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Background The most common cause of preventable death after injury is haemorrhage. Resuscitative endovascular balloon occlusion of the aorta is intended to provide earlier, temporary haemorrhage control, to facilitate transfer to an operating theatre or interventional radiology suite for definitive haemostasis. Objective To compare standard care plus resuscitative endovascular balloon occlusion of the aorta versus standard care in patients with exsanguinating haemorrhage in the emergency department. Design Pragmatic, multicentre, Bayesian, group-sequential, registry-enabled, open-label, parallel-group randomised controlled trial to determine the clinical and cost-effectiveness of standard care plus resuscitative endovascular balloon occlusion of the aorta, compared to standard care alone. Setting United Kingdom Major Trauma Centres. Participants Trauma patients aged 16 years or older with confirmed or suspected life-threatening torso haemorrhage deemed amenable to adjunctive treatment with resuscitative endovascular balloon occlusion of the aorta. Interventions Participants were randomly assigned 1 : 1 to: standard care, as expected in a major trauma centre standard care plus resuscitative endovascular balloon occlusion of the aorta. Main outcome measures Primary: Mortality at 90 days. Secondary: Mortality at 6 months, while in hospital, and within 24, 6 and 3 hours; need for haemorrhage control procedures, time to commencement of haemorrhage procedure, complications, length of stay (hospital and intensive care unit-free days), blood product use. Health economic: Expected United Kingdom National Health Service perspective costs, life-years and quality-adjusted life-years, modelled over a lifetime horizon. Data sources Case report forms, Trauma Audit and Research Network registry, NHS Digital (Hospital Episode Statistics and Office of National Statistics data). Results Ninety patients were enrolled: 46 were randomised to standard care plus resuscitative endovascular balloon occlusion of the aorta and 44 to standard care. Mortality at 90 days was higher in the standard care plus resuscitative endovascular balloon occlusion of the aorta group (54%) compared to the standard care group (42%). The odds ratio was 1.58 (95% credible interval 0.72 to 3.52). The posterior probability of an odds ratio > 1 (indicating increased odds of death with resuscitative endovascular balloon occlusion of the aorta) was 86.9%. The overall effect did not change when an enthusiastic prior was used or when the estimate was adjusted for baseline characteristics. For the secondary outcomes (3, 6 and 24 hours mortality), the posterior probability that standard care plus resuscitative endovascular balloon occlusion of the aorta was harmful was higher than for the primary outcome. Additional analyses to account for intercurrent events did not change the direction of the estimate for mortality at any time point. Death due to haemorrhage was more common in the standard care plus resuscitative endovascular balloon occlusion of the aorta group than in the standard care group. There were no serious adverse device effects. Resuscitative endovascular balloon occlusion of the aorta is less costly (probability 99%), due to the competing mortality risk but also substantially less effective in terms of lifetime quality-adjusted life-years (probability 91%). Limitations The size of the study reflects the relative infrequency of exsanguinating traumatic haemorrhage in the United Kingdom. There were some baseline imbalances between groups, but adjusted analyses had little effect on the estimates. Conclusions This is the first randomised trial of the addition of resuscitative endovascular balloon occlusion of the aorta to standard care in the management of exsanguinating haemorrhage. All the analyses suggest that a strategy of standard care plus resuscitative endovascular balloon occlusion of the aorta is potentially harmful. Future work The role (if any) of resuscitative endovascular balloon occlusion of the aorta in the pre-hospital setting remains unclear. Further research to clarify its potential (or not) may be required. Trial registration This trial is registered as ISRCTN16184981. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/199/09) and is published in full in Health Technology Assessment; Vol. 28, No. 54. See the NIHR Funding and Awards website for further award information. Plain language summary Trauma (physical injury) is a major cause of death and disability. The most common cause of preventable death after injury is uncontrolled bleeding. Resuscitative endovascular balloon occlusion of the aorta is a technique whereby a small balloon is inflated in the aorta (main blood vessel) which aims to limit blood loss until an operation can be done to stop the bleeding. In this study, which is the first randomised trial in the world of this technique, we investigated whether adding resuscitative endovascular balloon occlusion of the aorta to the standard care received in a major trauma centre reduced the risk of death in trauma patients who had life-threatening uncontrolled bleeding. The study took place in 16 major trauma centres in the United Kingdom. Ninety adult trauma patients with confirmed or suspected uncontrolled bleeding took part and were randomly divided into two groups: (1) those who received standard care and (2) those who received standard care plus resuscitative endovascular balloon occlusion of the aorta. We followed participants for 6 months using routinely collected data from the National Health Service and from the Trauma Audit Research Network registry. We also contacted surviving patients at 6 months to ask about their quality of life. In the standard care group, 42% of participants died within 90 days of their injury compared to 54% of participants in the standard care plus resuscitative endovascular balloon occlusion of the aorta group. Risk of death was also higher in the standard care plus resuscitative endovascular balloon occlusion of the aorta group at all other time points (3, 6 and 24 hours, in hospital and at 6 months). Overall, the study showed that the use of resuscitative endovascular balloon occlusion of the aorta in hospital increased the risk of death. Scientific summary Background Trauma is a major cause of death and disability. Trauma (physical injury) disproportionately affects the young, killing those who might otherwise have lived long and productive lives. The most common cause of preventable death after injury is haemorrhage. The addition of resuscitative endovascular balloon occlusion of the aorta (REBOA) to current standard care is intended to provide earlier, temporary haemorrhage control, to facilitate transfer to an operating theatre or interventional radiology suite, for definitive haemostasis. Objectives The UK-REBOA trial was a pragmatic, multicentre, Bayesian, open-label, group-sequential, parallel-group randomised controlled trial comparing standard care plus REBOA versus standard care in patients with exsanguinating haemorrhage in the emergency room. The study included an elicitation exercise, an embedded mixed-methods process evaluation and a health economic evaluation. The primary clinical outcome was 90-day mortality (defined as death within 90 days of injury, before or after discharge from hospital). Secondary clinical outcomes included 3-, 6- and 24-hour mortality, in-hospital mortality, 6-month mortality, length of stay (in hospital and intensive care unit), 24-hour blood product use, need for haemorrhage control procedures (operation or angioembolisation), time to commencement of haemorrhage control procedure, complications/safety data and functional outcome [measured using the extended Glasgow Outcome Scale (GOS-E)] at discharge. Economic outcomes were 6-month (within trial) and lifetime (modelled) UK NHS perspective costs, life-years and quality-adjusted life-years (QALYs) [calculated using EuroQol Group’s 5-dimension health status 5-level questionnaire (EQ-5D-5L)], 6-month quality of life (measured using EQ-5D-5L). Methods Trauma patients were recruited in 16 UK major trauma centres. Trauma patients aged (or believed to be aged) 16 years or older, with confirmed or suspected life-threatening torso haemorrhage thought to be amenable to adjunctive treatment with REBOA were eligible. Women known (or thought to be) pregnant and those with injuries deemed unsurvivable were excluded. The trauma team leader assessed the patients for eligibility. Patients who were eligible for inclusion in the trial were incapacitated and unable to give consent at the time of eligibility assessment and randomisation. There was also not sufficient time to consult a surrogate decision-maker, or even an independent medical practitioner, for advice about including the patient. Enrolment therefore took place without prior consent following Research Ethics Committee approval for this approach. Consent for continuing participation (i.e. data collection) was sought by a member of the UK-REBOA trial team once patients were no longer in a critical condition (defined as being cared for in a ward area rather than an intensive care unit or high-dependency unit) or from a personal (or nominated professional) consultee. The trauma team leader enrolled the participant using a dedicated, secure website, available on a handheld device (smartphone, tablet) or desktop computer which is linked directly to the 24-hour randomisation system at the Centre for Healthcare Randomised Trials, based in the Health Services Research Unit, University of Aberdeen. Patients were randomised into one of the two intervention arms, in a 1 : 1 allocation ratio, in randomly generated blocks of two or four. Standard care: Patients allocated to the control group received ‘standard care’, as expected in a specialist major trauma centre. Such treatment typically included intubation, blood transfusion including blood products in a 1 : 1 : 1 ratio, interventions such as tourniquet application, and early operative or endovascular haemorrhage control. Treatment could also have included open aortic occlusion of the thoracic or abdominal aorta. Standard care plus REBOA: Patients allocated to this arm of the trial additionally received the technique of endovascular aortic occlusion, for the purpose of resuscitation, as part of an overall treatment strategy. The addition of REBOA to current standard care was intended to provide earlier, temporary haemorrhage control, to facilitate transfer to an operating theatre or interventional radiology suite for definitive haemostasis. The trial sought to evaluate the technique of REBOA rather than a specific brand of device, and therefore permitted the use of any licensed occlusion balloon, and did not prescribe or mandate a particular product. The trial had an integrated training programme to ensure familiarity with the REBOA procedure. In patients who had been randomised to the standard care plus REBOA arm of the trial, clinicians could decide not to insert the balloon occlusion device if: the patient’s haemodynamic status improved (as a result of other resuscitative measures), if they were deemed to no longer have life-threatening torso haemorrhage requiring adjunctive treatment with REBOA; they deteriorated (to the point of imminent death); or there was technical difficulty in obtaining arterial access, and it was felt that operative control of haemorrhage could be obtained more quickly. The data collection strategy for the UK-REBOA trial was designed to minimise the burden on participants and clinicians, and for the avoidance of duplication. The randomisation system collected balloon inflation/deflation times. The trial drew on routinely collected data, primarily from the Trauma Audit and Research Network (TARN) registry which includes demographic, injury, treatment and outcome data (including the GOS-E and EQ-5D-5L). Mortality and hospital resource use data were also sought from NHS Digital. The main analysis was based on the intention-to-treat principle. There were two planned interim analyses of survival and a final analysis of all outcomes after follow-up was complete. Baseline and follow-up data were summarised using descriptive statistics and graphical summaries. Treatment effects are presented with 95% credible intervals for the primary and secondary outcomes. Elicitation exercise An elicitation exercise involving 20 subject matter experts (12 emergency medicine physicians, 3 pre-hospital care doctors, 4 surgeons and 1 intensivist) was undertaken to derive prior probability distributions to help contextualise the interpretation for the primary and secondary outcomes of the trial. Subject matter experts, on average, estimated in-hospital and 90-day mortality in this patient group, without the use of REBOA, to be in excess of 50%. Mortality at earlier time points (6 and 24 hours) was estimated to be closer to 25%. The elicited data, and the resulting prior probability distributions, indicate that the experts, on average, had a favourable opinion of REBOA, that is they expect the addition of REBOA to standard care to improve mortality at all time points. Clinical results Sixteen recruitment sites were opened in a staggered manner. Recruitment commenced in October 2017, was halted in March 2020 due to COVID-19, and restarted in July 2020. The second interim analysis (including 80 participants) triggered one of the pre-specified stopping rules, and recruitment closed in March 2022, by which time 90 participants had been recruited. Forty-four participants were randomised to standard care (2 of whom did receive REBOA) and 46 were randomised to standard care plus REBOA (19 of whom had the catheter inserted and balloon inserted and the remaining 27 progressed to different time points along this pathway). The groups were well-matched in terms of age, gender, comorbidities, mechanism of injury and injury severity. In the standard care arm, the median age was 39 years (interquartile range 30–56 years) and 77% were male. In the standard care plus REBOA arm, the median age was 46 years (interquartile range 33–62) and 61% were male. The median Injury Severity Score in both arms was 41 (interquartile range 29–50), with the majority classed as having very severe injury. Of the 46 patients allocated to standard care plus REBOA treatment, 25 (54%) died within 90 days. Of the 43 standard care patients for whom primary outcome data are available, 18 (42%) died within 90 days. Using the minimally informative prior, the odds of 90-day mortality were 1.58 for patients allocated to the standard care plus REBOA arm (95% credible interval 0.72 to 3.52). The posterior probability of an odds ratio > 1 (i.e. that REBOA was harmful) was 86.9%. The direction of the estimate did not change when an enthusiastic (the elicited) prior was used or when the estimate was adjusted for baseline characteristics. For the secondary outcomes (3-, 6- and 24-hour mortality), the posterior probability that REBOA was harmful was higher than for the primary outcome. Additional analyses to account for intercurrent events did not change the direction of the estimate for mortality at 3, 6 and 24 hours, at 90 days or 6 months, or in-hospital mortality. Death due to haemorrhage was more common in the standard care plus REBOA group than in the standard care group. The mean number of days spent in intensive care and in hospital were lower in the standard care plus REBOA group compared to the standard care group, partly because of the higher number of earlier deaths in the standard care plus REBOA arm. There were no serious adverse device effects. Health economics We costed individual components of resources and summed these to generate a total cost for the whole initial hospitalisation admission period. Total NHS resource use for the index hospitalisation was obtained from patient-level data in TARN and the key resource use variables for costing included time of arrival, time of emergency department departure, time of first operation, time of death/discharge, number and type of operative procedures and volume of blood transfusions that were required. Secondary care contacts and episodes of care that were commenced between the date of discharge from the index hospitalisation through 6 months post randomisation were sourced, where available, through linkage of patient records to the Hospital Episode Statistics database. All costs are reported from a UK NHS perspective in Great British pounds (GBP) (year 2020-1). Quality of life was measured using the EQ-5D-5L prior to patient’s discharge from their index hospitalisation and at 6 months post admission. EQ-5D-5L asks respondents to report any problems on a given day across five dimensions of mobility, self-care, usual activities, anxiety/depression and pain. The data were available from TARN and supplemented with data collected by the local trial teams. EQ-5D-5L data were cross-walked to the 3L version and valued using UK general population preference tariffs. Baseline utility was set equal to the unconscious state (−0.402) and utility following death was set to 0. QALYs were calculated using an area under the curve approach assuming linear extrapolation between time points. From the within-trial health economic analysis, participants in the standard care plus REBOA arm of the study incurred lower costs {index hospital admission: mean cost £57,384 [standard deviation (SD) £62,863]} compared to those in standard care [mean cost £116,064 (SD £128,957)]. Lower costs in the standard care plus REBOA arm of the study were mainly due to lower use of hospital resources (length of stay, etc.) due to the competing risk of death (i.e. a higher number of deaths in the REBOA plus standard care group). Similarly, life-years accrued and QALYs over 6 months post randomisation were also lower in standard care plus REBOA compared to standard care due to a greater proportion of trial participants dying, with mortality also occurring earlier in the follow-up period for the REBOA arm. The mean life-years gained in the standard care plus REBOA arm was 0.232 (SD 0.247) compared to 0.305 (SD 0.236) in the standard care arm. When modelled over a full lifetime horizon, standard care plus REBOA is less costly (probability 99%), due to the competing risk of mortality but is also substantially less effective in terms of QALYs accrued over a lifetime horizon (probability 91%). The findings are robust to a range of scenario analyses undertaken, with the probability of standard care being the optimal treatment strategy ranging from 66% to 81% at a threshold value of a QALY = £50,000. Process evaluation The process evaluation was conducted in two phases; both phases involved interviews with clinical and research staff based at recruitment sites. Phase 1 was designed to identify barriers during trial initial and set-up; Phase 2 focused on exploring barriers and facilitators of recruitment into the trial and intervention delivery. A behavioural framework was used in Phase 2 to direct analysis and generate solutions designed to enhance trial practices, which included regular online meetings between the principal investigators from each site, updates to training materials and delivery, and e-mail/Twitter feedback on recruitment activity. Conclusions This is the first randomised trial ever to be conducted examining the potential clinical effectiveness of REBOA for the management of exsanguinating haemorrhage. All the analyses conducted suggest with high probability that a strategy of standard care plus REBOA is harmful. Implications for health care: The continuing use of REBOA, at least in the UK in-hospital setting, should be re-evaluated. Implications for research: The role (if any) of REBOA in the pre-hospital setting remains unclear. Further research to clarify its potential (or not) may be required. Trial registration This trial is registered as ISRCTN16184981. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/199/09) and will be published in full in Health Technology Assessment; Vol. 28, No. 54. See the NIHR Funding and Awards website for further award information.

Background Gallstone disease is a common gastrointestinal disorder in industrialised societies. The prevalence of gallstones in the adult population is estimated to be approximately 10–15%, and around 80% remain asymptomatic. At present, cholecystectomy is the default option for people with symptomatic gallstone disease. Objectives To assess the clinical and cost-effectiveness of observation/conservative management compared with laparoscopic cholecystectomy for preventing recurrent symptoms and complications in adults presenting with uncomplicated symptomatic gallstones in secondary care. Design Parallel group, multicentre patient randomised superiority pragmatic trial with up to 24 months follow-up and embedded qualitative research. Within-trial cost–utility and 10-year Markov model analyses. Development of a core outcome set for uncomplicated symptomatic gallstone disease. Setting Secondary care elective settings. Participants Adults with symptomatic uncomplicated gallstone disease referred to a secondary care setting were considered for inclusion. Interventions Participants were randomised 1: 1 at clinic to receive either laparoscopic cholecystectomy or observation/conservative management. Main outcome measures The primary outcome was quality of life measured by area under the curve over 18 months using the Short Form-36 bodily pain domain. Secondary outcomes included the Otago gallstones’ condition-specific questionnaire, Short Form-36 domains (excluding bodily pain), area under the curve over 24 months for Short Form-36 bodily pain domain, persistent symptoms, complications and need for further treatment. No outcomes were blinded to allocation. Results Between August 2016 and November 2019, 434 participants were randomised (217 in each group) from 20 United Kingdom centres. By 24 months, 64 (29.5%) in the observation/conservative management group and 153 (70.5%) in the laparoscopic cholecystectomy group had received surgery, median time to surgery of 9.0 months (interquartile range, 5.6–15.0) and 4.7 months (interquartile range 2.6–7.9), respectively. At 18 months, the mean Short Form-36 norm-based bodily pain score was 49.4 (standard deviation 11.7) in the observation/conservative management group and 50.4 (standard deviation 11.6) in the laparoscopic cholecystectomy group. The mean area under the curve over 18 months was 46.8 for both groups with no difference: mean difference –0.0, 95% confidence interval (–1.7 to 1.7); p-value 0.996; n = 203 observation/conservative, n = 205 cholecystectomy. There was no evidence of differences in quality of life, complications or need for further treatment at up to 24 months follow-up. Condition-specific quality of life at 24 months favoured cholecystectomy: mean difference 9.0, 95% confidence interval (4.1 to 14.0), p

Abstract Background Various washout policies are widely used in adults living with long-term catheters (LTC). There is currently insufficient evidence on the benefits and potential harms of prophylactic LTC washout policies in the prevention of blockages and other LTC-related adverse events, such as urinary tract infections. CATHETER II tests the hypothesis that weekly prophylactic LTC washouts (normal saline or citric acid) in addition to standard LTC care reduce the incidence of catheter blockage requiring intervention compared to standard LTC care only in adults living with LTC. Methods CATHETER II is a pragmatic three-arm open multi-centre superiority randomised controlled trial with an internal pilot, economic analysis, and embedded qualitative study. Eligible participants are adults aged ≥ 18 years, who have had a LTC in use for ≥ 28 days, have no plans to discontinue the use of the catheter, are able to undertake the catheter washouts, and complete trial documentation or have a carer able to help them. Participants are identified from general practitioner practices, secondary/tertiary care, community healthcare, care homes, and via public advertising strategies. Participants are randomised 1:1:1 to receive a weekly saline (0.9%) washout in addition to standard LTC care, a weekly citric acid (3.23%) washout in addition to standard LTC care or standard LTC care only. Participants and/or carers will receive training to administer the washouts. Patient-reported outcomes are collected at baseline and for 24 months post-randomisation. The primary clinical outcome is catheter blockage requiring intervention up to 24 months post-randomisation expressed per 1000 catheter days. Secondary outcomes include symptomatic catheter-associated urinary tract infection requiring antibiotics, catheter change, adverse events, NHS/ healthcare use, and impact on quality of life. Discussion This study will guide treatment decision-making and clinical practice guidelines regarding the effectiveness of various prophylactic catheter washout policies in men and women living with LTC. This research has received ethical approval from Wales Research Ethics Committee 6 (19/WA/0015). Trial registration ISRCTN ISRCTN17116445 . Registered prospectively on 06 November 2019

Abstract Randomised trials, especially those intended to directly inform clinical practice and policy, should be designed to reflect all those who could benefit from the intervention under test should it prove effective. This does not always happen. The UK National Institute for Health and Care Research (NIHR) INCLUDE project identified many groups in the UK that are under-served by trials, including ethnic minorities. This guidance document presents four key recommendations for designing and running trials that include the ethnic groups needed by the trial. These are (1) ensure eligibility criteria and recruitment pathway do not limit participation in ways you do not intend, (2) ensure your trial materials are developed with inclusion in mind, (3) ensure staff are culturally competent and (4) build trusting partnerships with community organisations that work with ethnic minority groups. Each recommendation comes with best practice advice, public contributor testimonials, examples of the inclusion problem tackled by the recommendation, or strategies to mitigate the problem, as well as a collection of resources to support implementation of the recommendations. We encourage trial teams to follow the recommendations and, where possible, evaluate the strategies they use to implement them. Finally, while our primary audience is those designing, running and reporting trials, we hope funders, grant reviewers and approvals agencies may also find our guidance useful.

Abstract Background Obesity increases the risk of type 2 diabetes, heart disease, stroke, mobility problems and some cancers, and its prevalence is rising. Men engage less than women in existing weight loss interventions. Game of Stones builds on a successful feasibility study and aims to find out if automated text messages with or without endowment incentives are effective and cost-effective for weight loss at 12 months compared to a waiting list comparator arm in men with obesity. Methods A 3-arm, parallel group, assessor-blind superiority randomised controlled trial with process evaluation will recruit 585 adult men with body mass index of 30 kg/m2 or more living in and around three UK centres (Belfast, Bristol, Glasgow), purposively targeting disadvantaged areas. Intervention groups: (i) automated, theory-informed text messages daily for 12 months plus endowment incentives linked to verified weight loss targets at 3, 6 and 12 months; (ii) the same text messages and weight loss assessment protocol; (iii) comparator group: 12 month waiting list, then text messages for 3 months. The primary outcome is percentage weight change at 12 months from baseline. Secondary outcomes at 12 months are as follows: quality of life, wellbeing, mental health, weight stigma, behaviours, satisfaction and confidence. Follow-up includes weight at 24 months. A health economic evaluation will measure cost-effectiveness over the trial and over modelled lifetime: including health service resource-use and quality-adjusted life years. The cost-utility analysis will report incremental cost per quality-adjusted life years gained. Participant and service provider perspectives will be explored via telephone interviews, and exploratory mixed methods process evaluation analyses will focus on mental health, multiple long-term conditions, health inequalities and implementation strategies. Discussion The trial will report whether text messages (with and without cash incentives) can help men to lose weight over 1 year and maintain this for another year compared to a comparator group; the costs and benefits to the health service; and men’s experiences of the interventions. Process analyses with public involvement and service commissioner input will ensure that this open-source digital self-care intervention could be sustainable and scalable by a range of NHS or public services. Trial registration ISRCTN 91974895 . Registered on 14/04/2021.

Abstract Background Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity, mortality and healthcare costs. Beta blockers are well-established drugs widely used to treat cardiovascular conditions. Observational studies consistently report that beta blocker use in people with COPD is associated with a reduced risk of COPD exacerbations. The bisoprolol in COPD study (BICS) investigates whether adding bisoprolol to routine COPD treatment has clinical and cost-effective benefits. A sub-study will risk stratify participants for heart failure to investigate whether any beneficial effect of bisoprolol is restricted to those with unrecognised heart disease. Methods BICS is a pragmatic randomised parallel group double-blind placebo-controlled trial conducted in UK primary and secondary care sites. The major inclusion criteria are an established predominant respiratory diagnosis of COPD (post-bronchodilator FEV1

Abstract Background Return of gastrointestinal (GI) function is fundamental to patient recovery after colorectal surgery and is required before patients can be discharged from hospital safely. Up to 40% of patients suffer delayed return of GI function after colorectal surgery, causing nausea, vomiting and abdominal discomfort, resulting in longer hospital stay. Small, randomised studies have suggested perioperative intravenous (IV) lidocaine, which has analgesic and anti-inflammatory effects, may accelerate return of GI function after colorectal surgery. The ALLEGRO trial is a pragmatic effectiveness study to assess the benefit of perioperative IV lidocaine in improving return of GI function after elective minimally invasive (laparoscopic or robotic) colorectal surgery. Methods United Kingdom (UK) multi-centre double blind placebo-controlled randomised controlled trial in 562 patients undergoing elective minimally invasive colorectal resection. IV lidocaine or placebo will be infused for 6–12 h commencing at the start of surgery as an adjunct to usual analgesic/anaesthetic technique. The primary outcome will be return of GI function. Discussion A 6–12-h perioperative intravenous infusion of 2% lidocaine is a cheap addition to usual anaesthetic/analgesic practice in elective colorectal surgery with a low incidence of adverse side-effects. If successful in achieving quicker return of gut function for more patients, it would reduce the rate of postoperative ileus and reduce the duration of inpatient recovery, resulting in reduced pain and discomfort with faster recovery and discharge from hospital. Since colorectal surgery is a common procedure undertaken in every acute hospital in the UK, a reduced length of stay and reduced rate of postoperative ileus would accrue significant cost savings for the National Health Service (NHS). Trial registration EudraCT Number 2017-003835-12; REC Number 17/WS/0210 the trial was prospectively registered (ISRCTN Number: ISRCTN52352431 ); date of registration 13 June 2018; date of enrolment of first participant 14 August 2018.

Abstract Background Ensuring that a trial is designed so that its participants reflect those who might benefit from the results, or be spared harms, is key to the potential benefits of the trial reaching all they should. This paper describes the process, facilitated by Trial Forge, that was used between July 2019 and October 2020 to develop the INCLUDE Ethnicity Framework, part of the wider INCLUDE initiative from the National Institute for Health Research to improve inclusion of under-served groups in clinical research studies. Methods Development of the Framework was done in seven phases: (1) outline, (2) initial draft, (3) stakeholder meeting, (4) modify draft, (5) Stakeholder feedback, (6) applying the Framework and (7) packaging. Phases 2 and 3 were face-to-face meetings. Consultation with stakeholders was iterative, especially phases 4 to 6. Movement to the next phase was done once all or most stakeholders were comfortable with the results of the current phase. When there was a version of the Framework that could be considered final, the Framework was applied to six trials to create a set of examples (phase 6). Finally, the Framework, guidance and examples were packaged ready for dissemination (phase 7). Results A total of 40 people from stakeholder groups including patient and public partners, clinicians, funders, academics working with various ethnic groups, trial managers and methodologists contributed to the seven phases of development. The Framework comprises two parts. The first part is a list of four key questions: 1. Who should my trial apply to? 2. Are the groups identified likely to respond in different ways? 3. Will my study intervention make it harder for some groups to engage? 4. Will the way I have designed the study make it harder for some groups to engage? The second part is a set of worksheets to help trial teams address these questions. The Framework can be used for any stage of trial, for a healthcare intervention in any disease area. The Framework was launched on 1st October 2020 and is available open access at the Trial Forge website: https://www.trialforge.org/trial-forge-centre/include/ . Conclusion Thinking about the number of people in our trials is not enough: we need to start thinking more carefully about who our participants are.

Abstract Background There is an ethical imperative to offer the results of trials to those who participated. Existing research highlights that less than a third of trials do so, despite the desire of participants to receive the results of the trials they participated in. This scoping review aimed to identify, collate, and describe the available evidence relating to any aspect of disseminating trial results to participants. Methods A scoping review was conducted employing a search of key databases (MEDLINE, EMBASE, PsycINFO, and the Cumulative Index to Nursing & Allied Health Literature (CINAHL) from January 2008 to August 2019) to identify studies that had explored any aspect of disseminating results to trial participants. The search strategy was based on that of a linked existing review. The evidence identified describes the characteristics of included studies using narrative description informed by analysis of relevant data using descriptive statistics. Results Thirty-three eligible studies, including 12,700 participants (which included patients, health care professionals, trial teams), were identified and included. Reporting of participant characteristics (age, gender, ethnicity) across the studies was poor. The majority of studies investigated dissemination of aggregate trial results. The most frequently reported mode of disseminating of results was postal. Overall, the results report that participants evaluated receipt of trial results positively, with reported benefits including improved communication, demonstration of appreciation, improved retention, and engagement in future research. However, there were also some concerns about how well the dissemination was resourced and done, worries about emotional effects on participants especially when reporting unfavourable results, and frustration about the delay between the end of the trial and receipt of results. Conclusions This scoping review has highlighted that few high-quality evaluative studies have been conducted that can provide evidence on the best ways to deliver results to trial participants. There have been relatively few qualitative studies that explore perspectives from diverse populations, and those that have been conducted are limited to a handful of clinical areas. The learning from these studies can be used as a platform for further research and to consider some core guiding principles of the opportunities and challenges when disseminating trial results to those who participated.

Background: The role of fractional exhaled nitric oxide in guiding asthma treatment in children is uncertain. Objective: To compare treatment guided by both fractional exhaled nitric oxide and symptoms (intervention) with treatment guided by symptoms alone (standard care) in children with asthma who are at risk of an asthma exacerbation, in terms of the number of asthma exacerbations over 12 months. Design: This was a pragmatic, multicentre, randomised controlled trial with embedded cost-effectiveness and qualitative process evaluations. Randomisation (1 : 1) was carried out using a remote web-based system and was minimised on recruitment centre, age, sex and British Thoracic Society treatment step. Clinical teams and participants were not blind to treatment allocation. Setting: The trial took place in 35 hospitals and seven primary care practices in the UK. Participants: Children aged 6–15 years with a diagnosis of asthma who were currently prescribed inhaled corticosteroids and who had one or more parent-/patient-reported asthma exacerbation treated with oral corticosteroids in the 12 months prior to recruitment. Interventions: Asthma treatment guided by symptoms alone (standard care) and asthma treatment guided by symptoms plus fractional exhaled nitric oxide (intervention). Treatment recommendations in both groups were protocolised within a web-based algorithm, incorporating inhaled corticosteroid adherence (objectively measured using an electronic logging device) and current treatment. Main outcome measures: The primary outcome measure was asthma exacerbations treated with oral corticosteroids in the year post randomisation. Secondary outcomes included time to first exacerbation, number of exacerbations, lung function, fractional exhaled nitric oxide, daily dose of inhaled corticosteroid, asthma control and quality of life. Results: In total, 509 eligible participants were recruited and the primary outcome was available for 506 participants. The primary outcome occurred in 123 out of 255 (48.2%) participants in the intervention group and 129 out of 251 (51.4%) participants in the standard-care group (adjusted odds ratio 0.88, 95% confidence interval 0.61 to 1.27). There was algorithm non-compliance on 21% of assessments. Per-protocol and complier-average causal effect analysis did not change the interpretation. This non-statistically significant estimate was consistent across predefined subgroups. There were no differences between the groups in secondary outcomes. There were no serious adverse events or deaths. No meaningful differences in health service costs, direct patient costs or indirect costs to society were identified between the groups. The economic evaluation does not provide evidence to support the cost-effectiveness of the intervention. In the qualitative process evaluation, 15 trial staff and six families were interviewed. Overall, their experiences were positive. The intervention was broadly acceptable, with caveats around clinicians using the algorithm recommendation as a guide and wariness around extreme step ups/downs in treatment in the light of contextual factors not being taken into account by the algorithm. Limitations: Potential limitations included the choice of cut-off point to define uncontrolled asthma and the change in fractional exhaled nitric oxide to trigger a change in treatment. Furthermore, the treatment decisions in the two groups may not have been sufficiently different to create a difference in outcomes. Conclusions: The RAACENO (Reducing Asthma Attacks in Children using Exhaled Nitric Oxide) trial findings do not support the routine use of fractional exhaled nitric oxide measurements as part of asthma management in a secondary care setting. The potential for other objective markers to guide asthma management in children needs to be evaluated. Trial registration: This trial was registered as ISRCTN67875351. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 4. See the NIHR Journals Library website for further project information.

Abstract The COVID-19 pandemic has presented unique challenges for the clinical trial community, both in the rapid establishment of COVID-19 clinical trials and many existing non-COVID-19 studies either being temporarily paused (whether that is a complete pause or pause in some activities) and/or adapting their processes. Trial managers have played a key role in decision-making, undertaking risk assessments and adapting trial processes, working closely with other members of the research team. This article presents some of the ways in which trial management processes have been altered and the key role that trial managers have played. It has been born out of discussions between trial managers in the UK who are members of the UK Trial Managers’ Network (UKTMN), a national network of trial management professionals managing non-commercial trials. In these unprecedented times, clinical trials have faced many uncertainties and broad-ranging challenges encompassing a range of activities including prioritising patient safety amidst the pandemic, consenting and recruiting new participants into trials, data collection and management and intervention delivery. In many cases, recruitment has been paused whilst mitigations have been put in place to continue data collection. Innovative solutions have been implemented to ensure we continue, where possible, to deliver high-quality clinical trials. Technology has provided many solutions to these challenges, and trial managers have adapted to new ways of working whilst continuing to deliver their clinical trials. Trial management groups are now faced with new uncertainties around re-starting clinical trials, and it is unclear currently how this will go, though working together with sponsors, funders and site teams is clearly a priority. Clinical trial teams have worked together to ensure their trials have adapted quickly whilst ensuring participant safety is given utmost importance. There are clear examples where the trial community have come together to share experiences and expertise, and this should continue in the future to ensure the innovative practices developed become embedded in the design and conduct of clinical trials in the future.

Abstract Whilst the issues around early termination of randomised controlled trials (RCTs) are well documented in the literature, trials can also be temporarily suspended with the real prospect that they may subsequently restart. There is little guidance in the literature as to how to manage such a temporary suspension. In this paper, we describe the temporary suspension of a trial within our clinical trials unit because of concerns over the safety of transvaginal synthetic mesh implants. We also describe the challenges, considerations, and lessons learnt during the suspension that we are now applying in the current COVID-19 pandemic which has led to activities in many RCTs across the world undergoing a temporary suspension. There were three key phases within the temporary suspension: the decision to suspend, implementation of the suspension, and restarting. Each of these phases presented individual challenges which are discussed within this paper, along with the lessons learnt. There were obvious challenges around recruitment, delivery of the intervention, and follow-up. Additional challenges included communication between stakeholders, evolving risk assessment, updates to trial protocol and associated paperwork, maintaining site engagement, data-analysis, and workload within the trial team and Sponsor organisation. Based on our experience of managing a temporary suspension, we developed an action plan and guidance (see Additional File 1) for managing a significant trial event, such as a temporary suspension. We have used this document to help us manage the suspension of activities within our portfolio of trials during the current COVID-19 pandemic.

Abstract Background Data collection consumes a large proportion of clinical trial resources. Each data item requires time and effort for collection, processing and quality control procedures. In general, more data equals a heavier burden for trial staff and participants. It is also likely to increase costs. Knowing the types of data being collected, and in what proportion, will be helpful to ensure that limited trial resources and participant goodwill are used wisely. Aim The aim of this study is to categorise the types of data collected across a broad range of trials and assess what proportion of collected data each category represents. Methods We developed a standard operating procedure to categorise data into primary outcome, secondary outcome and 15 other categories. We categorised all variables collected on trial data collection forms from 18, mainly publicly funded, randomised superiority trials, including trials of an investigational medicinal product and complex interventions. Categorisation was done independently in pairs: one person having in-depth knowledge of the trial, the other independent of the trial. Disagreement was resolved through reference to the trial protocol and discussion, with the project team being consulted if necessary. Key results Primary outcome data accounted for 5.0% (median)/11.2% (mean) of all data items collected. Secondary outcomes accounted for 39.9% (median)/42.5% (mean) of all data items. Non-outcome data such as participant identifiers and demographic data represented 32.4% (median)/36.5% (mean) of all data items collected. Conclusion A small proportion of the data collected in our sample of 18 trials was related to the primary outcome. Secondary outcomes accounted for eight times the volume of data as the primary outcome. A substantial amount of data collection is not related to trial outcomes. Trialists should work to make sure that the data they collect are only those essential to support the health and treatment decisions of those whom the trial is designed to inform.

Abstract Background Researchers often rely on trial participants to self-report clinical outcomes (for example, fractures, re-operations). Little information exists as to the ‘accuracy’ of participant-reported clinical outcomes, particularly in randomised controlled trials (RCTs). To help address this evidence gap, we report four case studies, nested within different RCTs where participant-reported clinical outcome data were compared with those reported by clinicians or extracted from medical notes. Methods Four publicly-funded RCTs with different methods of verifying participant-reported outcomes were identified. In KAT, the participants were asked about hospital admissions for any reason. Where it was thought to be relevant to the trial knee, further information was sought from the lead surgeon at the admitting site to confirm whether or not the admission was relevant to the trial knee. In REFLUX, participants were asked about hospital admissions for any reason. For participants who reported a re-operation, further information was sought from the lead surgeon at the admitting site to confirm this. In RECORD, participants were asked three questions regarding broken bones. Where low-trauma fractures were reported, clinical verification was sought, initially from the research nurse at the site. In CATHETER, participants were asked about urinary tract infections (UTIs), and a prescription of antibiotics was provided for the treatment of UTIs following urethral catheterisation. The GPs of those who reported a UTI were contacted to confirm that an antibiotic prescription had been issued for the suspected UTI. Results In KAT, 397 of 6882 (6%) participant-reported hospital admissions were confirmed as relevant to the trial knee. In REFLUX, 16 of 19 participants (84%) who appeared to have had a re-operation were confirmed as having had one. In RECORD, 473 of 781 (61%) fractures reported by participants were confirmed as being low-trauma fractures. In CATHETER, 429 of 830 participant-reported UTIs (52%) were confirmed as such by the GPs. Conclusions We used different approaches in our verification of participant-reported outcomes in clinical trials, and we believe there is no one optimal solution. Consideration of issues such as what information is sought from participants, the phrasing of questions, whether the medical records are a true ‘gold standard’ and costs and benefits to the RCT may help determine the appropriate approach.

Abstract The evidence base available to trialists to support trial process decisions—e.g. how best to recruit and retain participants, how to collect data or how to share the results with participants—is thin. One way to fill gaps in evidence is to run Studies Within A Trial, or SWATs. These are self-contained research studies embedded within a host trial that aim to evaluate or explore alternative ways of delivering or organising a particular trial process. SWATs are increasingly being supported by funders and considered by trialists, especially in the UK and Ireland. At some point, increasing SWAT evidence will lead funders and trialists to ask: given the current body of evidence for a SWAT, do we need a further evaluation in another host trial? A framework for answering such a question is needed to avoid SWATs themselves contributing to research waste. This paper presents criteria on when enough evidence is available for SWATs that use randomised allocation to compare different interventions.

Background: Urinary incontinence is prevalent in nursing and residential care homes, and has a profound impact on residents’ dignity and quality of life. Treatment options are limited in these care contexts and care homes predominantly use absorbent pads to contain incontinence, rather than actively treat it. Transcutaneous posterior tibial nerve stimulation is a non-invasive, safe, low-cost intervention that is effective in reducing urinary incontinence in adults. Objective: To determine the clinical effectiveness of transcutaneous posterior tibial nerve stimulation to treat urinary incontinence in care home residents and to determine the associated costs of the treatment. Design: A multicentre, pragmatic, participant and outcome assessor-blind, randomised placebo-controlled trial. Setting: A total of 37 UK residential and nursing care homes. Participants: Care home residents with at least weekly urinary incontinence that is contained using absorbent pads and who are able to use a toilet/toilet aid with or without assistance. Interventions: Residents were randomised (1 : 1) to receive 12 30-minute sessions of transcutaneous posterior tibial nerve stimulation or sham stimulation over a 6-week period. Main outcome measures: Primary outcome – change in volume of urine leaked over a 24-hour period at 6 weeks. Secondary outcomes – number of pads used, Perception of Bladder Condition, toileting skills, quality of life and resource use. Results: A total of 408 residents were randomised (transcutaneous posterior tibial nerve stimulation, n = 197; sham stimulation, n = 209); two exclusions occurred post randomisation. Primary outcome data were available for 345 (85%) residents (transcutaneous posterior tibial nerve stimulation, n = 167; sham stimulation, n = 178). Adherence to the intervention protocol was as follows: 78% of the transcutaneous posterior tibial nerve stimulation group and 71% of the sham group received the correct stimulation. Primary intention-to-treat adjusted analysis indicated a mean change of –5 ml (standard deviation 362 ml) urine leakage from baseline in the transcutaneous posterior tibial nerve stimulation group and –66 ml (standard deviation 394 ml) urine leakage in the sham group, which was a statistically significant, but not clinically important, between-group difference of 68-ml urine leakage (95% confidence interval 0 to 136 ml; p = 0.05) in favour of the sham group. Sensitivity analysis supported the primary analysis. No meaningful differences were detected in any of the secondary outcomes. No serious adverse events related to transcutaneous posterior tibial nerve stimulation were reported. Economic evaluation assessed the resources used. The training and support costs for the staff to deliver the intervention were estimated at £121.03 per staff member. Estimated costs for delivery of transcutaneous posterior tibial nerve stimulation during the trial were £81.20 per participant. No significant difference was found between participants’ scores over time, or between transcutaneous posterior tibial nerve stimulation and sham groups at any time point, for resident or proxy quality-of-life measures. Conclusions: The ELECTRIC (ELECtric Tibial nerve stimulation to Reduce Incontinence in Care homes) trial showed, in the care home context (with a high proportion of residents with poor cognitive capacity and limited independent mobility), that transcutaneous posterior tibial nerve stimulation was not effective in reducing urinary incontinence. No economic case for transcutaneous posterior tibial nerve stimulation was made by the cost–consequences analysis; however, the positive reception of learning about urinary incontinence for care home staff supports a case for routine education in this care context. Limitations: Completing 24-hour pad collections was challenging for care home staff, resulting in some missing primary outcome data. Future work: Research should investigate transcutaneous posterior tibial nerve stimulation in residents with urgency urinary incontinence to determine whether or not targeted stimulation is effective. Research should evaluate the effects of continence training for staff on continence care in care homes. Trial registration: Current Controlled Trials ISRCTN98415244 and ClinicalTrials.gov NCT03248362. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 41. See the NIHR Journals Library website for further project information.

Abstract Background Previous studies have shown that woman attending their first cervical screening or colposcopy appointment experience negative emotions, primarily anxiety and fear. With the introduction of the Human Papillomavirus (HPV) vaccine, it is unknown whether these emotions will have altered or whether the information needs of vaccinated women will have changed. The objective of this study is to determine the knowledge, understanding and concerns that young women have about HPV when attending colposcopy and whether their information needs are met. Methods This is a qualitative study using semi-structured interviews which were audiotaped and transcribed. Data was analysed thematically, with recruitment until data saturation was reached. Women born after 01/09/1990 and attending colposcopy as a result of abnormal cytology were eligible to join the study. Recruitment took place in an out-patient regional colposcopy clinic, Aberdeen, Scotland. Results Fifteen women were interviewed. The majority of participants had some knowledge and understanding of HPV, cervical screening and colposcopy. Knowledge about the HPV vaccine was more limited; a third of participants misunderstood the effectiveness of the vaccine believing that is provided complete protection, and were left feeling that it had failed them. Some also felt that they were “test cases” for the vaccine. Conclusion With the introduction of the HPV vaccine, the information and support needs of young women attending colposcopy are not fully met, leaving women with unanswered questions. With increasing numbers of vaccinated women entering the screening programme, it is timely to review the information available to these women.

Background: Despite widespread use of therapies such as inhaled corticosteroids (ICSs), people with chronic obstructive pulmonary disease (COPD) continue to suffer, have reduced life expectancy and utilise considerable NHS resources. Laboratory investigations have demonstrated that at low plasma concentrations (1–5 mg/l) theophylline markedly enhances the anti-inflammatory effects of corticosteroids in COPD. Objective: To determine the clinical effectiveness and cost-effectiveness of adding low-dose theophylline to a drug regimen containing ICSs in people with COPD at high risk of exacerbation. Design: A multicentre, pragmatic, double-blind, randomised, placebo-controlled clinical trial. Setting: The trial was conducted in 121 UK primary and secondary care sites. Participants: People with COPD [i.e. who have a forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) of

IntroductionThe subjective assessment of the adequacy of informed consent for clinical trials, and the potential difficulties associated with it, has led several studies to develop objective measures of informed consent for clinical trials. These objective measures of informed consent are often specific to a particular population or clinical condition and largely focus on understanding of (some or all of) the key elements of informed consent. Many of the developed tools are study-specific, but some validated measures exist. Of these validated measures, those which are reported by participants are of particular interest. Whether these objective tools conceptualize and measure informed consent in the same way is not known. As such, it is not clear whether meta-analyzing data from studies reporting different tools is worthwhile. The aim of this systematic review was to critically appraise the evidence on the overall conceptualisation and item content of validated patient reported measures of informed consent for clinical trials, and to identify core domains of potential importance for informed consent.MethodsA systematic search of the literature was conducted to identify relevant articles that described the development, and/or validation, of patient-reported measures of adequacy of informed consent for randomised controlled trials. Data was synthesised by classifying the items identified into domains and sub-domains which were determined by the nomenclature reported in included studies. Both for descriptions of included studies and of the instruments reported in those studies, descriptive statistics were used to describe general information and instrument detail. A narrative synthesis of the instruments and their inter-related domains and subdomains was conducted to identify areas of both convergence and divergence.ResultsThe search identified 8193 citations. After screening titles and abstracts, 29 full text articles were retrieved for further assessment. Of these 29, 14 complied with our pre-specified inclusion criteria with 15 not being eligible. Of the 14 instruments, three explicitly reported a theoretical or conceptual framework underpinning their development, a further three implicitly referred to the 'conceptual dimensions of informed consent' or 'principles of research ethics' as informing their development and eight reported no guiding theoretical framework. Only three of the 14 studies reported patient or public involvement in the development of the tool. One hundred and seventy nine items were included across the 14 instruments. The primary focus of the instruments was on understanding. Five core domains were identified which included: Autonomy; Consequences; Expectations; Purpose; and Individualisation. There was substantial variability in the coverage of different domains across measures.ConclusionsThis study demonstrated the variability in the theoretical underpinning, development and domain coverage of existing patient-reported measures of informed consent for clinical trials. The conceptualisation of informed consent could benefit from being extended from a narrow focus on understanding to include broader considerations of decision-making. Meaningful involvement of potential trial participants during development of measures critical for tool relevance is also lacking. The identification of the key domains relevant to all stakeholders which could be measured to assess the informed consent process for clinical trials is needed.

Large numbers of women who participate in cervical screening require follow-up for minor cytological abnormalities. Little is known about the psychological consequences of alternative management policies for these women. We compared, over 30-months, psychosocial outcomes of two policies: cytological surveillance (repeat cervical cytology tests in primary care) and a hospital-based colposcopy examination.Women attending for a routine cytology test within the UK NHS Cervical Screening Programmes were eligible to participate. 3399 women, aged 20-59 years, with low-grade abnormal cytology, were randomised to cytological surveillance (six-monthly tests; n = 1703) or initial colposcopy with biopsies and/or subsequent treatment based on colposcopic and histological findings (n = 1696). At 12, 18, 24 and 30-months post-recruitment, women completed the Hospital Anxiety and Depression Scale (HADS). A subgroup (n = 2354) completed the Impact of Event Scale (IES) six weeks after the colposcopy episode or first surveillance cytology test. Primary outcomes were percentages over the entire follow-up period of significant depression (≥ 8) and significant anxiety (≥ 11; "30-month percentages"). Secondary outcomes were point prevalences of significant depression, significant anxiety and procedure-related distress (≥ 9). Outcomes were compared between arms by calculating fully-adjusted odds ratios (ORs) for initial colposcopy versus cytological surveillance.There was no significant difference in 30-month percentages of significant depression (OR = 0.99, 95% CI 0.80-1.21) or anxiety (OR = 0.97, 95% CI 0.81-1.16) between arms. At the six-week assessment, anxiety and distress, but not depression, were significantly less common in the initial colposcopy arm (anxiety: 7.9% vs 13.4%; OR = 0.55, 95% CI 0.38-0.81; distress: 30.6% vs 39.3%, OR = 0.67 95% CI 0.54-0.84). Neither anxiety nor depression differed between arms at subsequent time-points.There was no difference in the longer-term psychosocial impact of management policies based on cytological surveillance or initial colposcopy. Policy-makers, clinicians, and women themselves can be reassured that neither management policy has a significantly greater psychosocial cost.Controlled-Trials.com ISRCTN 34841617.