The STAR care pathway for patients with chronic pain after total knee replacement: four-year follow-up of a randomised controlled trial.

BACKGROUND: The Support and Treatment After Replacement (STAR) care pathway is a clinically important and cost-effective intervention found to improve pain outcomes over one year for people with chronic pain three months after total knee replacement (TKR). We followed up STAR trial participants to evaluate the longer-term clinical- and cost-effectiveness of this care pathway. METHODS: Participants who remained enrolled on the trial at one year were contacted by post at a median of four years after randomisation and invited to complete a questionnaire comprising the same outcomes collected during the trial. We captured pain (co-primary outcome using the Brief Pain Inventory (BPI) pain severity and interference scales; scored 0-10, best to worst), function, neuropathic characteristics, emotional aspects of pain, health-related quality of life, and satisfaction. Electronic hospital informatics data on hospital resource use for the period of one to four years post-randomisation were collected from participating hospital sites. The economic evaluation took an National Health Service (NHS) secondary care perspective, with a four-year time horizon. RESULTS: Overall, 226/337 (67%) of participants returned completed follow-up questionnaires, yielding adjusted between-group differences in BPI means of -0.42 (95% confidence interval, CI (-1.07, 0.23); p = 0.20) for pain severity and - 0.64 (95% CI -1.41, 0.12); p = 0.10) for pain interference. Analysis using a multiple imputed data set (n = 337) showed an incremental net monetary benefit in favour of the STAR care pathway of £3,525 (95% CI -£990 to £8,039) at a £20,000/QALY willingness-to-pay threshold, leading to a probability that the intervention was cost-effective of 0.94. CONCLUSIONS: The magnitude of the longer-term benefits of the STAR care pathway are uncertain due to attrition of trial participants; however, there is a suggestion of some degree of sustained clinical benefit at four years. The care pathway remained cost-effective at four years. TRIAL REGISTRATION: ISRCTN: 92,545,361.

The effectiveness and cost-effectiveness of a group domestic abuse perpetrator programme: protocol for a randomised controlled trial.

BACKGROUND: In contrast to evidence for interventions supporting victim/survivors of domestic violence and abuse (DVA), the effectiveness of perpetrator programmes for reduction of abuse is uncertain. This study aims to estimate the effectiveness and cost-effectiveness of a perpetrator programme for men. METHODS: Pragmatic two-group individually randomised controlled trial (RCT) with embedded process and economic evaluation. Five centres in southwest England and South Wales aim to recruit 316 (reduced from original target of 366) male domestic abuse perpetrators. These will be randomised 2:1 to a community-based domestic abuse perpetrator programme (DAPP) or usual care comparator with 12-month follow-up. Female partners/ex-partners will be invited to join the study. The intervention for men comprises 23 weekly sessions of a group programme delivered in voluntary sector domestic abuse services. The intervention for female partners/ex-partners is one-to-one support from a safety worker. Men allocated to usual care receive no intervention; however, they are free to access other services. Their partners/ex-partners will be signposted to support services. Data is collected at baseline, and 4, 8 and 12 months' follow-up. The primary outcome is men's self-reported abusive behaviour measured by the Abusive Behaviour Inventory (ABI-29) at 12 months. Secondary measures include physical and mental health status and resource use alongside the abuse measure ABI (ABI-R) for partners/ex-partners and criminal justice contact for men. A mixed methods process evaluation and qualitative study will explore mechanisms of effectiveness, judge fidelity to the intervention model using interviews and group observations. The economic evaluation, over a 1-year time horizon from three perspectives (health and social care, public sector and society), will employ a cost-consequences framework reporting costs alongside economic outcomes (Quality-Adjusted Life Years derived from EQ-5D-5L, SF-12 and CHU-9D, and ICECAP-A) as well as the primary and other secondary outcomes. DISCUSSION: This trial will provide evidence of the (cost)effectiveness of a DAPP. The embedded process evaluation will further insights in the experiences and contexts of participants and their journey through a perpetrator programme, and the study will seek to address the omission in other studies of economic evaluations. TRIAL REGISTRATION: ISRCTN15804282, April 1, 2019.

Integrated therapist and online CBT for depression in primary care (INTERACT): study protocol for a multi-centre randomised controlled trial.

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for depression. Self-directed online CBT interventions have made CBT more accessible at a lower cost. However, adherence is often poor and, in the absence of therapist support, effects are modest and short-term. Delivering CBT online using instant messaging is clinically and cost-effective; however, most existing platforms are limited to instant messaging sessions, without the support of between-session "homework" activities. The INTERACT intervention integrates online CBT materials and 'high-intensity' therapist-led CBT, delivered remotely in real-time. The INTERACT trial will evaluate this novel integration in terms of clinical and cost-effectiveness, and acceptability to therapists and clients. METHODS: Pragmatic, two parallel-group multi-centre individually randomised controlled trial, with 434 patients recruited from primary care practices in Bristol, London and York. Participants with depression will be identified via General Practitioner record searches and direct referrals. INCLUSION CRITERIA: aged ≥ 18 years; score ≥ 14 on Beck Depression Inventory (BDI-II); meeting International Classification of Diseases (ICD-10) criteria for depression. EXCLUSION CRITERIA: alcohol or substance dependency in the past year; bipolar disorder; schizophrenia; psychosis; dementia; currently under psychiatric care for depression (including those referred but not yet seen); cannot complete questionnaires unaided or requires an interpreter; currently receiving CBT/other psychotherapy; received high-intensity CBT in the past four years; participating in another intervention trial; unwilling/unable to receive CBT via computer/laptop/smartphone. Eligible participants will be randomised to integrated CBT or usual care. Integrated CBT utilises the standard Beckian intervention for depression and comprises nine live therapist-led sessions, with (up to) a further three if clinically appropriate. The first session is 60-90 min via videocall, with subsequent 50-min sessions delivered online, using instant messaging. Participants allocated integrated CBT can access integrated online CBT resources (worksheets/information sheets/videos) within and between sessions. Outcome assessments at 3-, 6-, 9- and 12-month post-randomisation. The primary outcome is the Beck Depression Inventory (BDI-II) score at 6 months (as a continuous variable). A nested qualitative study and health economic evaluation will be conducted. DISCUSSION: If clinically and cost-effective, this model of integrated CBT could be introduced into existing psychological services, increasing access to, and equity of, CBT provision. TRIAL REGISTRATION: ISRCTN, ISRCTN13112900. Registered on 11/11/2020. Currently recruiting participants. Trial registration data are presented in Table 1.

A clinical tool to identify older women with back pain at high risk of osteoporotic vertebral fractures (Vfrac): a population-based cohort study with exploratory economic evaluation.

BACKGROUND: osteoporotic vertebral fractures (OVFs) identify people at high risk of future fractures, but despite this, less than a third come to clinical attention. The objective of this study was to develop a clinical tool to aid health care professionals decide which older women with back pain should have a spinal radiograph. METHODS: a population-based cohort of 1,635 women aged 65+ years with self-reported back pain in the previous 4 months were recruited from primary care. Exposure data were collected through self-completion questionnaires and physical examination, including descriptions of back pain and traditional risk factors for osteoporosis. Outcome was the presence/absence of OVFs on spinal radiographs. Logistic regression models identified independent predictors of OVFs, with the area under the (receiver operating) curve calculated for the final model, and a cut-point was identified. RESULTS: mean age was 73.9 years and 209 (12.8%) had OVFs. The final Vfrac model comprised 15 predictors of OVF, with an AUC of 0.802 (95% CI: 0.764-0.840). Sensitivity was 72.4% and specificity was 72.9%. Vfrac identified 93% of those with more than one OVF and two-thirds of those with one OVF. Performance was enhanced by inclusion of self-reported back pain descriptors, removal of which reduced AUC to 0.742 (95% CI: 0.696-0.788) and sensitivity to 66.5%. Health economic modelling to support a future trial was favourable. CONCLUSIONS: the Vfrac clinical tool appears to be valid and is improved by the addition of self-reported back pain symptoms. The tool now requires testing to establish real-world clinical and cost-effectiveness.

A Validation Study of the EQ-5D-5L and ICEpop Capability Measure for Older People Among Older Individuals With Depressive Symptoms in Brazil.

OBJECTIVES: This study aimed to assess the known-groups validity of the EQ-5D-5L and the ICEpop Capability Measure for Older People (ICECAP-O), 2 outcome measures used in economic evaluation, among older adults with depressive symptoms in socioeconomically deprived areas of Brazil. We also explored the role of education and income on responses to these measures. METHODS: This cross-sectional study used baseline data from PROACTIVE, a cluster randomized controlled trial to evaluate a psychosocial intervention for late-life depression among older adults. Participants aged ≥60 years with a 9-item Patient Health Questionnaire score ≥10 were recruited from 20 primary healthcare clinics. Ordered logistic regression models assessed the association between depressive symptoms severity, income, and education and dimension-level responses on the EQ-5D-5L and ICECAP-O. Multivariable regression models investigated the ability of EQ-5D-5L and ICECAP-O scores to discriminate between depressive symptoms severity levels and other characteristics, including education level and household income. RESULTS: A total of 715 participants were included in the study. Depressive symptoms severity was associated with all EQ-5D-5L and ICECAP-O dimensions, except the ICECAP-O enjoyment attribute. In contrast, household income was only associated with the ICECAP-O security attribute. Higher severity of depressive symptoms (9-item Patient Health Questionnaire scores) was also strongly associated with lower (ie, worse) scores on both measures in all models. Education level and household income showed no association with either EQ-5D-5L or ICECAP-O scores. CONCLUSIONS: To best of our knowledge, this is the first study that investigated the validity of these 2 measures among older adults in Brazil. Both EQ-5D-5L and ICECAP-O showed evidence of validity in differentiating depressive symptom severity.

Challenges in Using Recommended Quality of Life Measures to Assess Fluctuating Health: A Think-Aloud Study to Understand How Recall and Timing of Assessment Influence Patient Responses.

BACKGROUND: It can be challenging to measure quality of life to calculate quality-adjusted life-years in recurrent fluctuating health states, as quality of life can constantly change. It is not clear how patients who experience fluctuations complete measures and how assessment timing and recall influence responses. OBJECTIVE: We aimed to understand how patients with fluctuating health complete widely recommended and commonly used measures (EQ-5D-5L, EORTC QLQ-C30 and SF-12) and the extent to which the recall period ('health today', 'past week' and 'past 4 weeks') and timing of assessment influence the way that patients complete these questionnaires. METHODS: Twenty-four adult patients undergoing chemotherapy for urological, gynaecological or bowel cancers in the UK participated in think-aloud interviews, while completing the measures, completed a pictorial task illustrating how quality of life changed during the chemotherapy cycle and took part in semi-structured interviews. Transcripts were analysed using constant comparison. RESULTS: Patients were consistent in describing their quality of life as changing considerably throughout a chemotherapy cycle. The shorter recall period of 'health today' does not adequately represent patients' quality of life because of fluctuations, patients remarked they could give a different answer depending on the timing of assessment, and many struggled to combine the "ups and downs" to answer measures with longer recall ('past week' and 'past 4 weeks'). Across all measures, patients attempted to provide averages, adopt the peak-end rule or focus on the best part of their experience. Patients commonly used more than one approach when completing a given questionnaire as well as across questionnaires. CONCLUSIONS: Patients who experience recurrent fluctuations in health are unable to provide meaningful responses about their quality of life when completing quality-of-life measures due to the recall period and timing of assessment. The use of such responses to calculate health state values in economic evaluations to inform resource allocation decisions in fluctuating conditions must be questioned.

Challenges in developing capability measures for children and young people for use in the economic evaluation of health and care interventions.

Methods for measuring outcomes suitable for economic evaluations of health and care interventions have primarily focused on adults. The validity of such methods for children and young people is questionable in areas including the outcome domains measured and how they are measured and valued, with most existing measures narrowly focusing on health. Novel methods for assessing benefits beyond health by focusing on a person's capability have also concentrated on adults to date. This paper aims to set out the rationale for capability measures in children and young people. It argues for the need to expand the evaluative space beyond health functioning towards broader capabilities, with children and young people playing an integral role in capability measure development. Drawing from existing literature, specific challenges related to the identification, measurement, and valuation of capabilities in children and young people are also discussed. Finally, the practical implications for conducting economic evaluation when measuring and valuing capabilities at different stages across the life-course are illustrated. We develop an alternative framework based on conceiving capabilities as evolving across the life-course. This framework may also be helpful in thinking about how to model health outcomes across the life-course.

Cost-Effectiveness of Different Formats for Delivery of Cognitive Behavioral Therapy for Depression: A Systematic Review Based Economic Model.

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

A collaborative care psychosocial intervention to improve late life depression in socioeconomically deprived areas of Guarulhos, Brazil: the PROACTIVE cluster randomised controlled trial protocol.

BACKGROUND: The elderly population has been growing in most low- and middle-income countries (LMIC), and depression is a common condition among these populations. The lack of integration between mental health and primary healthcare services and the shortage of mental health specialists in the public health system contribute to underdiagnosis and undertreatment of depression. One of the strategies to reduce this gap is task shifting and collaborative care treatments. This study therefore aims to evaluate the effectiveness and cost-effectiveness of a collaborative care psychosocial intervention to improve the clinical management of depression among elderly people in poor neighbourhoods in Guarulhos, Brazil. METHODS: Two-arm, cluster randomised controlled trial with Basic Health Units as the clusters and a 1:1 allocation ratio. Twenty Basic Health Units have been randomly selected and randomised to control or intervention arms. We aim to recruit 1440 adults (72 per cluster) aged 60 years or over identified with depression (9-item Patient Health Questionnaire (PHQ-9) score ≥ 10). The control arm participants will receive an enhanced usual care, while the intervention arm participants will receive an enhanced usual care and a 17-week psychosocial intervention programme delivered at home by community health workers with the help of an application installed on tablet computers. The primary outcome is the proportion with depression recovery (PHQ-9 < 10) at 8 months' follow-up. We will also assess the maintenance of any earlier clinical gains and the cost-effectiveness of the intervention at 12 months. DISCUSSION: This is the first randomised trial to investigate a collaborative care intervention to treat depression among poor elderly in LMIC/Latin America. This is a major public health problem worldwide, but in these countries, there are no locally tested, evidence-based interventions available to date. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN57805470 . Registered on 25 April 2019.

Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer: the ProtecT three-arm RCT.

BACKGROUND: Prostate cancer is the most common cancer among men in the UK. Prostate-specific antigen testing followed by biopsy leads to overdetection, overtreatment as well as undertreatment of the disease. Evidence of treatment effectiveness has lacked because of the paucity of randomised controlled trials comparing conventional treatments. OBJECTIVES: To evaluate the effectiveness of conventional treatments for localised prostate cancer (active monitoring, radical prostatectomy and radical radiotherapy) in men aged 50-69 years. DESIGN: A prospective, multicentre prostate-specific antigen testing programme followed by a randomised trial of treatment, with a comprehensive cohort follow-up. SETTING: Prostate-specific antigen testing in primary care and treatment in nine urology departments in the UK. PARTICIPANTS: Between 2001 and 2009, 228,966 men aged 50-69 years received an invitation to attend an appointment for information about the Prostate testing for cancer and Treatment (ProtecT) study and a prostate-specific antigen test; 82,429 men were tested, 2664 were diagnosed with localised prostate cancer, 1643 agreed to randomisation to active monitoring (n = 545), radical prostatectomy (n = 553) or radical radiotherapy (n = 545) and 997 chose a treatment. INTERVENTIONS: The interventions were active monitoring, radical prostatectomy and radical radiotherapy. TRIAL PRIMARY OUTCOME MEASURE: Definite or probable disease-specific mortality at the 10-year median follow-up in randomised participants. SECONDARY OUTCOME MEASURES: Overall mortality, metastases, disease progression, treatment complications, resource utilisation and patient-reported outcomes. RESULTS: There were no statistically significant differences between the groups for 17 prostate cancer-specific (p = 0.48) and 169 all-cause (p = 0.87) deaths. Eight men died of prostate cancer in the active monitoring group (1.5 per 1000 person-years, 95% confidence interval 0.7 to 3.0); five died of prostate cancer in the radical prostatectomy group (0.9 per 1000 person-years, 95% confidence interval 0.4 to 2.2 per 1000 person years) and four died of prostate cancer in the radical radiotherapy group (0.7 per 1000 person-years, 95% confidence interval 0.3 to 2.0 per 1000 person years). More men developed metastases in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring, n = 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy, n = 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy, n = 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years; p = 0.004). There were higher rates of disease progression in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring (n = 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy (n = 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy (n = 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years; p < 0.001). Radical prostatectomy had the greatest impact on sexual function/urinary continence and remained worse than radical radiotherapy and active monitoring. Radical radiotherapy's impact on sexual function was greatest at 6 months, but recovered somewhat in the majority of participants. Sexual and urinary function gradually declined in the active monitoring group. Bowel function was worse with radical radiotherapy at 6 months, but it recovered with the exception of bloody stools. Urinary voiding and nocturia worsened in the radical radiotherapy group at 6 months but recovered. Condition-specific quality-of-life effects mirrored functional changes. No differences in anxiety/depression or generic or cancer-related quality of life were found. At the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year, the probabilities that each arm was the most cost-effective option were 58% (radical radiotherapy), 32% (active monitoring) and 10% (radical prostatectomy). LIMITATIONS: A single prostate-specific antigen test and transrectal ultrasound biopsies were used. There were very few non-white men in the trial. The majority of men had low- and intermediate-risk disease. Longer follow-up is needed. CONCLUSIONS: At a median follow-up point of 10 years, prostate cancer-specific mortality was low, irrespective of the assigned treatment. Radical prostatectomy and radical radiotherapy reduced disease progression and metastases, but with side effects. Further work is needed to follow up participants at a median of 15 years. TRIAL REGISTRATION: Current Controlled Trials ISRCTN20141297. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 37. See the National Institute for Health Research Journals Library website for further project information.

Prostate cancer is the most common cancer in men and is often found through a blood test called a prostate-specific antigen test and through biopsies of the prostate. Over the years, these tests led to the detection of many small cancers that do not cause harm. Some prostate cancers are harmful, but it is difficult to recognise them early. When cancer is still inside the prostate, the conventional treatments are surgery or radiotherapy, which carry side effects including leaking urine and difficulty getting an erection, so another option is repeat investigations at regular intervals (active monitoring), with treatments given if the cancer progresses. These options needed to be compared in a study called a 'randomised trial' in which men agree to be allocated to one of the three treatments. In the Prostate testing for cancer and Treatment (ProtecT) study, 200,000 men aged 50­69 years were invited to have a prostate-specific antigen test. Of the 82,849 men who agreed to be tested, 1643 of whom had prostate cancer that was still contained in the prostate agreed to be allocated to one of the three treatments. After an average of 10 years of follow-up, 99% of men were alive in each of the treatment groups. However, when compared with active monitoring, surgery and radiotherapy reduced the risk of disease spreading outside the prostate by half. Patients reported that urinary leakage and sexual function were worst with surgery, and sexual and bowel functions were affected by radiotherapy. Men on active monitoring had a gradual decline in their urinary and sexual function, particularly as around half of them later had surgery or radiotherapy. Radiotherapy was the treatment that seemed to be the best value for money. The findings from the Prostate testing for cancer and Treatment (ProtecT) study can help men make decisions about being tested and which treatment to have if they are found to have cancer within the prostate. We now need to find out the longer-term effects of these treatments on how long men live and their quality of life.

The ProtecT randomised trial cost-effectiveness analysis comparing active monitoring, surgery, or radiotherapy for prostate cancer.

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

Cost-Effectiveness of Sertraline in Primary Care According to Initial Severity and Duration of Depressive Symptoms: Findings from the PANDA RCT.

BACKGROUND: Antidepressants are commonly prescribed for depression, but it is unclear whether treatment efficacy depends on severity and duration of symptoms and how prescribing might be targeted cost-effectively. OBJECTIVES: We investigated the cost-effectiveness of the antidepressant sertraline compared with placebo in subgroups defined by severity and duration of depressive symptoms. METHODS: We undertook a cost-effectiveness analysis from the perspective of the NHS and Personal and Social Services (PSS) in the UK alongside the PANDA (What are the indications for Prescribing ANtiDepressants that will leAd to a clinical benefit?) randomised controlled trial (RCT), which compared sertraline with placebo over a 12-week period. Quality of life data were collected at baseline and at 2, 6, and 12 weeks post-randomisation using EQ-5D-5L, from which we calculated quality-adjusted life years (QALYs). Costs (in 2017/18£) were collected using patient records and from resource use questionnaires administered at each follow-up interval. Differences in mean costs and mean QALYs and net monetary benefits were estimated. Our primary analysis used net monetary benefit regressions to identify any interaction between the cost-effectiveness of sertraline and subgroups defined by baseline symptom severity (0-11; 12-19; 20+ on the Clinical Interview Schedule-Revised) and, separately, duration of symptoms (greater or less than 2 years duration). A secondary analysis estimated the cost-effectiveness of sertraline versus placebo, irrespective of duration or severity. RESULTS: There was no evidence of an association between the baseline severity of depressive symptoms and the cost-effectiveness of sertraline. Compared to patients with low symptom severity, the expected net benefits in patients with moderate symptoms were £24 (95% CI - £280 to £328; p value 0.876) and the expected net benefits in patients with high symptom severity were £37 (95% CI - £221 to £296; p value 0.776). Patients who had a longer history of depressive symptoms at baseline had lower expected net benefits from sertraline than those with a shorter history; however, the difference was uncertain (- £27 [95% CI - £258 to £204]; p value 0.817). In the secondary analysis, patients treated with sertraline had higher expected net benefits (£122 [95% CI £18 to £226]; p value 0.101) than those in the placebo group. Sertraline had a high probability (> 95%) of being cost-effective if the health system was willing to pay at least £20,000 per QALY gained. CONCLUSIONS: We found insufficient evidence of a prespecified threshold based on severity or symptom duration that GPs could use to target prescribing to a subgroup of patients where sertraline is most cost-effective. Sertraline is probably a cost-effective treatment for depressive symptoms in UK primary care. TRIAL REGISTRATION: Controlled Trials ISRCTN Registry, ISRCTN84544741.

Association of proximal elements of social disadvantage with children's language development at 2 years: an analysis of data from the Children in Focus (CiF) sample from the ALSPAC birth cohort.

BACKGROUND: An association between social disadvantage and early language development is commonly reported in the literature, but less attention has been paid to the way that different aspects of social disadvantage affect both expressive and receptive language in the first 2 years of life. AIMS: To examine the contributions of gender, parental report of early language skills and proximal social variables (the amount of stimulation in the home, the resources available to the child and the attitudes/emotional status of the primary carer and the support available to him/her) controlling for distal social variables (family income and maternal education) to children's expressive and receptive language development at 2 years in a community ascertained population cohort. METHODS & PROCEDURES: Data from 1314 children in the Children in Focus (CiF) sample from the Avon Longitudinal Study of Parents and Children (ALSPAC) were analyzed. Multivariable regression models identified the contribution of proximal (what parents do with their children) measures of social disadvantage adjusting for more distal (e.g., family income and material wealth) measures as well as early language development at 15 months to the development of verbal comprehension, expressive vocabulary and expressive grammar (word combinations) at 2 years of age. OUTCOME & RESULTS: In the final multivariable models gender, earlier language and proximal social factors, co-varying for distal factors predicted 36% of the variance for expressive vocabulary, 22% for receptive language and 27% for word combinations at 2 years. Language development at 15 months remained a significant predictor of outcomes at 24 months. Environmental factors were associated with both expressive scales but the picture was rather more mixed for receptive language suggesting that there may be different mechanisms underlying the different processes. CONCLUSIONS & IMPLICATIONS: This study supports the argument that social advantage makes a strong contribution to children's language development in the early years. The results suggest that what parents/carers do with their children is critical even when structural aspects of social disadvantage such as family income and housing have been taken into consideration although this relationship varies for different aspects of language. This has the potential to inform the targeting of public health interventions focusing on early language and pre-literacy skills on the one hand and home learning environments on the other and, potentially, the two in combination.

Combining mirtazapine with SSRIs or SNRIs for treatment-resistant depression: the MIR RCT.

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

Clinical- and cost-effectiveness of the STAR care pathway compared to usual care for patients with chronic pain after total knee replacement: study protocol for a UK randomised controlled trial.

BACKGROUND: Approximately 20% of patients experience chronic pain after total knee replacement. There is little evidence for effective interventions for the management of this pain, and current healthcare provision is patchy and inconsistent. Given the complexity of this condition, multimodal and individualised interventions matched to pain characteristics are needed. We have undertaken a comprehensive programme of work to develop a care pathway for patients with chronic pain after total knee replacement. This protocol describes the design of a randomised controlled trial to evaluate the clinical- and cost-effectiveness of a complex intervention care pathway compared with usual care. METHODS: This is a pragmatic two-armed, open, multi-centred randomised controlled trial conducted within secondary care in the UK. Patients will be screened at 2 months after total knee replacement and 381 patients with chronic pain at 3 months postoperatively will be recruited. Recruitment processes will be optimised through qualitative research during a 6-month internal pilot phase. Patients are randomised using a 2:1 intervention:control allocation ratio. All participants receive usual care as provided by their hospital. The intervention comprises an assessment clinic appointment at 3 months postoperatively with an Extended Scope Practitioner and up to six telephone follow-up calls over 12 months. In the assessment clinic, a standardised protocol is followed to identify potential underlying causes for the chronic pain and enable appropriate onward referrals to existing services for targeted and individualised treatment. Outcomes are assessed by questionnaires at 6 and 12 months after randomisation. The co-primary outcomes are pain severity and pain interference assessed using the Brief Pain Inventory at 12 months after randomisation. Secondary outcomes relate to resource use, function, neuropathic pain, mental well-being, use of pain medications, satisfaction with pain relief, pain frequency, capability, health-related quality of life and bodily pain. After trial completion, up to 30 patients in the intervention group will be interviewed about their experiences of the care pathway. DISCUSSION: If shown to be clinically and cost-effective, this care pathway intervention could improve the management of chronic pain after total knee replacement. TRIAL REGISTRATION: ISRCTN registry ( ISRCTN92545361 ), prospectively registered on 30 August 2016.

Health Care Needs and Support for Patients Undergoing Treatment for Prosthetic Joint Infection following Hip or Knee Arthroplasty: A Systematic Review.

BACKGROUND: Hip and knee arthroplasty are common interventions for the treatment of joint conditions, most notably osteoarthritis. Although many patients benefit from surgery, approximately 1% of patients develop infection afterwards known as deep prosthetic joint infection (PJI), which often requires further major surgery. OBJECTIVE: To assess support needs of patients undergoing treatment for PJI following hip or knee arthroplasty and to identify and evaluate what interventions are routinely offered to support such patients. DESIGN: Systematic review. DATA SOURCES: MEDLINE, EMBASE, Web of Science, PsycINFO, Cinahl, Social Science Citation Index, The Cochrane Library, and reference lists of relevant studies from January 01, 1980 to October 05, 2016. SELECTION CRITERIA: Observational (prospective or retrospective cohort, nested case-control or case-control) studies, qualitative studies, or clinical trials conducted in patients treated for PJI and/or other major adverse occurrences following hip or knee arthroplasty. REVIEW METHODS: Data were extracted by two independent investigators and consensus was reached with involvement of a third. Given the heterogeneous nature of study designs, methods, and limited number of studies, a narrative synthesis is presented. RESULTS: Of 4,213 potentially relevant citations, we identified one case-control, one prospective cohort and two qualitative studies for inclusion in the synthesis. Patients report that PJI and treatment had a profoundly negative impact affecting physical, emotional, social and economic aspects of their lives. No study evaluated support interventions. CONCLUSION: The findings demonstrate that patients undergoing treatment for PJI have extensive physical, psychological, social and economic support needs. The interpretation of study results is limited by variation in study design, outcome measures and the small number of relevant eligible studies. However, our review highlights a lack of evidence about support strategies for patients undergoing treatment for PJI and other adverse occurrences following hip or knee arthroplasty. There is a need to design, implement and evaluate interventions to support these patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2015: CRD42015027175.

Using willingness-to-pay to establish patient preferences for cancer testing in primary care.

BACKGROUND: Shared decision making is a stated aim of several healthcare systems. In the area of cancer, patients' views have informed policy on screening and treatment but there is little information about their views on diagnostic testing in relation to symptom severity. METHODS: We used the technique of willingness-to-pay to determine public preferences around diagnostic testing for colorectal, lung, and pancreatic cancer in primary care in the UK. Participants were approached in general practice waiting rooms and asked to complete a two-stage electronic survey that described symptoms of cancer, the likelihood that the symptoms indicate cancer, and information about the appropriate diagnostic test. Part 1 asked for a binary response (yes/no) as to whether they would choose to have a test if it were offered. Part 2 elicited willingness-to-pay values of the tests using a payment scale followed by a bidding exercise, with the aim that these values would provide a strength of preference not detectable using the binary approach. RESULTS: A large majority of participants chose to be tested for all cancers, with only colonoscopy (colorectal cancer) demonstrating a risk gradient. In the willingness-to-pay exercise participants placed a lower value on an X-ray (lung cancer) than the tests for colorectal or pancreatic cancer and X-ray was the only test where risk was clearly related to the willingness-to-pay value. CONCLUSION: Willingness-to-pay values did not enhance the binary responses in the way intended; participants appeared to be motivated differently when responding to the two parts of the questionnaire. More work is needed to understand how participants perceive risk in this context and how they respond to questions about willingness-to-pay. Qualitative methods could provide useful insights.

Long-term effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: follow-up of the CoBalT randomised controlled trial.

BACKGROUND: Cognitive behavioural therapy (CBT) is an effective treatment for people whose depression has not responded to antidepressants. However, the long-term outcome is unknown. In a long-term follow-up of the CoBalT trial, we examined the clinical and cost-effectiveness of cognitive behavioural therapy as an adjunct to usual care that included medication over 3-5 years in primary care patients with treatment-resistant depression. METHODS: CoBalT was a randomised controlled trial done across 73 general practices in three UK centres. CoBalT recruited patients aged 18-75 years who had adhered to antidepressants for at least 6 weeks and had substantial depressive symptoms (Beck Depression Inventory [BDI-II] score ≥14 and met ICD-10 depression criteria). Participants were randomly assigned using a computer generated code, to receive either usual care or CBT in addition to usual care. Patients eligible for the long-term follow-up were those who had not withdrawn by the 12 month follow-up and had given their consent to being re-contacted. Those willing to participate were asked to return the postal questionnaire to the research team. One postal reminder was sent and non-responders were contacted by telephone to complete a brief questionnaire. Data were also collected from general practitioner notes. Follow-up took place at a variable interval after randomisation (3-5 years). The primary outcome was self-report of depressive symptoms assessed by BDI-II score (range 0-63), analysed by intention to treat. Cost-utility analysis compared health and social care costs with quality-adjusted life-years (QALYs). This study is registered with isrctn.com, number ISRCTN38231611. FINDINGS: Between Nov 4, 2008, and Sept 30, 2010, 469 eligible participants were randomised into the CoBalT study. Of these, 248 individuals completed a long-term follow-up questionnaire and provided data for the primary outcome (136 in the intervention group vs 112 in the usual care group). At follow-up (median 45·5 months [IQR 42·5-51·1]), the intervention group had a mean BDI-II score of 19·2 (SD 13·8) compared with a mean BDI-II score of 23·4 (SD 13·2) for the usual care group (repeated measures analysis over the 46 months: difference in means -4·7 [95% CI -6·4 to -3·0, p<0·001]). Follow-up was, on average, 40 months after therapy ended. The average annual cost of trial CBT per participant was £343 (SD 129). The incremental cost-effectiveness ratio was £5374 per QALY gain. This represented a 92% probability of being cost effective at the National Institute for Health and Care Excellence QALY threshold of £20 000. INTERPRETATION: CBT as an adjunct to usual care that includes antidepressants is clinically effective and cost effective over the long-term for individuals whose depression has not responded to pharmacotherapy. In view of this robust evidence of long-term effectiveness and the fact that the intervention represented good value-for-money, clinicians should discuss referral for CBT with all those for whom antidepressants are not effective. FUNDING: National Institute for Health Research Health Technology Assessment.

The Reporting of Treatment Nonadherence and Its Associated Impact on Economic Evaluations Conducted Alongside Randomized Trials: A Systematic Review.

OBJECTIVES: To review trial-based economic evaluations, identifying 1) the proportion reporting adherence, 2) methods for assigning intervention costs according to adherence, 3) which participants were included in the economic analysis, and 4) statistical methods to estimate cost-effectiveness in those who adhered. We provide recommendations on handling nonadherence in economic evaluations. METHODS: The National Health Service Economic Evaluation Database was searched for recently published trials. We extracted information on the methods used to assign shared costs in the presence of nonadherence and methods to account for nonadherence in the economic analysis. RESULTS: Ninety-six eligible trials were identified. For one-off interventions, 86% reported the number of participants initiating treatment. For recurring interventions, 56% and 73%, respectively, reported the number initiating and completing treatment, whereas 66% reported treatment intensity. Most studies (23 of 31 [74%] trials and 42 of 53 [79%] trials of one-off and recurring interventions, respectively) reported strict intention-to-treat or complete case analyses. A minority (3 of 31 [10%] and 7 of 53 [13%], respectively), however, performed a per-protocol analysis. No studies used statistical methods to adjust for nonadherence directly in the economic evaluation. Only 13 studies described patient-level allocation of intervention costs; there was variation in how fixed costs were assigned according to adherence. CONCLUSIONS: Most of the trials reported a measure of adherence, but reporting was not comprehensive. A nontrivial proportion of studies report a primary per-protocol analysis that potentially produces biased results. Alongside primary intention-to-treat analysis, statistical methods for obtaining an unbiased estimate of cost-effectiveness in adherers should be considered.

Intervention fidelity in a school-based diet and physical activity intervention in the UK: Active for Life Year 5.

BACKGROUND: Active for Life Year 5 (AFLY5) is an educational programme for Year 5 children (aged 9-10) designed to increase children's physical activity, decrease sedentary behaviour and increase fruit and vegetable intake. This paper reports findings from a process evaluation embedded within a randomised controlled trial evaluating the programme's effectiveness. It considers the fidelity of implementation of AFLY5 with a focus on three research questions: 1. To what extent was the intervention delivered as planned? 2. In what ways, if any, did the teachers amend the programme? and 3. What were the reasons for any amendments? METHODS: Mixed methods were used including data collection via observation of the intervention delivery, questionnaire, teacher's intervention delivery log and semi-structured interviews with teachers and parents. Qualitative data were analysed thematically and quantitative data were summarised using descriptive statistics. RESULTS: Following training, 42 of the 43 intervention school teachers/teaching staff (98%) were confident they could deliver the nutrition and physical activity lessons according to plan. The mean number of lessons taught was 12.3 (s.d. 3.7), equating to 77% of the intervention. Reach was high with 95% of children in intervention schools receiving lessons. A mean of 6.2 (s.d. 2.6) out of 10 homeworks were delivered. Median lesson preparation time was 10 min (IQR 10-20) and 28% of lessons were reported as having been amended. Qualitative findings revealed that those who amended the lessons did so to differentiate for student ability, update them for use with new technologies and to enhance teacher and student engagement. Teachers endorsed the aims of the intervention, but some were frustrated with having to adapt the lesson materials. Teachers also a reported tendency to delegate the physical activity lessons to other staff not trained in the intervention. CONCLUSIONS: Fidelity of intervention implementation was good but teachers' enthusiasm for the AFLY5 programme was mixed despite them believing that the messages behind the lessons were important. This may have meant that the intervention messages were not delivered as anticipated and explain why the intervention was found not to be effective. TRIAL REGISTRATION: ISRCTN50133740.