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Abstract Background Heart failure is a major global health challenge incurring a high rate of mortality, morbidity and hospitalisation. Effective medicines management at the time of hospital discharge into the community could reduce poor outcomes for people with heart failure. Within the Improving the Safety and Continuity Of Medicines management at Transitions of care (ISCOMAT) programme, the Medicines at Transitions Intervention (MaTI) was co-designed to improve such transitions, with a cluster randomised controlled trial to test effectiveness. The MaTI includes a patient toolkit and transfer of discharge medicines information to community pharmacy. This paper aims to determine the degree to which the intervention was delivered, and identify barriers and facilitators experienced by staff for the successful implementation of the intervention. Methods The study was conducted in six purposively selected intervention sites. A mixed-methods design was employed using hospital staff interviews, structured and unstructured ward observations, and routine trial data about adherence to the MaTI. A parallel mixed analysis was applied. Qualitative data were analysed thematically using the Framework method. Data were synthesised, triangulated and mapped to the Consolidated Framework for Implementation Research (CFIR). Results With limited routines of communication between ward staff and community pharmacy, hospital staff found implementing community pharmacy-related steps of the intervention challenging. Staff time was depleted by attempts to bridge system barriers, sometimes leading to steps not being delivered. Whilst the introduction of the patient toolkit was often completed and valued as important patient education and a helpful way to explain medicines, the medicines discharge log within it was not, as this was seen as a duplication of existing systems. Within the CFIR the most applicable constructs were identified as ‘intervention complexity’ and ‘cosmopolitanism’ based on how well hospitals were networked with community pharmacies, and the availability of hospital resources to facilitate this. Conclusion The MaTI was generally successfully implemented, particularly the introduction of the toolkit. However, implementation involving community pharmacy was more challenging and more effective communication systems are needed to support wider implementation. Trial registration 11/04/2018 ISRCTN66212970. https://www.isrctn.com/ISRCTN66212970 .

Background Irritable bowel syndrome, characterised by abdominal pain and a change in stool form or frequency, is most often managed in primary care. When first-line therapies are ineffective, National Institute for Health and Care Excellence guidelines suggest considering low-dose tricyclic antidepressants as second-line treatment, but their effectiveness in primary care is unknown and they are infrequently prescribed by general practitioners. Objective To evaluate the clinical and cost-effectiveness of low-dose titrated amitriptyline as a second-line treatment for irritable bowel syndrome in primary care. Design A pragmatic, randomised, multicentre, two-arm, double-blind, placebo-controlled trial. A nested, qualitative study explored participant and general practitioner experiences of treatments and trial participation, and implications for wider use of amitriptyline for irritable bowel syndrome in primary care. Participants, clinicians, investigators and analysts were masked to allocation. Setting Fifty-five general practices in three regions in England (Wessex, West of England, West Yorkshire). Participants Patients aged ≥ 18 years meeting Rome IV criteria for irritable bowel syndrome with ongoing symptoms after trying first-line treatments and no contraindications to TCAs. Intervention Amitriptyline 10 mg once-daily, self-titrated by participants to a maximum of 30 mg once-daily or matched placebo for 6 months. Participants randomised 1 : 1 with most having the option to continue blinded treatment for a further 6 months. Main outcome measures The primary participant-reported outcome was the effect of amitriptyline on global irritable bowel syndrome symptoms at 6 months, measured using the irritable bowel syndrome Severity Scoring System, with a 35-point between-group difference defined as the minimum clinically important difference. The key secondary outcome was the proportion of participants reporting subjective global assessment of relief at 6 months, defined as somewhat, considerable, or complete relief of symptoms. Other secondary outcomes included: effect on global symptoms, via the irritable bowel syndrome Severity Scoring System, and subjective global assessment of relief of irritable bowel syndrome symptoms at 3 and 12 months; effect on somatic symptom-reporting at 6 months; anxiety an–d depression scores; ability to work and participate in other activities at 3, 6 and 12 months; acceptability, tolerability and adherence to trial medication. Results Four hundred and sixty-three participants were randomised to amitriptyline (232) or placebo (231). An intention-to-treat analysis of the primary outcome showed a significant difference in favour of amitriptyline for irritable bowel syndrome Severity Scoring System score between arms at 6 months [−27.0, 95% confidence interval (CI) −46.9 to −7.10; p = 0.008]. For the key secondary outcome of subjective global assessment of relief of irritable bowel syndrome symptoms, amitriptyline was superior to placebo at 6 months (odds ratio 1.78, 95% CI 1.19 to 2.66; p = 0.005). Amitriptyline was superior to placebo across a range of other irritable bowel syndrome symptom measures but had no impact on somatoform symptom-reporting, anxiety, depression, or work and social adjustment scores. Adverse event trial withdrawals were more common with amitriptyline (12.9% vs. 8.7% for placebo) but most adverse events were mild. The qualitative study thematically analysed 77 semistructured interviews with 42 participants and 16 GPs. Most participants found the self-titration process acceptable and empowering. Conclusions General practitioners should offer low-dose amitriptyline to patients with irritable bowel syndrome whose symptoms do not improve with first-line therapies. Guidance and resources should support GP–patient communication to distinguish amitriptyline for irritable bowel syndrome from use as an antidepressant and to support patients managing their own dose titration. Study registration This trial is registered as ISRCTN48075063. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/162/01) and is published in full in Health Technology Assessment Vol. 28, No. 66. See the NIHR Funding and Awards website for further award information. Plain language summary Background People with irritable bowel syndrome experience stomach (abdominal) pain and changes to their bowel movements. Irritable bowel syndrome can have a serious impact on people’s lives. Previous small trials suggest that a drug called amitriptyline used at a low dose may help irritable bowel syndrome. Amitriptyline is already used to treat other conditions. It is available for irritable bowel syndrome but is not used much by general practitioners. Methods We recruited adults aged ≥ 18 years with irritable bowel syndrome from UK general practices who did not have any issues preventing the use of amitriptyline. Patients received either low-dose amitriptyline or placebo (a dummy tablet) for 6 months. Patients could adjust the dose according to symptoms and side effects. Neither the researchers nor the patients knew which treatment they were getting. Participants recorded symptoms using a questionnaire containing an irritable bowel syndrome severity score. We looked at the difference in average irritable bowel syndrome severity score between patients receiving amitriptyline and placebo. We also looked at effects of amitriptyline on mood, ability to work, and non-gut symptoms related to irritable bowel syndrome, as well as safety and acceptability. Some patients and general practitioners were interviewed about their experiences. Results Four hundred and sixty-three patients took part. Participants receiving amitriptyline reported a bigger improvement in their irritable bowel syndrome severity scores at 6 months, compared with patients on placebo. Amitriptyline was better across a range of irritable bowel syndrome symptom measures but did not impact anxiety, depression or ability to work. Forty-six people (19.8%) stopped taking amitriptyline and 59 (25.5%) stopped the placebo before 6 months. Patients liked being able to adjust their dose and valued contact with the research team. Conclusion This study showed that amitriptyline is more effective than a placebo and is safe. General practitioners should offer low-dose amitriptyline to people with irritable bowel syndrome if symptoms do not improve with other standard treatments. Patients should be supported and helped to adjust their dose as needed. The dose adjustment sheet used in this trial will be made available. Scientific summary Background Irritable bowel syndrome (IBS) affects 5% of the population, accounting for > 3% of all consultations in primary care in England and Wales. Symptoms include abdominal pain in association with a change in stool form or frequency. The condition impacts on quality of life and ability to work and limits social activities. The medical management of IBS is unsatisfactory, with no therapy proven to alter the long-term natural history and, at best, modest symptom reduction. Previous meta-analyses of trials conducted in secondary and tertiary care suggest low-dose tricyclic antidepressants (TCAs) may be efficacious, probably because of their pain-modifying properties, as well as their influence on gut motility, rather than any effects on mood. Although National Institute for Health and Care Excellence guidelines for the management of IBS in primary care suggest considering low-dose TCAs as second-line treatment, their effectiveness in this setting is unknown and they are infrequently prescribed by general practitioners (GPs). Objectives Our objective was to determine the clinical and cost-effectiveness of low-dose titrated amitriptyline compared with placebo for 6 months as a second-line treatment in adults with IBS in primary care. Methods ATLANTIS was a pragmatic, randomised, multicentre, parallel-group, two-arm, double-blind, placebo-controlled trial. A nested, qualitative study explored participant and GP experiences of treatments and trial participation. A within-study cost-effectiveness analysis was planned but, due to the coronavirus disease discovered in 2019 (COVID-19) pandemic, health economic analyses were removed after obtaining additional funding to complete the trial to prioritise funds for participant recruitment. These will be subject to further funding. Participants, their GPs, investigators, the research team, and the analysis team were all masked to treatment allocation throughout the trial. Patients meeting Rome IV criteria for IBS who had tried first-line treatments and with ongoing IBS symptoms [score of ≥ 75 on the IBS Severity Scoring System (IBS-SSS)] were recruited via mail-out from 55 general practices in three regions in England. Participants were randomised 1 : 1 to receive either low-dose titrated amitriptyline or placebo. Both treatments were supplied for 6 months, with the dose commenced at 10 mg o.d. and titrated to a maximum of 30 mg o.d. or a minimum of 10 mg alternate days. Dose titration was participant-led according to IBS symptoms and side effects, with support from the trial team and a dose titration document developed with input via patient and public involvement. Participants recruited earlier to the trial had the option to continue blinded treatment for an additional 6 months. The primary outcome was the effect of amitriptyline on global IBS symptom scores at 6 months. The key secondary outcome was the proportion of participants with relief of IBS symptoms at 6 months. Other secondary outcomes included effect on global IBS symptoms and relief of IBS symptoms at 3 and 12 months, effect on IBS-associated somatic symptoms at 6 months, effect on quality of life, anxiety, and depression scores, and ability to work and participate in other activities at 3, 6 and 12 months, as well as acceptability and tolerability of, and adherence to, treatment. Patient-reported questionnaires at baseline and 3, 6 and 12 months post randomisation (unless otherwise indicated) were used to assess IBS symptom severity (measured via the IBS-SSS), relief of IBS symptoms [measured by subjective global assessment (SGA) of relief], adequate relief of IBS symptoms (measured by a weekly response to the question ‘Have you had adequate relief of your IBS symptoms?’), IBS-associated somatic symptoms [using the Patient Health Questionnaire-12 (PHQ-12)], mood [using the Hospital Anxiety and Depression Scale (HADS)], ability to work and participate in other activities [using the Work and Social Adjustment Scale (WSAS)], quality of life (using the EQ-5D-3L), healthcare use (using a bespoke health resource use questionnaire), and tolerability [using the Antidepressant Side-Effect Checklist (ASEC)]. Numbers of participants reporting serious adverse events (SAEs), including serious adverse reactions (SARs), were reported for each treatment group. An evaluable sample size of 414 participants would provide 90% power to detect a minimum clinically important difference of 35 points between amitriptyline and placebo at 6 months on the IBS-SSS. This sample size provided at least 85% power to detect a 15% absolute difference in the key secondary outcome of SGA of relief of IBS symptoms at 6 months. We planned to recruit 518 participants, allowing for 20% loss to follow-up. Effectiveness outcomes were analysed in the intention-to-treat population, defined as all participants randomised, regardless of adherence. All statistical testing used two-sided 5% significance levels. The primary outcome was analysed using a linear regression model, adjusted for minimisation variables and baseline IBS-SSS score. Missing data were imputed by treatment arm, via multiple imputation, and results were expressed as point estimates with 95% confidence intervals (CIs). Secondary binary outcomes were analysed in logistic or ordinal regression models, with results expressed as odds ratios (ORs) with 95% CIs. Continuous secondary outcomes, including PHQ-12, HADS and WSAS scores, were analysed as for the primary outcome, adjusted for the respective baseline score. All participants receiving at least one dose of trial medication, according to medication received, were included in the safety analysis. The nested, qualitative study aimed to identify factors that would facilitate or impede prescribing of, acceptability of, and adherence to, low-dose amitriptyline in IBS, to identify participants’ and GPs’ perspectives on the broader impact of the trial, and to explore psychosocial and contextual factors that might shape wider use of amitriptyline for IBS. Familiarity with amitriptyline may both hinder uptake, given its association with depression, and facilitate it, given that it is a known drug, taken in a low dose distinct from the antidepressant dose, already used for a range of other painful conditions and has comparatively mild, and in some cases potentially beneficial, side effects such as on sleep. Semi-structured audio-recorded telephone interviews were conducted with a diverse sub-sample of trial participants and GPs involved in the trial and transcribed verbatim. The final sample size was dependent on saturation, to achieve a rigorous, credible analysis in relation to the aims. Topic guides allowed flexible exploration of all required topics, while remaining open to participants’ individual experiences and perspectives. To enhance trustworthiness of the analysis, all qualitative study team members contributed to avoid producing idiosyncratic interpretations, a negative case analysis was undertaken, and an audit trail was produced to enhance transparency, including detailed coding manuals and interviewer field notes. Reflexive thematic analysis, incorporating techniques from grounded theory, was used to analyse the qualitative data. Data collection and initial analyses proceeded iteratively, and informed subsequent interviews. Analysis was primarily inductive, with researchers identifying themes in the data rather than imposing any pre-existing interpretive framework. Qualitative findings were related to the main trial findings by comparing themes across subgroups and against the quantitative data. Clinical results In total, 15,672 potentially eligible patients were invited to take part, of whom 1253 were interested and were screened. Of those screened, 463 (37.0%) were randomised {mean age 48.5 years [standard deviation (SD) 16.1 years], 315 (68.0%) female}, to amitriptyline (n = 232) or placebo (n = 231). Six-month follow-up was achieved for 401 (86.6%) participants, 204 (87.9%) in the amitriptyline arm, and 197 (85.3%) in the placebo arm. Participants were well balanced between treatment arms according to demographics and baseline characteristics, IBS symptom severity, PHQ-12 scores, HADS-depression and HADS-anxiety scores, and previous first-line treatments. Among participants, 80.4% had IBS-D or IBS-M, 84.2% had a normal HADS-depression score, and 84.7% had moderate to severe scores on the IBS-SSS, with a mean IBS-SSS score in all participants of 272.8 (SD 90.3). The median duration of IBS was 10 years. In total, 338 (73.0%) participants completed 6 months of treatment, 173 (74.6%) randomised to amitriptyline and 165 (71.4%) to placebo. Discontinuation of trial medication before 6 months occurred in 105 (22.7%) participants, 46 (19.8%) allocated to amitriptyline and 59 (25.5%) to placebo. The most common reason for discontinuing trial medication was adverse events (AEs) in 30 (12.9%) participants allocated to amitriptyline and 20 (8.7%) to placebo, followed by lack of benefit in 7 (3.0%) randomised to amitriptyline and 18 (7.8%) to placebo. There were a further 17 (3.7%) participants lost to follow-up and 3 (0.6%) who did not commence trial medication. By 3 months, similar proportions of participants randomised to amitriptyline had titrated their dose to 20 mg o.d. (35.2%) or 30 mg o.d. (37.8%), although by 6 months this had increased to 42.8% taking 30 mg o.d. However, in the placebo arm, 57.0% of participants titrated their dose to 30 mg o.d. within 3 months and this proportion was similar at 6 months. For the primary outcome, amitriptyline was superior to placebo at 6 months in the intention-to-treat analysis, with a significant difference in mean IBS-SSS score between arms (−27.0, 95% CI −46.9 to −7.1; p = 0.008). For the key secondary outcome, SGA of relief of IBS symptoms, amitriptyline was also superior to placebo (OR for relief of IBS symptoms = 1.78, 95% CI 1.19 to 2.66; p = 0.005). At 3 months, the difference in mean change in IBS-SSS score also favoured amitriptyline (−23.3, 95% CI −42.0 to −4.6; p = 0.014), as did the SGA of relief of IBS symptoms (OR = 1.70, 95% CI 1.15 to 2.53; p = 0.008). In a sensitivity analysis using an alternative definition of SGA of relief of IBS symptoms, where only those reporting considerable or complete relief of IBS symptoms at 3 or 6 months were classed as responders, the effect size in the amitriptyline arm increased at both 3 (OR = 1.81, 95% CI 1.17 to 2.79) and 6 months (OR = 1.88, 95% CI 1.20 to 2.95). Other sensitivity analyses on the per-protocol population for the primary outcome and on participants with complete data for the primary and key secondary outcomes gave consistent results, albeit with larger estimated treatment effects. In terms of adequate relief of IBS symptoms, amitriptyline was also superior to placebo with increased odds of adequate relief across all 25 weeks (OR = 1.56, 95% CI 1.20 to 2.03; p < 0.001), and a higher proportion of participants reporting adequate relief for ≥ 13 of 25 weeks [90/222 (40.5%) vs. 67/221 (30.3%)]. Significantly higher numbers of participants taking amitriptyline reported the drug to be acceptable and would have been willing to continue taking it at 6 months (OR = 1.60, 95% CI 1.08 to 2.35; p = 0.018). Adherence at 3 months was identical in the two treatment arms, but it was higher in the amitriptyline arm at 6 months [172/232 (74.1%) vs. 155/228 (68.0%)]. Amitriptyline had no significant effect on PHQ-12 scores at 6 months, or HADS-anxiety, HADS-depression or WSAS scores at either 3 or 6 months. In terms of treatment-emergent AEs, there was a statistically significant increase in the total ASEC score in those receiving amitriptyline compared with placebo at 3 months (1.39, 95% CI 0.29 to 2.50; p = 0.013) but not at 6 months (0.26, 95% CI −0.98 to 1.51; p = 0.681). The AEs reported in participants receiving amitriptyline in excess of those reported by the placebo arm mainly related to its known anticholinergic effects, including dry mouth, drowsiness, blurred vision and problems with urination. However, rates of treatment-emergent AEs fell between 3 and 6 months and few were severe. The commonest AEs leading to discontinuation in the amitriptyline arm were drowsiness and deterioration of mood. In total, there were five SARs, two in the amitriptyline arm and three in the placebo arm. There were five SAEs unrelated to trial medication, of which four occurred in the amitriptyline arm and one in the placebo arm. In the subset of participants recruited to 12 months’ follow-up and with the choice to continue treatment beyond 6 months, 44% of participants completed 12 months’ treatment. Despite the mixed sample, in the 12-month ITT population, weak evidence of a significant effect in favour of low-dose amitriptyline remained on the mean IBS-SSS (−22.6, 95% CI −49.35 to −4.16; p = 0.098) and the SGA of relief of global IBS symptoms (OR = 1.58, 95% CI 0.94 to 2.64; p = 0.083). In contrast to 6-month results, there was a statistically significant effect on the HADS-depression (−0.88, 95% CI −1.71 to 0.06; p = 0.036) and WSAS (−2.14, 95% CI −3.80 to −0.49; p = 0.011) scores in favour of low-dose amitriptyline. Qualitative results The qualitative study conducted and thematically analysed 77 semistructured interviews with 42 participants and 16 GPs. A multidisciplinary team including patient collaborators explored multiple aspects of participants’ and GPs’ experiences of treatments and participating in the ATLANTIS trial. The qualitative analysis of barriers and facilitators suggests that low-dose amitriptyline for IBS is acceptable to, and is often welcomed by, GPs and patients as an additional treatment option. Addressing concerns and promoting facilitators could facilitate wider use of low-dose amitriptyline for IBS which may be achieved through: Clear communication to clinicians, for example in clinical guidelines, that distinguishes low-dose amitriptyline for IBS from amitriptyline use for other conditions (especially depression). Resources to support GP–patient communication to distinguish low-dose amitriptyline for IBS from amitriptyline for other conditions (especially depression). This might include, for example, tips for GPs when discussing amitriptyline for IBS with patients, online materials to support or reinforce messages given during consultations, tailored packaging and patient inserts, and education for pharmacists. Clear guidance about low-dose amitriptyline for IBS and anticholinergic burden. This should highlight that low-dose amitriptyline has lower potential risk and that currently anticholinergic burden risk scores do not account for dose, so can overinterpret risk with low-dose amitriptyline. Guidance and resources for GPs and patients to support patients managing their own dose titration. The dose-titration document used in ATLANTIS was well received by GPs and patients. Conclusions In the largest trial of a TCA 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. The results of ATLANTIS strongly support use of titrated low-dose amitriptyline in this setting. GPs 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. Trial registration This trial is registered as ISRCTN48075063. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/162/01) and is published in full in Health Technology Assessment; Vol. 28, No. 66. See the NIHR Funding and Awards website for further award information.

BackgroundType 2 diabetes is 2 to 3 times more common among people with severe mental illness (SMI). Self-management is crucial, with additional challenges faced by people with SMI. Therefore, it is essential that any diabetes self-management program for people with SMI addresses the unique needs of people living with both conditions and the inequalities they experience within health care services. ObjectiveWe combined theory, empirical evidence, and co-design approaches to develop a type 2 diabetes self-management intervention for people with SMI. MethodsThe development process encompassed 4 steps: step 1 involved prioritizing the mechanisms of action (MoAs) and behavior change techniques (BCTs) for the intervention. Using findings from primary qualitative research and systematic reviews, we selected candidate MoAs to target in the intervention and candidate BCTs to use. Expert stakeholders then ranked these MoAs and BCTs using a 2-phase survey. The average scores were used to generate a prioritized list of MoAs and BCTs. During step 2, we presented the survey results to an expert consensus workshop to seek expert agreement with the definitive list of MoAs and BCTs for the intervention and identify potential modes of delivery. Step 3 involved the development of trigger films using the evidence from steps 1 and 2. We used animations to present the experiences of people with SMI managing diabetes. These films were used in step 4, where we used a stakeholder co-design approach. This involved a series of structured workshops, where the co-design activities were informed by theory and evidence. ResultsUpon the completion of the 4-step process, we developed the DIAMONDS (diabetes and mental illness, improving outcomes and self-management) intervention. It is a tailored self-management intervention based on the synthesis of the outputs from the co-design process. The intervention incorporates a digital app, a paper-based workbook, and one-to-one coaching designed to meet the needs of people with SMI and coexisting type 2 diabetes. ConclusionsThe intervention development work was underpinned by the MoA theoretical framework and incorporated systematic reviews, primary qualitative research, expert stakeholder surveys, and evidence generated during co-design workshops. The intervention will now be tested for feasibility before undergoing a definitive evaluation in a pragmatic randomized controlled trial.

Abstract Background How to meaningfully partner with patients as data analysts remains obscure. A process evaluation of the ‘Improving the Safety and Continuity Of Medicines management at care Transitions’ (ISCOMAT) cluster randomised control trial of an intervention for improving medicines use for people living with heart failure is being conducted. The intervention includes patient held information on heart medicines and care, enhanced communication between hospital and community pharmacists, and increased engagement of community pharmacists with patient care post‐hospital discharge. ISCOMAT patients living with heart failure were interviewed about experiences with the intervention. We sought to gain insights from patients on data collected to enhance our understanding of experiences with the intervention. Objective To develop a method for involving patients as analysts of qualitative data in a process evaluation. Design Patients and researchers co‐analysed qualitative data. A framework method was applied involving; familiarisation, coding, developing an analytical framework and interpretation. The process was facilitated through home working and a workshop with a training component. Results The co‐designed framework enabled researchers to map all further patient interview data. Patients' specialist knowledge enhanced understanding of how the ISCOMAT intervention can be best implemented. Conclusions Patients’ unique experiences can enhance validity and rigour in data analysis through sharing their interpretations of qualitative data. The involvement process is crucial in elucidating knowledge and avoiding tokenism. As analysts, patients gain an appreciation of research processes, building trust between researchers and patients. Group dynamics and involving patients throughout the whole research process are important considerations.

Background: National clinical audit programmes aim to improve patient care by reviewing performance against explicit standards and directing action towards areas not meeting those standards. Their impact can be improved by (1) optimising feedback content and format, (2) strengthening audit cycles and (3) embedding randomised trials evaluating different ways of delivering feedback. Objectives: The objectives were to (1) develop and evaluate the effects of modifications to feedback on recipient responses, (2) identify ways of strengthening feedback cycles for two national audits and (3) explore opportunities, costs and benefits of national audit participation in a programme of trials. Design: An online fractional factorial screening experiment (objective 1) and qualitative interviews (objectives 2 and 3). Setting and participants: Participants were clinicians and managers involved in five national clinical audits – the National Comparative Audit of Blood Transfusions, the Paediatric Intensive Care Audit Network, the Myocardial Ischaemia National Audit Project, the Trauma Audit & Research Network and the National Diabetes Audit – (objective 1); and clinicians, members of the public and researchers (objectives 2 and 3). Interventions: We selected and developed six online feedback modifications through three rounds of user testing. We randomised participants to one of 32 combinations of the following recommended specific actions: comparators reinforcing desired behaviour change; multimodal feedback; minimised extraneous cognitive load for feedback recipients; short, actionable messages followed by optional detail; and incorporating ‘the patient voice’ (objective 1). Main outcome measures: The outcomes were intended actions, including enactment of audit standards (primary outcome), comprehension, user experience and engagement (objective 1). Results: For objective 1, the primary analysis included 638 randomised participants, of whom 566 completed the outcome questionnaire. No modification independently increased intended enactment of audit standards. Minimised cognitive load improved comprehension (+0.1; p = 0.014) and plans to bring audit findings to colleagues’ attention (+0.13, on a –3 to +3 scale; p = 0.016). We observed important cumulative synergistic and antagonistic interactions between modifications, participant role and national audit. The analysis in objective 2 included 19 interviews assessing the Trauma Audit Research Network and the National Diabetes Audit. The identified ways of strengthening audit cycles included making performance data easier to understand and guiding action planning. The analysis in objective 3 identified four conditions for effective collaboration from 31 interviews: compromise – recognising capacity and constraints; logistics – enabling data sharing, audit quality and funding; leadership – engaging local stakeholders; and relationships – agreeing shared priorities and needs. The perceived benefits of collaboration outweighed the risks. Limitations: The online experiment assessed intended enactment as a predictor of actual clinical behaviour. Interviews and surveys were subject to social desirability bias. Conclusions: National audit impacts may be enhanced by strengthening all aspects of feedback cycles, particularly effective feedback, and considering how different ways of reinforcing feedback act together. Future work: Embedded randomised trials evaluating different ways of delivering feedback within national clinical audits are acceptable and may offer efficient, evidence-based and cumulative improvements in outcomes. Trial registration: This trial is registered as ISRCTN41584028. Funding details: This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 15. See the NIHR Journals Library website for further project information.

BackgroundThe rise in opioid prescribing in primary care represents a significant international public health challenge, associated with increased psychosocial problems, hospitalisations, and mortality. We evaluated the effects of a comparative feedback intervention with persuasive messaging and action planning on opioid prescribing in primary care.Methods and findingsA quasi-experimental controlled interrupted time series analysis used anonymised, aggregated practice data from electronic health records and prescribing data from publicly available sources. The study included 316 intervention and 130 control primary care practices in the Yorkshire and Humber region, UK, serving 2.2 million and 1 million residents, respectively. We observed the number of adult patients prescribed opioid medication by practice between July 2013 and December 2017. We excluded adults with coded cancer or drug dependency. The intervention, the Campaign to Reduce Opioid Prescribing (CROP), entailed bimonthly, comparative, and practice-individualised feedback reports to practices, with persuasive messaging and suggested actions over 1 year. Outcomes comprised the number of adults per 1,000 adults per month prescribed any opioid (main outcome), prescribed strong opioids, prescribed opioids in high-risk groups, prescribed other analgesics, and referred to musculoskeletal services. The number of adults prescribed any opioid rose pre-intervention in both intervention and control practices, by 0.18 (95% CI 0.11, 0.25) and 0.36 (95% CI 0.27, 0.46) per 1,000 adults per month, respectively. During the intervention period, prescribing per 1,000 adults fell in intervention practices (change -0.11; 95% CI -0.30, -0.08) and continued rising in control practices (change 0.54; 95% CI 0.29, 0.78), with a difference of -0.65 per 1,000 patients (95% CI -0.96, -0.34), corresponding to 15,000 fewer patients prescribed opioids. These trends continued post-intervention, although at slower rates. Prescribing of strong opioids, total opioid prescriptions, and prescribing in high-risk patient groups also generally fell. Prescribing of other analgesics fell whilst musculoskeletal referrals did not rise. Effects were attenuated after feedback ceased. Study limitations include being limited to 1 region in the UK, possible coding errors in routine data, being unable to fully account for concurrent interventions, and uncertainties over how general practices actually used the feedback reports and whether reductions in prescribing were always clinically appropriate.ConclusionsRepeated comparative feedback offers a promising and relatively efficient population-level approach to reduce opioid prescribing in primary care, including prescribing of strong opioids and prescribing in high-risk patient groups. Such feedback may also prompt clinicians to reconsider prescribing other medicines associated with chronic pain, without causing a rise in referrals to musculoskeletal clinics. Feedback may need to be sustained for maximum effect.

Background: People with severe mental illness experience poorer health outcomes than the general population. Diabetes contributes significantly to this health gap. Objectives: The objectives were to identify the determinants of diabetes and to explore variation in diabetes outcomes for people with severe mental illness. Design: Under a social inequalities framework, a concurrent mixed-methods design combined analysis of linked primary care records with qualitative interviews. Setting: The quantitative study was carried out in general practices in England (2000–16). The qualitative study was a community study (undertaken in the North West and in Yorkshire and the Humber). Participants: The quantitative study used the longitudinal health records of 32,781 people with severe mental illness (a subset of 3448 people had diabetes) and 9551 ‘controls’ (with diabetes but no severe mental illness), matched on age, sex and practice, from the Clinical Practice Research Datalink (GOLD version). The qualitative study participants comprised 39 adults with diabetes and severe mental illness, nine family members and 30 health-care staff. Data sources: The Clinical Practice Research Datalink (GOLD) individual patient data were linked to Hospital Episode Statistics, Office for National Statistics mortality data and the Index of Multiple Deprivation. Results: People with severe mental illness were more likely to have diabetes if they were taking atypical antipsychotics, were living in areas of social deprivation, or were of Asian or black ethnicity. A substantial minority developed diabetes prior to severe mental illness. Compared with people with diabetes alone, people with both severe mental illness and diabetes received more frequent physical checks, maintained tighter glycaemic and blood pressure control, and had fewer recorded physical comorbidities and elective admissions, on average. However, they had more emergency admissions (incidence rate ratio 1.14, 95% confidence interval 0.96 to 1.36) and a significantly higher risk of all-cause mortality than people with diabetes but no severe mental illness (hazard ratio 1.89, 95% confidence interval 1.59 to 2.26). These paradoxical results may be explained by other findings. For example, people with severe mental illness and diabetes were more likely to live in socially deprived areas, which is associated with reduced frequency of health checks, poorer health outcomes and higher mortality risk. In interviews, participants frequently described prioritising their mental illness over their diabetes (e.g. tolerating antipsychotic side effects, despite awareness of harmful impacts on diabetes control) and feeling overwhelmed by competing treatment demands from multiple morbidities. Both service users and practitioners acknowledged misattributing physical symptoms to poor mental health (‘diagnostic overshadowing’). Limitations: Data may not be nationally representative for all relevant covariates, and the completeness of recording varied across practices. Conclusions: People with severe mental illness and diabetes experience poorer health outcomes than, and deficiencies in some aspects of health care compared with, people with diabetes alone. Future work: These findings can inform the development of targeted interventions aimed at addressing inequalities in this population. Study registration: National Institute for Health Research (NIHR) Central Portfolio Management System (37024); and ClinicalTrials.gov NCT03534921. Funding: This project was funded by the NIHR Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 10. See the NIHR Journals Library website for further project information.

Introduction A key priority for the UK National Health Service and patients is to ensure that medicines are used safely and effectively. However, medication changes are not always optimally communicated and implemented when patients transfer from hospital into community settings. Heart failure is a common reason for admission to hospital. Patients with heart failure have a high burden of morbidity, mortality and complex pharmacotherapeutic regimens. The Improving the Safety and Continuity Of Medicines management at Transitions of care programme comprises a cluster randomised controlled trial which will test the effectiveness of a complex behavioural intervention aimed at improving medications management at the interface between hospitals discharge and community care. We will conduct a rigorous process evaluation to inform interpretation of the trial findings, inform implementation of the intervention on a wider scale and aid dissemination of the intervention.Methods and analysis The process evaluation will be conducted in six purposively selected intervention sites (ie, hospital trusts and associated community pharmacies) using a mixed-methods design. Fidelity and barriers/enablers of implementation of the Medicines at Transitions Intervention (MaTI) will be explored using observation, interviews (20 patients, 40 healthcare professionals), surveys and routine trial data collection on adherence to MaTI. A parallel mixed analysis will be applied. Qualitative data will be thematically analysed using Framework analysis and survey data will be analysed descriptively. Data will be synthesised, triangulated and mapped to the Consolidated Framework for Implementation Research where appropriate. The process evaluation commenced on June 2018 and is due to end on February 2021.Ethics and dissemination Approved by Research Ethics Committee and the UK Health Research Authority REC: 18/YH/0017/IRAS: 231 431. Findings will be disseminated via academic and policy conferences, peer-reviewed publications and social media.Trial registration number ISRCTN66212970.

People with severe mental illness (SMI) have reduced life expectancy compared with the general population, which can be explained partly by their increased risk of diabetes. We conducted a meta-analysis to determine the clinical effectiveness of pharmacological and non-pharmacological interventions for improving glycaemic control in people with SMI (PROSPERO registration: CRD42015015558). A systematic literature search was performed on 30/10/2015 to identify randomised controlled trials (RCTs) in adults with SMI, with or without a diagnosis of diabetes that measured fasting blood glucose or glycated haemoglobin (HbA1c). Screening and data extraction were carried out independently by two reviewers. We used random effects meta-analysis to estimate effectiveness, and subgroup analysis and univariate meta-regression to explore heterogeneity. The Cochrane Collaboration's tool was used to assess risk of bias. We found 54 eligible RCTs in 4,392 adults (40 pharmacological, 13 behavioural, one mixed intervention). Data for meta-analysis were available from 48 RCTs (n = 4052). Both pharmacological (mean difference (MD), -0.11mmol/L; 95% confidence interval (CI), [-0.19, -0.02], p = 0.02, n = 2536) and behavioural interventions (MD, -0.28mmol//L; 95% CI, [-0.43, -0.12], p

Abstract Background Medicines are often suboptimally managed for heart failure patients across the transition from hospital to home, potentially leading to poor patient outcomes. The Improving the Safety and Continuity Of Medicines management at Transitions of care programme included: understanding the problems faced by patients and healthcare professionals; developing and co‐designing the Medicines at Transitions of care Intervention (MaTI); a cluster randomized controlled trial testing the effectiveness of a complex behavioural MaTI aimed at improving medicines management at the interface between hospitals discharge and community care for patients with heart failure; and a process evaluation. The MaTI included a patient‐held My Medicines Toolkit; enhanced communication between the hospital and the patient's community pharmacist and increased engagement of the community pharmacist postdischarge. This paper reports on the patients' experiences of the MaTI and its implementation from the process evaluation. Design Twenty one‐to‐one semi‐structured patient interviews from six intervention sites were conducted between November 2018 and January 2020. Data were analysed using the Framework method, involving patients as co‐analysts. Interview data were triangulated with routine trial data, the Consolidated Framework for Implementation Research and a logic model. Results Within the hospital setting patients engaged with the toolkit according to whether staff raised awareness of the My Medicines Toolkit's importance and the time and place of its introduction. Patients' engagement with community pharmacy depended on their awareness of the community pharmacist's role, support sources and perceptions of involvement in medicines management. The toolkit's impact on patients' medicines management at home included reassurance during gaps in care, increased knowledge of medicines, enhanced ability to monitor health and seek support and supporting sharing medicines management between formal and informal care networks. Conclusion Many patients perceived that the MaTI offered them support in their medicines management when transitioning from hospital into the community. Importantly, it can be incorporated into and built upon patients' lived experiences of heart failure. Key to its successful implementation is the quality of engagement of healthcare professionals in introducing the intervention. Patient or Public Contribution Patients were involved in the study design, as qualitative data co‐analysts and as co‐authors.

Abstract 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.

Abstract Background There is a significant variation among individual primary care providers in prescribing of potentially problematic, low-value medicines which cause avoidable patient harm. Audit and feedback is generally effective at improving prescribing. However, progress has been hindered by research waste, leading to unanswered questions about how to include audit and feedback for specific problems and circumstances. Trials of different ways of providing audit and feedback in implementation laboratories have been proposed as a way of improving population healthcare while generating robust evidence on feedback effects. However, there is limited experience in their design and delivery. Aim To explore priorities, feasibility, and ethical challenges of establishing a primary care prescribing audit and feedback implementation laboratory. Design and setting Two-stage Delphi consensus process involving primary care pharmacy leads, audit and feedback researchers, and patient and public. Method Participants initially scored statements relating to priorities, feasibility, and ethical considerations for an implementation laboratory. These covered current feedback practice, priority topics for feedback, usefulness of feedback in improving prescribing and different types of prescribing data, acceptability and desirability of different organization levels of randomization, options for trial consent, different methods of delivering feedback, and interest in finding out how effective different ways of presenting feedback would be. After receiving collated results, participants then scored the items again. The consensus was defined using the GRADE criteria. The results were analyzed by group and overall score. Results Fourteen participants reached consensus for 38 out of 55 statements. Addressing antibiotic and opioid prescribing emerged as the highest priorities for action. The panel supported statements around addressing high-priority prescribing issues, taking an “opt-out” approach to practice consent if waiving consent was not permitted, and randomizing at lower rather than higher organizational levels. Participants supported patient-level prescribing data and further research evaluating most of the different feedback methods we presented them with. Conclusions There is a good level of support for evaluating a wide range of potential enhancements to improve the effects of feedback on prescribing. The successful design and delivery of a primary care audit and feedback implementation laboratory depend on identifying shared priorities and addressing practical and ethical considerations.