Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial.

Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening. Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small. Trial Registration: isrctn.org Identifier: ISRCTN92187251.

Modelled cost-effectiveness analysis of the Support and Treatment After Replacement (STAR) care pathway for chronic pain after total knee replacement compared with usual care.

BACKGROUND: The aim of the study was to estimate the long-term cost-effectiveness of the Support and Treatment After Replacement (STAR) care pathway for chronic pain after total knee replacement compared with usual postoperative care. METHODS: Study design: A decision-analytic (cohort Markov) model was used for the simulation with time dependent annual transition probabilities and a time horizon of five years. SETTING: Patients treated by National Health Service (NHS) hospitals in England and Wales. STUDY POPULATION: Adults classified as having chronic pain three months after undergoing a total knee replacement. INTERVENTION: The STAR care pathway following a total knee replacement. COMPARATOR: Usual postoperative care following a total knee replacement. PERSPECTIVE: The study was undertaken from the perspective of the NHS. OUTCOME MEASURES: Quality-adjusted life years and healthcare costs. Discounting: A rate of 3.5% for both costs and health utility. RESULTS: Model results indicate that the STAR intervention would dominate current practice by providing a gain in quality-adjusted life years (QALYs) of 0.086 and a reduction of £375 (per person) in costs over the first five years. The incremental net monetary benefit of the STAR intervention was estimated at £2,086 (at a threshold of £20,000 per QALY). Probabilistic sensitivity analysis suggests the STAR intervention is likely to be cost-effective with a probability of 0.62. The results remain robust to changes in model assumptions on comparator utility and the timing of the start of the intervention. If hospital admission costs are assumed not to be reduced by the STAR intervention, it would no longer be cost saving, but it would likely be cost-effective based on probabilistic sensitivity analysis (0.59). CONCLUSION: Evidence from the economic model suggests that the STAR care pathway is likely to be cost-effective and potentially dominant from an NHS perspective. TRIAL REGISTRATION: The STAR trial is registered with ISRCTN, ISRCTN92545361.

Lower urinary tract symptoms in men: the TRIUMPH cluster RCT.

Background: Conservative therapies are recommended as initial treatment for male lower urinary tract symptoms. However, there is a lack of evidence on effectiveness and uncertainty regarding approaches to delivery. Objective: The objective was to determine whether or not a standardised and manualised care intervention delivered in primary care achieves superior symptomatic outcome for lower urinary tract symptoms to usual care. Design: This was a two-arm cluster randomised controlled trial. Setting: The trial was set in 30 NHS general practice sites in England. Participants: Participants were adult men (aged ≥ 18 years) with bothersome lower urinary tract symptoms. Interventions: Sites were randomised 1 : 1 to deliver the TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions trial intervention or usual care to all participants. The TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions intervention comprised a standardised advice booklet developed for the trial from the British Association of Urological Surgeons' patient information sheets, with patient and expert input. Patients were directed to relevant sections by general practice or research nurses/healthcare assistants following urinary symptom assessment, providing the manualised element. The healthcare professional provided follow-up contacts over 12 weeks to support adherence to the intervention. Main outcome measures: The primary outcome was the validated patient-reported International Prostate Symptom Score 12 months post consent. Rather than the minimal clinically important difference of 3.0 points for overall International Prostate Symptom Score, the sample size aimed to detect a difference of 2.0 points, owing to the recognised clinical impact of individual symptoms. Results: A total of 1077 men consented to the study: 524 in sites randomised to the intervention arm (n = 17) and 553 in sites randomised to the control arm (n = 13). A difference in mean International Prostate Symptom Score at 12 months was found (adjusted mean difference of -1.81 points, 95% confidence interval -2.66 to -0.95 points), with a lower score in the intervention arm, indicating less severe symptoms. Secondary outcomes of patient-reported urinary symptoms, quality of life specific to lower urinary tract symptoms and perception of lower urinary tract symptoms all showed evidence of a difference between the arms favouring the intervention. No difference was seen between the arms in the proportion of urology referrals or adverse events. In qualitative interviews, participants welcomed the intervention, describing positive effects on their symptoms, as well as on their understanding of conservative care and their attitude towards the experience of lower urinary tract symptoms. The interviews highlighted that structured, in-depth self-management is insufficiently embedded within general practitioner consultations. From an NHS perspective, mean costs and quality-adjusted life-years were similar between trial arms. The intervention arm had slightly lower mean costs (adjusted mean difference of -£29.99, 95% confidence interval -£109.84 to £22.63) than the usual-care arm, and a small gain in quality-adjusted life-years (adjusted mean difference of 0.001, 95% confidence interval -0.011 to 0.014). Conclusions: The intervention showed a small, sustained benefit for men's lower urinary tract symptoms and quality of life across a range of outcome measures in a UK primary care setting. Qualitative data showed that men highly valued the intervention. Intervention costs were marginally lower than usual-care costs. Limitations of the study included that trial participants were unmasked, with limited diversity in ethnicity and deprivation level. Additional research is needed to assess the applicability of the intervention for a more ethnically diverse population.. Trial registration: This trial is registered as ISRCTN11669964. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/90/03) and is published in full in Health Technology Assessment; Vol. 28, No. 13. See the NIHR Funding and Awards website for further award information.

Urinary problems among men become more common with age. Nearly one-third of all men aged > 65 years experience some urinary symptoms, which can have a substantial effect on their daily lives. Symptoms include needing to pass urine more often, urgently or during the night, and difficulties in passing urine. Men are usually diagnosed and treated by their general practitioner, and should be offered advice on controlling their symptoms themselves (e.g. lifestyle changes and exercises) before trying tablets or surgery. However, it is not known how helpful such advice is, and how general practices can effectively provide it. Thirty general practices in the West of England and Wessex took part in the study. Practices were split into two groups, with each practice providing either the TReatIng Urinary symptoms in Men in Primary Health care using non-pharmacological and non-surgical interventions care package or the practice's usual care to all of its patients in the trial. The TReatIng Urinary symptoms in Men in Primary Healthcare using nonpharmacological and non-surgical interventions care package included a booklet of advice to help control urinary symptoms, with a nurse or healthcare assistant directing men to relevant sections according to their symptoms, and providing follow-up contacts. We mainly assessed the benefits of the TReatIng Urinary symptoms in Men in Primary Healthcare using nonpharmacological and non-surgical interventions care package, compared with usual care, by using a questionnaire on urinary symptoms completed by participants. A total of 1077 men with urinary symptoms that bothered them joined the study. The main result was that men reported greater improvement in urinary symptoms with the TRIUMPH care package than with usual care, 12 months after joining the study. We also found that men receiving the TRIUMPH care package had a slight improvement in quality of life and outlook on their urinary symptoms. There was no difference between the two groups in the number of patients referred to hospital for treatment, the type, number and severity of side effects or cost to the NHS. Overall, the TRIUMPH care package was more effective in treating men with urinary symptoms than usual care by their general practice.

Identification and prioritisation of items for a draft participant-reported questionnaire to measure use of social care, informal care, aids and adaptations.

BACKGROUND: Resource-use measurement is integral for assessing cost-effectiveness within trial-based economic evaluations. Methods for gathering resource-use data from participants are not well developed, with questionnaires typically produced for each trial and rarely validated. The healthcare module of a generic, modular resource-use measure, designed for collecting self-report resource-utilisation data, has recently been developed in the UK. The objective of this research is to identify and prioritise items for new, bolt-on modules, covering informal care, social care and personal expenses incurred due to health and care needs. METHODS: Identification and prioritisation, conducted between April and December 2021, involved a rapid review of questionnaires included in the Database of Instruments for Resource Use Measurement and economic evaluations published from 2011 to 2021 to identify candidate items, an online survey of UK-based social care professionals to identify omitted social care items and focus groups with UK-based health economists and UK-based people who access social care services either for themselves or as carers to prioritise items. RESULTS: The review identified 203 items. Over half of the 24 survey respondents reported no missing items. Five academic health economists and four people who access social care services participated in focus groups. Feedback shaped the social and informal care modules and indicated that no specific personal expenses were essential to collect in all trials. Aids/adaptations were highlighted as costly personal expenses when relevant; therefore, the personal expenses module was narrowed to aids/adaptations only. CONCLUSION: Draft informal care, social care and aids/adaptations modules were developed, ready for further testing.

Cost-effectiveness of a primary healthcare intervention to treat male lower urinary tract symptoms: the TRIUMPH cluster randomised controlled trial.

OBJECTIVES: To estimate the cost-effectiveness of a primary care intervention for male lower urinary tract symptoms (LUTS) compared with usual care. DESIGN: Economic evaluation alongside a cluster randomised controlled trial from a UK National Health Service (NHS) perspective with a 12-month time horizon. SETTING: Thirty NHS general practice sites in England. PARTICIPANTS: 1077 men aged 18 or older identified in primary care with bothersome LUTS. INTERVENTIONS: A standardised and manualised intervention for the treatment of bothersome LUTS was compared with usual care. The intervention group (n=524) received a standardised information booklet with guidance on conservative treatment for LUTS, urinary symptom assessment and follow-up contacts for 12 weeks. The usual care group (n=553) followed local guidelines between general practice sites. MEASURES: Resource use was obtained from electronic health records, trial staff and participants, and valued using UK reference costs. Quality-adjusted life-years (QALYs) were calculated from the EQ-5D-5L questionnaire. Adjusted mean differences in costs and QALYs and incremental net monetary benefit were estimated. RESULTS: 866 of 1077 (80.4%) participants had complete data and were included in the base-case analysis. Over the 12-month follow-up period, intervention and usual care arms had similar mean adjusted costs and QALYs. Mean differences were lower in the intervention arm for adjusted costs -£29.99 (95% CI -£109.84 to £22.63) while higher in the intervention arm for adjusted QALYs 0.001 (95% CI -0.011 to 0.014). The incremental net monetary benefit statistic was £48.01 (95% CI -£225.83 to £321.85) at the National Institute for Health and Care Excellence UK threshold of £20 000 per QALY. The cost-effectiveness acceptability curve showed a 63% probability of the intervention arm being cost-effective at this threshold. CONCLUSIONS: Costs and QALYs were similar between the two arms at 12 months follow-up. This indicates that the intervention can be implemented in general practice at neutral cost. TRIAL REGISTRATION NUMBER: ISRCTN11669964.

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.

Treatment of lower urinary tract symptoms in men in primary care using a conservative intervention: cluster randomised controlled trial.

OBJECTIVE: To determine whether a standardised and manualised care intervention in men in primary care could achieve superior improvement of lower urinary tract symptoms (LUTS) compared with usual care. DESIGN: Cluster randomised controlled trial. SETTING: 30 National Health Service general practice sites in England. PARTICIPANTS: Sites were randomised 1:1 to the intervention and control arms. 1077 men (≥18 years) with bothersome LUTS recruited between June 2018 and August 2019: 524 were assigned to the intervention arm (n=17 sites) and 553 were assigned to the usual care arm (n=13 sites). INTERVENTION: Standardised information booklet developed with patient and expert input, providing guidance on conservative and lifestyle interventions for LUTS in men. After assessment of urinary symptoms (manualised element), general practice nurses and healthcare assistants or research nurses directed participants to relevant sections of the manual and provided contact over 12 weeks to assist with adherence. MAIN OUTCOME MEASURES: The primary outcome was patient reported International Prostate Symptom Score (IPSS) measured 12 months after participants had consented to take part in the study. The target reduction of 2.0 points on which the study was powered reflects the minimal clinically important difference where baseline IPSS is <20. Secondary outcomes were patient reported quality of life, urinary symptoms and perception of LUTS, hospital referrals, and adverse events. The primary intention-to-treat analysis included 887 participants (82% of those recruited) and used a mixed effects multilevel linear regression model adjusted for site level variables used in the randomisation and baseline scores. RESULTS: Participants in the intervention arm had a lower mean IPSS at 12 months (adjusted mean difference -1.81 points, 95% confidence interval -2.66 to -0.95) indicating less severe urinary symptoms than those in the usual care arm. LUTS specific quality of life, incontinence, and perception of LUTS also improved more in the intervention arm than usual care arm at 12 months. The proportion of urology referrals (intervention 7.3%, usual care 7.9%) and adverse events (intervention seven events, usual care eight events) were comparable between the arms. CONCLUSIONS: A standardised and manualised intervention in primary care showed a sustained reduction in LUTS in men at 12 months. The mean difference of -1.81 points (95% confidence interval -0.95 to -2.66) on the IPSS was less than the predefined target reduction of 2.0 points. TRIAL REGISTRATION: ISRCTN Registry ISRCTN11669964.

Protocol for the development and validation of a patient-reported experience measure (PREM) for people with hearing loss: the PREM-HeLP.

INTRODUCTION: Hearing loss is a common chronic health condition and adversely affects communication and social function resulting in loneliness, social isolation and depression. We know little about the patient experience of living with hearing loss and their views on the quality of the audiology service. In this study, we will develop and validate the first patient-reported experience measure (PREM) to understand patients' experiences of living with hearing loss and their healthcare interactions with audiology services. METHODS AND ANALYSIS: We will develop the PREM in three phases: (1) development of PREM prototype (items/statements) derived from previous qualitative work and narrative review, (2) cognitive interview testing of the PREM prototype using a 'think aloud' technique to examine the acceptability and comprehensibility of the tool and refine accordingly and (3) psychometric testing of the modified PREM with 300 participants to assess the reliability and validity of the tool using Rasch analyses with sequential item reduction. Eligible participants will be young people and adults aged 16 years and over who have hearing loss. Participants will be recruited from three clinical sites located in England (Bath, Bristol) and Scotland (Tayside) and non-clinical settings (eg, lip-reading classes, residential care settings, national charity links, social media). ETHICS AND DISSEMINATION: The study was approved by the West of Scotland Research Ethics Service (approval date: 6 May 2022; ref: 22/WS/0057) and the Health Research Authority and Health and Care Research Wales (HCRW) Approval (approval date: 14 June 2022; IRAS project ID: 308816). Findings will be shared with our patient and public involvement groups, academics, audiology communities and services and local commissioners via publications and presentations. The PREM will be made available to clinicians and researchers without charge.

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.

Development of a brief, generic, modular resource-use measure (ModRUM): piloting with patients.

BACKGROUND: Bespoke self-report resource-use measures (RUMs) are commonly developed or adapted for each new randomised controlled trial. Consequently, RUMs lack standardisation and validation is rarely conducted. A new generic RUM, ModRUM, has been developed using a rigorous process, including consultation with health economists and patients. ModRUM includes a concise core healthcare module, designed to be included in all trials, and depth-adding questions, which can replace or be added to core questions as needed. Modules covering other sectors are under development. The aim of this study was to test the acceptability, feasibility, and criterion and construct validity of the healthcare module of ModRUM. METHODS: Patients who had a recent appointment at their GP practice were invited to complete ModRUM (core module or core module with depth questions), a characteristics form and the EQ-5D-5L. Acceptability was assessed via response rates and questionnaire completion time. Feasibility was assessed by reviewing issues observed in participants' responses and question completion rates. Construct validity was tested via hypothesis testing and known-group analyses, using Wilcoxon rank-sum and Kruskal-Wallis tests, and a generalised linear model. Criterion validity was tested by comparing ModRUM results with primary care medical records. Sensitivity, specificity, and agreement using Lin's concordance correlation coefficient (pc) were estimated. RESULTS: One hundred patients participated from five GP practices in the South-West of England. Acceptability was higher for the core module (20% versus 10% response rate). Question completion rates were high across both versions (> 90%). Some support was observed for construct validity, with results suggesting that healthcare costs differ dependent on the number of long-term conditions (p < 0.05) and are negatively associated with health-related quality of life (p < 0.01). Sensitivity was high for all questions (> 0.83), while specificity varied (0.33-0.88). There was a good level of agreement for GP contacts and costs, and prescribed medication costs (pc > 0.6). CONCLUSION: This study provided preliminary evidence of the acceptability, feasibility, and criterion and construct validity of ModRUM. Further testing is required within trials and with groups that were less well represented in this study.

Impact of PSA testing on secondary care costs in England and Wales: estimates from the Cluster randomised triAl of PSA testing for Prostate cancer (CAP).

BACKGROUND: Screening men for prostate cancer using prostate-specific antigen (PSA) testing remains controversial. We aimed to estimate the likely budgetary impact on secondary care in England and Wales to inform screening decision makers. METHODS: The Cluster randomised triAl of PSA testing for Prostate cancer study (CAP) compared a single invitation to men aged 50-69 for a PSA test with usual care (no screening). Routinely collected hospital care data were obtained for all men in CAP, and NHS reference costs were mapped to each event via Healthcare Resource Group (HRG) codes. Secondary-care costs per man per year were calculated, and cost differences (and population-level estimates) between arms were derived annually for the first five years following randomisation. RESULTS: In the first year post-randomisation, secondary-care costs averaged across all men (irrespective of a prostate cancer diagnosis) in the intervention arm (n = 189279) were £44.80 (95% confidence interval: £18.30-£71.30) higher than for men in the control arm (n = 219357). Extrapolated to a population level, the introduction of a single PSA screening invitation could lead to additional secondary care costs of £314 million. CONCLUSIONS: Introducing a single PSA screening test for men aged 50-69 across England and Wales could lead to very high initial secondary-care costs.

Development of an Instrument for the Assessment of Health-Related Multi-sectoral Resource Use in Europe: The PECUNIA RUM.

BACKGROUND: Measuring objective resource-use quantities is important for generating valid cost estimates in economic evaluations. In the absence of acknowledged guidelines, measurement methods are often chosen based on practicality rather than methodological evidence. Furthermore, few resource-use measurement (RUM) instruments focus on the measurement of resource use in multiple societal sectors and their development process is rarely described. Thorn and colleagues proposed a stepwise approach to the development of RUM instruments, which has been used for developing cost questionnaires for specific trials. However, it remains unclear how this approach can be translated into practice and whether it is applicable to the development of generic self-reported RUM instruments and instruments measuring resource use in multiple sectors. This study provides a detailed description of the practical application of this stepwise approach to the development of a multi-sectoral RUM instrument developed within the ProgrammE in Costing, resource use measurement and outcome valuation for Use in multi-sectoral National and International health economic evaluAtions (PECUNIA) project. METHODS: For the development of the PECUNIA RUM, the methodological approach was based on best practice guidelines. The process included six steps, including the definition of the instrument attributes, identification of cost-driving elements in each sector, review of methodological literature and development of a harmonized cross-sectorial approach, development of questionnaire modules and their subsequent harmonization. RESULTS: The selected development approach was, overall, applicable to the development of the PECUNIA RUM. However, due to the complexity of the development of a multi-sectoral RUM instrument, additional steps such as establishing a uniform methodological basis, harmonization of questionnaire modules and involvement of a broader range of stakeholders (healthcare professionals, sector-specific experts, health economists) were needed. CONCLUSION: This is the first study that transparently describes the development process of a generic multi-sectoral RUM instrument in health economics and provides insights into the methodological aspects and overall validity of its development process.

Clinical and cost effectiveness of single stage compared with two stage revision for hip prosthetic joint infection (INFORM): pragmatic, parallel group, open label, randomised controlled trial.

OBJECTIVES: To determine whether patient reported outcomes improve after single stage versus two stage revision surgery for prosthetic joint infection of the hip, and to determine the cost effectiveness of these procedures. DESIGN: Pragmatic, parallel group, open label, randomised controlled trial. SETTING: High volume tertiary referral centres or orthopaedic units in the UK (n=12) and in Sweden (n=3), recruiting from 1 March 2015 to 19 December 2018. PARTICIPANTS: 140 adults (aged ≥18 years) with a prosthetic joint infection of the hip who required revision (65 randomly assigned to single stage and 75 to two stage revision). INTERVENTIONS: A computer generated 1:1 randomisation list stratified by hospital was used to allocate participants with prosthetic joint infection of the hip to a single stage or a two stage revision procedure. MAIN OUTCOME MEASURES: The primary intention-to-treat outcome was pain, stiffness, and functional limitations 18 months after randomisation, measured by the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) score. Secondary outcomes included surgical complications and joint infection. The economic evaluation (only assessed in UK participants) compared quality adjusted life years and costs between the randomised groups. RESULTS: The mean age of participants was 71 years (standard deviation 9) and 51 (36%) were women. WOMAC scores did not differ between groups at 18 months (mean difference 0.13 (95% confidence interval -8.20 to 8.46), P=0.98); however, the single stage procedure was better at three months (11.53 (3.89 to 19.17), P=0.003), but not from six months onwards. Intraoperative events occurred in five (8%) participants in the single stage group and 20 (27%) in the two stage group (P=0.01). At 18 months, nine (14%) participants in the single stage group and eight (11%) in the two stage group had at least one marker of possible ongoing infection (P=0.62). From the perspective of healthcare providers and personal social services, single stage revision was cost effective with an incremental net monetary benefit of £11 167 (95% confidence interval £638 to £21 696) at a £20 000 per quality adjusted life years threshold (£1.0; $1.1; €1.4). CONCLUSIONS: At 18 months, single stage revision compared with two stage revision for prosthetic joint infection of the hip showed no superiority by patient reported outcome. Single stage revision had a better outcome at three months, fewer intraoperative complications, and was cost effective. Patients prefer early restoration of function, therefore, when deciding treatment, surgeons should consider patient preferences and the cost effectiveness of single stage surgery. TRIAL REGISTRATION: ISRCTN registry ISRCTN10956306.

The STAR care pathway for patients with pain at 3 months after total knee replacement: a multicentre, pragmatic, randomised, controlled trial.

BACKGROUND: Approximately 20% of people experience chronic pain after total knee replacement, but effective treatments are not available. We aimed to evaluate the clinical effectiveness and cost-effectiveness of a new care pathway for chronic pain after total knee replacement. METHODS: We did an unmasked, parallel group, pragmatic, superiority, randomised, controlled trial at eight UK National Health Service (NHS) hospitals. People with chronic pain at 3 months after total knee replacement surgery were randomly assigned (2:1) to the Support and Treatment After Replacement (STAR) care pathway plus usual care, or to usual care alone. The STAR intervention aimed to identify underlying causes of chronic pain and enable onward referrals for targeted treatment through a 3-month post-surgery assessment with an extended scope practitioner and telephone follow-up over 12 months. Co-primary outcomes were self-reported pain severity and pain interference in the replaced knee, assessed with the Brief Pain Inventory (BPI) pain severity and interference scales at 12 months (scored 0-10, best to worst) and analysed on an as-randomised basis. Resource use, collected from electronic hospital records and participants, was valued with UK reference costs. Quality-adjusted life-years (QALYs) were calculated from EQ-5D-5L responses. This trial is registered with ISRCTN, ISRCTN92545361. FINDINGS: Between Sept 6, 2016, and May 31, 2019, 363 participants were randomly assigned to receive the intervention plus usual care (n=242) or to receive usual care alone (n=121). Participants had a median age of 67 years (IQR 61 to 73), 217 (60%) of 363 were female, and 335 (92%) were White. 313 (86%) patients provided follow-up data at 12 months after randomisation (213 assigned to the intervention plus usual care and 100 assigned to usual care alone). At 12 months, the mean between-group difference in the BPI severity score was -0·65 (95% CI -1·17 to -0·13; p=0·014) and the mean between-group difference in the BPI interference score was -0·68 (-1·29 to -0·08; p=0·026), both favouring the intervention. From an NHS and personal social services perspective, the intervention was cost-effective (greater improvement with lower cost), with an incremental net monetary benefit of £1256 (95% CI 164 to 2348) at £20 000 per QALY threshold. One adverse reaction of participant distress was reported in the intervention group. INTERPRETATION: STAR is a clinically effective and cost-effective intervention to improve pain outcomes over 1 year for people with chronic pain at 3 months after total knee replacement surgery. FUNDING: National Institute for Health Research.

Immediate oral versus immediate topical versus delayed oral antibiotics for children with acute otitis media with discharge: the REST three-arm non-inferiority electronic platform-supported RCT.

BACKGROUND: Acute otitis media is a painful infection of the middle ear that is commonly seen in children. In some children, the eardrum spontaneously bursts, discharging visible pus (otorrhoea) into the outer ear. OBJECTIVE: To compare the clinical effectiveness of immediate topical antibiotics or delayed oral antibiotics with the clinical effectiveness of immediate oral antibiotics in reducing symptom duration in children presenting to primary care with acute otitis media with discharge and the economic impact of the alternative strategies. DESIGN: This was a pragmatic, three-arm, individually randomised (stratified by age < 2 vs. ≥ 2 years), non-inferiority, open-label trial, with economic and qualitative evaluations, supported by a health-record-integrated electronic trial platform [TRANSFoRm (Translational Research and Patient Safety in Europe)] with an internal pilot. SETTING: A total of 44 English general practices. PARTICIPANTS: Children aged ≥ 12 months and < 16 years whose parents (or carers) were seeking medical care for unilateral otorrhoea (ear discharge) following recent-onset (≤ 7 days) acute otitis media. INTERVENTIONS: (1) Immediate ciprofloxacin (0.3%) solution, four drops given three times daily for 7 days, or (2) delayed 'dose-by-age' amoxicillin suspension given three times daily (clarithromycin twice daily if the child was penicillin allergic) for 7 days, with structured delaying advice. All parents were given standardised information regarding symptom management (paracetamol/ibuprofen/fluids) and advice to complete the course. COMPARATOR: Immediate 'dose-by-age' oral amoxicillin given three times daily (or clarithromycin given twice daily) for 7 days. Parents received standardised symptom management advice along with advice to complete the course. MAIN OUTCOME MEASURE: Time from randomisation to the first day on which all symptoms (pain, fever, being unwell, sleep disturbance, otorrhoea and episodes of distress/crying) were rated 'no' or 'very slight' problem (without need for analgesia). METHODS: Participants were recruited from routine primary care appointments. The planned sample size was 399 children. Follow-up used parent-completed validated symptom diaries. RESULTS: Delays in software deployment and configuration led to small recruitment numbers and trial closure at the end of the internal pilot. Twenty-two children (median age 5 years; 62% boys) were randomised: five, seven and 10 to immediate oral, delayed oral and immediate topical antibiotics, respectively. All children received prescriptions as randomised. Seven (32%) children fully adhered to the treatment as allocated. Symptom duration data were available for 17 (77%) children. The median (interquartile range) number of days until symptom resolution in the immediate oral, delayed oral and immediate topical antibiotic arms was 6 (4-9), 4 (3-7) and 4 (3-6), respectively. Comparative analyses were not conducted because of small numbers. There were no serious adverse events and six reports of new or worsening symptoms. Qualitative clinician interviews showed that the trial question was important. When the platform functioned as intended, it was liked. However, staff reported malfunctioning software for long periods, resulting in missed recruitment opportunities. Troubleshooting the software placed significant burdens on staff. LIMITATIONS: The over-riding weakness was the failure to recruit enough children. CONCLUSIONS: We were unable to answer the main research question because of a failure to reach the required sample size. Our experience of running an electronic platform-supported trial in primary care has highlighted challenges from which we have drawn recommendations for the National Institute for Health Research (NIHR) and the research community. These should be considered before such a platform is used again. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12873692 and EudraCT 2017-003635-10. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 67. See the NIHR Journals Library website for further project information.

Ear infections are common in childhood. Some are complicated by a burst eardrum, followed by discharge from the ear. The usual treatment for this is a short course of antibiotics taken by mouth. However, alternative treatment using antibiotic drops, or a 'wait and see' policy before starting antibiotics, would result in less antibiotic use and reduce the subsequent risk of antibiotic resistance, which is bad for both patients and the environment. This study set out to see if these alternative treatments were as effective as the usual treatment for children with ear discharge. Although ear infections are common, only one in six children develops ear discharge, so only a few children might be available to take part at each general practice. We planned to use an electronic recruitment system to help us to gather enough patients. The system [called the 'TRANSFoRm' (Translational Research and Patient Safety in Europe) platform] was designed to remind busy general practitioners and nurses about the study and take them through the recruitment process step by step, as well as to support trial processes. Although the TRANSFoRm platform had been developed and tested, it had not been used in general practices before. We were surprised to find that there were many technical problems in setting up the TRANSFoRm platform in general practices, and staff were too busy and/or did not have the skills to overcome the technical issues. As a result, recruiting patients was slow and the study was halted before we had enough children to answer the main research question. In total, we managed to get 44 general practices and 22 children, but this was not enough. We still think that this kind of research and electronic trial platforms are important. We have noted many system and technical issues that need to be solved to enable funders and researchers to use this recruitment approach in the future.

Aspects and Challenges of Resource Use Measurement in Health Economics: Towards a Comprehensive Measurement Framework.

BACKGROUND: While the methods for conducting health economics research in general are improving, current guidelines provide limited guidance regarding resource use measurement (RUM). Consequently, a variety of methods exists, yet there is no overview of aspects to consider when deciding on the most appropriate RUM methodology. Therefore, this study aims to (1) identify and categorize existing knowledge regarding aspects of RUM, and (2) develop a framework that provides a comprehensive overview of methodological aspects regarding RUM. METHODS: Relevant articles were identified by enrolling a search string in six databases and handsearching the DIRUM database. Included articles were descriptively reviewed and served as input for a comprehensive framework. Health economics experts were involved during the process to establish the framework's face validity. RESULTS: Forty articles were included in the scoping review. The RUM framework consists of four methodological RUM domains: 'Whom to measure', addressing whom to ask and whom to measure; 'How to measure', addressing the different approaches of measurement; 'How often to measure', addressing recall period and measurement patterns; and 'Additional considerations', which covers additional aspects that are essential for further refining the methodologies for measurement. Evidence retrieved from the scoping review was categorized according to these domains. CONCLUSION: This study clustered the aspects of RUM methodology in health economics into a comprehensive framework. The results may guide health economists in their decision making regarding the selection of appropriate RUM methods and developing instruments for RUM. Furthermore, policy makers may use these findings to review study results from an evidence-based perspective.

Content of Health Economics Analysis Plans (HEAPs) for Trial-Based Economic Evaluations: Expert Delphi Consensus Survey.

OBJECTIVES: Health economics analysis plans (HEAPs) currently lack consistency, with uncertainty surrounding appropriate content. We aimed to develop a list of essential items that should be included in HEAPs for economic evaluations conducted alongside randomized trials. METHODS: A list of potential items for inclusion was developed by examining existing HEAPs. An electronic Delphi survey was conducted among professional health economists. Respondents were asked to rate potential items from 1 (least important) to 9 (most important), suggest additional items, and comment on proposed items (round 1). A second survey (round 2) was emailed to participants, including the participant's own scores from round 1 along with summary results from the whole panel; participants were asked to rerate each item. Consensus criteria for inclusion in the final list were predefined as >70% of participants rating an item 7-9 and <15% rating it 1-3 after round 2. A final item selection meeting was held to scrutinize the results and adjudicate on items lacking consensus. RESULTS: 62 participants completed round 1 of the survey. The initial list included 72 potential items; all 72 were carried forward to round 2, and no new items were added. 48 round 1 respondents (77.4%) completed round 2 and reached consensus on 53 items. At the final meeting, the expert panel (n = 9) agreed that 58 items should be included in the essential list, moved 9 items to an optional list, and dropped 5 items. CONCLUSIONS: Via expert consensus opinion, this study identified 58 items that are considered essential in a HEAP.

Development of a brief, generic, modular resource-use measure (ModRUM): cognitive interviews with patients.

BACKGROUND: Self-report resource-use measures (RUMs) are often used to collect healthcare use data from participants in healthcare studies. However, RUMs are typically adapted from existing measures on a study-by-study basis, resulting in a lack of standardisation which limits comparability across studies. Psychometric testing of RUMs is rarely conducted. This paper reports on cognitive interviews with patients to test the content validity and acceptability of a new RUM (ModRUM). ModRUM is a brief, generic RUM with a core module on healthcare use and questions/modules to increase depth and breadth. METHODS: A purposeful sampling strategy with maximum variation was used to recruit patients from primary care to participate in "think-aloud" interviews with retrospective probing. Participants verbalised their thought processes as they completed ModRUM, which allowed errors (issues with completion) to be identified. The interviewer asked follow-up and probing questions to investigate errors, clarity and acceptability. Interviews were audio-recorded and transcribed verbatim. Research team members independently scored transcripts to identify errors in comprehension, recall, judgement and response. Members met to agree on final scores. Interview transcripts were analysed qualitatively using techniques of constant comparison, to identify common themes and ideas for improvement. Data collection and analysis were performed concurrently and in rounds. RESULTS: Twenty participants were interviewed between December 2019 and March 2020. Interviews were conducted in three rounds, with revisions made iteratively and in response to interview findings. Seven participants completed the core module and 13 completed the core module plus depth questions. Of 71 issues, 28 were in comprehension, 14 in retrieval, 10 in judgement, 18 in response and 1 uncategorised. Most issues (21 issues by 2 participants) were due to participants including family healthcare use. Other issues included using incorrect recall periods (5 issues) and overlooking questions leading to missing responses (9 issues). Common participant suggestions included highlighting important details and providing additional definition or examples for some terms. The length, content and layout were acceptable to most participants. CONCLUSIONS: A generic RUM is needed to increase study comparability. RUM development requires thorough testing to demonstrate and enhance validity. Cognitive interviewing has demonstrated the acceptability and content validity of ModRUM.

What are the inpatient and day case costs following primary total hip replacement of patients treated for prosthetic joint infection: a matched cohort study using linked data from the National Joint Registry and Hospital Episode Statistics.

BACKGROUND: Prosthetic joint infection (PJI) following total hip replacement (THR) surgery is a serious complication that negatively impacts patients' lives and is financially burdensome for healthcare providers. As the number of THRs increases, so does this financial burden. This research estimates the economic burden with respect to inpatient and day case hospital admissions for patients receiving revision surgery for PJI following primary THR. METHODS: In this matched cohort study, the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man (NJR) was used to identify patients. Patients revised for PJI with a one- or two-stage revision following THR and patients not revised for PJI were matched on several characteristics using exact and radius matching. Hospital inpatient and day case healthcare records from the English Hospital Episode Statistics database were obtained for 5 years following the identified patient's primary THR. UK national unit costs were applied to hospital admissions and the 5-year total cost was estimated. A two-part model (Probit and generalised linear model) was employed to estimate the incremental difference in costs between those revised and not revised for PJI. RESULTS: Between 2006 and 2009, 1914 revisions for PJI were identified in the NJR. The matching resulted in 422 patients revised for PJI and 1923 matches not revised for PJI who were included in the analysis. The average cost of inpatient and day case admissions in the 5 years following primary THR was approximately £42,000 for patients revised for PJI and £8000 for patients not revised for PJI. The difference in costs over the 5 years was £33,452 (95% CI £30,828 to £36,077; p < 0.00). CONCLUSIONS: In the 5 years following primary THR, patients who develop PJI and have revision surgery cost approximately £33,000 (over 5-fold) more than patients not revised for PJI based on their hospital inpatient and day case admissions alone. The total burden of PJI is likely to be much higher when also considering outpatient, primary and community care costs. This highlights the need to find both ways to reduce the incidence of PJI following THR and cost-effective treatment strategies if PJI occurs.

Urodynamics tests for the diagnosis and management of bladder outlet obstruction in men: the UPSTREAM non-inferiority RCT.

BACKGROUND: Lower urinary tract symptoms (LUTS) in men may indicate bladder outlet obstruction (BOO) or weakness, known as detrusor underactivity (DU). Severe bothersome LUTS are a common indication for surgery. The diagnostic tests may include urodynamics (UDS) to confirm whether BOO or DU is the cause, potentially reducing the number of people receiving (inappropriate) surgery. OBJECTIVES: The primary objective was to determine whether a care pathway including UDS is no worse for symptom outcome than one in which it is omitted, at 18 months after randomisation. Rates of surgery was the key secondary outcome. DESIGN: This was a pragmatic, multicentre, two-arm (unblinded) randomised controlled trial, incorporating a health economic analysis and qualitative research. SETTING: Urology departments of 26 NHS hospitals in England. PARTICIPANTS: Men (aged ≥ 18 years) seeking further treatment, potentially including surgery, for bothersome LUTS. Exclusion criteria were as follows: unable to pass urine without a catheter, having a relevant neurological disease, currently undergoing treatment for prostate or bladder cancer, previously had prostate surgery, not medically fit for surgery and/or unwilling to be randomised. INTERVENTIONS: Men were randomised to a care pathway based on non-invasive routine tests (control) or routine care plus invasive UDS (intervention arm). MAIN OUTCOME MEASURES: The primary outcome was International Prostate Symptom Score (IPSS) at 18 months after randomisation and the key secondary outcome was rates of surgery. Additional secondary outcomes included adverse events (AEs), quality of life, urinary and sexual symptoms, UDS satisfaction, maximum urinary flow rate and cost-effectiveness. RESULTS: A total of 820 men were randomised (UDS, 427; routine care, 393). Sixty-seven men withdrew before 18 months and 11 died (unrelated to trial procedures). UDS was non-inferior to routine care for IPSS 18 months after randomisation, with a confidence interval (CI) within the margin of 1 point (-0.33, 95% CI -1.47 to 0.80). A lower surgery rate in the UDS arm was not found (38% and 36% for UDS and routine care, respectively), with overall rates lower than expected. AEs were similar between the arms at 43-44%. There were more cases of acute urinary retention in the routine care arm. Patient-reported outcomes for LUTS improved in both arms and satisfaction with UDS was high in men who received it. UDS was more expensive than routine care. From a secondary care perspective, UDS cost an additional £216 over an 18-month time horizon. Quality-adjusted life-years (QALYs) were similar, with a QALY difference of 0.006 in favour of UDS over 18 months. It was established that UDS was acceptable to patients, and valued by both patients and clinicians for its perceived additional insight into the cause and probable best treatment of LUTS. LIMITATIONS: The trial met its predefined recruitment target, but surgery rates were lower than anticipated. CONCLUSIONS: Inclusion of UDS in the diagnostic tests results in a symptom outcome that is non-inferior to a routine care pathway, but does not affect surgical rates for treating BOO. Results do not support the routine use of UDS in men undergoing investigation of LUTS. FUTURE WORK: Focus should be placed on indications for selective utilisation of UDS in individual cases and long-term outcomes of diagnosis and therapy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN56164274. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 42. See the NIHR Journals Library website for further project information.

After hospital referral, men with bothersome lower urinary tract symptoms (LUTS) are assessed with standard tests. These include measurement of urine flow rate, bladder diaries and questionnaires, including the International Prostate Symptom Score (IPSS). UPSTREAM (Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods) researched whether or not including an extra test, urodynamics (UDS), helps when considering treatment options. UDS is a more invasive test and measures pressure in the bladder to check whether or not the prostate is causing obstruction. It was presumed that, if there is no obstruction, surgery would not be offered, so that using UDS would reduce the number of prostate operations. Each man participating (820 in total) was assessed with the standard tests. Around half of them had no extra tests (the 'routine care' arm of the trial); the rest had the UDS tests (the 'UDS' arm). Men then went on to have treatment, which they chose having discussed their test results with a urologist. IPSS and other symptom scores were examined for each man 18 months after joining the trial. At 18 months, surgery outcomes were known for 792 men and IPSS was known for 669 men. We investigated if the two trial arms showed similar changes in the IPSS and if there were fewer operations done in the UDS arm. We identified similar reductions in the IPSS in both arms. However, UDS tests did not reduce the number of operations. Analysing all the costs, it was found that a pathway including UDS costs more than routine care. Interviews were conducted that showed that men found UDS acceptable, and that the additional information helped both the men and their doctors consider which treatment would be most appropriate. These results do not support the routine use of UDS in the assessment of every man considering prostate surgery for LUTS. Further exploration of the data may identify circumstances in which UDS could be helpful.