Getting our ducks in a row: The need for data utility comparisons of healthcare systems data for clinical trials.

BACKGROUND: Better use of healthcare systems data, collected as part of interactions between patients and the healthcare system, could transform planning and conduct of randomised controlled trials. Multiple challenges to widespread use include whether healthcare systems data captures sufficiently well the data traditionally captured on case report forms. "Data Utility Comparison Studies" (DUCkS) assess the utility of healthcare systems data for RCTs by comparison to data collected by the trial. Despite their importance, there are few published UK examples of DUCkS. METHODS-AND-RESULTS: Building from ongoing and selected recent examples of UK-led DUCkS in the literature, we set out experience-based considerations for the conduct of future DUCkS. Developed through informal iterative discussions in many forums, considerations are offered for planning, protocol development, data, analysis and reporting, with comparisons at "patient-level" or "trial-level", depending on the item of interest and trial status. DISCUSSION: DUCkS could be a valuable tool in assessing where healthcare systems data can be used for trials and in which trial teams can play a leading role. There is a pressing need for trials to be more efficient in their delivery and research waste must be reduced. Trials have been making inconsistent use of healthcare systems data, not least because of an absence of evidence of utility. DUCkS can also help to identify challenges in using healthcare systems data, such as linkage (access and timing) and data quality. We encourage trial teams to incorporate and report DUCkS in trials and funders and data providers to support them.

Using healthcare systems data for outcomes in clinical trials: issues to consider at the design stage.

BACKGROUND: Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community. METHODS: The PRIMORANT study had three phases. First, an initial workshop was held to scope the issues faced by trialists when considering whether to use HSDs for trial outcomes. Second, a consultation exercise was undertaken with clinical trials unit (CTU) staff, trialists, methodologists, clinicians, funding panels and data providers. Third, a final discussion workshop was held, at which the results of the consultation were fed back, case studies presented, and issues considered in small breakout groups. RESULTS: Key topics included in the consultation process were the validity of outcome data, timeliness of data capture, internal pilots, data-sharing, practical issues, and decision-making. A majority of consultation respondents (n = 78, 95%) considered the development of guidance for trialists to be feasible. Guidance was developed following the discussion workshop, for the five broad areas of terminology, feasibility, internal pilots, onward data sharing, and data archiving. CONCLUSIONS: We provide guidance to inform decisions about whether or not to use HSDs for outcomes, and if so, to assist trialists in working with registries and other HSD providers to improve the design and delivery of trials.

Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Most patients with irritable bowel syndrome (IBS) are managed in primary care. When first-line therapies for IBS are ineffective, the UK National Institute for Health and Care Excellence guideline suggests considering low- dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown, and they are infrequently prescribed in this setting. METHODS: This randomised, double-blind, placebo-controlled trial (Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment [ATLANTIS]) was conducted at 55 general practices in England. Eligible participants were aged 18 years or older, with Rome IV IBS of any subtype, and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥75 points) despite dietary changes and first-line therapies, a normal full blood count and C-reactive protein, negative coeliac serology, and no evidence of suicidal ideation. Participants were randomly assigned (1:1) to low-dose oral amitriptyline (10 mg once daily) or placebo for 6 months, with dose titration over 3 weeks (up to 30 mg once daily), according to symptoms and tolerability. Participants, their general practitioners, investigators, and the analysis team were all masked to allocation throughout the trial. The primary outcome was the IBS-SSS score at 6 months. Effectiveness analyses were according to intention-to-treat; safety analyses were on all participants who took at least one dose of the trial medication. This trial is registered with the ISRCTN Registry (ISRCTN48075063) and is closed to new participants. FINDINGS: Between Oct 18, 2019, and April 11, 2022, 463 participants (mean age 48·5 years [SD 16·1], 315 [68%] female to 148 [32%] male) were randomly allocated to receive low-dose amitriptyline (232) or placebo (231). Intention-to-treat analysis of the primary outcome showed a significant difference in favour of low-dose amitriptyline in IBS-SSS score between groups at 6 months (-27·0, 95% CI -46·9 to -7·10; p=0·0079). 46 (20%) participants discontinued low-dose amitriptyline (30 [13%] due to adverse events), and 59 (26%) discontinued placebo (20 [9%] due to adverse events) before 6 months. There were five serious adverse reactions (two in the amitriptyline group and three in the placebo group), and five serious adverse events unrelated to trial medication. INTERPRETATION: To our knowledge, this is the largest trial of a tricyclic antidepressant in IBS ever conducted. Titrated low-dose amitriptyline was superior to placebo as a second-line treatment for IBS in primary care across multiple outcomes, and was safe and well tolerated. General practitioners should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration, such as the self-titration document developed for this trial. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme (grant reference 16/162/01).

The detection and management of attempted fraud during an online randomised trial.

BACKGROUND: Online studies offer an efficient method of recruiting participants and collecting data. Whilst delivering an online randomised trial, we detected unusual recruitment activity. We describe our approach to detecting and managing suspected fraud and share lessons for researchers. METHODS: Our trial investigated the single and combined effects of different ways of presenting clinical audit and feedback. Clinicians and managers who received feedback from one of five United Kingdom national clinical audit programmes were emailed invitations that contained a link to the trial website. After providing consent and selecting their relevant audit, participants were randomised automatically to different feedback versions. Immediately after viewing their assigned feedback, participants completed a questionnaire and could request a financial voucher by entering an email address. Email addresses were not linked to trial data to preserve participant anonymity. We actively monitored participant numbers, questionnaire completions, and voucher claims. RESULTS: Following a rapid increase in trial participation, we identified 268 new voucher claims from three email addresses that we had reason to believe were linked. Further scrutiny revealed duplicate trial completions and voucher requests from 24 email addresses. We immediately suspended the trial, improved security measures, and went on to successfully complete the study. We found a peak in questionnaires completed in less than 20 seconds during a likely contamination period. Given that study and personal data were not linked, we could not directly identify the trial data from the 268 duplicate entries within the 603 randomisations occurring during the same period. We therefore excluded all 603 randomisations from the primary analysis, which was consequently based on 638 randomisations. A sensitivity analysis, including all 961 randomisations over the entire study except for questionnaire completions of less than 20 seconds, found only minor differences from the primary analysis. CONCLUSION: Online studies offering incentives for participation are at risk of attempted fraud. Systematic monitoring and analysis can help detect such activity. Measures to protect study integrity include linking participant identifiers to study data, balancing study security and ease of participation, and safeguarding the allocation of participant incentives. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN41584028. Registration date is August 17, 2017.

Amitriptyline at low-dose and titrated for irritable bowel syndrome as second-line treatment (The ATLANTIS trial): protocol for a randomised double-blind placebo-controlled trial in primary care.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional bowel disorder that has a considerable impact on patient quality of life and substantial societal and health care resource costs. Current treatments are often ineffective. Tricyclic antidepressants have shown promise in secondary care populations but their effectiveness in a primary care setting remains unclear. METHODS: ATLANTIS is a randomised, multi-centre, parallel-group, two-arm, double-blind, placebo-controlled trial of low-dose amitriptyline as a second-line treatment for IBS in primary care. Participants will be invited by letter, or recruited opportunistically, from general practices in three regions of England (West Yorkshire, Wessex, and West of England) and screened for eligibility. A total of 518 adult patients with IBS, who are symptomatic despite first-line therapies, will be randomised 1:1 to amitriptyline or identical placebo for 6 months. Treatment will commence at a dose of 10 mg (or one placebo tablet) daily at night, with dose titration up to a maximum of 30 mg at night, depending on side effects and response to treatment. Participant-reported assessments will be conducted at baseline and 3, 6, and 12 months post-randomisation. The primary objective is to determine the effectiveness of amitriptyline, compared with placebo, in improving participant-reported global symptoms of IBS at 6 months (using the IBS Severity Scoring System). Secondary outcomes include relief of IBS symptoms, effect on IBS-associated somatic symptoms (Patient Health Questionnaire-12), anxiety and depression (Hospital Anxiety and Depression Scale), ability to work and participate in other activities (Work and Social Adjustment Scale), acceptability and tolerability of treatment, self-reported health care use, health-related quality of life (EQ-5D-3L), and cost-effectiveness. A nested, qualitative study will explore patient and general practitioner experiences of treatments and trial participation, including acceptability, adherence, unanticipated effects, and implications for wider use of amitriptyline for IBS in primary care. DISCUSSION: Determining the clinical and cost-effectiveness of low-dose amitriptyline as a second-line treatment for IBS in primary care will provide robust evidence to inform management decisions. TRIAL REGISTRATION: ISRCTN ISRCTN48075063 . Registered on 7th June 2019.

A randomised fractional factorial screening experiment to predict effective features of audit and feedback.

BACKGROUND: Audit and feedback aims to improve patient care by comparing healthcare performance against explicit standards. It is used to monitor and improve patient care, including through National Clinical Audit (NCA) programmes in the UK. Variability in effectiveness of audit and feedback is attributed to intervention design; separate randomised trials to address multiple questions about how to optimise effectiveness would be inefficient. We evaluated different feedback modifications to identify leading candidates for further "real-world" evaluation. METHODS: Using an online fractional factorial screening experiment, we randomised recipients of feedback from five UK NCAs to different combinations of six feedback modifications applied within an audit report excerpt: use effective comparators, provide multimodal feedback, recommend specific actions, provide optional detail, incorporate the patient voice, and minimise cognitive load. Outcomes, assessed immediately after exposure to the online modifications, included intention to enact audit standards (primary outcome, ranked on a scale of -3 to +3, tailored to the NCA), comprehension, user experience, and engagement. RESULTS: We randomised 1241 participants (clinicians, managers, and audit staff) between April and October 2019. Inappropriate repeated participant completion occurred; we conservatively excluded participant entries during the relevant period, leaving a primary analysis population of 638 (51.4%) participants. None of the six feedback modifications had an independent effect on intention across the five NCAs. We observed both synergistic and antagonistic effects across outcomes when modifications were combined; the specific NCA and whether recipients had a clinical role had dominant influences on outcome, and there was an antagonistic interaction between multimodal feedback and optional detail. Among clinical participants, predicted intention ranged from 1.22 (95% confidence interval 0.72, 1.72) for the least effective combination in which multimodal feedback, optional detail, and reduced cognitive load were applied within the audit report, up to 2.40 (95% CI 1.88, 2.93) for the most effective combination including multimodal feedback, specific actions, patient voice, and reduced cognitive load. CONCLUSION: Potentially important synergistic and antagonistic effects were identified across combinations of feedback modifications, audit programmes, and recipients, suggesting that feedback designers must explicitly consider how different features of feedback may interact to achieve (or undermine) the desired effects. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN41584028.

Cancer patients' needs assessment in primary care: study protocol for a cluster randomised controlled trial (cRCT), economic evaluation and normalisation process theory evaluation of the needs assessment tool cancer (CANAssess).

INTRODUCTION: Unmet needs in patients with cancer and their carers are common but poorly identified and addressed. The Needs Assessment Tool-Cancer (NAT-C) is a structured consultation guide to identify and triage patient and carer unmet needs. The NAT-C is validated, but its effectiveness in reducing unmet patient and carer needs in primary care is unknown. METHODS AND ANALYSIS: Cluster randomised controlled trial with internal pilot and embedded process evaluation to test the clinical and cost effectiveness of the NAT-C in primary care for people with active cancer in reducing unmet patient and carer need, compared with usual care. We will recruit 1080 patients with active cancer (and carers if relevant) from 54 general practices in England.Participating practices will be randomised 1:1 to either deliver an NAT-guided clinical consultation plus usual care or to usual care alone. Consenting participants with active cancer and their carers (if nominated) will be asked to complete study questionnaires at baseline, 1 and 3 months for all, 6 months except for those recruited outside of the last 3 months of recruitment, and attend an NAT-C appointment if allocated to an intervention practice. An internal pilot will assess: site and participant recruitment, intervention uptake and follow-up rates. The primary outcome, the proportion of patients with an unmet need on the Supportive Care Needs Survey Short Form 34 at 3 months postregistration, will be analysed using a multilevel logistic regression. Mixed-methods process evaluation informed by Normalisation Process Theory will use quantitative survey and interview data from clinicians and key stakeholders in cancer care to develop an implementation strategy for nationwide rollout of the NAT-C if the intervention is cost-effective. ETHICS AND DISSEMINATION: Ethical approval from London-Surrey REC (20/LO/0312). Results will be peer-reviewed, published and made available to research participants. TRIAL REGISTRATION NUMBER: ISRCTN15497400.

Reducing Self-harm in Adolescents. An individual participant data meta-analysis (RISA-IPD): systematic review protocol.

INTRODUCTION: Up to 10% of adolescents report self-harm in the previous year. Non-fatal repetition is common (18% in 1 year), death from any cause shows a fourfold and suicide a 10-fold excess. Despite the scale of the problem, there is insufficient evidence for effective interventions for self-harm. Those who self-harm do so for a variety of different reasons. Different treatments may be more effective for subgroups of adolescents; however, little is known about which subgroups are appropriate for further study. This protocol outlines a systematic review and individual participant data meta-analysis (IPD-MA) to identify subgroups of adolescents for which therapeutic interventions for self-harm show some evidence of benefit. METHODS AND ANALYSIS: A systematic literature search was conducted in August 2019 (including Cochrane Library, Embase, trial registers and other databases). An update search is planned. Study selection will identify randomised controlled trials examining interventions to reduce self-harm in adolescents who have self-harmed and presented to services. Identified research teams will be invited to contribute data and form a collaborative group. Two-stage IPD-MA will be used to evaluate effectiveness of different therapeutic interventions compared with any active or non-active control on repetition of self-harm, general psychopathology, depression, suicidal ideation, quality of life and death. Subgroup analyses will identify adolescent subgroups in whom different therapeutic interventions may be more effective. Meta-regression will explore moderating study and intervention effects. Sensitivity analyses will incorporate aggregate data from studies lacking IPD and test the robustness of results to methods for handling missing data, within-study clustering, non-adherence and study quality. ETHICS AND DISSEMINATION: Ethical approval is provided by the University of Leeds, Faculty of Medicine and Health Ethics Committee (18-098). Outcomes will inform research recommendations and will be disseminated internationally through the collaborative group, a service user advisory group, open-access peer-reviewed publication and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42019152119.

A cluster randomised trial of a Needs Assessment Tool for adult Cancer patients and their carers (NAT-C) in primary care: A feasibility study.

BACKGROUND: People with cancer often have unidentified symptoms and social care needs. The Needs Assessment Tool-Cancer (NAT-C) is a validated, structured method of assessing patient/carer concerns and prompting action, to address unmet need. AIMS: Assess feasibility and acceptability of a definitive two-armed cluster randomised trial of NAT-C in primary care by evaluating: recruitment of GP practices, patients and carers; most effective approach of ensuring NAT-C appointments, acceptability of study measures and follow-up. METHODS: Non-blinded, feasibility study in four General Practices, with cluster randomisation to method of NAT-C appointment delivery, and process evaluation. Adults with active cancer were invited to participate with or without carer. Practices cluster randomised (1:1) to Arm I: promotion and use of NAT-C with a NAT-C trained clinician or Arm II: clinician of choice irrespective of training status. Participants completed study questionnaires at: baseline, 1, 3 and 6 months. Patients booked a 20 minute needs-assessment appointment post-baseline. Patients, carers and GP practice staff views regarding the study sought through interviews/focus groups. Quantitative data were analysed descriptively. Qualitative data were analysed thematically, informed by Normalisation Process Theory. Progression to a definitive trial was assessed against feasibility outcomes, relating to: recruitment rate, uptake and delivery of the NAT-C, data collection and quality. RESULTS: Five GP practices approached, four recruited and trained to use the NAT-C. Forty-seven participants and 17 carers recruited. At baseline, 34/47 (72%) participants reported at least one moderate-severe unmet need, confirming study rationale. 32/47 (68%) participants received a NAT-C-guided consultation, 19 of which on Arm I. Study attrition at one month (n = 44 (94%), n = 16 (94%)), three months (n = 38 (81%), n = 14 (82%)) and six months (n = 32 (68%), n = 10 (59%)). Fifteen patient interviews conducted across the whole study and one focus group at each GP practice. Participants supported a definitive study and found measures acceptable. CONCLUSION: The feasibility trial indicated that recruitment rate, intervention uptake and data collection were appropriate, with refinements, for a definitive multi-centre cluster randomised controlled trial. Feasibility outcomes informed the design of a 2-armed cluster randomised controlled trial to test the effectiveness and cost-effectiveness of the NAT-C compared with usual care.

Problem-solving therapy rather than treatment as usual for adults after self-harm: a pragmatic, feasibility, randomised controlled trial (the MIDSHIPS trial).

BACKGROUND: Non-fatal self-harm is one of the commonest reasons for adults' emergency hospital attendance. Although strongly associated with fatal and non-fatal repetition, there is weak evidence about effective interventions-and no clear NICE guidance or clinical consensus concerning aftercare. We examined the practicability of a definitive trial to evaluate problem-solving therapy (PST) to reduce repetition of self-harm; MIDSHIPS is a single-centre, parallel-group, individually randomised controlled feasibility trial comparing treatment-as-usual (TAU) alone to TAU plus up to six sessions of brief problem-solving therapy (PST) with adults who had recently attended hospital because of self-harm. Objectives were to adapt the intervention for a UK setting, train therapists, recruit and randomise patients, deliver PST under supervision, and establish comparative outcomes, assessed blindly. METHODS: We adapted the problem-solving intervention from an earlier trial and trained a mental-health nurse to deliver it. Adult patients attending the general hospital for self-harm were recruited while undergoing psychosocial assessment by the mental health team, and 62 were randomly allocated (32 TAU, 30 PST). The primary outcome assessed repeat hospital attendance due to further self-harm 6 months post-randomisation. Secondary outcomes included participant-reported outcomes and service use at 3 and 6 months post-randomisation. RESULTS: The recruitment period had to be extended and 710 patients screened in order to establish a trial sample of the planned size (N = 62). A quarter of participants allocated to PST did not undertake the therapy offered; those who received PST attended a median of three sessions. Secondary outcomes were established for 49 (79%) participants at 6 months; all participants' hospital records were retrieved. Repetition of self-harm leading to hospital presentation occurred in 19 of the 62 participants (30.6%, 95% CI 19.2%, 42.1%) within 6 months of randomisation. Promising differential rates of self-harm were observed with an event rate of 23.3% (95% CI 8.2%, 38.5%) in the PST arm; and 37.5% (95% CI 20.7%, 54.3%) in TAU. Economic findings were also encouraging, with a small QALY gain (0.0203) in the PST arm together with less reported use of the NHS in the PST arm (average £2120) than with TAU-only (£2878). CONCLUSIONS: The feasibility trial achieved its objectives despite considerable difficulties with recruitment-adapting the PST, training a therapist, recruiting patients who had recently self-harmed, delivering the therapy, and establishing primary and secondary outcomes. These data provide a robust platform for a definitive multicentre randomised controlled trial of brief problem-solving therapy after hospital attendance due to self-harm. TRIAL REGISTRATION: Identification number and URL: ISRCTN54036115 http://www.isrctn.com/search?q=midships. Registered: 13 January 2012.

Problem-solving training: assessing the feasibility and acceptability of delivering and evaluating a problem-solving training model for front-line prison staff and prisoners who self-harm.

OBJECTIVES: Problem-solving skills training is adaptable, inexpensive and simple to deliver. However, its application with prisoners who self-harm is unknown. The study assessed the feasibility and acceptability of a problem-solving training (PST) intervention for prison staff and prisoners who self-harm, to inform the design of a large-scale study. DESIGN AND SETTING: A mixed-methods design used routinely collected data, individual outcome measures, an economic protocol and qualitative interviews at four prisons in Yorkshire and Humber, UK. PARTICIPANTS: (i) Front-line prison staff, (ii) male and female prisoners with an episode of self-harm in the previous 2 weeks. INTERVENTION: The intervention comprised a 1 hour staff training session and a 30 min prisoner session using adapted workbooks and case studies. OUTCOMES: We assessed the study processes-coverage of training; recruitment and retention rates and adequacy of intervention delivery-and available data (completeness of outcome data, integrity of routinely collected data and access to the National Health Service (NHS) resource information). Prisoner outcomes assessed incidence of self-harm, quality of life and depression at baseline and at follow-up. Qualitative findings are presented elsewhere. RESULTS: Recruitment was higher than anticipated for staff n=280, but lower for prisoners, n=48. Retention was good with 43/48 (89%) prisoners completing the intervention, at follow-up we collected individual outcome data for 34/48 (71%) of prisoners. Access to routinely collected data was inconsistent. Prisoners were frequent users of NHS healthcare. The additional cost of training and intervention delivery was deemed minimal in comparison to 'treatment as usual'. Outcome measures of self-harm, quality of life and depression were found to be acceptable. CONCLUSIONS: The intervention proved feasible to adapt. Staff training was delivered but on the whole it was not deemed feasible for staff to deliver the intervention. A large-scale study is warranted, but modifications to the implementation of the intervention are required.

Developing and feasibility testing of data collection methods for an economic evaluation of a supported selfmanagement programme for adults with a learning disability and type 2 diabetes.

BACKGROUND: The challenges of conducting research with hard to reach vulnerable groups are particularly pertinent for people with learning disabilities. Data collection methods for previous cost and cost-effectiveness analyses of health and social care interventions targeting people with learning disabilities have relied on health care/health insurance records or data collection forms completed by the service provider rather than by people with learning disabilities themselves. This paper reports on the development and testing of data collection methods for an economic evaluation within a randomised controlled trial (RCT) for a supported self-management programme for people with mild/moderate learning disabilities and type 2 diabetes. METHODS: A case finding study was conducted to identify types of health and social care use and data collection methods employed in previous studies with this population. Based on this evidence, resource use questionnaires for completion by GP staff and interviewer-administered participant questionnaires (covering a wider cost perspective and health-related quality of life) were tested within a feasibility RCT. Interviewer-administered questionnaires included the EQ-5D-3L (the NICE recommended measure for use in economic evaluation). Participants were adults > 18 years with a mild or moderate learning disability and type 2 diabetes, with mental capacity to give consent to research participation. RESULTS: Data collection for questionnaires completed by GP staff requesting data for the last 12 months proved time intensive and difficult. Whilst 82.3% (121/147) of questionnaires were returned, up to 17% of service use items were recorded as unknown. Subsequently, a shorter recall period (4 months) led to a higher return rate but with a higher rate of missing data. Missing data for interviewer-administered participant questionnaires was > 8% but the interviewers reported difficulty with participant recall. Almost 60% (48/80) of participants had difficulty completing the EQ-5D-3L. CONCLUSIONS: Further investigation as to how service use can be recorded is recommended. Concerns about the reliability of identifying service use data directly from participants with a learning disability due to challenges in completion, specifically around recall, remain. The degree of difficulty to complete EQ-5D-3L indicates concerns regarding the appropriateness of using this measure in its current form in research with this population. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41897033 (registered 21 January 2013).

Managing with Learning Disability and Diabetes: OK-Diabetes - a case-finding study and feasibility randomised controlled trial.

BACKGROUND: Obesity and type 2 diabetes are common in adults with a learning disability. It is not known if the principles of self-management can be applied in this population. OBJECTIVES: To develop and evaluate a case-finding method and undertake an observational study of adults with a learning disability and type 2 diabetes, to develop a standardised supported self-management (SSM) intervention and measure of adherence and to undertake a feasibility randomised controlled trial (RCT) of SSM versus treatment as usual (TAU). DESIGN: Observational study and an individually randomised feasibility RCT. SETTING: Three cities in West Yorkshire, UK. PARTICIPANTS: In the observational study: adults aged > 18 years with a mild or moderate learning disability, who have type 2 diabetes that is not being treated with insulin and who are living in the community. Participants had mental capacity to consent to research and to the intervention. In the RCT participants had glycated haemoglobin (HbA1c) levels of > 6.5% (48 mmol/mol), a body mass index (BMI) of > 25 kg/m2 or self-reported physical activity below national guideline levels. INTERVENTIONS: Standardised SSM. TAU supported by an easy-read booklet. MAIN OUTCOME MEASURES: (1) The number of eligible participants identified and sources of referral; (2) current living and support arrangements; (3) current health state, including level of HbA1c, BMI and waist circumference, blood pressure and lipids; (4) mood, preferences for change; (5) recruitment and retention in RCT; (6) implementation and adherence to the intervention; (7) completeness of data collection and values for candidate primary outcomes; and (8) qualitative data on participant experience of the research process and intervention. RESULTS: In the observational study we identified 147 eligible consenting participants. The mean age was 54.4 years. In total, 130 out of 147 (88%) named a key supporter, with 113 supporters (77%) being involved in diabetes management. The mean HbA1c level was 54.5 mmol/mol [standard deviation (SD) 14.8 mmol/mol; 7.1%, SD 1.4%]. The BMI of 65% of participants was > 30 kg/m2 and of 21% was > 40 kg/m2. Many participants reported low mood, dissatisfaction with lifestyle and diabetes management and an interest in change. Non-response rates were high (45/147, 31%) for medical data requested from the primary care team. In the RCT, 82 participants were randomised. The mean baseline HbA1c level was 56 mmol/mol (SD 16.5 mmol/mol; 7.3%, SD 1.5%) and the mean BMI was 34 kg/m2 (SD 7.6 kg/m2). All SSM sessions were completed by 35 out of 41 participants. The adherence measure was obtained in 37 out of 41 participants. The follow-up HbA1c level and BMI was obtained for 75 out of 82 (91%) and 77 out of 82 (94%) participants, respectively. Most participants reported a positive experience of the intervention. A low response rate and difficulty understanding the EuroQol-5 Dimensions were challenges in obtaining data for an economic analysis. LIMITATIONS: We recruited from only 60% of eligible general practices, and 90% of participants were on a general practice learning disability register, which meant that we did not recruit many participants from the wider population with milder learning disability. CONCLUSIONS: A definitive RCT is feasible and would need to recruit 194 participants per arm. The main barrier is the resource-intensive nature of recruitment. Future research is needed into the effectiveness of obesity treatments in this population, particularly estimating the longer-term outcomes that are important for health benefit. Research is also needed into improving ways of assessing quality of life in adults with a learning disability. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41897033. 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. 22, No. 26. See the NIHR Journals Library website for further project information.

Improving the management of pain from advanced cancer in the community: study protocol for a pragmatic multicentre randomised controlled trial.

INTRODUCTION: For patients with advanced cancer, research shows that pain is frequent, burdensome and undertreated. Evidence-based approaches to support cancer pain management have been developed but have not been implemented within the context of the UK National Health Service. This protocol is for a pragmatic multicentre randomised controlled trial (RCT) to assess feasibility, acceptability, effectiveness and cost-effectiveness for a multicomponent intervention for pain management in patients with advanced cancer. METHODS AND ANALYSIS: This trial will assess the feasibility of implementation and uptake of evidence-based interventions, developed and piloted as part of the Improving the Management of Pain from Advanced Cancer in the Community Programme grant, into routine clinical practice and determine whether there are potential differences with respect to patient-rated pain, patient pain knowledge and experience, healthcare use, quality of life and cost-effectiveness. 160 patients will receive either the intervention (usual care plus supported self-management) delivered within the oncology clinic and palliative care services by locally assigned community palliative care nurses, consisting of a self-management educational intervention and eHealth intervention for routine pain assessment and monitoring; or usual care. The primary outcomes are to assess implementation and uptake of the interventions, and differences in terms of pain severity. Secondary outcomes include pain interference, participant pain knowledge and experience, and cost-effectiveness. Outcome assessment will be blinded and patient-reported outcome measures collected via post at 6 and 12 weeks following randomisation. ETHICS AND DISSEMINATION: This RCT has the potential to significantly influence National Health Service delivery to community-based patients with pain from advanced cancer. We aim to provide definitive evidence of whether two simple interventions delivered by community palliative care nurse in palliative care that support-self-management are clinically effective and cost-effective additions to standard community palliative care. TRIAL REGISTRATION NUMBER: ISRCTN18281271; Pre-results.

Routine hospital data - is it good enough for trials? An example using England's Hospital Episode Statistics in the SHIFT trial of Family Therapy vs. Treatment as Usual in adolescents following self-harm.

BACKGROUND: Use of routine data sources within clinical research is increasing and is endorsed by the National Institute for Health Research to increase trial efficiencies; however there is limited evidence for its use in clinical trials, especially in relation to self-harm. One source of routine data, Hospital Episode Statistics, is collated and distributed by NHS Digital and contains details of admissions, outpatient, and Accident and Emergency attendances provided periodically by English National Health Service hospitals. We explored the reliability and accuracy of Hospital Episode Statistics, compared to data collected directly from hospital records, to assess whether it would provide complete, accurate, and reliable means of acquiring hospital attendances for self-harm - the primary outcome for the SHIFT (Self-Harm Intervention: Family Therapy) trial evaluating Family Therapy for adolescents following self-harm. METHODS: Participant identifiers were linked to Hospital Episode Statistics Accident and Emergency, and Admissions data, and episodes combined to describe participants' complete hospital attendance. Attendance data were initially compared to data previously gathered by trial researchers from pre-identified hospitals. Final comparison was conducted of subsequent attendances collected through Hospital Episode Statistics and researcher follow-up. Consideration was given to linkage rates; number and proportion of attendances retrieved; reliability of Accident and Emergency, and Admissions data; percentage of self-harm episodes recorded and coded appropriately; and percentage of required data items retrieved. RESULTS: Participants were first linked to Hospital Episode Statistics with an acceptable match rate of 95%, identifying a total of 341 complete hospital attendances, compared to 139 reported by the researchers at the time. More than double the proportion of Hospital Episode Statistics Accident and Emergency episodes could not be classified in relation to self-harm (75%) compared to 34.9% of admitted episodes, and of overall attendances, 18% were classified as self-harm related and 20% not related, while ambiguity or insufficient information meant 62% were unclassified. Of 39 self-harm-related attendances reported by the researchers, Hospital Episode Statistics identified 24 (62%) as self-harm related while 15 (38%) were unclassified. Based on final data received, 1490 complete hospital attendances were identified and comparison to researcher follow-up found Hospital Episode Statistics underestimated the number of self-harm attendances by 37.2% (95% confidence interval 32.6%-41.9%). CONCLUSION: Advantages of routine data collection via NHS Digital included the acquisition of more comprehensive and timely trial outcome data, identifying more than double the number of hospital attendances than researchers. Disadvantages included ambiguity in the classification of self-harm relatedness. Our resulting primary outcome data collection strategy used routine data to identify hospital attendances supplemented by targeted researcher data collection for attendances requiring further self-harm classification.

CODIFI (Concordance in Diabetic Foot Ulcer Infection): a cross-sectional study of wound swab versus tissue sampling in infected diabetic foot ulcers in England.

OBJECTIVE: To determine the extent of agreement and patterns of disagreement between wound swab and tissue samples in patients with an infected diabetic foot ulcer (DFU). DESIGN: Multicentre, prospective, cross-sectional study. SETTING: Primary and secondary care foot ulcer/diabetic outpatient clinics and hospital wards across England. PARTICIPANTS: Inclusion criteria: consenting patients aged ≥18 years; diabetes mellitus; suspected infected DFU. EXCLUSION CRITERIA: clinically inappropriate to take either sample. INTERVENTIONS: Wound swab obtained using Levine's technique; tissue samples collected using a sterile dermal curette or scalpel. OUTCOME MEASURES: Coprimary: reported presence, and number, of pathogens per sample; prevalence of resistance to antimicrobials among likely pathogens. Secondary: recommended change in antibiotic therapy based on blinded clinical review; adverse events; sampling costs. RESULTS: 400 consenting patients (79% male) from 25 centres.Most prevalent reported pathogens were Staphylococcus aureus (43.8%), Streptococcus (16.7%) and other aerobic Gram-positive cocci (70.6%). At least one potential pathogen was reported from 70.1% of wound swab and 86.1% of tissue samples. Pathogen results differed between sampling methods in 58% of patients, with more pathogens and fewer contaminants reported from tissue specimens.The majority of pathogens were reported significantly more frequently in tissue than wound swab samples (P<0.01), with equal disagreement for S. aureus and Pseudomonas aeruginosa. Blinded clinicians more often recommended a change in antibiotic regimen based on tissue compared with wound swab results (increase of 8.9%, 95% CI 2.65% to 15.3%). Ulcer pain and bleeding occurred more often after tissue collection versus wound swabs (pain: 9.3%, 1.3%; bleeding: 6.8%, 1.5%, respectively). CONCLUSION: Reports of tissue samples more frequently identified pathogens, and less frequently identified non-pathogens compared with wound swab samples. Blinded clinicians more often recommended changes in antibiotic therapy based on tissue compared with wound swab specimens. Further research is needed to determine the effect of the additional information provided by tissue samples. TRIAL REGISTRATION NUMBER: ISRCTN52608451.

Effectiveness of systemic family therapy versus treatment as usual for young people after self-harm: a pragmatic, phase 3, multicentre, randomised controlled trial.

BACKGROUND: Self-harm in adolescents is common and repetition occurs in a high proportion of these cases. Scarce evidence exists for effectiveness of interventions to reduce self-harm. METHODS: This pragmatic, multicentre, randomised, controlled trial of family therapy versus treatment as usual was done at 40 UK Child and Adolescent Mental Health Services (CAMHS) centres. We recruited young people aged 11-17 years who had self-harmed at least twice and presented to CAMHS after self-harm. Participants were randomly assigned (1:1) to receive manualised family therapy delivered by trained and supervised family therapists or treatment as usual by local CAMHS. Participants and therapists were aware of treatment allocation; researchers were masked. The primary outcome was hospital attendance for repetition of self-harm in the 18 months after group assignment. Primary and safety analyses were done in the intention-to-treat population. The trial is registered at the ISRCTN registry, number ISRCTN59793150. FINDINGS: Between Nov 23, 2009, and Dec 31, 2013, 3554 young people were screened and 832 eligible young people consented to participation and were randomly assigned to receive family therapy (n=415) or treatment as usual (n=417). Primary outcome data were available for 795 (96%) participants. Numbers of hospital attendances for repeat self-harm events were not significantly different between the groups (118 [28%] in the family therapy group vs 103 [25%] in the treatment as usual group; hazard ratio 1·14 [95% CI 0·87-1·49] p=0·33). Similar numbers of adverse events occurred in both groups (787 in the family therapy group vs 847 in the treatment as usual group). INTERPRETATION: For adolescents referred to CAMHS after self-harm, having self-harmed at least once before, our family therapy intervention conferred no benefits over treatment as usual in reducing subsequent hospital attendance for self-harm. Clinicians are therefore still unable to recommend a clear, evidence-based intervention to reduce repeated self-harm in adolescents. FUNDING: National Institute for Health Research Health Technology Assessment programme.

Self-management toolkit and delivery strategy for end-of-life pain: the mixed-methods feasibility study.

BACKGROUND: Pain affects most people approaching the end of life and can be severe for some. Opioid analgesia is effective, but evidence is needed about how best to support patients in managing these medicines. OBJECTIVES: To develop a self-management support toolkit (SMST) and delivery strategy and to test the feasibility of evaluating this intervention in a future definitive trial. DESIGN: Phase I - evidence synthesis and qualitative interviews with patients and carers. Phase II - qualitative semistructured focus groups and interviews with patients, carers and specialist palliative care health professionals. Phase III - multicentre mixed-methods single-arm pre-post observational feasibility study. PARTICIPANTS: Phase I - six patients and carers. Phase II - 15 patients, four carers and 19 professionals. Phase III - 19 patients recruited to intervention that experienced pain, living at home and were treated with strong opioid analgesia. Process evaluation interviews with 13 patients, seven carers and 11 study nurses. INTERVENTION: Self-Management of Analgesia and Related Treatments at the end of life (SMART) intervention comprising a SMST and a four-step educational delivery approach by clinical nurse specialists in palliative care over 6 weeks. MAIN OUTCOME MEASURES: Recruitment rate, treatment fidelity, treatment acceptability, patient-reported outcomes (such as scores on the Brief Pain Inventory, Self-Efficacy for Managing Chronic Disease Scale, Edmonton Symptom Assessment Scale, EuroQol-5 Dimensions, Satisfaction with Information about Medicines Scale, and feasibility of collecting data on health-care resource use for economic evaluation). RESULTS: Phase I - key themes on supported self-management were identified from evidence synthesis and qualitative interviews. Phase II - the SMST was developed and refined. The delivery approach was nested within a nurse-patient consultation. Phase III - intervention was delivered to 17 (89%) patients, follow-up data at 6 weeks were available on 15 patients. Overall, the intervention was viewed as acceptable and valued. Descriptive analysis of patient-reported outcomes suggested that interference from pain and self-efficacy were likely to be candidates for primary outcomes in a future trial. No adverse events related to the intervention were reported. The health economic analysis suggested that SMART could be cost-effective. We identified key limitations and considerations for a future trial: improve recruitment through widening eligibility criteria, refine the SMST resources content, enhance fidelity of intervention delivery, secure research nurse support at recruiting sites, refine trial procedures (including withdrawal process and data collection frequency), and consider a cluster randomised design with nurse as cluster unit. LIMITATIONS: (1) The recruitment rate was lower than anticipated. (2) The content of the intervention was focused on strong opioids only. (3) The fidelity of intervention delivery was limited by the need for ongoing training and support. (4) Recruitment sites where clinical research nurse support was not secured had lower recruitment rates. (5) The process for recording withdrawal was not sufficiently detailed. (6) The number of follow-up visits was considered burdensome for some participants. (7) The feasibility trial did not have a control arm or assess randomisation processes. CONCLUSIONS: A future randomised controlled trial is feasible and acceptable. STUDY AND TRIAL REGISTRATION: This study is registered as PROSPERO CRD42014013572; Current Controlled Trials ISRCTN35327119; and National Institute for Health Research (NIHR) Portfolio registration 162114. FUNDING: The NIHR Health Technology Assessment programme.

Concordance in diabetic foot ulceration: a cross-sectional study of agreement between wound swabbing and tissue sampling in infected ulcers.

BACKGROUND: There is inadequate evidence to advise clinicians on the relative merits of swabbing versus tissue sampling of infected diabetic foot ulcers (DFUs). OBJECTIVES: To determine (1) concordance between culture results from wound swabs and tissue samples from the same ulcer; (2) whether or not differences in bacterial profiles from swabs and tissue samples are clinically relevant; (3) concordance between results from conventional culture versus polymerase chain reaction (PCR); and (4) prognosis for patients with an infected DFU at 12 months' follow-up. METHODS: This was a cross-sectional, multicentre study involving patients with diabetes and a foot ulcer that was deemed to be infected by their clinician. Microbiology specimens for culture were taken contemporaneously by swab and by tissue sampling from the same wound. In a substudy, specimens were also processed by PCR. A virtual 'blinded' clinical review compared the appropriateness of patients' initial antibiotic regimens based on the results of swab and tissue specimens. Patients' case notes were reviewed at 12 months to assess prognosis. RESULTS: The main study recruited 400 patients, with 247 patients in the clinical review. There were 12 patients in the PCR study and 299 patients in the prognosis study. Patients' median age was 63 years (range 26-99 years), their diabetes duration was 15 years (range 2 weeks-57 years), and their index ulcer duration was 1.8 months (range 3 days-12 years). Half of the ulcers were neuropathic and the remainder were ischaemic/neuroischaemic. Tissue results reported more than one pathogen in significantly more specimens than swabs {86.1% vs. 70.1% of patients, 15.9% difference [95% confidence interval (CI) 11.8% to 20.1%], McNemar's p-value < 0.0001}. The two sampling techniques reported a difference in the identity of pathogens for 58% of patients. The number of pathogens differed in 50.4% of patients. In the clinical review study, clinicians agreed on the need for a change in therapy for 73.3% of patients (considering swab and tissue results separately), but significantly more tissue than swab samples required a change in therapy. Compared with traditional culture, the PCR technique reported additional pathogens for both swab and tissue samples in six (50%) patients and reported the same pathogens in four (33.3%) patients and different pathogens in two (16.7%) patients. The estimated healing rate was 44.5% (95% CI 38.9% to 50.1%). At 12 months post sampling, 45 (15.1%) patients had died, 52 (17.4%) patients had a lower-extremity ipsilateral amputation and 18 (6.0%) patients had revascularisation surgery. LIMITATIONS: We did not investigate the potential impact of microbiological information on care. We cannot determine if the improved information yield from tissue sampling is attributable to sample collection, sample handling, processing or reporting. CONCLUSIONS: Tissue sampling reported both more pathogens and more organisms overall than swabbing. Both techniques missed some organisms, with tissue sampling missing fewer than swabbing. Results from tissue sampling more frequently led to a (virtual) recommended change in therapy. Long-term prognosis for patients with an infected foot ulcer was poor. FUTURE WORK: Research is needed to determine the effect of sampling/processing techniques on clinical outcomes and antibiotic stewardship. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Self-Harm Intervention: Family Therapy (SHIFT), a study protocol for a randomised controlled trial of family therapy versus treatment as usual for young people seen after a second or subsequent episode of self-harm.

BACKGROUND: Self-harm is common in the community with a lifetime prevalence of 13 %. It is associated with an elevated risk of overall mortality and suicide. People who harm themselves are high users of public services. Estimates of the 1-year risk of repetition vary between 5 and 15 % per year. Currently, limited evidence exists on the effectiveness of clinical interventions for young people who engage in self-harm. Recent reviews have failed to demonstrate any effect on reducing repetition of self-harm among adolescents receiving a range of treatment approaches. Family factors are particularly important risk factors associated with fatal and non-fatal self-harm among children and adolescents. Family therapy focuses on the relationships, roles and communication patterns between family members, but there have been relatively few studies of specifically family-focused interventions with this population. The Self-Harm Intervention: Family Therapy (SHIFT) Trial was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (grant no. 07/33/01) following a commissioned call for this research. METHODS/DESIGN: SHIFT is a pragmatic, phase III, multicentre, individually randomised, controlled trial comparing Family Therapy (FT) with treatment as usual (TAU) for adolescents aged 11 to 17 who have engaged in at least two episodes of self-harm. Both therapeutic interventions were delivered within the National Health Service (NHS) Child and Adolescent Mental Health Services (CAMHS) in England. Participants and therapists were, of necessity, aware of treatment allocation, but the researchers were blind to the allocations to allow unbiased collection of follow-up data. Primary outcome data (repetition of self-harm leading to hospital attendance 18 months post-randomisation) were collected from the Health and Social Care Information Centre (HSCIC), augmented by directed searches of medical records at Acute Trusts. Secondary outcome data (including suicidal intent, depression, hopelessness and health economics) were collected at 12 and 18 months post-randomisation via researcher-participant interviews and by post at 3 and 6 months. DISCUSSION: SHIFT will provide a well-powered evaluation of the clinical and cost effectiveness of Family Therapy for young people who have self-harmed on more than one occasion. The study will be reported in 2016, and the results will inform clinical practice thereafter. TRIAL REGISTRATION: ISRCTN59793150 . 26 January 2009.