Effects of an increased financial incentive on follow-up in an online, automated smoking cessation trial: A randomised controlled Study Within a Trial (SWAT).

INTRODUCTION: Poor retention in clinical trials can impact on statistical power, reliability, validity and generalisability of findings and is a particular challenge in smoking cessation studies. In online trials with automated follow up mechanisms, poor response also increases resource-need for manual follow up. This study compared two financial incentives on response rates at 6 months follow up, in an online, automated smoking cessation feasibility trial of a cessation smartphone app (Quit Sense). METHODS: A study within a trial (SWAT), embedded within a host randomised controlled trial. Host trial participants were randomised 1:1 to receive either a £10 or £20 voucher incentive, for completing the 6-month questionnaire. Stratification for randomisation to the SWAT was by minimisation to ensure an even split of host trial arm participants, and by 6-week response rate. Outcome measures were: questionnaire completion rate, time to completion, number of completers requiring manual follow up and completeness of responses. RESULTS: 204 participants were randomised to the SWAT. The £20 and £10 incentives did not differ in completion rate at 6 months (79% versus 74%; p=0.362) but did reduce the proportion of participants requiring manual follow up (46% versus 62%; p=0.018) and the median completion time (7 days versus 15 days; p=0.008). Measure response completeness rates were higher among £20 incentive participants, though differences were small for the host trial's primary smoking outcome. CONCLUSIONS: Benefits to using relatively modest increases in incentive for online smoking cessation trials include more rapid completion of follow up questionnaires and reduced manual follow up. IMPLICATIONS: A modest increase in incentive (from £10 to £20) to promote the completion of follow up questionnaires in online smoking cessation trials may not increase overall response rates but could lead to more rapid data collection, a reduced need for manual follow-up and reduced missing data among those who initiate completing a questionnaire. Such an improvement may help to reduce bias, increase validity and generalisability, and improve statistical power in smoking cessation trials.

A pragmatic, multicentre, double-blind, placebo-controlled randomised trial to assess the safety, clinical and cost-effectiveness of mirtazapine and carbamazepine in people with Alzheimer's disease and agitated behaviours: the HTA-SYMBAD trial.

Background: Agitation is common and impacts negatively on people with dementia and carers. Non-drug patient-centred care is first-line treatment, but we need other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics. Objectives: To assess clinical and cost-effectiveness and safety of mirtazapine and carbamazepine in treating agitation in dementia. Design: Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine over 12 weeks (carbamazepine arm discontinued). Setting: Twenty-six UK secondary care centres. Participants: Eligibility: probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, Cohen-Mansfield Agitation Inventory score ≥ 45. Interventions: Mirtazapine (target 45 mg), carbamazepine (target 300 mg) and placebo. Outcome measures: Primary: Cohen-Mansfield Agitation Inventory score 12 weeks post randomisation. Main economic outcome evaluation: incremental cost per six-point difference in Cohen-Mansfield Agitation Inventory score at 12 weeks, from health and social care system perspective. Data from participants and informants at baseline, 6 and 12 weeks. Long-term follow-up Cohen-Mansfield Agitation Inventory data collected by telephone from informants at 6 and 12 months. Randomisation and blinding: Participants allocated 1 : 1 : 1 ratio (to discontinuation of the carbamazepine arm, 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, with treatment as usual. Random allocation was block stratified by centre and residence type with random block lengths of three or six (after discontinuation of carbamazepine, two or four). Double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, trial management team and research workers who did assessments were masked to group allocation. Results: Two hundred and forty-four participants recruited and randomised (102 mirtazapine, 102 placebo, 40 carbamazepine). The carbamazepine arm was discontinued due to slow overall recruitment; carbamazepine/placebo analyses are therefore statistically underpowered and not detailed in the abstract. Mean difference placebo-mirtazapine (-1.74, 95% confidence interval -7.17 to 3.69; p = 0.53). Harms: The number of controls with adverse events (65/102, 64%) was similar to the mirtazapine group (67/102, 66%). However, there were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1). Post hoc analysis suggests this was of marginal statistical significance (p = 0.065); this difference did not persist at 6- and 12-month assessments. At 12 weeks, the costs of unpaid care by the dyadic carer were significantly higher in the mirtazapine than placebo group [difference: £1120 (95% confidence interval £56 to £2184)]. In the cost-effectiveness analyses, mean raw and adjusted outcome scores and costs of the complete cases samples showed no differences between groups. Limitations: Our study has four important potential limitations: (1) we dropped the proposed carbamazepine group; (2) the trial was not powered to investigate a mortality difference between the groups; (3) recruitment beyond February 2020, was constrained by the COVID-19 pandemic; and (4) generalisability is limited by recruitment of participants from old-age psychiatry services and care homes. Conclusions: The data suggest mirtazapine is not clinically or cost-effective (compared to placebo) for agitation in dementia. There is little reason to recommend mirtazapine for people with dementia with agitation. Future work: Effective and cost-effective management strategies for agitation in dementia are needed where non-pharmacological approaches are unsuccessful. Study registration: This trial is registered as ISRCTN17411897/NCT03031184. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 23. See the NIHR Journals Library website for further project information.

It is common for people with Alzheimer's disease to experience agitation, for example feeling restless or unsettled. If left untreated, agitation can lead to poorer quality of life and increased hospitalisation and strain for family carers. Often these symptoms are treated with medications that are usually used to manage psychosis (antipsychotic drugs), but such medication has limited effectiveness and can cause serious adverse effects to patients, including risk of increased death. Two medications that are already commonly prescribed for other health issues, mirtazapine (an antidepressant) and carbamazepine (a drug used to treat epilepsy), had been identified as a possible alternative way of treating agitation in Alzheimer's disease that might not have the harms associated with antipsychotic medication. In this study, we compared the effects of giving mirtazapine or carbamazepine with a dummy drug (placebo) in people with Alzheimer's disease who were experiencing agitation. The results of the study showed that neither medication was any more effective than the placebo in reducing agitation over 12 weeks in terms of improving symptoms, or in economic terms. Mirtazapine may lead to additional carer costs as compared to placebo. The study findings are stronger for mirtazapine than carbamazepine because the carbamazepine arm was stopped when it had recruited less than half the numbers needed. That was done because the study was not recruiting quickly enough to support both the mirtazapine and the carbamazepine arms. The findings from this study show that mirtazapine should not be recommended to treat agitation in Alzheimer's disease. More work is needed to formulate effective ways and to test new drug and non-drug treatments for agitation in dementia.

Cost-effectiveness of mirtazapine for agitated behaviors in dementia: findings from a randomized controlled trial.

OBJECTIVES: To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up. DESIGN: Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo. SETTING: Community settings and care homes in 26 UK centers. PARTICIPANTS: People with probable or possible Alzheimer's disease and agitation. MEASUREMENTS: Primary outcome included incremental cost of participants' health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants' and unpaid carers' gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives. RESULTS: One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment. CONCLUSIONS: On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful.

PERFECTED enhanced recovery pathway (PERFECT-ER) versus standard acute hospital care for people after hip fracture surgery who have cognitive impairment: a feasibility cluster randomised controlled trial.

OBJECTIVES: Assess feasibility of a cluster randomised controlled trial (RCT) to measure clinical and cost-effectiveness of an enhanced recovery pathway for people with hip fracture and cognitive impairment (CI). DESIGN: Feasibility trial undertaken between 2016 and 2018. SETTING: Eleven acute hospitals from three UK regions. PARTICIPANTS: 284 participants (208 female:69 male). INCLUSION CRITERIA: aged >60 years, confirmed proximal hip fracture requiring surgical fixation and CI; preoperative AMTS ≤8 in England or a 4AT score ≥1 in Scotland; minimum of 5 days on study ward; a 'suitable informant' able to provide proxy measures, recruited within 7 days of hip fracture surgery. EXCLUSION CRITERIA: no hip surgery; not expected to survive beyond 4 weeks; already enrolled in a clinical trial. INTERVENTION: PERFECT-ER, an enhanced recovery pathway with 15 quality targets supported by a checklist and manual, a service improvement lead a process lead and implemented using a plan-do-study-act model. PRIMARY AND SECONDARY OUTCOME MEASURES: Feasibility outcomes: recruitment and attrition, intervention acceptability, completion of participant reported outcome measures, preliminary estimates of potential effectiveness using mortality, EQ-5D-5L, economic and clinical outcome scores. RESULTS: 282 participants were consented and recruited (132, intervention) from a target of 400. Mean recruitment rates were the same in intervention and control sites, (range: 1.2 and 2.7 participants/month). Retention was 230 (86%) at 1 month and 54%(144) at 6 months. At 3 months a relatively small effect (one quarter of an SD) was observed on health-related quality of life of the patient measured with EQ-5D-5L proxy in the intervention group. CONCLUSION: This trial design was feasible with modifications to recruitment. Mechanisms for delivering consistency in the PERFECT-ER intervention and participant retention need to be addressed. However, an RCT may be a suboptimal research design to evaluate this intervention due to the complexity of caring for people with CI after hip fracture. TRIAL REGISTRATION NUMBER: ISRCTN99336264.

Clinical and cost-effectiveness of social recovery therapy for the prevention and treatment of long-term social disability among young people with emerging severe mental illness (PRODIGY): randomised controlled trial.

BACKGROUND: Young people with social disability and severe and complex mental health problems have poor outcomes, frequently struggling with treatment access and engagement. Outcomes may be improved by enhancing care and providing targeted psychological or psychosocial intervention. AIMS: We aimed to test the hypothesis that adding social recovery therapy (SRT) to enhanced standard care (ESC) would improve social recovery compared with ESC alone. METHOD: A pragmatic, assessor-masked, randomised controlled trial (PRODIGY: ISRCTN47998710) was conducted in three UK centres. Participants (n = 270) were aged 16-25 years, with persistent social disability, defined as under 30 hours of structured activity per week, social impairment for at least 6 months and severe and complex mental health problems. Participants were randomised to ESC alone or SRT plus ESC. SRT was an individual psychosocial therapy delivered over 9 months. The primary outcome was time spent in structured activity 15 months post-randomisation. RESULTS: We randomised 132 participants to SRT plus ESC and 138 to ESC alone. Mean weekly hours in structured activity at 15 months increased by 11.1 h for SRT plus ESC (mean 22.4, s.d. = 21.4) and 16.6 h for ESC alone (mean 27.7, s.d. = 26.5). There was no significant difference between arms; treatment effect was -4.44 (95% CI -10.19 to 1.31, P = 0.13). Missingness was consistently greater in the ESC alone arm. CONCLUSIONS: We found no evidence for the superiority of SRT as an adjunct to ESC. Participants in both arms made large, clinically significant improvements on all outcomes. When providing comprehensive evidence-based standard care, there are no additional gains by providing specialised SRT. Optimising standard care to ensure targeted delivery of existing interventions may further improve outcomes.

Social recovery therapy for young people with emerging severe mental illness: the Prodigy RCT.

BACKGROUND: Young people with social disability and non-psychotic severe and complex mental health problems are an important group. Without intervention, their social problems can persist and have large economic and personal costs. Thus, more effective evidence-based interventions are needed. Social recovery therapy is an individual therapy incorporating cognitive-behavioural techniques to increase structured activity as guided by the participant's goals. OBJECTIVE: This trial aimed to test whether or not social recovery therapy provided as an adjunct to enhanced standard care over 9 months is superior to enhanced standard care alone. Enhanced standard care aimed to provide an optimal combination of existing evidence-based interventions. DESIGN: A pragmatic, single-blind, superiority randomised controlled trial was conducted in three UK centres: Sussex, Manchester and East Anglia. Participants were aged 16-25 years with persistent social disability, defined as < 30 hours per week of structured activity with social impairment for at least 6 months. Additionally, participants had severe and complex mental health problems, defined as at-risk mental states for psychosis or non-psychotic severe and complex mental health problems indicated by a Global Assessment of Functioning score ≤ 50 persisting for ≥ 6 months. Two hundred and seventy participants were randomised 1 : 1 to either enhanced standard care plus social recovery therapy or enhanced standard care alone. The primary outcome was weekly hours spent in structured activity at 15 months post randomisation. Secondary outcomes included subthreshold psychotic, negative and mood symptoms. Outcomes were collected at 9 and 15 months post randomisation, with maintenance assessed at 24 months. RESULTS: The addition of social recovery therapy did not significantly increase weekly hours in structured activity at 15 months (primary outcome treatment effect -4.44, 95% confidence interval -10.19 to 1.31). We found no evidence of significant differences between conditions in secondary outcomes at 15 months: Social Anxiety Interaction Scale treatment effect -0.45, 95% confidence interval -4.84 to 3.95; Beck Depression Inventory-II treatment effect -0.32, 95% confidence interval -4.06 to 3.42; Comprehensive Assessment of At-Risk Mental States symptom severity 0.29, 95% confidence interval -4.35 to 4.94; or distress treatment effect 4.09, 95% confidence interval -3.52 to 11.70. Greater Comprehensive Assessment of At-Risk Mental States for psychosis scores reflect greater symptom severity. We found no evidence of significant differences at 9 or 24 months. Social recovery therapy was not estimated to be cost-effective. The key limitation was that missingness of data was consistently greater in the enhanced standard care-alone arm (9% primary outcome and 15% secondary outcome missingness of data) than in the social recovery therapy plus enhanced standard care arm (4% primary outcome and 9% secondary outcome missingness of data) at 15 months. CONCLUSIONS: We found no evidence for the clinical superiority or cost-effectiveness of social recovery therapy as an adjunct to enhanced standard care. Both arms made large improvements in primary and secondary outcomes. Enhanced standard care included a comprehensive combination of evidence-based pharmacological, psychotherapeutic and psychosocial interventions. Some results favoured enhanced standard care but the majority were not statistically significant. Future work should identify factors associated with the optimal delivery of the combinations of interventions that underpin better outcomes in this often-neglected clinical group. TRIAL REGISTRATION: Current Controlled Trials ISRCTN47998710. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment Vol. 25, No. 70. See the NIHR Journals Library website for further project information.

Young people with social disability and non-psychotic severe and complex mental health problems are an important group. Their problems are often long-standing and they often have difficulty doing 'structured activity', such as work, sports and leisure activities (e.g. going shopping or to the cinema). They often avoid such activities because of anxiety or low mood. Other barriers may include financial and practical issues, and stigma from activity providers. Non-participation in structured activity increases the risk that mental health problems will continue and prevent these young people from reaching meaningful goals. We tested whether or not social recovery therapy might help. This is a talking and activity therapy, in which young people (participants) work individually with a social recovery therapy therapist. Social recovery therapy aims to help participants identify what activities they would like to do, practise spending more time doing them, and work through barriers to maintaining increased activity. By improving structured activity, young people feel more hopeful and better able to manage their symptoms. However, social recovery therapy has never been evaluated properly using the best research methods. The best way to evaluate treatments like this is a randomised controlled trial in which participants are allocated by chance, like tossing a coin, to have the new therapy or not to have the therapy. Both groups are followed up for a period to see if the new therapy works. We tested social recovery therapy in this way. We also tested whether or not it was cost-effective. We recruited 270 16- to 25-year-old participants in Sussex, East Anglia and Manchester. Participants had non-psychotic severe and complex mental health problems (not psychosis) and were doing < 30 hours of structured activity per week at the start of the study. All participants had enhanced standard care. This involved standard NHS treatment plus a full assessment and feedback from the study team, and a best practice guide to local support services that encouraged the best provision of standard evidence-based interventions. Half of the participants were randomly allocated to have social recovery therapy in addition to enhanced standard care over 9 months. All participants were invited to assessments 9, 15 and 24 months later. Therapists recorded the tasks and activities undertaken with participants. We asked both participants and therapists what they thought of the trial and the social recovery therapy. We found no evidence that adding social recovery therapy improved outcomes. Participants in both arms made large and clinically worthwhile improvements in structured activity and mental health outcomes. If anything, there was some evidence that people allocated to enhanced standard care improved more than those allocated to social recovery therapy plus enhanced standard care. The differences were small, however, and could have occurred by chance.

The Reflective Fostering Programme-improving the wellbeing of children in care through a group intervention for foster carers: a randomised controlled trial.

BACKGROUND: The needs of children in care are a government priority, yet the evidence base for effective interventions to support the emotional wellbeing of children in care is lacking. Research suggests that supporting the carer-child relationship, by promoting the carer's reflective parenting, may be an effective approach to improving the wellbeing of these children. METHODS: The study comprises a definitive, superiority, two-armed, parallel, pragmatic, randomised controlled trial, with embedded process evaluation and economic evaluation, and an internal pilot, to evaluate the effectiveness, and cost-effectiveness, of the Reflective Fostering Programme. Randomisation is at the individual level using a 1:1 allocation ratio. The study is being conducted in local authority sites across England, and is targeted at foster carers (including kinship carers) looking after children aged 4 to 13. Consenting participants are randomly allocated to the Reflective Fostering Programme (intervention arm) in addition to usual support or usual support alone (control arm). The primary outcome is behavioural and emotional wellbeing of the child 12 months post-baseline, and secondary outcomes include the following: foster carer's level of stress, quality of life, reflective capacity, compassion fatigue and burnout, placement stability, the quality of the child-carer relationship, child's capacity for emotional regulation, and achievement of personalised goals set by the carer. DISCUSSION: A feasibility study has indicated effectiveness of the Programme in improving the child-carer relationship and emotional and behavioural wellbeing of children in care. This study will test the effectiveness and cost-effectiveness of implementing the Reflective Fostering Programme as an additional aid to the support already available to local authority foster carers. TRIAL REGISTRATION: ISRCTN 70832140 .

Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia. METHODS: This parallel-group, double-blind, placebo-controlled trial-the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)-was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897. FINDINGS: Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference -1·74, 95% CI -7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065). INTERPRETATION: This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Protocol for the process evaluation of a cluster randomised controlled trial to determine the effectiveness and cost-effectiveness of independent pharmacist prescribing in care home: the CHIPPS study.

BACKGROUND: Prescribing, monitoring and administration of medicines in care homes could be improved. A cluster randomised controlled trial (RCT) is ongoing to evaluate the effectiveness of an independent prescribing pharmacist assuming responsibility for medicines management in care homes compared to usual care. AIMS AND OBJECTIVES: To conduct a mixed-methods process evaluation of the RCT, in line with Medical Research Council (MRC) process evaluation guidance, to inform interpretation of main trial findings and if the service is found to be effective and efficient, to inform subsequent implementation. OBJECTIVES: 1. To describe the intervention as delivered in terms of quality, quantity, adaptations and variations across triads and time. 2. To explore the effects of individual intervention components on the primary outcomes. 3. To investigate the mechanisms of impact. 4. To describe the perceived effectiveness of relevant intervention components [including pharmacist independent prescriber (PIP) training and care home staff training] from participant [general practitioner (GP), care home, PIP and resident/relative] perspectives. 5. To describe the characteristics of GP, care home, PIP and resident participants to assess reach. 6. To estimate the extent to which intervention delivery is normalised among the intervention healthcare professionals and related practice staff. METHODS: A mix of quantitative (surveys, record reviews) and qualitative (interviews) approaches will be used to collect data on the extent of the delivery of detailed tasks required to implement the new service, to collect data to confirm the mechanism of impact as hypothesised in the logic model, to collect explanatory process and final outcome data, and data on contextual factors which could have facilitated or hindered effective and efficient delivery of the service. DISCUSSION: Recruitment is ongoing and the trial should complete in early 2020. The systematic and comprehensive approach that is being adopted will ensure data is captured on all aspects of the study, and allow a full understanding of the implementation of the service and the RCT findings. With so many interrelated factors involved it is important that a process evaluation is undertaken to enable us to identify which elements of the service were deemed to be effective, explain any differences seen, and identify enablers, barriers and future adaptions. TRIAL REGISTRATION: ISRCTN17847169. Date registered: 15 December 2017.

Protocol for a cluster randomised controlled trial to determine the effectiveness and cost-effectiveness of independent pharmacist prescribing in care homes: the CHIPPS study.

BACKGROUND: Prescribing, monitoring and administration of medicines in care homes could be improved. Research has identified the need for one person to assume overall responsibility for the management of medicines within each care home. and shown that a pharmacist independent prescriber service is feasible in this context. AIMS AND OBJECTIVES: To conduct a cluster randomised controlled trial to determine the effectiveness and cost-effectiveness of a pharmacist-independent prescribing service in care homes compared to usual general practitioner (GP)-led care. OBJECTIVES: To perform a definitive randomised controlled trial (RCT) with an internal pilot to determine the intervention's effectiveness and cost-effectiveness and enable modelling beyond the end of the trial. METHODS: This protocol is for a cluster RCT with a 3-month internal pilot to confirm that recruitment is achievable, and there are no safety concerns. The unit of randomisation is a triad comprising a pharmacist-independent prescriber (PIP) based in a GP practice with sufficient registered patients resident in one or more care homes to allow recruitment of an average of 20 participants. In the intervention group, the PIP will, in collaboration with the GP: assume responsibility for prescribing and managing residents' medicines including medication review and pharmaceutical care planning; support systematic ordering and administration in the care home, GP practice and supplying pharmacy; train care home and GP practice staff; communicate with GP practice, care home, supplying community pharmacy and study team. The intervention will last 6 months. The primary outcome will be resident falls at 6 months. Secondary outcomes include resident health-related quality of life, falls at 3 months, medication burden, medication appropriateness, mortality and hospitalisations. A full health economic analysis will be undertaken. The target sample size is 880 residents (440) in each arm) from 44 triads. This number is sufficient to detect a decrease in fall rate from 1.5 per individual to 1.178 (relative reduction of 21%) with 80% power and an ICC of 0.05 or less. DISCUSSION: Recruitment is on-going and the trial should complete in early 2020. The trial results will have implications for the future management of residents in care homes and the ongoing implementation of independent pharmacist prescribing. TRIAL REGISTRATION: ISRCTN, ID: 17847169. Registered on 15 December 2017.

The Cost-Effectiveness of Screening in the Community to Reduce Osteoporotic Fractures in Older Women in the UK: Economic Evaluation of the SCOOP Study.

The SCOOP study was a two-arm randomized controlled trial conducted in the UK in 12,483 eligible women aged 70 to 85 years. It compared a screening program using the FRAX® risk assessment tool in addition to bone mineral density (BMD) measures versus usual management. The SCOOP study found a reduction in the incidence of hip fractures in the screening arm, but there was no evidence of a reduction in the incidence of all osteoporosis-related fractures. To make decisions about whether to implement any screening program, we should also consider whether the program is likely to be a good use of health care resources, ie, is it cost-effective? The cost per gained quality adjusted life year of screening for fracture risk has not previously been demonstrated in an economic evaluation alongside a clinical trial. We conducted a "within trial" economic analysis alongside the SCOOP study from the perspective of a national health payer, the UK National Health Service (NHS). The main outcome measure in the economic analysis was the cost per quality adjusted life year (QALY) gained over a 5-year time period. We also estimated cost per osteoporosis-related fracture prevented and the cost per hip fracture prevented. The screening arm had an average incremental QALY gain of 0.0237 (95% confidence interval -0.0034 to 0.0508) for the 5-year follow-up. The incremental cost per QALY gained was £2772 compared with the control arm. Cost-effectiveness acceptability curves indicated a 93% probability of the intervention being cost-effective at values of a QALY greater than £20,000. The intervention arm prevented fractures at a cost of £4478 and £7694 per fracture for osteoporosis-related and hip fractures, respectively. The current study demonstrates that a systematic, community-based screening program of fracture risk in older women in the UK represents a highly cost-effective intervention. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Protocol for a feasibility randomised controlled trial of Screening and Enhanced Risk management for Vascular Event-related Decline in Memory (SERVED Memory).

INTRODUCTION: Stroke is a leading cause of death and disability. The development of dementia after stroke is common. Vascular risk factors (VRF) which contribute to stroke risk can also contribute to cognitive decline, especially in vascular dementia (VaD). There is no established treatment for VaD, therefore strategies for prevention could have major health resource implications. This study was designed to assess whether patients with early cognitive decline after stroke/transient ischaemic attack (TIA) can be easily identified and whether target-driven VRF management can prevent progression to dementia. OBJECTIVES: The primary objective is to establish the feasibility of recruitment and retention of patients with early cognitive decline to a randomised controlled trial of enhanced VRF management. Secondary objectives include: (a) to determine the potential clinical benefit of the intervention; (b) to estimate the sample size for a future definitive multicentre randomised controlled trial; (c) to inform a future economic evaluation; (d) to explore the link between VRF control and the incidence of cognitive impairment on longitudinal follow-up in a UK population after stroke/TIA with current routine management. METHODS: 100 patients with cognitive decline poststroke/TIA will be recruited from stroke services at the Norfolk and Norwich University Hospital. After collection of baseline data, they will be randomised to intervention (3 monthly follow-up with enhanced management) or control (treatment as usual by the general practitioner). At 12 months outcomes (repeat cognitive testing, VRF assessment) will be assessed. A further 100 patients without cognitive decline will be recruited to a parallel observational group from the same site. At 12 months they will have repeat cognitive testing. ETHICS AND DISSEMINATION: Ethical approval has been granted in England. Dissemination is planned via publication in peer-reviewed medical journals and presentation at relevant conferences. TRIAL REGISTRATION NUMBER: 42688361; Pre-results.

Association of psychological distress, quality of life and costs with carpal tunnel syndrome severity: a cross-sectional analysis of the PALMS cohort.

OBJECTIVES: The Prediciting factors for response to treatment in carpal tunnel syndrome (PALMS) study is designed to identify prognostic factors for outcome from corticosteroid injection and surgical decompression for carpal tunnel syndrome (CTS) and predictors of cost over 2 years. The aim of this paper is to explore the cross-sectional association of baseline patient-reported and clinical severity with anxiety, depression, health-related quality of life and costs of CTS in patients referred to secondary care. METHODS: Prospective, multicentre cohort study initiated in 2013. We collected baseline data on patient-reported symptom severity (CTS-6), psychological status (Hospital Anxiety and Depression Scale), hand function (Michigan Hand Questionnaire) comorbidities, EQ-5D-3L (3-level version of EuroQol-5 dimension) and sociodemographic variables. Nerve conduction tests classified patients into five severity grades (mild to very severe). Data were analysed using a general linear model. RESULTS: 753 patients with CTS provided complete baseline data. Multivariable linear regression adjusting for age, sex, ethnicity, duration of CTS, smoking status, alcohol consumption, employment status, body mass index and comorbidities showed a highly statistically significant relationship between CTS-6 and anxiety, depression and the EQ-5D (p<0.0001 in each case). Likewise, a significant relationship was observed between electrodiagnostic severity and anxiety (p=0.027) but not with depression (p=0.986) or the EQ-5D (p=0.257). National Health Service (NHS) and societal costs in the 3 months prior to enrolment were significantly associated with self-reported severity (p<0.0001) but not with electrodiagnostic severity. CONCLUSIONS: Patient-reported symptom severity in CTS is significantly and positively associated with anxiety, depression, health-related quality of life, and NHS and societal costs even when adjusting for age, gender, body mass index, comorbidities, smoking, drinking and occupational status. In contrast, there is little or no evidence of any relationship with objectively derived CTS severity. Future research is needed to understand the impact of approaches and treatments that address psychosocial stressors as well as biomedical factors on relief of symptoms from carpal tunnel syndrome.

Cognitive bias modification for social anxiety in adults who stutter: a feasibility study of a randomised controlled trial.

OBJECTIVE: To determine the feasibility and acceptability of a computerised treatment for social anxiety disorder for adults who stutter including identification of recruitment, retention and completion rates, large cost drivers and selection of most appropriate outcome measure(s) to inform the design of a future definitive trial. DESIGN: Two-group parallel design (treatment vs placebo), double-blinded feasibility study. PARTICIPANTS: 31 adults who stutter. INTERVENTION: Attention training via an online probe detection task in which the stimuli were images of faces displaying neutral and disgusted expressions. MAIN OUTCOME MEASURES: Psychological measures: Structured Clinical Interview Global Assessment of Functioning score; Liebowitz Social Anxiety Scale; Social Phobia and Anxiety Inventory; State-Trait Anxiety Inventory; Unhelpful Thoughts and Beliefs about Stuttering. Speech fluency: percent syllables stuttered. Economic evaluation: resource use questionnaire; EuroQol three-dimension questionnaire.Acceptability: Likert Scale questionnaire of experience of trial, acceptability of the intervention and randomisation procedure. RESULTS: Feasibility of recruitment strategy was demonstrated. Participant feedback indicated that the intervention and definitive trial, including randomisation, would be acceptable to adults who stutter. Of the 31 participants who were randomised, 25 provided data at all three data collection points. CONCLUSIONS: The feasibility study informed components of the intervention. Modifications to the design are needed before a definitive trial can be undertaken. TRIAL REGISTRATION NUMBER: I SRCTN55065978; Post-results.

Prevention and treatment of long-term social disability amongst young people with emerging severe mental illness with social recovery therapy (The PRODIGY Trial): study protocol for a randomised controlled trial.

BACKGROUND: Young people who have social disability associated with severe and complex mental health problems are an important group in need of early intervention. Their problems often date back to childhood and become chronic at an early age. Without intervention, the long-term prognosis is often poor and the economic costs very large. There is a major gap in the provision of evidence-based interventions for this group, and therefore new approaches to detection and intervention are needed. This trial provides a definitive evaluation of a new approach to early intervention with young people with social disability and severe and complex mental health problems using social recovery therapy (SRT) over a period of 9 months to improve mental health and social recovery outcomes. METHODS: This is a pragmatic, multi-centre, single blind, superiority randomised controlled trial. It is conducted in three sites in the UK: Sussex, Manchester and East Anglia. Participants are aged 16 to 25 and have both persistent and severe social disability (defined as engaged in less than 30 hours per week of structured activity) and severe and complex mental health problems. The target sample size is 270 participants, providing 135 participants in each trial arm. Participants are randomised 1:1 using a web-based randomisation system and allocated to either SRT plus optimised treatment as usual (enhanced standard care) or enhanced standard care alone. The primary outcome is time use, namely hours spent in structured activity per week at 15 months post-randomisation. Secondary outcomes assess typical mental health problems of the group, including subthreshold psychotic symptoms, negative symptoms, depression and anxiety. Time use, secondary outcomes and health economic measures are assessed at 9, 15 and 24 months post-randomisation. DISCUSSION: This definitive trial will be the first to evaluate a novel psychological treatment for social disability and mental health problems in young people presenting with social disability and severe and complex non-psychotic mental health problems. The results will have important implications for policy and practice in the detection and early intervention for this group in mental health services. TRIAL REGISTRATION: Trial Registry: International Standard Randomised Controlled Trial Number (ISRCTN) Registry. TRIAL REGISTRATION NUMBER: ISRCTN47998710 (registered 29/11/2012).

Economic Evaluation Alongside a Randomized Controlled Crossover Trial of Modified Group Cognitive-Behavioral Therapy for Anxiety Compared to Treatment-as-Usual in Adults With Asperger Syndrome.

Background: There is a growing interest in using group cognitive-behavioral therapy (CBT) with people who have Asperger syndrome (AS) and comorbid mental health problems. This study aims to assess the cost-effectiveness of modified group CBT for adults with AS experiencing co-occurring anxiety compared to treatment-as-usual. Methods: Economic evaluation alongside a pilot, multicenter, single-blind, randomized controlled crossover trial. Costs from the UK public sector (National Health Service and Social Services) and societal perspectives, quality-adjusted life years (QALYs), incremental net (monetary) benefit (INB), expected value of perfect information, expected value of sample information, expected net gain of sampling, and efficient sample size of a future trial are reported. Results: Over 48 weeks, from the societal perspective, CBT results in additional costs of £6,647, with only a 0.015 incremental gain in QALYs, leading to a negative INB estimate of £6,206 and a 23% probability of cost-effectiveness at a threshold of £30,000/QALY. Results from sensitivity analyses support the unlikely cost-effectiveness of CBT but indicate the potential for cost-effectiveness over longer time horizons. Eliminating decision uncertainty is valued at £277 million, and the efficient sample size for a future trial is estimated at 1,200 participants per arm. Limitations: Relatively small sample size and prevalence of missing data present challenges to the interpretation of the results. Conclusions: Current evidence from this small pilot study suggests that, on average, modified group CBT is not cost-effective. However, there is much decision uncertainty so such a conclusion could be wrong. A large, full-scale trial to reduce uncertainty would be an efficient investment for the UK health economy.

The feasibility of determining the effectiveness and cost-effectiveness of medication organisation devices compared with usual care for older people in a community setting: systematic review, stakeholder focus groups and feasibility randomised controlled trial.

BACKGROUND: Medication organisation devices (MODs) provide compartments for a patient's medication to be organised into the days of the week and the recommended times the medication should be taken. AIM: To define the optimal trial design for testing the clinical effectiveness and cost-effectiveness of MODs. DESIGN: The feasibility study comprised a systematic review and focus groups to inform a randomised controlled trial (RCT) design. The resulting features were tested on a small scale, using a 2 × 2 factorial design to compare MODs with usual packaging and to compare weekly with monthly supply. The study design was then evaluated. SETTING: Potential participants were identified by medical practices. PARTICIPANTS: Aged over 75 years, prescribed at least three solid oral dosage form medications, unintentionally non-adherent and self-medicating. Participants were excluded if deemed by their health-care team to be unsuitable. INTERVENTIONS: One of three MODs widely used in routine clinical practice supplied either weekly or monthly. OBJECTIVES: To identify the most effective method of participant recruitment, to estimate the prevalence of intentional and unintentional non-adherence in an older population, to provide a point estimate of the effect size of MODs relative to usual care and to determine the feasibility and acceptability of trial participation. METHODS: The systematic review included MOD studies of any design reporting medication adherence, health and social outcomes, resource utilisation or dispensing or administration errors. Focus groups with patients, carers and health-care professionals supplemented the systematic review to inform the RCT design. The resulting design was implemented and then evaluated through questionnaires and group discussions with participants and health-care professionals involved in trial delivery. RESULTS: Studies on MODs are largely of poor quality. The relationship between adherence and health outcomes is unclear. Of the limited studies reporting health outcomes, some reported a positive relationship while some reported increased hospitalisations associated with MODs. The pre-trial focus groups endorsed the planned study design, but suggested a minimum recruitment age of 50-60 years. A total of 35.4% of patients completing the baseline questionnaire were excluded because they already used a MOD. Active recruitment yielded a higher consent rate, but passive recruitment was more cost-effective. The prevalence of intentional non-adherence was 24.7% [n = 71, 95% confidence interval (CI) 19.7% to 29.6%] of participants. Of the remaining 76 participants, 46.1% (95% CI 34.8% to 57.3%) were unintentionally non-adherent. There was no indication of a difference in adherence between the study arms. Participants reported a high level of satisfaction with the design. Five adverse/serious adverse events were identified in the MOD study arms and none was identified in the control arms. There was no discernible difference in health economic outcomes between the four study arms; the mean intervention cost was £20 per month greater for MOD monthly relative to usual supply monthly. CONCLUSIONS: MOD provision to unintentionally non-adherent older people may cause medication-related adverse events. The primary outcome for a definitive MOD trial should be health outcomes. Such a trial should recruit patients by postal invitation and recruit younger patients. FUTURE WORK: A study examining the association between MOD initiation and adverse effects is necessary and a strategy to safely introduce MODs should be explored. A definitive study testing the clinical effectiveness and cost-effectiveness of MODs is also required. STUDY REGISTRATION: Current Controlled Trials ISRCTN 30626972 and UKCRN 12739. FUNDING: This project was funded by National Institute for Health Research (NIHR) Health Technology Assessment Programme and will be published in full in Health Technology Assessment; Vol. 20, No. 50. See the NIHR Journals Library website for further project information.

Efficient Research Design: Using Value-of-Information Analysis to Estimate the Optimal Mix of Top-down and Bottom-up Costing Approaches in an Economic Evaluation alongside a Clinical Trial.

In designing economic evaluations alongside clinical trials, analysts are frequently faced with alternative methods of collecting the same data, the extremes being top-down ("gross costing") and bottom-up ("micro-costing") approaches. A priori, bottom-up approaches may be considered superior to top-down approaches but are also more expensive to collect and analyze. In this article, we use value-of-information analysis to estimate the efficient mix of observations on each method in a proposed clinical trial. By assigning a prior bivariate distribution to the 2 data collection processes, the predicted posterior (i.e., preposterior) mean and variance of the superior process can be calculated from proposed samples using either process. This is then used to calculate the preposterior mean and variance of incremental net benefit and hence the expected net gain of sampling. We apply this method to a previously collected data set to estimate the value of conducting a further trial and identifying the optimal mix of observations on drug costs at 2 levels: by individual item (process A) and by drug class (process B). We find that substituting a number of observations on process A for process B leads to a modest £ 35,000 increase in expected net gain of sampling. Drivers of the results are the correlation between the 2 processes and their relative cost. This method has potential use following a pilot study to inform efficient data collection approaches for a subsequent full-scale trial. It provides a formal quantitative approach to inform trialists whether it is efficient to collect resource use data on all patients in a trial or on a subset of patients only or to collect limited data on most and detailed data on a subset.

The outcome and cost-effectiveness of nurse-led care in the community for people with rheumatoid arthritis: a non-randomised pragmatic study.

OBJECTIVE: To determine the outcome and cost-effectiveness of nurse-led care in the community for people with rheumatoid arthritis (RA). DESIGN: Non-randomised pragmatic study. SETTING: Primary (7 primary care practices) and secondary care (single centre) in the UK. METHODS: In a single area, pragmatic non-randomised study, we assessed the outcome, cost-effectiveness of community-based nurse-led care (NLC) compared with rheumatologist-led outpatient care (RLC). Participants were 349 adults (70% female) with stable RA assessed at baseline, 6 and 12 months. In the community NLC arm there were 192 participants. Outcome was assessed using Stanford Health Assessment Questionnaire (HAQ). The economic evaluation (healthcare perspective) estimated cost relative to change in HAQ and quality-adjusted life years (QALY) derived from EQ-5D-3L. We report complete case and multiple imputation results from regression analyses. RESULTS: The demographics and baseline characteristics of patients in the community group were comparable to those under hospital care apart from use of biological disease-modifying antirheumatic drugs (DMARDS), which were adjusted for in the analysis. The mean incremental cost was estimated to be £224 less for RLC compared to the community NLC, with wide CIs (CI -£213 to £701, p=0.296). Levels of functional disability were not clinically significantly higher in the community NLC group: HAQ 0.096 (95% CI -0.026 to 0.206; p=0.169) and QALY 0.023 (95% CI -0.059 to 0.012; p=0.194). CONCLUSIONS: The results suggest that community care may be associated with non-significant higher costs with no significant differences in clinical outcomes, and this suggests a low probability that it is cost-effective.

Can paramedics use FRAX (the WHO Fracture Risk Assessment Tool) to help GPs improve future fracture risk in patients who fall? Protocol for a randomised controlled feasibility study.

INTRODUCTION: Currently identification, and therefore, management of patients at risk of osteoporotic fracture in the UK is suboptimal. As the majority of patients who fracture have fallen, it follows that people who fall can usefully be targeted in any programme that aims to reduce osteoporotic fracture. Targeting vulnerable patients who are likely to benefit from intervention may help shift the management of fracture prevention into primary care, away from emergency departments. Paramedics who attend to patients who have fallen may be well placed to assess future fracture risk, using the Fracture Risk Assessment Tool (FRAX) and communicate that information directly to general practitioners (GPs). METHODS AND ANALYSIS: This feasibility study takes the form of a pragmatic, randomised controlled trial aimed at exploring and refining issues of study design, recruitment, retention, sample size and acceptability preceding a large-scale study with fracture as the end point. Patients (aged >50) who fall, call an ambulance, are attended by a study paramedic and give verbal consent will be asked FRAX and fall questions. Patients who subsequently formally consent to participation will be randomised to control (usual care) or intervention groups. Intervention will constitute transmission of calculated future fracture risk to the patients' GP with suitable, evidence-based recommendations for investigation or treatment. 3 months after the index fall, data (proportion of patients in each group undergoing investigation or starting new treatment, quality of life and health economic) will be collected and analysed using descriptive statistics. A nested qualitative study will explore issues of acceptability and study design with patients, paramedics and GPs. ETHICS AND DISSEMINATION: This protocol was approved by NRES Committee South Central Oxford C in October 2012. Research Ethics Committee ref.12/SC/0604. The study findings will be disseminated through peer-reviewed journals, conference presentations and local public events. A publication plan and authorship criteria have been preagreed. TRIAL REGISTRATION NUMBER ISRCTN: 36245726.