility. Findings: In 2016, there were 27·08 million (95% uncertainty interval [UI] 24·30–30·30 million) new cases of TBI and 0·93 million (0·78–1·16 million) new cases of SCI, with age-standardised incidence rates of 369 (331–412) per 100 000 population for TBI and 13 (11–16) per 100 000 for SCI. In 2016, the number of prevalent cases of TBI was 55·50 million (53·40–57·62 million) and of SCI was 27·04 million (24·98–30·15 million). From 1990 to 2016, the age-standardised prevalence of TBI increased by 8·4% (95% UI 7·7 to 9·2), whereas that of SCI did not change significantly (−0·2% [–2·1 to 2·7]). Age-standardised incidence rates increased by 3·6% (1·8 to 5·5) for TBI, but did not change significantly for SCI (−3·6% [–7·4 to 4·0]). TBI caused 8·1 million (95% UI 6·0–10·4 million) YLDs and SCI caused 9·5 million (6·7–12·4 million) YLDs in 2016, corresponding to age-standardised rates of 111 (82–141) per 100 000 for TBI and 130 (90–170) per 100 000 for SCI. Falls and road injuries were the leading causes of new cases of TBI and SCI in most regions. Interpretation: TBI and SCI constitute a considerable portion of the global injury burden and are caused primarily by falls and road injuries. The increase in incidence of TBI over time might continue in view of increases in population density, population ageing, and increasing use of motor vehicles, motorcycles, and bicycles. The number of individuals living with SCI is expected to increase in view of population growth, which is concerning because of the specialised care that people with SCI can require. Our study was limited by data sparsity in some regions, and it will be important to invest greater resources in collection of data for TBI and SCI to improve the accuracy of future assessments. Funding: Bill & Melinda Gates Foundation

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation

Studies within a trial priorities to improve the evidence to inform recruitment and retention practice in clinical trials

Background: trial execution commonly relies on experience and judgement because there is a lack of evidence to inform how best to design and deliver clinical trials. Recruitment and retention are critical determinants to trial success have been persistent challenges that impact various stakeholders including funders, researchers, and the public. Studies within a trial (SWATs) are a way to discover best practices for recruitment and retention strategies, however, the current SWAT landscape has not been formally explored to date. This study aimed to (i) identify where current activity is taking place (ii) understand if SWATs are addressing PRioRiTY questions (iii) highlight gaps in the literature for future research.Methods: in November 2020, registered SWATs in the SWAT repository store were extracted and categorised into ‘recruitment’, ‘retention’ or ‘other’ based on the primary outcome. Recruitment and retention SWATs were subsequently mapped against PRioRiTY 1 and 2 questions and descriptive statistics were used to present the findings.Results: 125 registered SWATs were extracted from the repository. 50 and 36 SWATs reported recruitment and retention as their primary outcome, respectively. A majority of recruitment SWATs investigated what and how information should be designed and delivered to potential trial participants (n = 23, 46%) and the advantages and disadvantages of using technology during the recruitment process (n = 9, 18%). Three of the Top 10 PRioRiTY 1 questions had no SWATs mapped against them. A majority of retention SWATs focused on the best ways to encourage participants to complete trial tasks (n = 24, 67%), how incentives should be implemented (n = 10, 28%) and strategies to make participants feel valued (n = 9, 25%). Five of the Top 10 PRioRiTY 2 questions had no SWATs mapped against them.Conclusions: this study identified a mismatch between registered SWAT activity and the priority questions in recruitment and retention. Trial teams should consider the PRioRiTy 1 and 2 questions for recruitment and retention, respectively, when designing a SWAT. In addition, there is a great breadth of research taking place, but replication of existing research is needed to produce confident evidence-based guidance for trialists and researchers to implement into their work