Acceptability of Four Intervention Components Supporting Medication Adherence in Women with Breast Cancer: a Process Evaluation of a Fractional Factorial Pilot Optimization Trial.

Adjuvant endocrine therapy (AET) reduces mortality in early-stage breast cancer, but adherence is low. We developed a multicomponent intervention to support AET adherence comprising: text messages, information leaflet, acceptance and commitment therapy (ACT), and side-effect website. Guided by the multiphase optimization strategy, the intervention components were tested in the ROSETA pilot optimization trial. Our mixed-methods process evaluation investigated component acceptability. The pilot optimization trial used a 24-1 fractional factorial design. Fifty-two women prescribed AET were randomized to one of eight experimental conditions, containing unique component combinations. An acceptability questionnaire was administered 4 months post-randomization, and semi-structured interviews with 20 participants further explored acceptability. Assessments were guided by four constructs of the theoretical framework of acceptability: affective attitude, burden, perceived effectiveness, and coherence. Quantitative and qualitative findings were triangulated to identify agreements/disagreements. There were high overall acceptability scores (median = 14-15/20, range = 11-20). There was agreement between the qualitative and quantitative findings when triangulated. Most participants "liked" or "strongly liked" all components and reported they required low effort to engage in. Between 50% (leaflet) and 65% (SMS) "agreed" or "strongly agreed," it was clear how each component would help adherence. Perceived effectiveness was mixed, with 35.0% (text messages) to 55.6% (ACT) of participants "agreeing" or "strongly agreeing" that each component would improve their adherence. Interview data provided suggestions for improvements. The four components were acceptable to women with breast cancer and will be refined. Mixed-methods and triangulation were useful methodological approaches and could be applied in other optimization trial process evaluations.

The impact of ankle haemarthropathy in patients with moderate haemophilia.

INTRODUCTION: Moderate haemophilia has traditionally been associated with less complications than severe haemophilia. Changes in treatment recommendations have highlighted the burden of moderate haemophilia with a subset of patients with a severe bleeding phenotype. The ankle joint is disproportionally affected by ankle haemarthropathy however the impact has not been evaluated in moderate haemophilia, nor the effect on health related quality of life (HRQoL) or foot and ankle outcomes. AIMS: To establish the impact of ankle haemarthropathy in patients with moderate haemophilia. METHODS: A multicentre questionnaire study recruited patients from 11 haemophilia centres in England, Scotland and Wales. The HAEMO-QoL-A and Manchester-Oxford foot and ankle questionnaire (MOXFQ) with total and domain scores measured impact. Measures of pain and ankle haemophilia joint health (HJHS) scores were also collected. RESULTS: Twenty-nine participants were recruited. HAEMO-QoL A mean (SD) total scores of 10.8 (5.2) of 100 (best health) and foot and ankle specific MOXFQ total scores of 45.5 (24.7) above zero (best outcome) indicate poor HRQoL and foot and ankle outcomes. Average ankle pain over past 6 months of (0-10) 5.5 (SD2.5) was reported and median (IQR) ankle HJHS of 3.0 (1;12.5) to 4.5 (0;9.5) for the left and right ankles. CONCLUSION: HRQoL and foot and ankle specific outcomes are poor in patients with moderate haemophilia and ankle haemarthropathy, driven by chronic levels of ankle joint pain. Despite moderate haemophilia being considered less affected by haemarthrosis and haemarthropathy, patients with a bleeding or haemarthropathy phenotype are clinically similar to patients with severe haemophilia A.

Optimization of an Information Leaflet to Influence Medication Beliefs in Women With Breast Cancer: A Randomized Factorial Experiment.

BACKGROUND: Adherence to adjuvant endocrine therapy (AET) is low in women with breast cancer. Negative beliefs about the necessity of AET and high concerns are barriers to adherence. PURPOSE: To use the multiphase optimization strategy to optimize the content of an information leaflet intervention, to change AET beliefs. METHODS: We conducted an online screening experiment using a 25 factorial design to optimize the leaflet. The leaflet had five components, each with two levels: (i) diagrams about AET mechanisms (on/off); (ii) infographics displaying AET benefits (enhanced/basic); (iii) AET side effects (enhanced/basic); (iv) answers to AET concerns (on/off); (v) breast cancer survivor (patient) input: quotes and photographs (on/off). Healthy adult women (n = 1,604), recruited via a market research company, were randomized to 1 of 32 experimental conditions, which determined the levels of components received. Participants completed the Beliefs about Medicines Questionnaire before and after viewing the leaflet. RESULTS: There was a significant main effect of patient input on beliefs about medication (ß = 0.063, p < .001). There was one significant synergistic two-way interaction between diagrams and benefits (ß = 0.047, p = .006), and one antagonistic two-way interaction between diagrams and side effects (ß = -0.029, p = .093). There was a synergistic three-way interaction between diagrams, concerns, and patient input (ß = 0.029, p = .085), and an antagonistic four-way interaction between diagrams, benefits, side effects, and concerns (ß = -0.038, p = .024). In a stepped approach, we screened in four components and screened out the side effects component. CONCLUSIONS: The optimized leaflet did not contain enhanced AET side effect information. Factorial experiments are efficient and effective for refining the content of information leaflet interventions.

Adjuvant endocrine therapy (AET) is a medication given to women to stop breast cancer from returning. Many women do not take AET every day or stop taking it before they should. Some women do not take AET because they do not believe it will help them, or they have concerns about the side effects. We ran an online study aiming to create the best information leaflet to help women understand how AET is helpful and to reduce their concerns. The leaflet had five sections; diagrams explaining how AET works, visual pictures of the benefits of AET, information about the side effects, answers to common concerns, and quotes from other women with breast cancer. 1,604 healthy women filled in a questionnaire before and after looking at an information leaflet about AET. Women received different combinations of the five sections of the information leaflet. We found quotes from other women with breast cancer led to more positive beliefs about AET. Some sections of the leaflet worked better in combination, while other sections were worse in combination. Our results led us to remove the detailed side effect information from the leaflet, as in combination with the other sections this negatively affected women's beliefs about AET.

A systematic review and narrative synthesis of footwear and orthotic devices used in the management of ankle haemarthrosis and haemarthropathy in haemophilia.

INTRODUCTION: Haemarthrosis is a clinical feature of haemophilia leading to haemarthropathy. The ankle joint is most commonly affected, resulting in significant pain, disability and a reduction in health-related quality of life. Footwear and orthotic devices are effective in other diseases that affect the foot and ankle, such as rheumatoid arthritis, but little is known about their effect in haemophilia. AIMS: To review the efficacy and effectiveness of footwear and orthotic devices in the management of ankle joint haemarthrosis and haemarthropathy in haemophilia. METHODS: A systematic literature review was conducted. Two review authors independently screened studies for inclusion and appraised methodological quality using Joanna Briggs Institute Critical Appraisal checklists. A narrative analysis was undertaken. RESULTS: Ten studies involving 271 male participants were eligible for inclusion. All studies were quasi-experimental; three employed a within-subject design. Two studies included an independent comparison or control group. A range of footwear and orthotic devices were investigated. Limited evidence from non-randomised studies suggested that footwear and orthotic devices improve the number of ankle joint bleeding episodes, gait parameters and patient-reported pain. CONCLUSION: This review demonstrates a lack of robust evidence regarding the efficacy and effectiveness of footwear and orthotic devices in the management of ankle joint haemarthrosis and haemarthropathy in haemophilia. Methodological heterogeneities and limitations with the study designs, small sample sizes and limited follow-up of participants exist. Future studies utilising randomised designs, larger sample sizes, long-term follow-up and validated patient-reported outcome measures are needed to inform the clinical management of ankle joint haemarthrosis and haemarthropathy.

A hypothesis test of feasibility for external pilot trials assessing recruitment, follow-up, and adherence rates.

The power of a large clinical trial can be adversely affected by low recruitment, follow-up, and adherence rates. External pilot trials estimate these rates and use them, via prespecified decision rules, to determine if the definitive trial is feasible and should go ahead. There is little methodological research underpinning how these decision rules, or the sample size of the pilot, should be chosen. In this article we propose a hypothesis test of the feasibility of a definitive trial, to be applied to the external pilot data and used to make progression decisions. We quantify feasibility by the power of the planned trial, as a function of recruitment, follow-up, and adherence rates. We use this measure to define hypotheses to test in the pilot, propose a test statistic, and show how the error rates of this test can be calculated for the common scenario of a two-arm parallel group definitive trial with a single normally distributed primary endpoint. We use our method to redesign TIGA-CUB, an external pilot trial comparing a psychotherapy with treatment as usual for children with conduct disorders. We then extend our formulation to include using the pilot data to estimate the standard deviation of the primary endpoint and incorporate this into the progression decision.

Bayesian design and analysis of external pilot trials for complex interventions.

External pilot trials of complex interventions are used to help determine if and how a confirmatory trial should be undertaken, providing estimates of parameters such as recruitment, retention, and adherence rates. The decision to progress to the confirmatory trial is typically made by comparing these estimates to pre-specified thresholds known as progression criteria, although the statistical properties of such decision rules are rarely assessed. Such assessment is complicated by several methodological challenges, including the simultaneous evaluation of multiple endpoints, complex multi-level models, small sample sizes, and uncertainty in nuisance parameters. In response to these challenges, we describe a Bayesian approach to the design and analysis of external pilot trials. We show how progression decisions can be made by minimizing the expected value of a loss function, defined over the whole parameter space to allow for preferences and trade-offs between multiple parameters to be articulated and used in the decision-making process. The assessment of preferences is kept feasible by using a piecewise constant parametrization of the loss function, the parameters of which are chosen at the design stage to lead to desirable operating characteristics. We describe a flexible, yet computationally intensive, nested Monte Carlo algorithm for estimating operating characteristics. The method is used to revisit the design of an external pilot trial of a complex intervention designed to increase the physical activity of care home residents.

Effectiveness of Dementia Care Mapping™ to reduce agitation in care home residents with dementia: an open-cohort cluster randomised controlled trial.

OBJECTIVES: Agitation is common and problematic in care home residents with dementia. This study investigated the (cost)effectiveness of Dementia Care Mapping™ (DCM) for reducing agitation in this population. METHOD: Pragmatic, cluster randomised controlled trial with cost-effectiveness analysis in 50 care homes, follow-up at 6 and 16 months and stratified randomisation to intervention (n = 31) and control (n = 19). Residents with dementia were recruited at baseline (n = 726) and 16 months (n = 261). Clusters were not blinded to allocation. Three DCM cycles were scheduled, delivered by two trained staff per home. Cycle one was supported by an external DCM expert. Agitation (Cohen-Mansfield Agitation Inventory (CMAI)) at 16 months was the primary outcome. RESULTS: DCM was not superior to control on any outcomes (cross-sectional sample n = 675: 287 control, 388 intervention). The adjusted mean CMAI score difference was -2.11 points (95% CI -4.66 to 0.44, p = 0.104, adjusted ICC control = 0, intervention 0.001). Sensitivity analyses supported the primary analysis. Incremental cost per unit improvement in CMAI and QALYs (intervention vs control) on closed-cohort baseline recruited sample (n = 726, 418 intervention, 308 control) was £289 and £60,627 respectively. Loss to follow-up at 16 months in the original cohort was 312/726 (43·0%) mainly (87·2%) due to deaths. Intervention dose was low with only a quarter of homes completing more than one DCM cycle. CONCLUSION: No benefits of DCM were evidenced. Low intervention dose indicates standard care homes may be insufficiently resourced to implement DCM. Alternative models of implementation, or other approaches to reducing agitation should be considered.

Validation of the Cohen-Mansfield Agitation Inventory Observational (CMAI-O) tool.

OBJECTIVES: Behaviours associated with agitation are common in people living with dementia. The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale widely used to assess agitation completed by a proxy (family carer or staff member). However, proxy informants introduce possible reporting bias when blinding to the treatment arm is not possible, and potential accuracy issues due to irregular contact between the proxy and the person with dementia over the reporting period. An observational measure completed by a blinded researcher may address these issues, but no agitation measures with comparable items exist. DESIGN: Development and validation of an observational version of the CMAI (CMAI-O), to assess its validity as an alternative or complementary measure of agitation. SETTING: Fifty care homes in England. PARTICIPANTS: Residents (N = 726) with dementia. MEASUREMENTS: Two observational measures (CMAI-O and PAS) were completed by an independent researcher. Measures of agitation, functional status, and neuropsychiatric symptoms were completed with staff proxies. RESULTS: The CMAI-O showed adequate internal consistency (α = .61), criterion validity with the PAS (r = .79, p = < .001), incremental validity in predicting quality of life beyond the Functional Assessment Staging of Alzheimer's disease (ß = 1.83, p < .001 at baseline) and discriminant validity from the Neuropsychiatric Inventory Apathy subscale (r = .004, p = .902). CONCLUSIONS: The CMAI-O is a promising research tool for independently measuring agitation in people with dementia in care homes. Its use alongside the CMAI could provide a more robust understanding of agitation amongst residents with dementia.

Validation of the Cohen-Mansfield Agitation Inventory Observational (CMAI-O) tool - ERRATUM.

The above article (Griffiths et al., 2019) published with an incorrect abstract.The correct abstract is as follows. OBJECTIVES: Behaviours associated with agitation are common in people living with dementia. The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale widely used to assess agitation completed by a proxy (family carer or staff member). However, proxy informants introduce possible reporting bias when blinding to the treatment arm is not possible, and potential accuracy issues due to irregular contact between the proxy and the person with dementia over the reporting period. An observational measure completed by a blinded researcher may address these issues, but no agitation measures with comparable items exist. DESIGN: Development and validation of an observational version of the CMAI (CMAI-O), to assess its validity as an alternative or complementary measure of agitation. SETTING: Fifty care homes in England. PARTICIPANTS: Residents (N = 726) with dementia. MEASUREMENTS: Two observational measures (CMAI-O and PAS) were completed by an independent researcher. Measures of agitation, functional status, and neuropsychiatric symptoms were completed with staff proxies. RESULTS: The CMAI-O showed adequate internal consistency (α = .61), criterion validity with the PAS (r = .79, p = < .001), incremental validity in predicting quality of life beyond the Functional Assessment Staging of Alzheimer's disease (ß = 1.83, p < .001 at baseline) and discriminant validity from the Neuropsychiatric Inventory Apathy subscale (r = .004, p = .902). CONCLUSIONS: The CMAI-O is a promising research tool for independently measuring agitation in people with dementia in care homes. Its use alongside the CMAI could provide a more robust understanding of agitation amongst residents with dementia.

TIGA-CUB-manualised psychoanalytic child psychotherapy versus treatment as usual for children aged 5-11 with treatment-resistant conduct disorders and their primary carers: results from a randomised controlled feasibility trial.

BACKGROUND: Parenting programmes are recommended for conduct disorders in 5-11 year olds, but ineffective for 25-33%. A feasibility trial was needed to determine whether a confirmatory trial of second-line, manualised short-term psychoanalytic child psychotherapy (mPCP) versus treatment as usual (TaU) is practicable. METHOD: This was a two-arm, pragmatic, parallel-group, multi-centre, individually-randomised controlled feasibility trial with blinded outcome assessment. Child-primary carer dyads were recruited from National Health Service Child and Adolescent Mental Health Services and mPCP delivered by routine child psychotherapists. RESULTS: Thirty-two dyads (50% of eligible, 95% CI 37 to 63%) were recruited, with 16 randomised to each arm. Eleven (69%) completed ≥50% of 12 week mPCP and 13 (81%) . Follow-up was obtained for 24 (75%) at 4 months and 14/16 (88%) at 8 months. Teacher follow-up was 16 (50%) ≥1 session. Manual adherence was good. Baseline candidate primary outcomes were 37.4 (SD 11.4) and 18.1 (SD 15.7) on the Child Behaviour Checklist/Teacher Report Form externalising scale and 102.8 (SD 28.4) and 58.8 (SD 38.9) on the total score. Health economics data collection was feasible and the trial acceptable to participants. CONCLUSION: Recruitment, teacher follow-up and the manual need some refinement. A confirmatory trial is feasible, subject to funding of research child psychotherapists.

Meta-analysis of standardised mean differences from randomised trials with treatment-related clustering associated with care providers.

In meta-analyses, where a continuous outcome is measured with different scales or standards, the summary statistic is the mean difference standardised to a common metric with a common variance. Where trial treatment is delivered by a person, nesting of patients within care providers leads to clustering that may interact with, or be limited to, one or more of the arms. Assuming a common standardising variance is less tenable and options for scaling the mean difference become numerous. Metrics suggested for cluster-randomised trials are within, between and total variances and for unequal variances, the control arm or pooled variances. We consider summary measures and individual-patient-data methods for meta-analysing standardised mean differences from trials with two-level nested clustering, relaxing independence and common variance assumptions, allowing sample sizes to differ across arms. A general metric is proposed with comparable interpretation across designs. The relationship between the method of standardisation and choice of model is explored, allowing for bias in the estimator and imprecision in the standardising metric. A meta-analysis of trials of counselling in primary care motivated this work. Assuming equal clustering effects across trials, the proposed random-effects meta-analysis model gave a pooled standardised mean difference of -0.27 (95% CI -0.45 to -0.08) using summary measures and -0.26 (95% CI -0.45 to -0.09) with the individual-patient-data. While treatment-related clustering has rarely been taken into account in trials, it is now recommended that it is considered in trials and meta-analyses. This paper contributes to the uptake of this guidance. Copyright © 2016 John Wiley & Sons, Ltd.

Measurement of adherence in a randomised controlled trial of a complex intervention: supported self-management for adults with learning disability and type 2 diabetes.

BACKGROUND: Reporting adherence to intervention delivery and uptake is a detailed way of describing what was actually delivered and received, in comparison to what was intended. Measuring and reporting adherence is not routinely done well in complex interventions. The OK Diabetes trial (ISRCTN41897033) aimed to develop and subsequently test the feasibility of implementing a supported self-management intervention in adults with a learning disability and type 2 diabetes. A key study objective was to develop a measure of adherence to the intervention. METHODS: We conducted a systematic review of published literature, extracting data from included papers using a standardised proforma. We undertook a narrative synthesis of papers to determine the form and content of methods for adherence measurement for self-management interventions in this population that had already been developed. We used the framework and data extraction form developed for the review as the basis for an adherence measurement tool that we applied in the OK Diabetes trial. RESULTS: The literature review found variability in the quality and content of adherence measurement and reporting, with no standardised approach. We were able to develop an adherence measure based upon the review, and populate it with data collected during the OK Diabetes trial. The adherence tool proved satisfactory for recording and measuring adherence in the trial. CONCLUSION: There remains a need for a standardised approach to adherence measurement in the field of complex interventions. We have shown that it is possible to produce a simple, feasible measure for assessing adherence in the OK Diabetes trial.

A Randomized Feasibility Trial of a New Lifestyle Referral Assessment Versus Usual Assessment in an Acute Cardiology Setting.

BACKGROUND: A healthy diet, taking exercise, and not smoking or consuming alcohol in excess are important to reduce the risk of cardiovascular disease either alone or in combination with statin medication. Health education, including providing information to patients on healthy living and guidance on how to achieve it, is a key nursing function. OBJECTIVES: This study aims first to assess the feasibility of conducting a full-scale trial of lifestyle referral assessment as shown by recruitment rate, data collection, and follow-up and second to assess proof of concept and explore possible mechanisms of change. METHODS: This was a single-center, randomized, 2-arm, parallel-group, unblinded feasibility trial conducted in an acute teaching hospital trust. Participants were followed up at 3 and 6 months after randomization. RESULTS: Eight hundred eighty-seven patients were screened for eligibility, of whom 132 (15%) were randomized into the trial. Of the patients allocated to the individualized assessment, 27% accepted referral or self-referred by 3 months in comparison to 5% allocated to the usual assessment. CONCLUSIONS: We demonstrated that a full-scale trial is feasible and that an individualized approach increased the number of patients accepting referral to a formal program and initiating lifestyle change. However, we should consider the aim of the assessment and ways in which the process of change can be optimized in order to produce long-term benefit for patients. TRIAL REGISTRATION: current controlled trials ISRCTN41781196.

Meta-analysis of absolute mean differences from randomised trials with treatment-related clustering associated with care providers.

Nesting of patients within care providers in trials of physical and talking therapies creates an additional level within the design. The statistical implications of this are analogous to those of cluster randomised trials, except that the clustering effect may interact with treatment and can be restricted to one or more of the arms. The statistical model that is recommended at the trial level includes a random effect for the care provider but allows the provider and patient level variances to differ across arms. Evidence suggests that, while potentially important, such within-trial clustering effects have rarely been taken into account in trials and do not appear to have been considered in meta-analyses of these trials. This paper describes summary measures and individual-patient-data methods for meta-analysing absolute mean differences from randomised trials with two-level nested clustering effects, contrasting fixed and random effects meta-analysis models. It extends methods for incorporating trials with unequal variances and homogeneous clustering to allow for between-arm and between-trial heterogeneity in intra-class correlation coefficient estimates. The work is motivated by a meta-analysis of trials of counselling in primary care, where the control is no counselling and the outcome is the Beck Depression Inventory. Assuming equal counsellor intra-class correlation coefficients across trials, the recommended random-effects heteroscedastic model gave a pooled absolute mean difference of -2.53 (95% CI -5.33 to 0.27) using summary measures and -2.51 (95% CI -5.35 to 0.33) with the individual-patient-data. Pooled estimates were consistently below a minimally important clinical difference of four to five points on the Beck Depression Inventory.

Reducing self-harm in adolescents: the RISA-IPD individual patient data meta-analysis and systematic review.

Background: Self-harm is common in adolescents and a major public health concern. Evidence for effective interventions is lacking. An individual patient data meta-analysis has the potential to provide more reliable estimates of the effects of therapeutic interventions for self-harm than conventional meta-analyses, to explore which treatments are best suited to certain groups. Method: A systematic review and individual patient data meta-analysis of randomised controlled trials of therapeutic interventions to reduce repeat self-harm in adolescents who had a history of self-harm and presented to clinical services. Primary outcome was repetition of self-harm. The methods employed for searches, study screening and selection, and risk of bias assessment are described, with an overview of the outputs of the searching, selection and quality assessment processes. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance is followed. Results: We identified a total 39 eligible studies, from 10 countries, where we sought Individual Patient Data (IPD), of which the full sample of participants were eligible in 18 studies and a partial sample of participants were eligible in 21 studies. We obtained IPD from 26 studies of 3448 eligible participants. For our primary outcome, repetition of self-harm, only 6 studies were rated as low risk of bias with 10 rated as high risk (although 2 of these were for secondary outcomes only). Conclusions: Obtaining individual patient data for meta-analyses is possible but very time-consuming, despite clear guidance from funding bodies that researchers should share their data appropriately. More attention needs to be paid to seeking appropriate consent from study participants for (pseudo) anonymised data-sharing and institutions need to collaborate on agreeing template data-sharing agreements. Researchers and funders need to consider issues of research design more carefully. Our next step is to analyse all the data we have collected to see if it will tell us more about how we might prevent repetition of self-harm in young people. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 17/117/11. A plain language summary of this research article is available on the NIHR Journals Library Website https://doi.org/10.3310/GTNT6331.

Self-harm is very common in young people and leads to an increased risk of death by suicide. Research so far has not provided clear evidence about which interventions can help to prevent self-harm repetition when young people present to services having harmed themselves. One way to understand what might help is to pool the results from lots of different clinical trials ­ this is known as a meta-analysis. This has already been done using the data published in research articles but has not led to clearer conclusions. In part this is because the information available in published articles is patchy and inconsistent which makes pooling the information and analysing it, difficult. A more useful approach is to ask researchers who led the clinical trials for their original 'raw' data and then pool and analyse all that data ­ this is known as an individual patient data meta-analysis. This has the added benefit that it is possible to include studies where only some of the participants are young people. We did this, and were able to identify many more study participants along with their data, compared to earlier meta-analyses. In this article, we describe how we searched for relevant research studies and the methods we used to obtain individual patient data from other researchers. We also describe our rating of the research quality of the studies we identified. We identified more studies, with many more participants in total, than in previous pooled study research. Gathering the data from other researchers was very time-consuming and not everyone was willing or able to share their data. When we rated the quality of the studies that we found, many were not of high quality. Our next step is to analyse all the data we have collected to see if it will tell us more about how we might prevent repetition of self-harm in young people.

Researchers' experiences of the design and conduct challenges associated with parallel-group cluster-randomised trials and views on a novel open-cohort design.

BACKGROUND: Two accepted designs exist for parallel-group cluster-randomised trials (CRTs). Closed-cohort designs follow the same individuals over time with a single recruitment period before randomisation, but face challenges in settings with high attrition. (Repeated) cross-sectional designs recruit at one or more timepoints before and/or after randomisation, collecting data from different individuals present in the cluster at these timepoints, but are unsuitable for assessment of individual change over time. An 'open-cohort' design allows individual follow-up with recruitment before and after cluster-randomisation, but little literature exists on acceptability to inform their use in CRTs. AIM: To document the views and experiences of expert trialists to identify: a) Design and conduct challenges with established parallel-group CRT designs,b) Perceptions of potential benefits and barriers to implementation of open-cohort CRTs,c) Methods for minimising, and investigating the impact of, bias in open-cohort CRTs. METHODS: Qualitative consultation via two expert workshops including triallists (n = 24) who had worked on CRTs over a range of settings. Workshop transcripts were analysed using Descriptive Thematic Analysis utilising inductive and deductive coding. RESULTS: Two central organising concepts were developed. Design and conduct challenges with established CRT designs confirmed that current CRT designs are unable to deal with many of the complex research and intervention circumstances found in some trial settings (e.g. care homes). Perceptions of potential benefits and barriers of open cohort designs included themes on: approaches to recruitment; data collection; analysis; minimising/investigating the impact of bias; and how open-cohort designs might address or present CRT design challenges. Open-cohort designs were felt to provide a solution for some of the challenges current CRT designs present in some settings. CONCLUSIONS: Open-cohort CRT designs hold promise for addressing the challenges associated with standard CRT designs. Research is needed to provide clarity around definition and guidance on application.

Cost-effectiveness analyses for mirtazapine and sertraline in dementia: randomised controlled trial.

BACKGROUND: Depression is a common and costly comorbidity in dementia. There are very few data on the cost-effectiveness of antidepressants for depression in dementia and their effects on carer outcomes. AIMS: To evaluate the cost-effectiveness of sertraline and mirtazapine compared with placebo for depression in dementia. METHOD: A pragmatic, multicentre, randomised placebo-controlled trial with a parallel cost-effectiveness analysis (trial registration: ISRCTN88882979 and EudraCT 2006-000105-38). The primary cost-effectiveness analysis compared differences in treatment costs for patients receiving sertraline, mirtazapine or placebo with differences in effectiveness measured by the primary outcome, total Cornell Scale for Depression in Dementia (CSDD) score, over two time periods: 0-13 weeks and 0-39 weeks. The secondary evaluation was a cost-utility analysis using quality-adjusted life years (QALYs) computed from the Euro-Qual (EQ-5D) and societal weights over those same periods. RESULTS: There were 339 participants randomised and 326 with costs data (111 placebo, 107 sertraline, 108 mirtazapine). For the primary outcome, decrease in depression, mirtazapine and sertraline were not cost-effective compared with placebo. However, examining secondary outcomes, the time spent by unpaid carers caring for participants in the mirtazapine group was almost half that for patients receiving placebo (6.74 v. 12.27 hours per week) or sertraline (6.74 v. 12.32 hours per week). Informal care costs over 39 weeks were £1510 and £1522 less for the mirtazapine group compared with placebo and sertraline respectively. CONCLUSIONS: In terms of reducing depression, mirtazapine and sertraline were not cost-effective for treating depression in dementia. However, mirtazapine does appear likely to have been cost-effective if costing includes the impact on unpaid carers and with quality of life included in the outcome. Unpaid (family) carer costs were lower with mirtazapine than sertraline or placebo. This may have been mediated via the putative ability of mirtazapine to ameliorate sleep disturbances and anxiety. Given the priority and the potential value of supporting family carers of people with dementia, further research is warranted to investigate the potential of mirtazapine to help with behavioural and psychological symptoms in dementia and in supporting carers.

Randomized controlled double-blind trial of optimal dose methylphenidate in children and adolescents with severe attention deficit hyperactivity disorder and intellectual disability.

BACKGROUND: Attention deficit hyperactivity disorder is increased in children with intellectual disability. Previous research has suggested stimulants are less effective than in typically developing children but no studies have titrated medication for individual optimal dosing or tested the effects for longer than 4 weeks. METHOD: One hundred and twenty two drug-free children aged 7-15 with hyperkinetic disorder and IQ 30-69 were recruited to a double-blind, placebo-controlled trial that randomized participants using minimization by probability, stratified by referral source and IQ level in a one to one ratio. Methylphenidate was compared with placebo. Dose titration comprised at least 1 week each of low (0.5 mg/kg/day), medium (1.0 mg/kg/day) and high dose (1.5 mg/kg/day). Parent and teacher Attention deficit hyperactivity disorder (ADHD) index of the Conners Rating Scale-Short Version at 16 weeks provided the primary outcome measures. Clinical response was determined with the Clinical Global Impressions scale (CGI-I). Adverse effects were evaluated by a parent-rated questionnaire, weight, pulse and blood pressure. Analyses were by intention to treat. TRIAL REGISTRATION: ISRCTN 68384912. RESULTS: Methylphenidate was superior to placebo with effect sizes of 0.39 [95% confidence intervals (CIs) 0.09, 0.70] and 0.52 (95% CIs 0.23, 0.82) for the parent and teacher Conners ADHD index. Four (7%) children on placebo versus 24 (40%) of those on methylphenidate were judged improved or much improved on the CGI. IQ and autistic symptoms did not affect treatment efficacy. Active medication was associated with sleep difficulty, loss of appetite and weight loss but there were no significant differences in pulse or blood pressure. CONCLUSIONS: Optimal dosing of methylphenidate is practical and effective in some children with hyperkinetic disorder and intellectual disability. Adverse effects typical of methylphenidate were seen and medication use may require close monitoring in this vulnerable group.

Design and analysis of non-pharmacological treatment trials with multiple therapists per patient.

In trials of physical and talking therapies, nesting of patients within therapists has statistical implications analogous to those of cluster randomised trials. Nevertheless, the clustering effect may be more complex, as it interacts with treatment. For some therapies, individual patients may receive care from multiple therapists of the same type, so that patients are no longer strictly nested within therapists, creating a 'multiple-membership' relationship between patients and therapists. This paper considers methods of analysis and sample size estimation for trials with multiple-membership clustering effects. It is motivated by a trial of a psychotherapy for the treatment of adolescent depression with cognitive behavioural therapy. We tested methods and issues in a Monte Carlo simulation study, simulating trials with multiple membership. Results demonstrate satisfactory performance in terms of convergence and give estimates of the intra-cluster correlation coefficient and empirical test size similar to a simple hierarchical design. We derive formulae for sample size and power for multiple-membership trial designs. We then compare estimates of power from this formula with empirical power derived from the simulation study. Finally, we show that we can easily extend formulae for sample size and power to allow consideration of power and sample size for certain types of more complex interventions. These include situations where therapists of different types deliver separate components of the intervention, creating a cross-classified relationship, or where several therapists deliver a group-administered treatment, creating further levels.