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BackgroundIdentifying men whose lower urinary tract symptoms (LUTS) may benefit from surgery is challenging.ObjectiveTo identify routine diagnostic and urodynamic measures associated with treatment decision-making, and outcome, in exploratory analyses of the UPSTREAM trial.Design, setting, and participantsA randomised controlled trial was conducted including 820 men, considering surgery for LUTS, across 26 hospitals in England (ISCTRN56164274).InterventionMen were randomised to a routine care (RC) diagnostic pathway (n = 393) or a pathway that included urodynamics (UDS) in addition to RC (n = 427).Outcome measurements and statistical analysisMen underwent uroflowmetry and completed symptom questionnaires, at baseline and 18 mo after randomisation. Regression models identified baseline clinical and symptom measures that predicted recommendation for surgery and/or surgical outcome (measured by the International Prostate Symptom Score [IPSS]). We explored the association between UDS and surgical outcome in subgroups defined by routine measures.Results and limitationsThe recommendation for surgery could be predicted successfully in the RC and UDS groups (area under the receiver operating characteristic curve 0.78), with maximum flow rate (Qmax) and age predictors in both groups. Surgery was more beneficial in those with higher symptom scores (eg, IPSS >16), age 47.6, and bladder contractility index >123.0. In the UDS group, urodynamic measures were more strongly predictive of surgical outcome for those with Qmax >15, although patient-reported outcomes were also more predictive in this subgroup.ConclusionsTreatment decisions were informed with UDS, when available, but without evidence of change in the decisions reached. Despite the small group sizes, exploratory analyses suggest that selective use of UDS could detect obstructive pathology, missed by routine measures, in certain subgroups.Patient summaryBaseline clinical and symptom measurements were able to predict treatment decisions. The addition of urodynamic test results, while useful, did not generally lead to better surgical decisions and outcomes over routine tests alone.

Background While patient and public involvement (PPI) in clinical trials is beneficial and mandated by some funders, formal guidance on how to implement PPI is limited and challenges have been reported. We aimed to investigate how PPI is approached within a UK Clinical Trials Unit (CTU)’s portfolio of randomised controlled trials, perceived barriers to/facilitators of its successful implementation, and perspectives on the CTU’s role in PPI. Methods A mixed-methods study design, involving (1) an online survey of 26 trial managers (TMs) and (2) Interviews with Trial Management Group members and public contributors from 8 case-study trials. Quantitative survey data were summarised using descriptive statistics and interview transcripts analysed thematically. Two public contributors advised throughout and are co-authors. Results (1) 21 TMs completed the survey; (2) 19 in-depth interviews were conducted with public contributors (n=8), TMs (n=5), chief investigators (n=3), PPI coordinators (n=2) and a researcher. 15/21 TMs surveyed reported that a public contributor was on the trial team, and 5 used another PPI method. 12/21 TMs reported that public contributors were paid (range £10–50/h). 5 TMs reported that training was provided for public contributors and few staff members had received any formal PPI training. The most commonly reported tasks undertaken by public contributors were the review of participant-facing materials/study documents and advising on recruitment/retention strategies. Public contributors wanted and valued feedback on changes made due to their input, but it was not always provided. Barriers to successful PPI included recruitment challenges, group dynamics, maintaining professional boundaries, negative attitudes to PPI amongst some researchers, a lack of continuity of trial staff, and the academic environment. Successful PPI required early and explicit planning, sharing of power and ownership of the trial with public contributors, building and maintaining relationships, and joint understanding and clarity about expectations/roles. CTUs have an important role to play in supporting recruitment, signposting and coordinating PPI. Conclusions While highly valuable, PPI in trials is currently variable. PPI representatives are recruited informally, may not be provided with any training and are paid inconsistently across trials. Study findings can help optimise PPI in trials and ensure researchers and public contributors are adequately supported.

BackgroundFalls are a common complication of Parkinson’s disease. There is a need for new therapeutic options to target this debilitating aspect of the disease. Cholinergic deficit has been shown to contribute to both gait and cognitive dysfunction seen in the condition. Potential benefits of using cholinesterase inhibitors were shown during a single centre phase 2 trial. The aim of this trial is to evaluate the effectiveness of a cholinesterase inhibitor on fall rate in people with idiopathic Parkinson’s disease.MethodsThis is a multi-centre, double-blind, randomised placebo-controlled trial in 600 people with idiopathic Parkinson’s disease (Hoehn and Yahr stages 1 to 4) with a history of a fall in the past year. Participants will be randomised to two groups, receiving either transdermal rivastigmine or identical placebo for 12 months. The primary outcome is the fall rate over 12 months follow-up. Secondary outcome measures, collected at baseline and 12 months either face-to-face or via remote video/telephone assessments, include gait and balance measures, neuropsychiatric indices, Parkinson’s motor and non-motor symptoms, quality of life and cost-effectiveness.DiscussionThis trial will establish whether cholinesterase inhibitor therapy is effective in preventing falls in Parkinson’s disease. If cost-effective, it will alter current management guidelines by offering a new therapeutic option in this high-risk population.Trial registrationREC reference: 19/SW/0043.EudraCT: 2018–003219-23.ISCRTN:41639809(registered 16/04/2019).ClinicalTrials.gov Identifier:NCT04226248Protocol at time of publicationVersion 7.0, 20th January 2021.

To describe the screening and recruitment process of a randomized trial and evaluate associations with knee pain and function 3 months after total knee replacement (TKR).In order to screen for a multicenter trial, a total of 5,036 patients were sent the Oxford Knee Score (OKS) questionnaire 10 weeks post-TKR. Patients who reported pain in their replaced knee (score of ≤14 on the OKS pain component) completed a second OKS questionnaire 12 weeks post-TKR. Those patients who were still experiencing pain 12 weeks post-TKR completed a detailed questionnaire 13 weeks post-TKR. These data were used to characterize pain in a cross-sectional analysis. Multivariable regression was performed in order to identify factors associated with pain and function at 13 weeks post-TKR.We received OKS questionnaires from 3,058 of 5,063 TKR patients (60%), and 907 of the 3,058 (30%) reported pain in their replaced knee 10 weeks post-TKR. By 12 weeks, 179 of 553 patients (32%) reported improved pain (score of14 on the OKS pain component). At 13 weeks, 192 of 363 patients (53%) who completed a detailed questionnaire reported neuropathic pain, 94 of 362 (26%) reported depression symptoms, and 95 of 363 (26%) anxiety symptoms. More severe pain at 13 weeks postoperatively was associated with poorer general health, poorer physical health, more pain worry, and lower satisfaction with surgery outcome. More severe functional limitation was associated with higher levels of depression, more pain worry, lower satisfaction with surgery outcome, and higher pain acceptance.Screening after TKR identified individuals with pain. We identified several potential targets (physical and mental health outcomes, acceptance of pain, and quality of life) for tailored intervention to improve outcomes for patients. Future trials of multidisciplinary interventions warranted.

AIM: The International Continence Society (ICS) has standardized quality control and interpretation of uroflowmetry and urodynamics. We evaluated traces from two large studies of male lower urinary tract symptoms (UPSTREAM and UNBLOCS) against ICS standards of urodynamic equipment and practice.METHODS: Ten percent of uroflowmetry and urodynamics traces were selected at random from hospital sites. A data capture template was designed from the ICS Fundamentals of Urodynamic Practice checklist. Two pretrained blinded assessors extracted the data, with a third assessor to arbitrate. Departmental records of calibration checks and equipment maintenance were scrutinized.RESULTS: Seven out of twenty-five (28%) departments reported no calibration checks. Four sites (16%) could not provide annual service records. In 32 out of 296 (10.8%) uroflowmetry traces, findings were affected by artifact. One hundred ten urodynamic study traces were reviewed; in 11 records (10%), key pressure traces were incompletely displayed. In 30 (27.2%), reference zero was not set to atmospheric pressure. Resting pressures were outside the expected range for 36 (32.7%). Pressure drift was seen in 18 traces (16.4%). At pressure-flow study commencement, permission to void was omitted in 15 (13.6%). Cough testing after voiding was done in 71.2%, but the resulting cough spikes were significantly different in 16.5%. Erroneous diagnosis of bladder outlet obstruction (BOO) was identified in six cases (5.5%).CONCLUSIONS: Erroneous diagnosis of BOO is a serious error of interpretation, as it could lead to unnecessary surgery. Other errors of standardization, testing, and interpretation were identified with lower risk of adverse implications. Inconsistent documentation of service records mean equipment accuracy is uncertain.

OBJECTIVES: The ProtecT (Prostate testing for cancer and Treatment) trial randomised 1,643 men with localised prostate cancer (PCa) to active monitoring, radical prostatectomy or radical radiotherapy. At 10-year median follow-up there were no differences in mortality between groups, but men receiving radical treatment had their disease progression reduced by half. We tested the hypothesis that the baseline clinico-pathological features of men who progressed (n=198) were different from those with stable disease (n=1,409).PATIENTS AND METHODS: We stratified the participants' cohort at baseline according to risk of progression using clinical disease stage, pathological grade and PSA, using Cox proportional hazard models.RESULTS: The findings demonstrated that 34% (n=505) of men had intermediate or high-risk disease, and 66% (n=973) had low-risk PCa. Of 198 men who progressed, 101 (51%) had baseline International Society of Urological Pathology (ISUP) Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5% respectively for 1,409 men without progression (pCONCLUSIONS: We demonstrate that one-third of the ProtecT cohort consists of intermediate / high risk disease, and the outcomes data at an average of 10-years follow-up are generalisable beyond men with low-risk PCa.

BackgroundHigh rates of depression are frequently reported in autistic adults. There have been no randomised trials investigating low-intensity psychological interventions for mild-moderate depression adapted for autistic adults.MethodThis qualitative evaluation investigated the acceptability of the ADEPT pilot randomised controlled trial (RCT) design and guided self-help intervention. Participants (autistic adults with a diagnosis of depression (PHQ-9 score ≥ 10)) were randomised to Guided Self-Help (GSH): low intensity psychological intervention based on Behavioural Activation adapted for autistic adults, or Treatment as Usual (TAU). 21 trial participants (14 GSH and 7 TAU), and 5 low intensity psychological therapists or ‘coaches’ were interviewed, and transcripts analysed thematically.ResultsAll participants and coaches welcomed an intervention for depression adapted for autistic adults due to current lack of provision in mainstream services. Interviews highlighted participants' preference for GSH over TAU. Dissatisfaction with prior experience of TAU was identified as a potential driver for differential attrition from the TAU arm. Participants who received GSH appreciated the coaches having a good understanding of autistic adults and were positive towards the aim and structure of the GSH intervention. Suggested improvements include more regularly checking progress with therapy goals.ConclusionsA full scale RCT to evaluate the effectiveness of this intervention is now warranted. Future trial study design needs to address potential for differential rate of participant recruitment and attrition between the treatment and comparison groups due to negative prior experience of TAU.

Background/aims: Clinical trial oversight is central to the safety of participants and production of robust data. The United Kingdom Medical Research Council originally set out an oversight structure comprising three committees in 1998. The first committee, led by the trial team, is hands-on with trial conduct/operations (‘Trial Management Group’) and essential. The second committee (Data Monitoring Committee), usually completely independent of the trial, reviews accumulating trial evidence and is used by most later phase trials. The Independent Data Monitoring Committee makes recommendations to the third oversight committee. The third committee, (‘Trial Steering Committee’), facilitates in-depth interactions of independent and non-independent trial members and gives broader oversight (blinded to comparative analysis). We investigated the roles and functioning of the third oversight committee with multiple research methods. We reflect upon these findings to standardise the committee’s remit and operation and to potentially increase its usage. Methods: We utilised findings from our recent published suite of research on the third oversight committee to inform guideline revision. In brief, we conducted a survey of 38 United Kingdom–registered Clinical Trials Units, reviewed a cohort of 264 published trials, observed 8 third oversight committee meetings and interviewed 52 trialists. We convened an expert panel to discuss third oversight committees. Subsequently, we interviewed nine patient/lay third committee members and eight committee Chairs. Results: In the survey, most Clinical Trials Units required a third committee for all their trials (27/38, 71%) with independent members (ranging from 1 to 6). In the survey and interviews, the independence of the third committee was valued to make unbiased consideration of Independent Data Monitoring Committee recommendations and to advise on trial progress, protocol changes and recruitment issues in conjunction with the trial leadership. The third committee also advised funders and sponsors about trial continuation and represented patients and the public by including lay members. Of the cohort of 264 published trials, 144 reported a ‘steering’ committee (55%), but the independence of these members was not described so these may have been internal Trial Management Groups. Around two thirds of papers (60%) reported having an Independent Data Monitoring Committee and 26.9% neither a steering nor an Independent Data Monitoring Committee. However, before revising the third committee charter (Terms of Reference), greater standardisation is needed around defining member independence, composition, primacy of decision-making, interactions with other committees and the lifespan. Conclusion: A third oversight committee has benefits for trial oversight and conduct, and a revised charter will facilitate greater standardisation and wider adoption.

Background Lower urinary tract symptoms (LUTS) can relate to urinary storage or voiding. In men, the prevalence and severity of LUTS increases with age, with a significant impact on quality of life. The majority of men presenting with LUTS are managed by their general practitioner (GP) in the first instance, with conservative therapies recommended as the initial treatment. However, the provision of conservative therapies in primary care is variable and can be time and resource limited. GPs require practical resources to enhance patient engagement with such interventions. TRIUMPH aims to determine whether a standardised and manualised care intervention delivered in primary care achieves superior symptomatic outcome for LUTS versus usual care. Methods/design TRIUMPH is a two-arm, cluster randomised controlled trial (RCT) being conducted in 30 National Health Service (NHS) general practices in England. The TRIUMPH intervention comprises a standardised LUTS advice booklet developed for the trial with patient and healthcare professional (HCP) consultation. The booklet is delivered to patients by nurses/healthcare assistants following assessment of their urinary symptoms. Patients are directed to relevant sections of the booklet, providing the manualised element of the intervention. To encourage adherence, HCPs provide follow-up contacts over 12 weeks. Practices are randomised 1:1 to either deliver the TRIUMPH intervention or a usual care pathway. The patient-reported International Prostate Symptom Score (IPSS) at 12 months post consent is the primary outcome. Secondary outcomes include cost-effectiveness, patient-reported outcomes on LUTS, quality of life, and patient and HCP acceptability and experience of the intervention. Primary analyses will be conducted on an intention-to-treat basis. Discussion It is unclear whether conservative therapies for male LUTS are effectively delivered in primary care using current approaches. This can lead to men being inappropriately referred to secondary care or experiencing persistent symptoms. Primary care, therefore, holds the key to effective treatment for these men. The TRIUMPH intervention, through its standardised and manualised approach, has been developed to support GP practices in delivering effective conservative care. This pragmatic, cluster RCT should provide robust evidence in a primary-care setting to inform future guidelines. Trial registration ISCRTN registry, ID: ISRCTN11669964. Registered on 12 April 2018. Electronic supplementary material The online version of this article (10.1186/s13063-019-3648-1) contains supplementary material, which is available to authorized users.

Background Acute otitis media (AOM) is a common reason for primary care consultations and antibiotic prescribing in children. Options for improved pain control may influence antibiotic prescribing and consumption. Objective The Children’s Ear Pain Study (CEDAR) investigated whether or not providing anaesthetic–analgesic ear drops reduced antibiotic consumption in children with AOM. Secondary objectives included pain control and cost-effectiveness. Design A multicentre, randomised, parallel-group (two-group initially, then three-group) trial. Setting Primary care practices in England and Wales. Participants 1- to 10-year-old children presenting within 1 week of suspected AOM onset with ear pain during the preceding 24 hours and not requiring immediate antibiotics. Participating children were logged into the study and allocated using a remote randomisation service. Interventions Two-group trial – unblinded comparison of anaesthetic–analgesic ear drops versus usual care. Three-group trial – blinded comparison of anaesthetic–analgesic ear drops versus placebo ear drops and unblinded comparison with usual care. Main outcome measures The primary outcome measure was parent-reported antibiotic use by the child over 8 days following enrolment. Secondary measures included ear pain at day 2 and NHS and societal costs over 8 days. Results Owing to a delay in provision of the placebo drops, the recruitment period was shortened and most participants were randomly allocated to the two-group study (n = 74) rather than the three-group study (n = 32). Comparing active drops with usual care in the combined two-group and three-group studies, 1 out of 39 (3%) children allocated to the active drops group and 11 out of 38 (29%) children allocated to the usual-care group consumed antibiotics in the 8 days following enrolment [unadjusted odds ratio 0.09, 95% confidence interval (CI) 0.02 to 0.55; p = 0.009; adjusted for delayed prescribing odds ratio 0.15, 95% CI 0.03 to 0.87; p = 0.035]. A total of 43% (3/7) of patients in the placebo drops group consumed antibiotics by day 8, compared with 0% (0/10) of the three-group study active drops groups (p = 0.051). The economic analysis of NHS costs (£12.66 for active drops and £11.36 for usual care) leads to an estimated cost of £5.19 per antibiotic prescription avoided, but with a high degree of uncertainty. A reduction in ear pain at day 2 in the placebo group (n = 7) compared with the active drops group (n = 10) (adjusted difference in means 0.67, 95% CI –1.44 to 2.79; p = 0.51) is consistent with chance. No adverse events were reported in children receiving active drops. Limitations Estimated treatment effects are imprecise because the sample size target was not met. It is not clear if delayed prescriptions of an antibiotic were written prior to randomisation. Few children received placebo drops, which hindered the investigation of ear pain. Conclusions This study suggests that reduced antibiotic use can be achieved in children with AOM by combining a no or delayed antibiotic prescribing strategy with anaesthetic–analgesic ear drops. Whether or not the active drops relieved ear pain was not established. Future work The observed reduction in antibiotic consumption following the prescription of ear drops requires replication in a larger study. Future work should establish if the effect of ear drops is due to pain relief. Trial registration Current Controlled Trials ISRCTN09599764. 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. 23, No. 34. See the NIHR Journals Library website for further project information. Alastair D Hay was funded by a NIHR Research Professorship (funding identifier NIHR-RP-02-12-012).

Background Many children do not meet the recommended level of daily physical activity, even with the widely acknowledged health benefits associated with being physically active. There is a need to establish factors related to physical activity in children so that public health interventions may be appropriately designed. We investigated the association between Pediatric Quality of Life Inventory (PedsQL), family expenditure on physical activity and objectively measured daily physical activity in 2–4-year-old children. Methods Cross-sectional study with a sample of 81 UK preschool children taking part in the NAPSACC UK feasibility randomized controlled trial. Descriptive statistics are presented. We undertook Student t-tests to establish differences in physical activity by gender, age, parental education and nursery versus non-nursery days. Mixed effects linear regressions were used to model the association between minutes spent physically activity, minutes spent in moderate-to-vigorous (MVPA) physical activity and PedsQL scores (physical and psychosocial) and family expenditure on physical activity. Results Most children (88.9%) did not engage in the recommended 180 min daily physical activity. There was mean (SD) of 141.9 (33.1) daily minutes of physically activity and 22.2 min per day (SD = 9.9) of MVPA. Boys and older children were more physically active. Children were more active on nursery days. There was no difference in physical activity by parental education. Half of the sample parents (50.6%) spent less than £9.00 weekly on their pre-schooler’s physical activity. Children within the highest tertile of PedsQL physical functioning scores had higher levels of MVPA (3.6, 95% CI: − 1.3–8.4, p-value 0.15), although confidence intervals crossed the null in the adjusted model. We found no evidence of an association between positive PedsQL psychosocial scores, or higher parental expenditure on physical activity, with the physical activity variables. Conclusions Children in this sample were not meeting the recommended 180 min of daily physical activity. The 2–4-year-olds were most active on nursery days. There is no evidence of an association between better PedsQL physical scores and higher levels of MVPA. There was no evidence of an association between expenditure on physical activity and time spent physically active. Further examination in larger representative datasets is needed. Electronic supplementary material The online version of this article (10.1186/s12889-019-7129-y) contains supplementary material, which is available to authorized users.

BackgroundLow participation in clinical trials is a major challenge to advancing clinical Alzheimer’s Disease (AD) research and care. Factors influencing recruitment to AD trials are not fully understood. AimsTo identify barriers to, and facilitators of, recruitment in a UK multi-centre, secondary care AD trial (Reducing pathology in Alzheimer’s Disease through Angiotensin TaRgeting (RADAR) trial) and implications for improving recruitment to AD trials.MethodsSemi-structured qualitative telephone interviews with a purposive sample of 17 trial site staff explored the RADAR trial recruitment pathway and views and experiences of recruitment. Interviews were analysed thematically. ResultsDiagnostic and care pathways hindered identifying patients with mild-moderate AD, with a lack of up-to-date patient records and data access problems affecting screening. Research is not routinely embedded in AD care but facilitated recruitment when it was. Clinicians’ and patients’ favourable view of the trial purpose facilitated recruitment, although the complexity of participant information sheets and requirement for study companion created challenges. ConclusionThese findings have important implications for the design of future AD trials and for planning how to best interface with clinical commitments to ensure sufficient and timely recruitment. Challenges to AD trial recruitment can occur at care pathway, clinician, and patient and companion levels. Recruitment can be facilitated by: improving diagnostic processes and systems for recording and sharing patient information, embedding research into routine patient care, collaborating with a range of services to identify and approach eligible patients, training and engaging trial staff, and providing patients with clear and concise study information.

BackgroundSeverity assessments of respiratory tract infection (RTI) in children are known to differ between parents and clinicians, but determinants of perceived severity are unknown.AimTo investigate the (dis)agreement between, and compare the determinants of, parent and clinician severity scores.Design and settingSecondary analysis of data from a prospective cohort study of 8394 children presenting to primary care with acute (≤28 days) cough and RTI.MethodData on sociodemographic factors, parent-reported symptoms, clinician-reported findings, and severity assessments were used. Kappa (κ)-statistics were used to investigate (dis) agreement, whereas multivariable logistic regression was used to identify the factors associated with illness severity.ResultsParents reported higher illness severity (mean 5.2 [standard deviation (SD) 1.8], median 5 [interquartile range (IQR) 4–7]), than clinicians (mean 3.1 [SD 1.7], median 3 [IQR 2–4], PConclusionClinicians and parents use different factors and make different judgements about the severity of children’s RTI. Improved understanding of the factors that concern parents could improve parent–clinician communication and consultation outcomes.

IntroductionRespiratory tract infections (RTIs) in children are common and present major resource implications for primary care. Unnecessary use of antibiotics is associated with the development and proliferation of antimicrobial resistance. In 2016, the National Institute for Health Research (NIHR)-funded ‘TARGET’ programme developed a prognostic algorithm to identify children with acute cough and RTI at very low risk of 30-day hospitalisation and unlikely to need antibiotics. The intervention includes: (1) explicit elicitation of parental concerns, (2) the results of the prognostic algorithm accompanied by prescribing guidance and (3) provision of a printout for carers including safety netting advice. The CHIldren’s COugh feasibility study suggested differential recruitment of healthier patients in control practices. This phase III ‘efficiently designed’ trial uses routinely collected data at the practice level, thus avoiding individual patient consent. The aim is to assess whether embedding a multifaceted intervention into general practitioner (GP) practice Information Technology (IT) systems will result in reductions of antibiotic prescribing without impacting on hospital attendance for RTI.Methods and analysisThe coprimary outcomes are (1) practice rate of dispensed amoxicillin and macrolide antibiotics, (2) hospital admission rate for RTI using routinely collected data by Clinical Commissioning Groups (CCGs). Data will be collected for children aged 0–9 years registered at 310 practices (155 intervention, 155 usual care) over a 12-month period. Recruitment and randomisation of practices (using the Egton Medical Information Systems web data management system) is conducted via each CCG stratified for children registered and baseline dispensing rates of each practice. Secondary outcomes will explore intervention effect modifiers. Qualitative interviews will explore intervention usage. The economic evaluation will be limited to a between-arm comparison in a cost–consequence analysis.Ethics and disseminationResearch ethics approval was given by London-Camden and Kings Cross Research Ethics Committee (ref:18/LO/0345). This manuscript refers to protocol V.4.0. Results will be disseminated through peer-reviewed journals and international conferences.Trial registration numberISRCTN11405239.

ObjectiveProstate surgery can improve lower urinary tract symptoms (LUTS) by relieving bladder outlet obstruction (BOO). However, surgery is less effective without BOO, or if detrusor underactivity (DU) is present. Urodynamics (UDS) can identify BOO and measure detrusor activity, but evidence in clinical practice is lacking. UPSTREAM (Urodynamics for Prostate Surgery Trial: Randomised Evaluation of Assessment Methods) evaluated whether a carepathway including UDS would reduce surgery without increasing urinary symptoms.Design, setting and participantsUPSTREAM is a pragmatic, non-inferiority randomised controlled trial in 26 hospitals in England (ISRCTN56164274) in men with bothersome LUTS where surgery was an option. InterventionParticipants were randomised (1:1) to routine care (RC) diagnostic tests, or routine care plus urodynamics (UDS).Outcome measuresThe primary outcome was International Prostate Symptom Score (IPSS; patient reported outcome scale from 0 to 35 points) 18-months post-randomisation, with a non-inferiority margin of one point. Urological surgery rates were a key secondary outcome.Statistical analysisThe primary outcome was compared between the arms using linear regression, analysed on an intention-to-treat basis.Results and limitationsBetween October 2014 and December 2016, 820 men (median age 68 years) were randomised (393 and 427 in RC and UDS arms, respectively). The UDS arm showed noninferiority of mean IPSS scores (UDS 12·6; RC 13.1; adjusted difference at 18 months -0·33 (95% CI -1·47, +0·80)). In the UDS arm, 153/408 (38%) received surgery compared with 138/384 (36%) for RC (adjusted OR 1·05; 95% CI 0·77, 1·43). 428 adverse events (UDS 234; RC 194) were recorded, with related events similar in both arms, and 11 unrelated deaths.Conclusion In this population, the UDS randomised group was non-inferior to RC for IPSS but did not reduce surgical rates. The study shows that routine use of UDS in evaluation of uncomplicated LUTS has a limited role and should be used selectively. Patient summaryFor men with uncomplicated lower urinary tract symptoms, the symptom improvements after treatment and the number of operations done are similar, whether or not urodynamic tests aredone in addition to routine tests. Accordingly, routine use of UDS has a limited role in this population group.

Background Lower urinary tract symptoms (LUTS) in men may indicate bladder outlet obstruction (BOO) or weakness, known as detrusor underactivity (DU). Severe bothersome LUTS are a common indication for surgery. The diagnostic tests may include urodynamics (UDS) to confirm whether BOO or DU is the cause, potentially reducing the number of people receiving (inappropriate) surgery. Objectives The primary objective was to determine whether a care pathway including UDS is no worse for symptom outcome than one in which it is omitted, at 18 months after randomisation. Rates of surgery was the key secondary outcome. Design This was a pragmatic, multicentre, two-arm (unblinded) randomised controlled trial, incorporating a health economic analysis and qualitative research. Setting Urology departments of 26 NHS hospitals in England. Participants Men (aged ≥ 18 years) seeking further treatment, potentially including surgery, for bothersome LUTS. Exclusion criteria were as follows: unable to pass urine without a catheter, having a relevant neurological disease, currently undergoing treatment for prostate or bladder cancer, previously had prostate surgery, not medically fit for surgery and/or unwilling to be randomised. Interventions Men were randomised to a care pathway based on non-invasive routine tests (control) or routine care plus invasive UDS (intervention arm). Main outcome measures The primary outcome was International Prostate Symptom Score (IPSS) at 18 months after randomisation and the key secondary outcome was rates of surgery. Additional secondary outcomes included adverse events (AEs), quality of life, urinary and sexual symptoms, UDS satisfaction, maximum urinary flow rate and cost-effectiveness. Results A total of 820 men were randomised (UDS, 427; routine care, 393). Sixty-seven men withdrew before 18 months and 11 died (unrelated to trial procedures). UDS was non-inferior to routine care for IPSS 18 months after randomisation, with a confidence interval (CI) within the margin of 1 point (–0.33, 95% CI –1.47 to 0.80). A lower surgery rate in the UDS arm was not found (38% and 36% for UDS and routine care, respectively), with overall rates lower than expected. AEs were similar between the arms at 43–44%. There were more cases of acute urinary retention in the routine care arm. Patient-reported outcomes for LUTS improved in both arms and satisfaction with UDS was high in men who received it. UDS was more expensive than routine care. From a secondary care perspective, UDS cost an additional £216 over an 18-month time horizon. Quality-adjusted life-years (QALYs) were similar, with a QALY difference of 0.006 in favour of UDS over 18 months. It was established that UDS was acceptable to patients, and valued by both patients and clinicians for its perceived additional insight into the cause and probable best treatment of LUTS. Limitations The trial met its predefined recruitment target, but surgery rates were lower than anticipated. Conclusions Inclusion of UDS in the diagnostic tests results in a symptom outcome that is non-inferior to a routine care pathway, but does not affect surgical rates for treating BOO. Results do not support the routine use of UDS in men undergoing investigation of LUTS. Future work Focus should be placed on indications for selective utilisation of UDS in individual cases and long-term outcomes of diagnosis and therapy. Trial registration Current Controlled Trials ISRCTN56164274. 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. 24, No. 42. See the NIHR Journals Library website for further project information.

ObjectiveTo determine the cost‐effectiveness of the current ‘gold standard’ operation of transurethral resection of the prostate (TURP) compared to the new laser technique of thulium laser transurethral vaporesection of the prostate (ThuVARP) in men with benign prostatic obstruction (BPO) within the UK National Health Service (NHS).Patients and MethodsThe trial was conducted across seven UK centres (four university teaching hospitals and three district general hospitals). A total of 410 men aged ≥18 years presenting with either bothersome lower urinary tract symptoms (LUTS) or urinary retention secondary to BPO, and suitable for surgery, were randomised (whilst under anaesthetic) 1:1 to receive the TURP or ThuVARP procedure. Resource use in relation to the operation, initial inpatient stay, and subsequent use of NHS services was collected for 12 months from randomisation (equivalent to primary effectiveness outcome) using hospital records and patient questionnaires. Resources were valued using UK reference costs. Quality adjusted life years (QALYs) were calculated from the EuroQoL five Dimensions five Levels (EQ‐5D‐5L) questionnaire completed at baseline, 3‐ and 12‐months. Total adjusted mean costs, QALYs and incremental Net Monetary Benefit statistics were calculated: cost‐effectiveness acceptability curves and sensitivity analyses addressed uncertainty.ResultsThe total adjusted mean secondary care cost over the 12 months in the TURP arm (£4244) was £9 (95% CI –£376, £359) lower than the ThuVARP arm (£4253). The ThuVARP operation took on average 21 min longer than TURP. The adjusted mean difference of QALYs (0.01 favouring TURP, 95% CI −0.01, 0.04) was similar between the arms. There is a 76% probability that TURP is the cost‐effective option compared with ThuVARP at the £20 000 per QALY willingness to pay threshold used by National Institute for Health and Care Excellence (NICE).ConclusionOne of the anticipated benefits of the laser surgery, reduced length of hospital stay with an associated reduction in cost, did not materialise within the study. The longer duration of the ThuVARP procedure is important to consider, both from a patient perspective in terms of increased time under anaesthetic, and from a service delivery perspective. TURP remains a highly cost‐effective treatment for men with BPO.

Low intensity cognitive behaviour therapy (CBT) including behavioural activation is an evidence based treatment for depression, a condition frequently co-occurring with autism. The feasibility of adapting low intensity CBT for depression to meet the needs of autistic adults via a randomised controlled trial (RCT) was investigated. The adapted intervention (Guided Self-Help; GSH) comprised materials for 9 individual sessions with a low intensity psychological therapist. Autistic adults (n=70) with depression (PHQ-9 score ≥10) recruited from National Health Service adult autism services and research cohorts were randomly allocated to GSH or Treatment as Usual (TAU). Outcomes at 10, 16 and 24 weeks post-randomisation were blind to treatment group. Rates of retention in the study differed by treatment group with more participants attending follow-up in the GSH group than TAU. The adapted intervention was well-received, 86% (n=30/35) of participants attended the pre-defined ‘dose’ of 5 sessions of treatment and 71% (25/35) attended all treatment sessions. The findings of this pilot RCT indicate that low intensity CBT informed by Behavioural Activation can be successfully adapted to meet the needs of autistic people. Evaluation of the effectiveness of this intervention in a full scale RCT is now warranted.

Background Transurethral resection of the prostate (TURP) is the standard operation for benign prostatic obstruction (BPO). Thulium laser transurethral vaporesection of the prostate (ThuVARP) is a technique with suggested advantages over TURP, including reduced complications and hospital stay. ThuVARP was compared to TURP in men suitable for BPO surgery. Methods In this randomised, controlled, blinded, parallel group, pragmatic equivalence trial, men with bothersome Lower Urinary Tract Symptoms (LUTS) or Urinary Retention (UR) secondary to BPO were randomised (1:1) at the point of surgery, in seven UK hospitals, to receive ThuVARP or TURP. Patients were blinded until follow-up completion. Co-primary outcomes were maximum urinary flow rate (Qmax) and International Prostate Symptom Score (IPSS), 12-months post-surgery. Equivalence was defined as a difference of ≤2·5 points for IPSS and ≤4ml/s for Qmax. Secondary outcomes included surgical, functional and quality of life (QoL) measures, and complications. Analysis was by intention to treat. Registered with the ISRCTN registry (ISRCTN00788389). Findings Between June 2014 and December 2016, 410 men were randomised, 205 per arm. TURP was superior for Qmax (means of 23·2ml/s (TURP, n=199) and 20·2ml/s (ThuVARP, n=197); adjusted difference in means -3·12 and 95% CI: -5·79, -0·45). Equivalence was demonstrated for IPSS (means of 6·3 (TURP, n=199) and 6·4 (ThuVARP, n=197); adjusted difference in means 0·28 and 95% CI: -0·92, 1·49). Mean hospital stay was 48hrs in both arms. Other functional, QoL and surgical outcomes (including blood transfusions) were comparable. 45% (91/204) versus 47% (96/203) of men experienced at least one complication for TURP and ThuVARP respectively. Interpretation TURP and ThuVARP were equivalent for urinary symptom improvement (IPSS), 12-months post surgery, whilst TURP was superior for Qmax. Anticipated laser benefits of reduced hospital stay and complications were not observed.

Objectives:Recruitment to pragmatic trials is often difficult, and little is known about factors associated with key participation and treatment decisions. These were explored in the Prostate cancer testing and Treatment (ProtecT) study. Study Design and Setting:Baseline sociodemographic, patient-reported outcome, clinical history, and prostate cancer biopsy data were collected for all patients eligible to take part in the ProtecT trial, in a comprehensive cohort design. Men who rejected randomization specified a preferred option and were followed up identically to the randomized cohort. Factors associated with participation decisions, patient preferences, and reasons for changing treatment were explored. Results:Of 2,664 men with clinically localized prostate cancer, 997 (37%) rejected randomization. Their treatment preferences and subsequent treatment choices/changes in both randomized and treatment choice cohorts were strongly associated with prostate cancer risk features: toward active monitoring for low-risk disease and toward radical options with higher risk prostate cancer. Among many factors measured, only a small number of weak associations were found for occupation groups and some patient symptoms. Similar percentages changed from the random allocation and initially stated preference. Conclusion:The comprehensive cohort design provided new insights into trial recruitment and participation decisions. Opportunities to improve recruitment by supporting recruiters with equipoise and patient preferences were identified.

Background Trial oversight is important for trial governance and conduct. Patients and/or lay members of the public are increasingly included in trial oversight committees, influenced by international patient and public involvement (PPI) initiatives to improve the quality and relevance of research. However, there is a lack of guidance on how to undertake PPI in trial oversight and tokenistic PPI remains an issue. This paper explores how PPI functions in existing trial oversight committees and provides recommendations to optimise PPI in future trials. This was part of a larger study investigating the role and function of oversight committees in trials facing challenges. Methods Using an ethnographic study design, we observed oversight meetings of eight UK trials and conducted semi-structured interviews with members of their trial steering committees (TSCs) and trial management groups (TMGs) including public contributors, trial sponsors and funders. Thematic analysis of data was undertaken, with findings integrated to provide a multi-perspective account of how PPI functions in trial oversight. Results Eight TSC and six TMG meetings from eight trials were observed, and 66 semi-structured interviews conducted with 52 purposively sampled oversight group members, including three public contributors. PPI was reported as beneficial in trial oversight, with public members contributing a patient voice and fulfilling a patient advocacy role. However, public contributors were not always active at oversight meetings and were sometimes felt to have a tokenistic role, with trialists reporting a lack of understanding of how to undertake PPI in trial oversight. To optimise PPI in trial oversight, the following areas were highlighted: the importance of planning effective strategies to recruit public contributors; considering the level of oversight and stage(s) of trial to include PPI; support for public contributors by the trial team between and during oversight meetings. Conclusions We present evidence-based recommendations to inform future PPI in trial oversight. Consideration should be given at trial design stage on how to recruit and involve public contributors within trial oversight, as well as support and mentorship for both public contributors and trialists (in how to undertake PPI effectively). Findings from this study further strengthen the evidence base on facilitating meaningful PPI within clinical trials.

Background Recruitment and retention of participants in randomised controlled trials (RCTs) is a key determinant of success but is challenging. Trialists and UK Clinical Research Collaboration (UKCRC) Clinical Trials Units (CTUs) are increasingly exploring the use of digital tools to identify, recruit and retain participants. The aim of this UK National Institute for Health Research (NIHR) study was to identify what digital tools are currently used by CTUs and understand the performance characteristics required to be judged useful. Methods A scoping of searches (and a survey with NIHR funding staff), a survey with all 52 UKCRC CTUs and 16 qualitative interviews were conducted with five stakeholder groups including trialists within CTUs, funders and research participants. A purposive sampling approach was used to conduct the qualitative interviews during March–June 2018. Qualitative data were analysed using a content analysis and inductive approach. Results Responses from 24 (46%) CTUs identified that database-screening tools were the most widely used digital tool for recruitment, with the majority being considered effective. The reason (and to whom) these tools were considered effective was in identifying potential participants (for both Site staff and CTU staff) and reaching recruitment target (for CTU staff/CI). Fewer retention tools were used, with short message service (SMS) or email reminders to participants being the most reported. The qualitative interviews revealed five themes across all groups: ‘security and transparency’; ‘inclusivity and engagement’; ‘human interaction’; ‘obstacles and risks’; and ‘potential benefits’. There was a high level of stakeholder acceptance of the use of digital tools to support trials, despite the lack of evidence to support them over more traditional techniques. Certain differences and similarities between stakeholder groups demonstrated the complexity and challenges of using digital tools for recruiting and retaining research participants. Conclusions Our studies identified a range of digital tools in use in recruitment and retention of RCTs, despite the lack of high-quality evidence to support their use. Understanding the type of digital tools in use to support recruitment and retention will help to inform funders and the wider research community about their value and relevance for future RCTs. Consideration of further focused digital tool reviews and primary research will help to reduce gaps in the evidence base.

Background: The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer (PCa) randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective: To determine report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, Setting, and Participants: This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention: Two cohorts included 1643 men who agreed to be randomised; 997 declined randomisation and chose treatment. Outcome Measurements and Statistical Analysis: Health-related quality of life impacts on urinary, bowel, and sexual function were assessed using patient-reported outcome measures. Analysis was carried out based on treatment received for each cohort and on pooled estimates using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and Limitations: According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and outdating of the interventions being evaluated during the lengthy follow-up required in trials of screen-detected PCa. Conclusions: Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient Summary: More than 90 out of every 100 men with localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are much better after active monitoring, but the risks of spreading of prostate cancer are more common.

Background Acute otitis media (AOM) is a common painful infection in children, with around 2.8 million cases presenting to primary care in England and Wales annually. Nearly all children who present to their general practitioner (GP) with AOM or AOM with discharge (AOMd) are treated with orally administered antibiotics. These can cause side effects; contribute to the growing problem of antimicrobial resistance, and more rarely, allergic reactions. Alternative treatments, such as an antibiotic eardrops, or ‘delayed’ orally administered antibiotics, could be at least as effective and safe as immediate orally administered antibiotics for children with AOMd. Methods/design REST is a pragmatic, three-arm, individually randomised, non-inferiority trial being conducted in 175 GP practices across the United Kingdom (UK). The study aims to recruit 399 children aged (≥ 12 months and Recruitment, including eligibility screening, randomisation and data collection, are conducted using the innovative, TRANSFoRm electronic trial management platform. Integrated within the primary care electronic medical records it provides automatic eligibility checking, part-filling of e-CRFs, study workflow management and routine NHS follow-up data collection. The primary outcome is time to resolution of all significant symptoms and will be collected by the parent using a Symptom Recovery Questionnaire (SRQ). Secondary outcomes, including cost-effectiveness, duration of moderately bad or worse symptoms and repeat AOMd episodes, will be collected at day-14 and at 3 months. Discussion It is unclear whether prescribing orally administered antibiotics to children with AOMd results in a reduction in symptoms or a shorter duration of illness. The REST trial should allow us to compare the non-inferiority of: immediate topically administered ciprofloxacin ear drops, or delayed orally administered amoxicillin (clarithromycin) against immediate orally administered amoxicillin (clarithromycin). We aim to recruit 399 patients from 175 practices in the UK. Using the TRANSFoRm software to randomise participants to the trial will enable recruitment for a relatively uncommon condition. Trial registration Name of Registry: ISCRTN Registration Number: ISRCTN12873692. This contains all items required to comply with the World Health Organization Trial Registration Data Set Date of Registration: 24 April 2018 Name of Registry: EudraCT Registration Number: 2017-003635-10 Date of Registration: 6 September 2017

Objective To evaluate the effectiveness and cost effectiveness of a complex intervention in primary care that aims to increase uptake of hepatitis C virus (HCV) case finding and treatment. Design Pragmatic, two armed, practice level, cluster randomised controlled trial and economic evaluation. Setting and participants 45 general practices in South West England (22 randomised to intervention and 23 to control arm). Outcome data were collected from all intervention practices and 21/23 control practices. Total number of flagged patients was 24 473 (about 5% of practice list). Intervention Electronic algorithm and flag on practice systems identifying patients with HCV risk markers (such as history of opioid dependence or HCV tests with no evidence of referral to hepatology), staff educational training in HCV, and practice posters/leaflets to increase patients’ awareness. Flagged patients were invited by letter for an HCV test (with one follow-up) and had on-screen pop-ups to encourage opportunistic testing. The intervention lasted one year, with practices recruited April to December 2016. Main outcome measures Primary outcome: uptake of HCV testing. Secondary outcomes: number of positive HCV tests and yield (proportion HCV positive); HCV treatment assessment at hepatology; cost effectiveness. Results Baseline HCV testing of flagged patients (six months before study start) was 608/13 097 (4.6%) in intervention practices and 380/11 376 (3.3%) in control practices. During the study 2071 (16%) of flagged patients in the intervention practices and 1163 (10%) in control practices were tested for HCV: overall intervention effect as an adjusted rate ratio of 1.59 (95% confidence interval 1.21 to 2.08; Pv 4.4%; adjusted risk ratio 1.40, 0.99 to 1.95). Referral and assessment increased in intervention practices compared with control practices (adjusted rate ratio 5.78, 1.6 to 21.6) with a risk difference of 1.3 per 1000 and a “number needed to help” of one extra HCV diagnosis, referral, and assessment per 792 (95% confidence interval 558 to 1883) patients flagged. The average cost of HCV case finding was £4.03 (95% confidence interval £2.27 to £5.80) per at risk patient and £3165 per additional patient assessed at hepatology. The incremental cost effectiveness ratio was £5783 per quality adjusted life year (QALY), with 93.3% probability of being below £20 000 per QALY. Conclusion HepCATT had a modest impact but is a low cost intervention that merits optimisation and implementation as part of an NHS strategy to increase HCV testing and treatment. Trial registration ISRCTN61788850.

Background: Hepatitis C virus infection is a key cause of liver disease but can be cured in over 95% of patients. Approximately 70,000 people with HCV infection in England may not have been diagnosed and many more not treated. National Institute for Health and Care Excellence (NICE) suggests that interventions to increase case finding in primary care are likely to be cost effective. However, evidence of effective interventions is lacking. The Hepatitis C Assessment to treatment trial (HepCATT) assessed whether a complex intervention in primary care could increase HCV case-finding, testing and treatment.Aim: To investigate the feasibility and acceptability of the HepCATT intervention. Design and setting: Qualitative interviews with fourteen primary care practice staff. Normalisation process theory, which outlines the social processes involved in intervention implementation, informed thematic data analysis.Results: Participants appreciated the HepCATT intervention for increasing HCV knowledge and awareness. Although some initial technical difficulties were reported, participants saw the benefits of using the audit tool to systematically identify patients with HCV infection risk factors and found it straightforward to use. Participants valued the opportunity to discuss HCV testing with patients, especially those that may not have been previously been aware of HCV risk. Future implementation should consider fully integrating software systems and additional resources to screen patient lists and conduct tests.Conclusion: When supported by a complex intervention, primary care can play a crucial role in identifying and caring for patients with HCV infection, to help stem the HCV epidemic and prevent HCV related illness.

Objectives Cognitive behavioral therapy (CBT) is an effective treatment for depression. Different CBT delivery formats (face-to-face [F2F], multimedia, and hybrid) and intensities have been used to expand access to the treatment. The aim of this study is to estimate the long-term cost-effectiveness of different CBT delivery modes. Methods A decision-analytic model was developed to evaluate the cost-effectiveness of different CBT delivery modes and variations in intensity in comparison with treatment as usual (TAU). The model covered an average treatment period of 4 months with a 5-year follow-up period. The model was populated using a systematic review of randomized controlled trials and various sources from the literature. Results Incremental cost-effectiveness ratios of treatments compared with the next best option after excluding all the dominated and extended dominated options are: £209/quality-adjusted life year (QALY) for 6 (sessions) × 30 (minutes) F2F-CBT versus TAU; £4 453/QALY for 8 × 30 F2F versus 6 × 30 F2F; £12 216/QALY for 8 × 60 F2F versus 8 × 30 F2F; and £43 072/QALY for 16 × 60 F2F versus 8 × 60 F2F. The treatment with the highest net monetary benefit for thresholds of £20 000 to £30 000/QALY was 8 × 30 F2F-CBT. Probabilistic sensitivity analysis illustrated 6 × 30 F2F-CBT had the highest probability (32.8%) of being cost-effective at £20 000/QALY; 16 × 60 F2F-CBT had the highest probability (31.0%) at £30 000/QALY. Conclusions All CBT delivery modes on top of TAU were found to be more cost-effective than TAU alone. Four F2F-CBT options (6 × 30, 8 × 30, 8 × 60, 16 × 60) are on the cost-effectiveness frontier. F2F-CBT with intensities of 6 × 30 and 16 × 60 had the highest probabilities of being cost-effective. The results, however, should be interpreted with caution owing to the high level of uncertainty.

ObjectivePatients with multiple chronic health conditions are often managed in a disjointed fashion in primary care, with annual review clinic appointments offered separately for each condition. This study aimed to determine the cost-effectiveness of the 3D intervention, which was developed to improve the system of care.DesignEconomic evaluation conducted alongside a pragmatic cluster-randomised trial.SettingGeneral practices in three centres in England and Scotland.Participants797 adults with three or more chronic conditions were randomised to the 3D intervention, while 749 participants were randomised to receive usual care.InterventionThe 3D approach: comprehensive 6-monthly general practitioner consultations, supported by medication reviews and nurse appointments.Primary and secondary outcome measuresThe primary economic evaluation assessed the cost per quality-adjusted life year (QALY) gained from the perspective of the National Health Service (NHS) and personal social services (PSS). Costs were related to changes in a range of secondary outcomes (QALYs accrued by both participants and carers, and deaths) in a cost–consequences analysis from the perspectives of the NHS/PSS, patients/carers and productivity losses.ResultsVery small increases were found in both QALYs (adjusted mean difference 0.007 (−0.009 to 0.023)) and costs (adjusted mean difference £126 (£−739 to £991)) in the intervention arm compared with usual care after 15 months. The incremental cost-effectiveness ratio was £18 499, with a 50.8% chance of being cost-effective at a willingness-to-pay threshold of £20 000 per QALY (55.8% at £30 000 per QALY).ConclusionsThe small differences in costs and outcomes were consistent with chance, and the uncertainty was substantial; therefore, the evidence for the cost-effectiveness of the 3D approach from the NHS/PSS perspective should be considered equivocal.Trial registration numberISCRTN06180958

Parkinson’s disease is the second most common neurodegenerative condition after Alzheimer’s disease. The number of patients will rise dramatically due to ageing of the population and possibly also due to environmental issues. It is widely recognised that the current models of care for people with Parkinson’s disease or a form of atypical parkinsonism lack continuity, are reactive to problems rather than proactive, and do not adequately support individuals to self-manage. Integrated models of care have been developed for other chronic conditions, with a range of positive effects. A multidisciplinary team of professionals in the United Kingdom and the Netherlands, all with a long history of caring for patients with movement disorders, used knowledge of deficiencies with the current model of care, an understanding of integrated care in chronic disease and the process of logic modelling, to develop a novel approach to the care of patients with Parkinson’s disease. We propose a new model, termed PRIME Parkinson (Proactive and Integrated Management and Empowerment in Parkinson’s Disease), which is designed to manage problems proactively, deliver integrated, multidisciplinary care, and empower patients and their carers. It has five main components: (1) personalised care management, (2) education and empowerment of patients and carers, (3) empowerment of healthcare professionals, (4) a population health approach, and (5) support of the previous four components by patient- and professional-friendly technology. Having mapped the processes required for the success of this initiative, there is now a requirement to assess its effect on health-related and quality of life outcomes as well as determining its cost-effectiveness. In the next phase of the project, we will implement PRIME Parkinson in selected areas of the United Kingdom and the Netherlands.

Background Depression is usually managed in primary care and antidepressants are often the first-line treatment, but only half of those treated respond to a single antidepressant. Objectives To investigate whether or not combining mirtazapine with serotonin–noradrenaline reuptake inhibitor (SNRI) or selective serotonin reuptake inhibitor (SSRI) antidepressants results in better patient outcomes and more efficient NHS care than SNRI or SSRI therapy alone in treatment-resistant depression (TRD). Design The MIR trial was a two-parallel-group, multicentre, pragmatic, placebo-controlled randomised trial with allocation at the level of the individual. Setting Participants were recruited from primary care in Bristol, Exeter, Hull/York and Manchester/Keele. Participants Eligible participants were aged ≥ 18 years; were taking a SSRI or a SNRI antidepressant for at least 6 weeks at an adequate dose; scored ≥ 14 points on the Beck Depression Inventory-II (BDI-II); were adherent to medication; and met the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, criteria for depression. Interventions Participants were randomised using a computer-generated code to either oral mirtazapine or a matched placebo, starting at a dose of 15 mg daily for 2 weeks and increasing to 30 mg daily for up to 12 months, in addition to their usual antidepressant. Participants, their general practitioners (GPs) and the research team were blind to the allocation. Main outcome measures The primary outcome was depression symptoms at 12 weeks post randomisation compared with baseline, measured as a continuous variable using the BDI-II. Secondary outcomes (at 12, 24 and 52 weeks) included response, remission of depression, change in anxiety symptoms, adverse events (AEs), quality of life, adherence to medication, health and social care use and cost-effectiveness. Outcomes were analysed on an intention-to-treat basis. A qualitative study explored patients’ views and experiences of managing depression and GPs’ views on prescribing a second antidepressant. Results There were 480 patients randomised to the trial (mirtazapine and usual care, n = 241; placebo and usual care, n = 239), of whom 431 patients (89.8%) were followed up at 12 weeks. BDI-II scores at 12 weeks were lower in the mirtazapine group than the placebo group after adjustment for baseline BDI-II score and minimisation and stratification variables [difference –1.83 points, 95% confidence interval (CI) –3.92 to 0.27 points; p = 0.087]. This was smaller than the minimum clinically important difference and the CI included the null. The difference became smaller at subsequent time points (24 weeks: –0.85 points, 95% CI –3.12 to 1.43 points; 12 months: 0.17 points, 95% CI –2.13 to 2.46 points). More participants in the mirtazapine group withdrew from the trial medication, citing mild AEs (46 vs. 9 participants). Conclusions This study did not find convincing evidence of a clinically important benefit for mirtazapine in addition to a SSRI or a SNRI antidepressant over placebo in primary care patients with TRD. There was no evidence that the addition of mirtazapine was a cost-effective use of NHS resources. GPs and patients were concerned about adding an additional antidepressant. Limitations Voluntary unblinding for participants after the primary outcome at 12 weeks made interpretation of longer-term outcomes more difficult. Future work Treatment-resistant depression remains an area of important, unmet need, with limited evidence of effective treatments. Promising interventions include augmentation with atypical antipsychotics and treatment using transcranial magnetic stimulation. Trial registration Current Controlled Trials ISRCTN06653773; EudraCT number 2012-000090-23. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 63. See the NIHR Journals Library website for further project information.

AIMS: To capture in-depth qualitative evidence regarding attitudes to and experiences of urodynamic testing among men with lower urinary tract symptoms (LUTS) at each end of the clinical pathway.METHODS: Semi-structured interview study conducted within the Urodynamics for Prostate Surgery: Randomized Evaluation of Assessment Methods (UPSTREAM) trial, which randomized men to a care pathway including urodynamics or routine non-invasive tests from 26 secondary care urology sites across England. Men were interviewed after assessments but prior to treatment, or after surgery for LUTS. Men were purposively sampled to include those who had urodynamics and those who did not, and diversity in demographic characteristics and symptom burden. Interviews were analyzed using inductive thematic analysis.RESULTS: Forty-one men participated (25 pre-treatment, 16 post-surgery), ages 52-89. The 16 men who had not previously experienced urodynamics said they would accept the test in their assessment, but some were apprehensive or wanted more information. The 25 men who had experienced urodynamics all found it acceptable, though some reported pain, infection, or embarrassment. Embarrassment was minimized by informing patients what the procedure would be like, and ensuring privacy. Urodynamics was valued for its perceived diagnostic insight. Information deficits were reported before, during, and after the test. How and when results were explained and the adequacy of explanations varied.CONCLUSIONS: Urodynamics is acceptable to men with LUTS and generally well-tolerated. To ensure patients are prepared and informed, good communication before and during the procedure is essential. Privacy should be prioritized, and test results discussed promptly and in sufficient detail. Staff require training and guidance in these areas.

Background Most adolescent girls in the UK do not meet government physical activity recommendations and effective interventions are needed. This study reports the results of a feasibility trial of PLAN-A, a novel school-based peer-led physical activity intervention for adolescent girls. Methods A two-arm cluster randomised controlled feasibility study was conducted in six English secondary schools (4 intervention & 2 control). Year 8 (age 12-13) girls were eligible and randomisation was at school-level. The intervention involved training Year 8 girls (out of school for two consecutive days, plus one top-up day 5 weeks later), who were identified by their peers as influential, to provide informal support to their friends to increase their physical activity. Feasibility of the intervention and the research was examined, including: recruitment, training attendance and data provision rates, evidence of promise of the intervention to affect weekday moderate-to-vigorous physical activity (MVPA), intervention cost and estimation of the sample size for a definitive trial. Accelerometer and questionnaire data were collected at the beginning of Year 8 (Time 0), the end of Year 8 (10-weeks after peer-supporter training) and the beginning of Year 9 (Time 2). Results Four hundred twenty-seven girls were recruited (95% recruitment rate). 55 girls consented to be a peer-supporter and 53 peer-supporters were trained (97% of those invited). Accelerometer return rates exceeded 85% at each time point and wear time criteria was met by 83%, 71% and 62% participants at Time 0, 1 and 2 respectively. Questionnaire data were provided by >91% of participants at each time point. Complete-case adjusted linear regression analysis showed evidence of a 6.09 minute (95% CI = 1.43, 10.76) between-arms difference in weekday MVPA at Time 2 in favour of the intervention arm. On average PLAN-A cost £2685 per school to deliver (£37 per Year 8 girl). There were no adverse events. A trial involving 20 schools would be adequately powered to detect a between-arms difference in weekday MVPA of at least six minutes. Conclusions The PLAN-A intervention adopts a novel peer-led approach, is feasible, and shows evidence of promise to positively affect girls’ physical activity levels. A definitive trial is warranted. Trial registration ISCTRN, ISRCTN12543546, Registered on 28/7/2015, URL of registry record: http://www.isrctn.com/ISRCTN12543546 Electronic supplementary material The online version of this article (10.1186/s12966-018-0682-4) contains supplementary material, which is available to authorized users.

Objectives\ud \ud Randomized controlled trials (RCTs) deliver robust internally valid evidence but generalizability is often neglected. Design features built into the Prostate testing for cancer and Treatment (ProtecT) RCT of treatments for localized prostate cancer (PCa) provided insights into its generalizability.\ud \ud \ud Study Design and Setting\ud \ud Population-based cluster randomization created a prospective study of prostate-specific antigen (PSA) testing and a comprehensive-cohort study including groups choosing treatment or excluded from the RCT, as well as those randomized. Baseline information assessed selection and response during RCT conduct.\ud \ud \ud Results\ud \ud The prospective study (82,430 PSA-tested men) represented healthy men likely to respond to a screening invitation. The extended comprehensive cohort comprised 1,643 randomized, 997 choosing treatment, and 557 excluded with advanced cancer/comorbidities. Men choosing treatment were very similar to randomized men except for having more professional/managerial occupations. Excluded men were similar to the randomized socio-demographically but different clinically, representing less healthy men with more advanced PCa.\ud \ud \ud Conclusion\ud The design features of the ProtecT RCT provided data to assess the representativeness of the prospective cohort and generalizability of the findings of the RCT. Greater attention to collecting data at the design stage of pragmatic trials would better support later judgments by clinicians/policy-makers about the generalizability of RCT findings in clinical practice.

Purpose To examine whether age-related reference ranges for “normal” prostate-specific antigen (PSA) change (determined in men without prostate cancer) can be used to identify men at high risk of having prostate cancer. Methods Subjects were men aged 50–69 years with PSA

ObjectiveInvestigate the effectiveness and cost-effectiveness of the Lightning Process (LP) in addition to specialist medical care (SMC) compared with SMC alone, for children with chronic fatigue syndrome/myalgic encephalitis (CFS/ME).DesignPragmatic randomised controlled open trial. Participants were randomly assigned to SMC, or SMC plus the LP (SMC+LP). Randomisation was minimised by age and gender.SettingSpecialist paediatric CFS/ME service.PatientsAged 12–18 years with mild/moderate CFS/ME.Main outcome measuresThe primary outcome was the SF-36 physical function subscale (PFS) at 6 months. Secondary outcomes included the SF-36-PFS at 3 and 12 months, and pain, anxiety, depression, school attendance and cost-effectiveness from a health service perspective at 3, 6 and 12 months.ResultsWe recruited 100 participants between September 2010 and September 2013. We tested the feasibility of running the trial with a feasibility phase (29 September 2010 to 18 September 2012). The full trial was registered in June 2012 when we had determined it was a feasible study. Of the 100 participants, 51 were randomised to SMC+LP. Data from 81 participants were analysed at 6 months. Physical function (SF-36-PFS) was better in those allocated SMC+LP (adjusted difference in means 12.5 [95% CI 4.5 to 20.5], p=0.003) and this improved further at 12 months (15.1 [95% CI 5.8 to 24.4], p=0.002). At 6 months, fatigue and anxiety were reduced and at 12 months, fatigue, anxiety, depression and school attendance had improved in the SMC+LP arm. Results were similar following multiple imputation. SMC+LP was more cost-effective in the multiple imputation data set (difference in means in net monetary benefit at 12 months £1474 [95% CI £111 to £2836], p=0.03) but not for complete cases.ConclusionThe LP is effective and is probably cost-effective when provided in addition to SMC for mild/moderately affected adolescents with CFS/ME.Trial registration numberISRCTN81456207.

Abstract The FITNET-NHS Trial is a UK, national, trial investigating whether an online cognitive behavioural therapy program (FITNET-NHS) for treating chronic fatigue syndrome/ME in adolescents is clinically effective and cost-effective in the NHS. At the time of writing (September 2019), the trial was recruiting participants. This article presents an update to the planned sample size and data collection duration previously published within the trial protocol. Trial registration ISRCTN, ID: 18020851. Registered 8 April 2016.

Background: Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer’s disease pathology and reduce the rate of disease progression. We report a phase II, two arm, double-blind, placebo-controlled, randomised trial (ISRCTN: 93682878; EudraCT: 2012-003641-15) of losartan to test the efficacy of Reducing pathology in Alzheimer’s Disease through Angiotensin TaRgeting (RADAR). Study population: Men and women aged at least 55 years with mild-to-moderate Alzheimer’s disease (AD) Interventions: Randomly allocated 100mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2 week open-label phase and 2 weeks placebo washout to establish drug tolerability. Outcomes: The primary outcome is the rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes include changes to (i) white matter hyperintensity (WMH) volume and cerebral blood flow (CBF) (also surrogate markers of cognitive decline and disease progression); (ii) performance on a standard series of assessments of memory, cognitive function, activities of daily living and quality of life. Assessments: Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods and reported side effects will occur during the open-label phase and during the majority of the post-randomisation dispensing visits. Sample Size: 228 participants to provide at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. Analysis: Intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimisation variables.

Background:Current management for men with lower urinary tract symptoms (LUTS) is a pathway that results in prostate surgery in a significant proportion. While helpful in relieving benign prostatic obstruction (BPO), surgery may be ineffective for men suffering from difficulties not relating to BPO. The UPSTREAM trial started recruitment in October 2014 with the aim of establishing whether a care pathway including urodynamics (a diagnostic tool for BPO and thus an indication of whether surgery is needed) is no worse for men, in terms of symptomatic outcome, than one without (routine care). Methods/Design:This analysis plan outlines the main outcomes of the study as well as specific design choices, such as non-inferiority margins. The trial is currently recruiting in 26 hospitals across the UK, randomising men to either urodynamics or routine care, with recruitment set to end on the 31st of December 2016. All outcomes will be measured 18 months after randomisation to allow sufficient time for surgical procedures and recovery. The primary outcome is based on a non-inferiority design with a margin of 1 point on the International Prostate Symptom Score (IPSS) scale. The key secondary outcome for this trial is surgery rate per arm, which is estimated to be at least 18% lower in the urodynamics arm. Surgery rates, adverse events, flow rate, urinary symptoms and sexual symptoms are secondary outcomes to be assessed for superiority. This is an update to the UPSTREAM protocol which has already been published in this journal.Discussion:This a priori statistical analysis plan aims to reduce reporting bias by allowing access to the trial’s objectives and plans in advance of recruitment end. The results of the trial are expected to be published soon after the trial end date of 30th September 2018.Trial registrationTrial registered 8 April 2014; ISRCTN registry (ISRCTN56164274).

Purpose The insulin-like growth factor (IGF) system is modifiable by diet and lifestyle, and has been linked to prostate cancer development and progression. Methods We conducted a prospective cohort study of 621 men diagnosed with localized prostate cancer to investigate the associations of dietary and lifestyle changes with post-diagnosis circulating levels of IGF-I and IGFBP-3. We used analysis of covariance to estimate the associations, controlling for baseline IGF-I or IGFBP-3, respectively. Results Mean IGF-I levels were 6.5% (95% CI −12.8, −0.3%, p = 0.04) lower in men who decreased their protein intake after diagnosis compared to men who did not change. Men who changed their fruit and vegetable intake had lower IGF-I levels compared to non-changers [Decreased intake: −10.1%, 95% CI −18.4, −1.8%, p = 0.02; Increased intake: −12.0%, 95% CI −18.4, −1.8%, p = 0.002]. IGFBP-3 was 14.6% (95% CI −24.5, −4.8%, p = 0.004) lower in men who achieved a healthy body mass index after diagnosis. Men who became inactive had 9.5% higher average IGF-I levels (95% CI 0.1, 18.9%, p = 0.05). Conclusions Decreased protein intake and body mass index, and increased physical activity and fruit and vegetable intake, following a prostate cancer diagnosis were associated with reduced post-diagnosis serum IGF-I and IGFBP-3. Counterintuitively, reduced fruit and vegetable intake was also associated with reduced IGF-I, but with weak statistical support, possibly implicating chance. If confirmed in other studies, our findings may inform potential lifestyle interventions in prostate cancer. ProtecT was registered at International Standard Randomised Controlled Trial Registry, http://isrctn.org as ISRCTN20141297.

Background Co-occurring depression frequently occurs in autism. Evidence-based psychological interventions have been successfully adapted to treat co-occurring anxiety, but there is little evidence about the usefulness of adapted cognitive–behavioural therapy for depression. To the authors’ knowledge, to date there have been no randomised trials investigating the usefulness of low-intensity cognitive–behavioural therapy for depression in autism. Objectives The objectives of the study were to (1) develop a low-intensity psychological intervention for depression adapted for autism, (2) assess the feasibility and patient and therapist acceptability of the intervention, (3) estimate the rates of recruitment and retention for a full-scale randomised controlled trial and (4) identify an appropriate measure of depression to be used in a full-scale randomised controlled trial. Design The study comprised a randomised controlled trial (n = 70) with a nested qualitative evaluation (n = 21). Seventy eligible and consenting participants were randomly allocated to guided self-help or to treatment as usual. Setting Adult autism services in two NHS regions. Participants Adults with a diagnosis of autism spectrum disorder with depression, that is, a Patient Health Questionnaire-9 items score of ≥ 10. People who had attended more than six sessions of cognitive–behavioural therapy in the previous 6 months were excluded. Interventions The low-intensity intervention (guided self-help) comprised materials for nine individual sessions, based on behavioural activation adapted for autism, facilitated by therapist guides (coaches) who were graduate-level psychologists who attended training and regular supervision. Treatment as usual was standard NHS care for depression. Main outcome measures Outcomes were measured 10, 16 and 24 weeks post randomisation using self-report and interview measures of depression, anxiety, obsessive–compulsive symptoms, social function and quality of life, and a health-care and service use questionnaire. As this was a feasibility study also designed to identify the most appropriate measure of depression, it was not possible to specify the primary outcome measure or outcome point a priori. Results The aims of the study were met in full. The guided self-help intervention was feasible and well received by participants and coaches. The majority of allocated participants attended the intervention in full. The most practical outcome point was determined to be 16 weeks. There were differential rates of attrition across the treatment groups: 86% of the guided self-help group remained in the study at 24 weeks, compared with 54% of treatment as usual group. The qualitative study suggested that guided self-help had enhanced credibility with participants at the point of randomisation. Inter-rater reliability of the interview measure of depression was less than adequate, limiting the conclusions that can be drawn from the prespecified sensitivity to change analyses. Conclusions The intervention was feasible and well received. Although this feasibility study was not a fully powered trial, it provided some evidence that the guided self-help intervention was effective in reducing depressive symptoms. A full-scale clinical effectiveness and cost-effectiveness trial of the intervention is warranted. Future work Improvements to the intervention materials as a result of qualitative interviews. Stakeholder consultation to consider future trial design, consider strategies to improve retention in a treatment as usual arm and select a self-report measure of depression to serve as the primary outcome measure. Trial registration Current Controlled Trials ISRCTN54650760. 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. 23, No. 68. See the NIHR Journals Library website for further project information. This study was also supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol.

Background Chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME) is relatively common in young people and causes significant disability. Graded exercise therapy (GET) and activity management are recommended by the National Institute for Health and Care Excellence (NICE) despite a limited evidence-base for either treatment in paediatric CFS/ME. This paper reports on feasibility and acceptability measures from the feasibility phase of the ongoing MAGENTA randomised controlled trial (RCT) investigating GET versus activity management for young people with CFS/ME. Methods Setting: Three specialist secondary care National Health Service (NHS) Paediatric CFS/ME services (Bath, Cambridge and Newcastle). Participants: Young people aged 8–17 years with a diagnosis of mild to moderate CFS/ME. Young people were excluded if they were severely affected, referred to cognitive behavioural therapy (CBT) at initial assessment or unable to attend clinical sessions. Interventions: GET and activity management delivered by physiotherapists, occupational therapists, nurses and psychologists. Families and clinicians decided the number (typically 8–12) and frequency of appointments (typically every 2–6 weeks). Outcome Measures: Recruitment and follow-up statistics. We used integrated qualitative methodology to explore the feasibility and acceptability of the trial processes and the interventions. Results 80/161 (49.7%) of eligible young people were recruited at two sites between September 2015 and August 2016, indicating recruitment to the trial was feasible. Most recruitment (78/80; 97.5%) took place at one centre. Recruitment consultations, online consent and interventions were acceptable, with less than 10% in each arm discontinuing trial treatment. Response rate to the primary outcome (the SF36-PFS at 6 months) was 91.4%. Recruitment, treatment and data collection were not feasible at one centre. The site was withdrawn from the study. In response to data collected, we optimised trial processes including using Skype for recruitment discussions; adapting recruiter training to improve recruitment discussions; amending the accelerometer information leaflets; shortening the resource use questionnaires; and offering interventions via Skype. These amendments have been incorporated into the full trial protocol. Conclusions Conducting an RCT investigating GET versus activity management is feasible and acceptable for young people with CFS/ME. Trial registration ISRCTN23962803 10.1186/ISRCTN23962803, date of registration: 03 September 2015

IntroductionSurgery (oesophagectomy), with neoadjuvant chemo(radio)therapy, is the main curative treatment for patients with oesophageal cancer. Several surgical approaches can be used to remove an oesophageal tumour. The Ivor Lewis (two-phase procedure) is usually used in the UK. This can be performed as an open oesophagectomy (OO), a laparoscopically assisted oesophagectomy (LAO) or a totally minimally invasive oesophagectomy (TMIO). All three are performed in the National Health Service, with LAO and OO the most common. However, there is limited evidence about which surgical approach is best for patients in terms of survival and postoperative health-related quality of life.Methods and analysisWe will undertake a UK multicentre randomised controlled trial to compare LAO with OO in adult patients with oesophageal cancer. The primary outcome is patient-reported physical function at 3 and 6 weeks postoperatively and 3 months after randomisation. Secondary outcomes include: postoperative complications, survival, disease recurrence, other measures of quality of life, spirometry, success of patient blinding and quality assurance measures. A cost-effectiveness analysis will be performed comparing LAO with OO. We will embed a randomised substudy to evaluate the safety and evolution of the TMIO procedure and a qualitative recruitment intervention to optimise patient recruitment. We will analyse the primary outcome using a multi-level regression model. Patients will be monitored for up to 3 years after their surgery.Ethics and disseminationThis study received ethical approval from the South-West Franchay Research Ethics Committee. We will submit the results for publication in a peer-reviewed journal.Trial registration numberNCT10386621.

Background There is limited evidence relating to the cost-effectiveness of treatments for localised prostate cancer. Methods The cost-effectiveness of active monitoring, surgery, and radiotherapy was evaluated within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial from a UK NHS perspective at 10 years’ median follow-up. Prostate cancer resource-use collected from hospital records and trial participants was valued using UK reference-costs. QALYs (quality-adjusted-life-years) were calculated from patient-reported EQ-5D-3L measurements. Adjusted mean costs, QALYs, and incremental cost-effectiveness ratios were calculated; cost-effectiveness acceptability curves and sensitivity analyses addressed uncertainty; subgroup analyses considered age and disease-risk. Results Adjusted mean QALYs were similar between groups: 6.89 (active monitoring), 7.09 (radiotherapy), and 6.91 (surgery). Active monitoring had lower adjusted mean costs (£5913) than radiotherapy (£7361) and surgery (£7519). Radiotherapy was the most likely (58% probability) cost-effective option at the UK NICE willingness-to-pay threshold (£20,000 per QALY). Subgroup analyses confirmed radiotherapy was cost-effective for older men and intermediate/high-risk disease groups; active monitoring was more likely to be the cost-effective option for younger men and low-risk groups. Conclusions Longer follow-up and modelling are required to determine the most cost-effective treatment for localised prostate cancer over a man’s lifetime. Trial registration Current Controlled Trials number, ISRCTN20141297: http://isrctn.org (14/10/2002); ClinicalTrials.gov number, NCT02044172: http://www.clinicaltrials.gov (23/01/2014).

IntroductionAtopic dermatitis/eczema affects around 20% of children and is characterised by inflamed, dry, itchy skin. Guidelines recommend ‘leave-on’ emollients that are applied directly to the skin to add or trap moisture and used regularly, they can soothe, enhance the skin barrier and may prevent disease ‘flares’. However, the suitability of the many different emollients varies between people and there is little evidence to help prescribers and parents and carers decide which type to try first.Methods and analysisDesign: pragmatic, multicentre, individually randomised, parallel group superiority trial of four types of emollient (lotions, creams, gel or ointments).Setting: general practitioner surgeries in England.Participants: children aged over 6 months and less than 12 years with mild-to-severe eczema and no known sensitivity to study emollients.Interventions: study-approved lotion, cream, gel or ointment as the only leave-on emollient for 16 weeks, with directions to apply twice daily and as required. Other treatments, such as topical corticosteroids, used as standard care.Follow-up: 52 weeks.Primary outcome: validated patient-orientated eczema measure measured weekly for 16 weeks.Secondary outcomes: eczema signs (Eczema Area Severity Index) by masked researcher, treatment use, parent satisfaction, adverse events, child and family quality of life (Atopic Dermatitis Quality of Life, Child Health Utility 9D and Dermatitis Family Impact).Sample size: 520 participants (130 per group).Analysis: intention-to-treat using linear mixed models for repeated measures.Nested qualitative study: audio-recording of sample of baseline appointments and up to 60 interviews with participants at 4 and 16 weeks, interviews to be transcribed and analysed thematically.Ethics and disseminationEthics approval granted by the NHS REC (South West - Central Bristol Research Ethics Committee 17/SW/0089). Findings will be presented at conferences, published in open-access peer-reviewed journals and the study website; and summaries shared with key stakeholders.Trial registration numberISRCTN84540529

Use of supporting materials in cognitive behavioural therapy (CBT) is widely advocated, and homework increases effectiveness. The study aimed to identify materials most frequently used by CBT therapists to support CBT for depression, and those perceived clinically most effective. Questionnaires were sent to 3665 accredited CBT therapists asking about their use of resources commonly described in CBT manuals, and their views on effectiveness. Of 3665 approached by post/email, 994 (27%) responded. Another 33 completed the questionnaire via the study website. 818/1027 (80%) of respondents were accredited practitioners who deliver one-to-one therapy. Symptom measures, lists of problems/goals, activity schedules, behavioural activation diaries/plans, and case formulation worksheets were used “frequently” or “very frequently” by over 85% of respondents. Sleep diaries and computerised CBT were used least. Most resources were used within and between sessions. Activity schedules, behavioural activation diaries/plans, case formulation worksheets, thought records, and resources to support the identification of conditional beliefs were regarded as most effective. Symptom measures, sleep diaries, and computerised/online materials were considered only moderately effective. Therapists use a wide range of materials to support individual CBT. For delivering CBT, technology-enabled approaches should incorporate a range of materials to enable therapists to tailor treatment effectively.

Supplemental Digital Content is available in the text., Whether prostate cancer (PCa) may be preventable by dietary interventions can be assessed in randomized trials using intermediate biomarkers of cancer risk or progression. We investigated whether lycopene or green tea modify circulating insulin-like growth factor (IGF) peptides in men at increased risk of PCa. Participants (aged 50–69 years) in one centre in the UK wide PCa testing and treatment trial (ProtecT) with prostate specific antigen between 2.0 and 2.95 ng/ml or negative biopsies, were randomized to daily lycopene (n = 44 assigned 15 mg capsules/day; 44 assigned a lycopene-rich diet; 45 assigned placebo) and green tea (n = 45 assigned 600 mg/day epigallocatechin gallate; 45 assigned green tea drink; 43 assigned placebo) for 6 months. The interventions significantly elevated the primary outcomes, serum epigallocatechin gallate and lycopene at 6 months of follow-up. We report here an exploratory analysis in which serum IGF-I, IGF-II, IGF binding protein (BP)-2 and IGFBP-3 were measured at baseline and 6 months of postintervention. A total of 133 men were randomized (34% of eligible men approached) and 130 had follow-up IGF peptides (98%). In intention-to-treat analyses, there was only weak evidence that lycopene or green tea influenced some aspects of serum IGF-I, IGF-II, IGFBP-2 or IGFBP-3. In men randomized to lycopene supplements, IGFBP-2 was nonsignificantly (50.9 ng/ml; 95% confidence interval: −51.2–152.9, P = 0.3) higher in comparison to placebo, whereas in men randomized to green tea supplements, IGFBP-3 was nonsignificantly (205.2 ng/ml; 95% confidence interval: −583.3–172.9, P = 0.3) lower than with placebo. In this small, pilot randomized controlled trial, there was little evidence that lycopene or green tea interventions influenced serum levels of IGF-I, IGF-II, IGFBBP-3 and IGFBP-2. However, the effects were imprecisely estimates and some observed trends may justify larger trials.

Background Clinical trials commonly have a dedicated trial manager and effective trial management is essential to the successful delivery of high-quality trials. Trial managers have diverse experience and currently there is no standardised structured career pathway. The UK Trial Managers’ Network (UKTMN) surveyed its members to understand what is important to them with respect to career development since this would be important in the development of any initiative intended to develop a skilled workforce. Methods We conducted an online survey of UKTMN members, who are trial management professionals, working on academic-led trials in the UK. Members were asked what they perceive as opportunities and barriers to career development. Two reminders were sent to facilitate completion of the survey, and responders were offered the opportunity to enter a prize draw for waived fees at the UKTMN annual meeting. Data were analysed descriptively by using Stata (version 15.1), and free-text responses were reviewed for themes. Results The survey was sent to 819 UKTMN members; 433 responses were received, although 13 were from non-UKTMN members; thus 420 respondents' data were included in analyses. Respondents were representative of UKTMN membership; however, more responses were received by trial managers based in registered clinical trials units (CTUs). The top three opportunities for career development were (i) training, (ii) helping design trials and (iii) undertaking relevant qualifications. The top three barriers were (i) funding, (ii) few opportunities to get involved in development activities aside from managing a trial and (iii) unclear organisational career pathway. Almost all respondents (401/420, 95.4%) considered career development either very or quite important. Although all respondents had a day-to-day role in managing trials, there was huge disparity between job titles. Conclusion Career development is important to trial managers yet there is a lack of a structured pathway. The enablers and disablers to career development for trial managers should be clearly considered by the clinical trial community and, in particular, employers, sponsors and funders in order to develop a highly skilled workforce of trial managers, who are key to the delivery of trials.

Background Fatigue is a major problem in rheumatoid arthritis (RA). There is evidence for the clinical effectiveness of cognitive–behavioural therapy (CBT) delivered by clinical psychologists, but few rheumatology units have psychologists. Objectives To compare the clinical effectiveness and cost-effectiveness of a group CBT programme for RA fatigue [named RAFT, i.e. Reducing Arthritis Fatigue by clinical Teams using cognitive–behavioural (CB) approaches], delivered by the rheumatology team in addition to usual care (intervention), with usual care alone (control); and to evaluate tutors’ experiences of the RAFT programme. Design A randomised controlled trial. Central trials unit computerised randomisation in four consecutive cohorts within each of the seven centres. A nested qualitative evaluation was undertaken. Setting Seven hospital rheumatology units in England and Wales. Participants Adults with RA and fatigue severity of ≥ 6 [out of 10, as measured by the Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scale (BRAF-NRS)] who had no recent changes in major RA medication/glucocorticoids. Interventions RAFT – group CBT programme delivered by rheumatology tutor pairs (nurses/occupational therapists). Usual care – brief discussion of a RA fatigue self-management booklet with the research nurse. Main outcome measures Primary – fatigue impact (as measured by the BRAF-NRS) at 26 weeks. Secondary – fatigue severity/coping (as measured by the BRAF-NRS); broader fatigue impact [as measured by the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ)]; self-reported clinical status; quality of life; mood; self-efficacy; and satisfaction. All data were collected at weeks 0, 6, 26, 52, 78 and 104. In addition, fatigue data were collected at weeks 10 and 18. The intention-to-treat analysis conducted was blind to treatment allocation, and adjusted for baseline scores and centre. Cost-effectiveness was explored through the intervention and RA-related health and social care costs, allowing the calculation of quality-adjusted life-years (QALYs) with the EuroQol-5 Dimensions, five-level version (EQ-5D-5L). Tutor and focus group interviews were analysed using inductive thematic analysis. Results A total of 308 out of 333 patients completed 26 weeks (RAFT, n/N = 156/175; control, n/N = 152/158). At 26 weeks, the mean BRAF-NRS impact was reduced for the RAFT programme (–1.36 units; p p p = 0.03, effect size 0.36], and this was sustained over 2 years (–0.49 units, 95% CI –0.83 to –0.14 units; p = 0.01). At 26 weeks, further fatigue differences favoured the RAFT programme (BRAF-MDQ fatigue impact: adjusted mean difference –3.42 units, 95% CI –6.44 to – 0.39 units, p = 0.03; living with fatigue: adjusted mean difference –1.19 units, 95% CI –2.17 to –0.21 units, p = 0.02; and emotional fatigue: adjusted mean difference –0.91 units, 95% CI –1.58 to –0.23 units, p = 0.01), and these fatigue differences were sustained over 2 years. Self-efficacy favoured the RAFT programme at 26 weeks (Rheumatoid Arthritis Self-Efficacy Scale: adjusted mean difference 3.05 units, 95% CI 0.43 to 5.6 units; p = 0.02), as did BRAF-NRS coping over 2 years (adjusted mean difference 0.42 units, 95% CI 0.08 to 0.77 units; p = 0.02). Fatigue severity and other clinical outcomes were not different between trial arms and no harms were reported. Satisfaction with the RAFT programme was high, with 89% of patients scoring ≥ 8 out of 10, compared with 54% of patients in the control arm rating the booklet (p p Limitations Primary outcome data were missing for 25 patients; the EQ-5D-5L might not capture fatigue change; and 30% of the 2-year economic data were missing. Conclusions The RAFT programme improves RA fatigue impact beyond usual care alone; this was sustained for 2 years with high patient satisfaction, enhanced team skills and no harms. The RAFT programme is Future work Given the paucity of RA fatigue interventions, rheumatology teams might investigate the pragmatic implementation of the RAFT programme, which is low cost. Trial registration Current Controlled Trials ISRCTN52709998. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 57. See the NIHR Journals Library website for further project information.

IntroductionHepatitis C virus (HCV) is the second largest contributor to liver disease in the UK, with injecting drug use as the main risk factor among the estimated 200 000 people currently infected. Despite effective prevention interventions, chronic HCV prevalence remains around 40% among people who inject drugs (PWID). New direct-acting antiviral (DAA) HCV therapies combine high cure rates (>90%) and short treatment duration (8 to 12 weeks). Theoretical mathematical modelling evidence suggests HCV treatment scale-up can prevent transmission and substantially reduce HCV prevalence/incidence among PWID. Our primary aim is to generate empirical evidence on the effectiveness of HCV ‘Treatment as Prevention’ (TasP) in PWID.Methods and analysisWe plan to establish a natural experiment with Tayside, Scotland, as a single intervention site where HCV care pathways are being expanded (including specialist drug treatment clinics, needle and syringe programmes (NSPs), pharmacies and prison) and HCV treatment for PWID is being rapidly scaled-up. Other sites in Scotland and England will act as potential controls. Over 2 years from 2017/2018, at least 500 PWID will be treated in Tayside, which simulation studies project will reduce chronic HCV prevalence among PWID by 62% (from 26% to 10%) and HCV incidence will fall by approximately 2/3 (from 4.2 per 100 person-years (p100py) to 1.4 p100py). Treatment response and re-infection rates will be monitored. We will conduct focus groups and interviews with service providers and patients that accept and decline treatment to identify barriers and facilitators in implementing TasP. We will conduct longitudinal interviews with up to 40 PWID to assess whether successful HCV treatment alters their perspectives on and engagement with drug treatment and recovery. Trained peer researchers will be involved in data collection and dissemination. The primary outcome – chronic HCV prevalence in PWID – is measured using information from the Needle Exchange Surveillance Initiative survey in Scotland and the Unlinked Anonymous Monitoring Programme in England, conducted at least four times before and three times during and after the intervention. We will adapt Bayesian synthetic control methods (specifically the Causal Impact Method) to generate the cumulative impact of the intervention on chronic HCV prevalence and incidence. We will use a dynamic HCV transmission and economic model to evaluate the cost-effectiveness of the HCV TasP intervention, and to estimate the contribution of the scale-up in HCV treatment to observe changes in HCV prevalence. Through the qualitative data we will systematically explore key mechanisms of TasP real world implementation from provider and patient perspectives to develop a manual for scaling up HCV treatment in other settings. We will compare qualitative accounts of drug treatment and recovery with a ‘virtual cohort’ of PWID linking information on HCV treatment with Scottish Drug treatment databases to test whether DAA treatment improves drug treatment outcomes.Ethics and disseminationExtending HCV community care pathways is covered by ethics (ERADICATE C,ISRCTN27564683, Super DOT C Trial clinicaltrials.gov:NCT02706223). Ethical approval for extra data collection from patients including health utilities and qualitative interviews has been granted (REC ref: 18/ES/0128) and ISCRCTN registration has been completed (ISRCTN72038467). Our findings will have direct National Health Service and patient relevance; informing prioritisation given to early HCV treatment for PWID. We will present findings to practitioners and policymakers, and support design of an evaluation of HCV TasP in England.

Background Girls are less active than boys and few adolescent girls meet physical activity (PA) guidelines. Peers are an important influence on the views and behaviours of adolescent girls, yet many PA interventions involving peers use formal approaches that may not harness the power of peer groups. More informal peer-led PA interventions, which work within proximal peer groups, may hold promise for increasing girls’ PA. Objectives To examine the feasibility, evidence of promise and cost of the Peer-Led physical Activity iNtervention for Adolescent girls (PLAN-A), a peer-led PA intervention. Design Phase 1 comprised formative work and a pilot study conducted in one secondary school. Phase 2 was a feasibility study comprising a pilot randomised controlled trial in six secondary schools, including process and economic evaluations. Setting Six secondary schools in South Gloucestershire and Wiltshire, recruited from schools above the median local Pupil Premium (i.e. more deprived). Participants Year 8 girls (aged 12–13 years). Intervention Year 8 girls nominated other girls in their year who are likely to be influential (e.g. who they look up to, are good listeners); the 18% most nominated were invited to be peer supporters (PSs). PSs attended 2 consecutive days of training (plus a top-up day 5 weeks later) outside the school site, led by pairs of PS trainers, to increase their knowledge about PA and their capabilities and confidence to promote PA in their friendship group. Main outcome measures Measures focused on establishing evidence for feasibility and promise: recruitment and retention of Year 8 girls and PSs, data provision rates [accelerometer and questionnaire collected pre randomisation/beginning of Year 8 (T0), end of Year 8 (T1) and beginning of Year 9 (T2)], intervention acceptability, PS training attendance, intervention cost, and the between-arm difference in weekday minutes of moderate to vigorous PA (MVPA). A process evaluation was conducted. Results Six schools were recruited: four PLAN-A (n = 269) and two control (n = 158). In total, 94.7% of Year 8 girls participated. A total of 55 (17–24% of Year 8 girls) PSs were trained (attendance rate 91–100%). Five girls were trained as PS trainers. Questionnaire data provision exceeded 92% at all time points. Accelerometer return rates were > 85% and wear-time criteria were met by 83%, 71% and 62% of participants at T0, T1 and T2, respectively. Mean weekday MVPA did not differ between intervention arms at T1 (1.1 minutes, 95% CI –4.3 to 6.5 minutes) but did at T2 (6.1 minutes, 95% CI 1.4 to 10.8 minutes), favouring PLAN-A. The mean cost of intervention delivery was £2685 per school or £37 per Year 8 girl. Process evaluation identified good fidelity, engagement and enjoyment of the PS training and peer-support strategies. PSs needed more guidance on how to start conversations. Limitations Accelerometer data provision was lowest at T2, suggesting a need for strategies to increase compliance. Conclusions Informal peer-led intervention approaches, such as PLAN-A, hold promise as a means of promoting PA to adolescent girls. Future work A definitive randomised controlled trial of PLAN-A is warranted. Trial registration Current Controlled Trials ISRCTN12543546. Funding This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 7, No. 16. See the NIHR Journals Library website for further project information. The work was undertaken with the support of the Centre for the Development and Evaluation of Complex Interventions for Public Health Improvement (DECIPHer), a UK Clinical Research Collaboration (UKCRC) Public Health Research Centre of Excellence. Joint funding (MR/KO232331/1) from the British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, the Welsh Government and the Wellcome Trust, under the auspices of the UKCRC, is gratefully acknowledged. This study was designed and delivered in collaboration with the Bristol Randomised Trials Collaboration (BRTC), a UK CRC-registered clinical trials unit in receipt of NIHR clinical trials unit support funding. The intervention costs were jointly funded by South Gloucestershire Council and Wiltshire Council.