Undertaking Studies Within A Trial to evaluate recruitment and retention strategies for randomised controlled trials: lessons learnt from the PROMETHEUS research programme.

Background: Randomised controlled trials ('trials') are susceptible to poor participant recruitment and retention. Studies Within A Trial are the strongest methods for testing the effectiveness of strategies to improve recruitment and retention. However, relatively few of these have been conducted. Objectives: PROMoting THE Use of Studies Within A Trial aimed to facilitate at least 25 Studies Within A Trial evaluating recruitment or retention strategies. We share our experience of delivering the PROMoting THE Use of Studies Within A Trial programme, and the lessons learnt for undertaking randomised Studies Within A Trial. Design: A network of 10 Clinical Trials Units and 1 primary care research centre committed to conducting randomised controlled Studies Within A Trial of recruitment and/or retention strategies was established. Promising recruitment and retention strategies were identified from various sources including Cochrane systematic reviews, the Study Within A Trial Repository, and existing prioritisation exercises, which were reviewed by patient and public members to create an initial priority list of seven recruitment and eight retention interventions. Host trial teams could apply for funding and receive support from the PROMoting THE Use of Studies Within A Trial team to undertake Studies Within A Trial. We also tested the feasibility of undertaking co-ordinated Studies Within A Trial, across multiple host trials simultaneously. Setting: Clinical trials unit-based trials recruiting or following up participants in any setting in the United Kingdom were eligible. Participants: Clinical trials unit-based teams undertaking trials in any clinical context in the United Kingdom. Interventions: Funding of up to £5000 and support from the PROMoting THE Use of Studies Within A Trial team to design, implement and report Studies Within A Trial. Main outcome measures: Number of host trials funded. Results: Forty-two Studies Within A Trial were funded (31 host trials), across 12 Clinical Trials Units. The mean cost of a Study Within A Trial was £3535. Twelve Studies Within A Trial tested the same strategy across multiple host trials using a co-ordinated Study Within A Trial design, and four used a factorial design. Two recruitment and five retention strategies were evaluated in more than one host trial. PROMoting THE Use of Studies Within A Trial will add 18% more Studies Within A Trial to the Cochrane systematic review of recruitment strategies, and 79% more Studies Within A Trial to the Cochrane review of retention strategies. For retention, we found that pre-notifying participants by card, letter or e-mail before sending questionnaires was effective, as was the use of pens, and sending personalised text messages to improve questionnaire response. We highlight key lessons learnt to guide others planning Studies Within A Trial, including involving patient and public involvement partners; prioritising and selecting strategies to evaluate and elements to consider when designing a Study Within A Trial; obtaining governance approvals; implementing Studies Within A Trial, including individual and co-ordinated Studies Within A Trials; and reporting Study Within A Trials. Limitations: The COVID-19 pandemic negatively impacted five Studies Within A Trial, being either delayed (n = 2) or prematurely terminated (n = 3). Conclusions: PROMoting THE Use of Studies Within A Trial significantly increased the evidence base for recruitment and retention strategies. When provided with both funding and practical support, host trial teams successfully implemented Studies Within A Trial. Future work: Future research should identify and target gaps in the evidence base, including widening Study Within A Trial uptake, undertaking more complex Studies Within A Trial and translating Study Within A Trial evidence into practice. Study registration: All Studies Within A Trial in the PROMoting THE Use of Studies Within A Trial programme had to be registered with the Northern Ireland Network for Trials Methodology Research Study Within A Trial Repository. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/55/80) and is published in full in Health Technology Assessment; Vol. 28, No. 2. See the NIHR Funding and Awards website for further award information.

A Study Within A Trial is a research study nested inside a larger 'host trial', promoting the use of Studies Within A Trial aimed to do Study Within A Trial routine practice in clinical trial units by funding and supporting at least 25 Studies Within A Trial. The best way to test health and social care treatments is to do a randomised controlled trial ('trial'), where some patients get the treatment being tested and some do not. The results of different groups are compared to see if the treatment improves care. Recruiting patients and keeping them involved in trials is often very difficult. Research teams often do not know how best to recruit and keep patients engaged as the methods have not been tested to see if they work. The best way to test these methods is by doing a Study Within A Trial. We test a programme of Studies Within A Trial for recruiting and keeping patients engaged in trials. Trial teams were able to apply for funding of up to £5000 and receive support from Promoting the use of Study Within A Trial team to do Studies Within A Trial. We used our experience of doing Studies Within A Trial to outline lessons learnt for doing Studies Within A Trial. We funded 42 Studies Within A Trial and gave teams necessary advice to do them. We significantly increased the knowledge for both recruitment and retention strategies, and found 'pre-notifying' before sending questionnaires, sending pens and personalised text messages were all effective for increasing responses by participants. We tested Studies Within A Trial across several different trials at the same time to find out more quickly whether their methods worked. We highlight key lessons learnt to guide others doing Studies Within A Trial, including involving patient partners; picking the right strategy to test; getting ethical approvals; how to do and report Studies Within A Trial. Promoting the use of studies within a trial was successful and supported more Studies Within A Trial than planned. We hope our experience will support those doing Studies Within A Trial in the future.

Investigating the impact of London's ultra low emission zone on children's health: children's health in London and Luton (CHILL) protocol for a prospective parallel cohort study.

BACKGROUND: Air pollution harms health across the life course. Children are at particular risk of adverse effects during development, which may impact on health in later life. Interventions that improve air quality are urgently needed both to improve public health now, and prevent longer-term increased vulnerability to chronic disease. Low Emission Zones are a public health policy intervention aimed at reducing traffic-derived contributions to urban air pollution, but evidence that they deliver health benefits is lacking. We describe a natural experiment study (CHILL: Children's Health in London and Luton) to evaluate the impacts of the introduction of London's Ultra Low Emission Zone (ULEZ) on children's health. METHODS: CHILL is a prospective two-arm parallel longitudinal cohort study recruiting children at age 6-9 years from primary schools in Central London (the focus of the first phase of the ULEZ) and Luton (a comparator site), with the primary outcome being the impact of changes in annual air pollutant exposures (nitrogen oxides [NOx], nitrogen dioxide [NO2], particulate matter with a diameter of less than 2.5micrograms [PM2.5], and less than 10 micrograms [PM10]) across the two sites on lung function growth, measured as post-bronchodilator forced expiratory volume in one second (FEV1) over five years. Secondary outcomes include physical activity, cognitive development, mental health, quality of life, health inequalities, and a range of respiratory and health economic data. DISCUSSION: CHILL's prospective parallel cohort design will enable robust conclusions to be drawn on the effectiveness of the ULEZ at improving air quality and delivering improvements in children's respiratory health. With increasing proportions of the world's population now living in large urban areas exceeding World Health Organisation air pollution limit guidelines, our study findings will have important implications for the design and implementation of Low Emission and Clean Air Zones in the UK, and worldwide. CLINICALTRIALS: GOV: NCT04695093 (05/01/2021).

Can we achieve better trial recruitment by presenting patient information through multimedia? Meta-analysis of 'studies within a trial' (SWATs).

BACKGROUND: People need high-quality information to make decisions about research participation. Providing information in written format alone is conventional but may not be the most effective and acceptable approach. We developed a structure for the presentation of information using multimedia which included generic and trial-specific content. Our aim was to embed 'Studies Within A Trial' (SWATs) across multiple ongoing trials to test whether multimedia presentation of patient information led to better rates of recruitment. METHODS: Five trials included a SWAT and randomised their participants to receive a multimedia presentation alongside standard information, or standard written information alone. We collected data on trial recruitment, acceptance and retention and analysed the pooled results using random effects meta-analysis, with the primary outcome defined as the proportion of participants randomised following an invitation to take part. RESULTS: Five SWATs provided data on the primary outcome of proportion of participants randomised. Multimedia alongside written information results in little or no difference in recruitment rates (pooled odds ratio = 0.96, 95% CI: 0.79 to 1.17, p-value = 0.671, I2 = 0%). There was no effect on any other outcomes. CONCLUSIONS: Multimedia alongside written information did not improve trial recruitment rates. TRIAL REGISTRATION: ISRCTN71952900, ISRCTN 06710391, ISRCTN 17160087, ISRCTN05926847, ISRCTN62869767.

Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: A randomized controlled trial.

AIM: The aim was to determine whether specialist-led habit training using Habit Training with Biofeedback (HTBF) is more effective than specialist-led habit training alone (HT) for chronic constipation and whether outcomes of interventions are improved by stratification to HTBF or HT based on diagnosis (functional defaecation disorder vs. no functional defaecation disorder) by radio-physiological investigations (INVEST). METHOD: This was a parallel three-arm randomized single-blinded controlled trial, permitting two randomized comparisons: HTBF versus HT alone; INVEST- versus no-INVEST-guided intervention. The inclusion criteria were age 18-70 years; attending specialist hospitals in England; self-reported constipation for >6 months; refractory to basic treatment. The main exclusions were secondary constipation and previous experience of the trial interventions. The primary outcome was the mean change in Patient Assessment of Constipation Quality of Life score at 6 months on intention to treat. The secondary outcomes were validated disease-specific and psychological questionnaires and cost-effectiveness (based on EQ-5D-5L). RESULTS: In all, 182 patients were randomized 3:3:2 (target 384): HT n = 68; HTBF n = 68; INVEST-guided treatment n = 46. All interventions had similar reductions (improvement) in the primary outcome at 6 months (approximately -0.8 points of a 4-point scale) with no statistically significant difference between HT and HTBF (-0.03 points; 95% CI -0.33 to 0.27; P = 0.85) or INVEST versus no-INVEST (0.22; -0.11 to 0.55; P = 0.19). Secondary outcomes showed a benefit for all interventions with no evidence of greater cost-effectiveness of HTBF or INVEST compared with HT. CONCLUSION: The results of the study at 6 months were inconclusive. However, with the caveat of under-recruitment and further attrition at 6 months, a simple, cheaper approach to intervention may be as clinically effective and more cost-effective than more complex and invasive approaches.

Group antenatal care: findings from a pilot randomised controlled trial of REACH Pregnancy Circles.

BACKGROUND: Antenatal care has the potential to impact positively on maternal and child outcomes, but traditional models of care in the UK have been shown to have limitations and particularly for those from deprived populations. Group antenatal care is an alternative model to traditional individual care. It combines conventional aspects of antenatal assessment with group discussion and support. Delivery of group antenatal care has been shown to be successful in various countries; there is now a need for a formal trial in the UK. METHOD: An individual randomised controlled trial (RCT) of a model of group care (Pregnancy Circles) delivered in NHS settings serving populations with high levels of deprivation and diversity was conducted in an inner London NHS trust. This was an external pilot study for a potential fully powered RCT with integral economic evaluation. The pilot aimed to explore the feasibility of methods for the full trial. Inclusion criteria included pregnant with a due date in a certain range, 16 + years and living within specified geographic areas. Data were analysed for completeness and usability in a full trial; no hypothesis testing for between-group differences in outcome measures was undertaken. Pre-specified progression criteria corresponding to five feasibility measures were set. Additional aims were to assess the utility of our proposed outcome measures and different data collection routes. A process evaluation utilising interviews and observations was conducted. RESULTS: Seventy-four participants were randomised, two more than the a priori target. Three Pregnancy Circles of eight sessions each were run. Interviews were undertaken with ten pregnant participants, seven midwives and four other stakeholders; two observations of intervention sessions were conducted. Progression criteria were met at sufficient levels for all five measures: available recruitment numbers, recruitment rate, intervention uptake and retention and questionnaire completion rates. Outcome measure assessments showed feasibility and sufficient completion rates; the development of an economic evaluation composite measure of a 'positive healthy birth' was initiated. CONCLUSION: Our pilot findings indicate that a full RCT would be feasible to conduct with a few adjustments related to recruitment processes, language support, accessibility of intervention premises and outcome assessment. TRIAL REGISTRATION: ISRCTN ISRCTN66925258. Retrospectively registered, 03 April 2017.

Supportive Self-Management Program for People With Chronic Headaches and Migraine: A Randomized Controlled Trial and Economic Evaluation.

BACKGROUND AND OBJECTIVES: Chronic headache disorders are a major cause of pain and disability. Education and supportive self-management approaches could reduce the burden of headache disability. We tested the effectiveness of a group educational and supportive self-management program for people living with chronic headaches. METHODS: This was a pragmatic randomized controlled trial. Participants were aged 18 years or older with chronic migraine or chronic tension-type headache, with or without medication overuse headache. We primarily recruited from general practices. Participants were assigned to either a 2-day group education and self-management program, a one-to-one nurse interview, and telephone support or to usual care plus relaxation material. The primary outcome was headache related-quality of life using the Headache Impact Test (HIT)-6 at 12 months. The primary analysis used intention-to-treat principles for participants with migraine and both baseline and 12-month HIT-6 data. RESULTS: Between April 2017 and March 2019, we randomized 736 participants. Because only 9 participants just had tension-type headache, our main analyses were on the 727 participants with migraine. Of them, 376 were allocated to the self-management intervention and 351 to usual care. Data from 586 (81%) participants were analyzed for primary outcome. There was no between-group difference in HIT-6 (adjusted mean difference = -0.3, 95% CI -1.23 to 0.67) or headache days (0.9, 95% CI -0.29 to 2.05) at 12 months. The Chronic Headache Education and Self-management Study intervention generated incremental adjusted costs of £268 (95% CI, £176-£377) (USD383 [95% CI USD252-USD539]) and incremental adjusted quality-adjusted life years (QALYs) of 0.031 (95% CI -0.005 to 0.063). The incremental cost-effectiveness ratio was £8,617 (USD12,322) per QALY gained. DISCUSSION: These findings conclusively show a lack of benefit for quality of life or monthly headache days from a brief group education and supportive self-management program for people living with chronic migraine or chronic tension-type headache with episodic migraine. TRIAL REGISTRATION INFORMATION: Registered on the International Standard Randomized Controlled Trial Number registry, ISRCTN79708100 16th December 2015 doi.org/10.1186/ISRCTN79708100. The first enrollment was April 24, 2017. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a brief group education and self-management program does not increase the probability of improvement in headache-related quality of life in people with chronic migraine.

Can we achieve better recruitment by providing better information? Meta-analysis of 'studies within a trial' (SWATs) of optimised participant information sheets.

BACKGROUND: The information given to people considering taking part in a trial needs to be easy to understand if those people are to become, and then remain, trial participants. However, there is a tension between providing comprehensive information and providing information that is comprehensible. User-testing is one method of developing better participant information, and there is evidence that user-tested information is better at informing participants about key issues relating to trials. However, it is not clear if user-testing also leads to changes in the rates of recruitment in trials, compared to standard trial information. As part of a programme of research, we embedded 'studies within a trial' (SWATs) across multiple ongoing trials to see if user-tested materials led to better rates of recruitment. METHODS: Seven 'host' trials included a SWAT evaluation and randomised their participants to receive routine information sheets generated by the research teams, or information sheets optimised through user-testing. We collected data on trial recruitment and analysed the results across these trials using random effects meta-analysis, with the primary outcome defined as the proportion of participants randomised in a host trial following an invitation to take part. RESULTS: Six SWATs (n=27,805) provided data on recruitment. Optimised participant information sheets likely result in little or no difference in recruitment rates (7.2% versus 6.8%, pooled odds ratio = 1.03, 95% CI 0.90 to 1.19, p-value = 0.63, I2 = 0%). CONCLUSIONS: Participant information sheets developed through user testing did not improve recruitment rates. The programme of work showed that co-ordinated testing of recruitment strategies using SWATs is feasible and can provide both definitive and timely evidence on the effectiveness of recruitment strategies. TRIAL REGISTRATION: Healthlines Depression (ISRCTN14172341) Healthlines CVD (ISRCTN27508731) CASPER (ISRCTN02202951) ISDR (ISRCTN87561257) ECLS (NCT01925625) REFORM (ISRCTN68240461) HeLP Diabetes (ISRCTN02123133).

Group antenatal care (Pregnancy Circles) for diverse and disadvantaged women: study protocol for a randomised controlled trial with integral process and economic evaluations.

BACKGROUND: Group antenatal care has been successfully implemented around the world with suggestions of improved outcomes, including for disadvantaged groups, but it has not been formally tested in the UK in the context of the NHS. To address this the REACH Pregnancy Circles intervention was developed and a randomised controlled trial (RCT), based on a pilot study, is in progress. METHODS: The RCT is a pragmatic, two-arm, individually randomised, parallel group RCT designed to test clinical and cost-effectiveness of REACH Pregnancy Circles compared with standard care. Recruitment will be through NHS services. The sample size is 1732 (866 randomised to the intervention and 866 to standard care). The primary outcome measure is a 'healthy baby' composite measured at 1 month postnatal using routine maternity data. Secondary outcome measures will be assessed using participant questionnaires completed at recruitment (baseline), 35 weeks gestation (follow-up 1) and 3 months postnatal (follow-up 2). An integrated process evaluation, to include exploration of fidelity, will be conducted using mixed methods. Analyses will be on an intention to treat as allocated basis. The primary analysis will compare the number of babies born "healthy" in the control and intervention arms and provide an odds ratio. A cost-effectiveness analysis will compare the incremental cost per Quality Adjusted Life Years and per additional 'healthy and positive birth' of the intervention with standard care. Qualitative data will be analysed thematically. DISCUSSION: This multi-site randomised trial in England is planned to be the largest trial of group antenatal care in the world to date; as well as the first rigorous test within the NHS of this maternity service change. It has a recruitment focus on ethnically, culturally and linguistically diverse and disadvantaged participants, including non-English speakers. TRIAL REGISTRATION: Trial registration; ISRCTN, ISRCTN91977441 . Registered 11 February 2019 - retrospectively registered. The current protocol is Version 4; 28/01/2020.

Predictors of moving on from mental health supported accommodation in England: national cohort study.

BACKGROUND: Around 60 000 people in England live in mental health supported accommodation. There are three main types: residential care, supported housing and floating outreach. Supported housing and floating outreach aim to support service users in moving on to more independent accommodation within 2 years, but there has been little research investigating their effectiveness. AIMS: A 30-month prospective cohort study investigating outcomes for users of mental health supported accommodation. METHOD: We used random sampling, accounting for relevant geographical variation factors, to recruit 87 services (22 residential care, 35 supported housing and 30 floating outreach) and 619 service users (residential care 159, supported housing 251, floating outreach 209) across England. We contacted services every 3 months to investigate the proportion of service users who successfully moved on to more independent accommodation. Multilevel modelling was used to estimate how much of the outcome and cost variations were due to service type and quality, after accounting for service-user characteristics. RESULTS: Overall 243/586 participants successfully moved on (residential care 15/146, supported housing 96/244, floating outreach 132/196). This was most likely for floating outreach service users (versus residential care: odds ratio 7.96, 95% CI 2.92-21.69, P < 0.001; versus supported housing: odds ratio 2.74, 95% CI 1.01-7.41, P < 0.001) and was associated with reduced costs of care and two aspects of service quality: promotion of human rights and recovery-based practice. CONCLUSIONS: Most people do not move on from supported accommodation within the expected time frame. Greater focus on human rights and recovery-based practice may increase service effectiveness.

Evaluating the effectiveness and cost-effectiveness of the Smoking Treatment Optimisation in Pharmacies (STOP) intervention: protocol for a cluster randomised controlled trial.

BACKGROUND: NHS community pharmacies provide effective smoking cessation services; however, there is scope for increasing throughput and improving quit rates. This trial examines whether the Smoking Treatment Optimisation in Pharmacies (STOP) intervention can improve smoker engagement to increase service throughput, retention and quitting. METHODS: This study is a pragmatic, cluster randomised controlled trial in 60 pharmacies in England and Wales. All workers in intervention pharmacies are offered STOP training while control pharmacies provide usual care. The STOP intervention, based on behavioural and organisational theories, comprises educational sessions for staff and environmental prompts in the pharmacy. Intervention fidelity is assessed by actors visiting pharmacies posing as smokers. The primary outcome is throughput, defined as the number of smokers who join the programme, set a firm quit date and undergo at least one stop smoking treatment session, and is measured using routinely collected data. Secondary outcomes include retention and quit rates at 4 weeks and continuous abstinence at 6 months verified by salivary cotinine. Cost-effectiveness is estimated using quality-adjusted life years and the probability that the intervention is effective at different levels of willingness to pay is calculated. DISCUSSION: The trial will generate evidence to inform the public health smoking cessation strategy in England and Wales, and may help to shape service commissioning decisions. The STOP intervention model may help inform the undertaking of a range of health behaviour change tasks in community pharmacies. TRIAL REGISTRATION: ClinicalTrials.gov, ISRCTN16351033. Retrospectively registered on 21 March 2017.

Evaluating NHS Stop Smoking Service engagement in community pharmacies using simulated smokers: fidelity assessment of a theory-based intervention.

OBJECTIVES: Smokers are more likely to quit if they use the National Health Service (NHS) Stop Smoking Service (SSS). However, community pharmacies experience low service uptake. The Smoking Treatment Optimisation in Pharmacies (STOP) programme aims to address this problem by enhancing staff training using a theory-based intervention. In this study, we evaluated intervention fidelity using simulated smokers (actors) to assess smoker engagement and enactment of key intervention components by STOP trained staff. DESIGN: An observational pilot study. SETTINGS: Five community pharmacies in North East London with an NHS SSS. METHODS: Six actors, representative of East London's population, were recruited and trained to complete intervention fidelity assessments. Consenting pharmacy staff from five participating pharmacies received STOP Intervention training. Four weeks after the staff training, the actors visited the participating pharmacies posing as smokers eligible for smoking cessation support. Engagement behaviour by pharmacy staff and enactment of intervention components was assessed using a scoring tool derived from the STOP logic model (scoring range of 0-36), and contemporaneous field notes taken by actors. RESULTS: 18 of 30 completed assessments were with STOP trained staff (10/18 were counter assistants). Mean score for smoker engagement was 24.4 (SD 9.0) points for trained and 16.9 (SD 7.8) for untrained staff, respectively. NHS SSS leaflets (27/30) were the most common smoking cessation materials seen on pharmacy visits. Most trained counter staff engaged with smokers using leaflets and a few proactively offered appointments with their cessation advisors. Appropriate use of body language was reported on 26/30 occasions alongside the use of key phrases from the STOP training session (n=8). Very few pharmacy staff wore STOP promotional badges (4/30). CONCLUSIONS: STOP training may change client engagement behaviour in pharmacy staff and could improve the uptake of the NHS SSS. A cluster randomised controlled trial is currently in progress to evaluate its effectiveness and cost-effectiveness. TRIAL REGISTRATION NUMBER: ISRCTN16351033.

Randomised controlled trial and economic evaluation of a task-based weight management group programme.

BACKGROUND: Obesity is a rising global threat to health and a major contributor to health inequalities. Weight management programmes that are effective, economical and reach underprivileged groups are needed. We examined whether a multi-modal group intervention structured to cater for clients from disadvantaged communities (Weight Action Programme; WAP) has better one-year outcomes than a primary care standard weight management intervention delivered by practice nurses (PNI). METHODS: In this randomised controlled trial, 330 obese adults were recruited from general practices in London and allocated (2:1) to WAP (N = 221) delivered over eight weekly group sessions or PNI (N = 109) who received four sessions over eight weeks. Both interventions covered diet, physical activity and self-monitoring. The primary outcome was the change in weight from baseline at 12 months. To indicate value to the NHS, a cost effectiveness analysis estimated group differences in cost and Quality-Adjusted Life-Years (QALYs) related to WAP. RESULTS: Participants were recruited from September 2012 to January 2014 with follow-up completed in February 2015. Most participants were not in paid employment and 60% were from ethnic minorities. 88% of participants in each study arm provided at least one recorded outcome and were included in the primary analysis. Compared with the PNI, WAP was associated with greater weight loss overall (- 4·2 kg vs. - 2·3 kg; difference = - 1·9 kg, 95% CI: -3·7 to - 0·1; P = 0·04) and was more likely to generate a weight loss of at least 5% at 12 months (41% vs. 27%, OR = 14·61 95% CI: 2·32 to 91·96, P = 0·004). With an incremental cost-effectiveness ratio (ICER) of £7742/QALY, WAP would be considered highly cost effective compared to PNI. CONCLUSIONS: The task-based programme evaluated in this study can provide a template for an effective and economical approach to weight management that can reach clients from disadvantaged communities. TRIAL REGISTRATION: ISRCTN ISRCTN45820471 . Registered 12/10/2012 (retrospectively registered).

The current use of feasibility studies in the assessment of feasibility for stepped-wedge cluster randomised trials: a systematic review.

BACKGROUND: Stepped-wedge cluster randomised trials (SW-CRTs) are a pragmatic trial design, providing an unprecedented opportunity to increase the robustness of evidence underpinning implementation and quality improvement interventions. Given the complexity of the SW-CRT, the likelihood of trials not delivering on their objectives will be mitigated if a feasibility study precedes the definitive trial. It is not currently known if feasibility studies are being conducted for SW-CRTs nor what the objectives of these studies are. METHODS: Searches were conducted of several databases to identify published feasibility studies which were designed to inform a future SW-CRT. For each eligible study, data were extracted on the characteristics of and rationale for the feasibility study; the process for determining progression to the main trial; how the feasibility study informed the main trial; and whether the main trial went ahead. A narrative synthesis and descriptive analysis are presented. RESULTS: Eleven feasibility studies were identified, which included eight completed study reports and three protocols. Three studies used a stepped-wedge design and these were the only studies to be randomised. Studies were predominantly of a mixed-methods design. Only one study assessed specific features related to the feasibility of using a SW-CRT and one investigated the time taken to complete the study procedures. The other studies were mostly assessing the feasibility and acceptability of the intervention. CONCLUSION: Published feasibility studies for SW-CRTs are scarce and those that are being reported do not investigate issues specific to the complexities of the trial design. When conducting feasibility studies in advance of a definitive SW-CRT, researchers should consider assessing the feasibility of study procedures, particularly those specific to the SW-CRT design, and ensure that the findings are published for the benefit of other researchers.

Case finding and therapy for chronic viral hepatitis in primary care (HepFREE): a cluster-randomised controlled trial.

BACKGROUND: The prevalence of viral hepatitis (hepatitis B virus and hepatitis C virus) in migrants is higher than among the general population in many high-income countries. We aimed to determine whether incentivising and supporting primary-care physicians in areas with a high density of migrants increases the numbers of adult migrants screened for viral hepatitis. METHODS: HepFREE was a multicentre, open, cluster-randomised controlled trial in general practices in areas of the UK with a high density of migrants (Bradford, Yorkshire, and northeast and southeast London). Participants were adult patients (aged 18 years or older) in primary care, who had been identified as a first or second generation migrant from a high-risk country. General practices were randomly assigned (1:2:2:2:2) to an opportunistic screening (control) group or to one of four targeted screening (interventional) groups: standard (ie, hospital-based) care and a standard invitation letter; standard care and an enhanced invitation letter; community care and a standard invitation letter; or community care and an enhanced invitation letter. In control screening, general practitioners (GPs) were given a teaching session on viral hepatitis and were asked to test all registered migrants. In the intervention, GPs were paid a nominal sum for setting up searches of records, reimbursed for signed consent forms, and supported by a dedicated clinician. Patients who were eligible for testing and tested positive for viral hepatitis in the intervention groups were eligible to enrol in a second embedded trial of community versus hospital based care. The primary outcomes were the proportion of patients eligible for screening, the proportion of those eligible who were sent an invitation letter in the intervention groups, the uptake of viral hepatitis screening (in the intention-to-treat population), the proportion of patients who tested positive for viral hepatitis, the proportion who complied with treatment, and the cost-effectiveness of the intervention. This trial is registered with ISRCTN, number ISRCTN54828633. FINDINGS: Recruitment and testing ran from Oct 31, 2013, to Feb 4, 2017, and each practice recruited for 18 consecutive calendar months. We approached 70 general practices in three areas with a high density of migrants, of which 63 general practices agreed to participate. Five practices withdrew and 58 practices were randomly assigned: eight to control and 50 to an intervention. In control practices, 26 046 (38·4%) of 67 820 patients who were initially registered were eligible for testing, as were 152 321 (43·3%) of 351 710 patients in the interventional groups in London and Bradford. Of 51 773 randomly selected eligible patients in the intervention groups in London and Bradford, letters were sent to 43 585 (84·2%) patients. In the eight control general practices, screening was taken up by 543 (1·7%) of 31 738 eligible participants, which included 5692 newly registered patients. However, in the 50 general practices that used the intervention, screening was taken up by 11 386 (19·5%) of 58 512 eligible participants (including 6739 newly registered patients; incidence rate ratio 3·70, 95% CI 1·30-10·51; p=0·014) and this intervention was cost-effective. 720 (4·5%) of 15 844 patients who received a standard letter versus 1032 (3·7%) of 28 095 patients who received the enhanced letter were tested (0·70, 0·38-1·31; p=0·26). In the control group, 17 patients tested positive for viral hepatitis, as did 220 patients (one with a co-infection) in the intervention groups. In the embedded study, 220 patients were randomly assigned to either hospital-based care or community care; 80 (87·9%) of 91 patients in the hospital setting complied with treatment versus 105 (81·4%) of 129 patients in the community setting. The intervention was cost-effective at willingness to pay thresholds in excess of £8540. One serious adverse event (thyroiditis) was noted. INTERPRETATION: Screening migrants for viral hepatitis in primary care is effective if doctors are incentivised and supported. Community care is expensive and there is no evidence that this offers benefits in this setting or that bespoke invitation letters add value. We suggest that bespoke invitation letters should not be used, and we suggest that outreach, community-based services for migrants should not be developed. FUNDING: National Institute for Health Research.

Testing the effectiveness of REACH Pregnancy Circles group antenatal care: protocol for a randomised controlled pilot trial.

BACKGROUND: Antenatal care is an important public health priority. Women from socially disadvantaged, and culturally and linguistically diverse groups often have difficulties with accessing antenatal care and report more negative experiences with care. Although group antenatal care has been shown in some settings to be effective for improving women's experiences of care and for improving other maternal as well as newborn health outcomes, these outcomes have not been rigorously assessed in the UK. A pilot trial will be conducted to determine the feasibility of, and optimum methods for, testing the effectiveness of group antenatal care in an NHS setting serving populations with high levels of social deprivation and cultural, linguistic and ethnic diversity. Outcomes will inform the protocol for a future full trial. METHODS: This protocol outlines an individual-level randomised controlled external pilot trial with integrated process and economic evaluations. The two trial arms will be group care and standard antenatal care. The trial will involve the recruitment of 72 pregnant women across three maternity services within one large NHS Acute Trust. Baseline, outcomes and economic data will be collected via questionnaires completed by the participants at three time points, with the final scheduled for 4 months postnatal. Routine maternity service data will also be collected for outcomes assessment and economic evaluation purposes. Stakeholder interviews will provide insights into the acceptability of research and intervention processes, including the use of interpreters to support women who do not speak English. Pre-agreed criteria have been selected to guide the decision about whether or not to progress to a full trial. DISCUSSION: This pilot trial will determine if it is appropriate to proceed to a full trial of group antenatal care in this setting. If progression is supported, the pilot will provide authoritative high-quality evidence to inform the design and conduct of a trial in this important area that holds significant potential to influence maternity care, outcomes and experience. TRIAL REGISTRATION: ISRCTN ISRCTN66925258. Registered 03 April 2017. Retrospectively registered.

Cost-effectiveness of a domestic violence and abuse training and support programme in primary care in the real world: updated modelling based on an MRC phase IV observational pragmatic implementation study.

OBJECTIVES: To evaluate the cost-effectiveness of the implementation of the Identification and Referral to Improve Safety (IRIS) programme using up-to-date real-world information on costs and effectiveness from routine clinical practice. A Markov model was constructed to estimate mean costs and quality-adjusted life-years (QALYs) of IRIS versus usual care per woman registered at a general practice from a societal and health service perspective with a 10-year time horizon. DESIGN AND SETTING: Cost-utility analysis in UK general practices, including data from six sites which have been running IRIS for at least 2 years across England. PARTICIPANTS: Based on the Markov model, which uses health states to represent possible outcomes of the intervention, we stipulated a hypothetical cohort of 10 000 women aged 16 years or older. INTERVENTIONS: The IRIS trial was a randomised controlled trial that tested the effectiveness of a primary care training and support intervention to improve the response to women experiencing domestic violence and abuse, and found it to be cost-effective. As a result, the IRIS programme has been implemented across the UK, generating data on costs and effectiveness outside a trial context. RESULTS: The IRIS programme saved £14 per woman aged 16 years or older registered in general practice (95% uncertainty interval -£151 to £37) and produced QALY gains of 0.001 per woman (95% uncertainty interval -0.005 to 0.006). The incremental net monetary benefit was positive both from a societal and National Health Service perspective (£42 and £22, respectively) and the IRIS programme was cost-effective in 61% of simulations using real-life data when the cost-effectiveness threshold was £20 000 per QALY gained as advised by National Institute for Health and Care Excellence. CONCLUSION: The IRIS programme is likely to be cost-effective and cost-saving from a societal perspective in the UK and cost-effective from a health service perspective, although there is considerable uncertainty surrounding these results, reflected in the large uncertainty intervals.

AntiEpileptic drug Monitoring in PREgnancy (EMPiRE): a double-blind randomised trial on effectiveness and acceptability of monitoring strategies.

BACKGROUND: Pregnant women with epilepsy on antiepileptic drugs (AEDs) may experience a reduction in serum AED levels. This has the potential to worsen seizure control. OBJECTIVE: To determine if, in pregnant women with epilepsy on AEDs, additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels. DESIGN: A double-blind, randomised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken. Stratified block randomisation with a 1 : 1 allocation method was carried out. SETTING: Fifty obstetric and epilepsy clinics in secondary and tertiary care units in the UK. PARTICIPANTS: Pregnant women with epilepsy on one or more of the following AEDs: lamotrigine, carbamazepine, phenytoin or levetiracetam. Women with a ≥ 25% decrease in serum AED level from baseline were randomised to therapeutic drug monitoring or clinical features monitoring strategies. INTERVENTIONS: In the therapeutic drug monitoring group, clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control. In the clinical features monitoring group, AED dosage adjustment was based only on clinical features. MAIN OUTCOME MEASURES: Primary outcome - seizure deterioration, defined as time to first seizure and to all seizures after randomisation per woman until 6 weeks post partum. Secondary outcomes - pregnancy complications in mother and offspring, maternal quality of life, seizure rates in cohorts with stable serum AED level, AED dose exposure and adverse events related to AEDs. ANALYSIS: Analysis of time to first and to all seizures after randomisation was performed using a Cox proportional hazards model, and multivariate failure time analysis by the Andersen-Gill model. The effects were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Secondary outcomes were reported as mean differences (MDs) or odds ratios. RESULTS: A total of 130 women were randomised to the therapeutic drug monitoring group and 133 to the clinical features monitoring group; 294 women did not have a reduction in serum AED level. A total of 127 women in the therapeutic drug monitoring group and 130 women in the clinical features monitoring group (98% of complete data) were included in the primary analysis. There were no significant differences in the time to first seizure (HR 0.82, 95% CI 0.55 to 1.2) or timing of all seizures after randomisation (HR 1.3, 95% CI 0.7 to 2.5) between both trial groups. In comparison with the group with stable serum AED levels, there were no significant increases in seizures in the clinical features monitoring (odds ratio 0.93, 95% CI 0.56 to 1.5) or therapeutic drug monitoring group (odds ratio 0.93, 95% CI 0.56 to 1.5) associated with a reduction in serum AED levels. Maternal and neonatal outcomes were similar in both groups, except for higher cord blood levels of lamotrigine (MD 0.55 mg/l, 95% CI 0.11 to 1 mg/l) or levetiracetam (MD 7.8 mg/l, 95% CI 0.86 to 14.8 mg/l) in the therapeutic drug monitoring group than in the clinical features monitoring group. There were no differences between the groups on daily AED exposure or quality of life. An increase in exposure to lamotrigine, levetiracetam and carbamazepine significantly increased the cord blood levels of the AEDs, but not maternal or fetal complications. Women with epilepsy perceived the need for weighing up their increased vulnerability to seizures during pregnancy against the side effects of AEDs. LIMITATIONS: Fewer women than the original target were recruited. CONCLUSION: There is no evidence to suggest that regular monitoring of serum AED levels in pregnancy improves seizure control or affects maternal or fetal outcomes. FUTURE WORK RECOMMENDATIONS: Further evaluation of the risks of seizure deterioration for various threshold levels of reduction in AEDs and the long-term neurodevelopment of infants born to mothers in both randomised groups is needed. An individualised prediction model will help to identify those women who need close monitoring in pregnancy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN01253916. 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. 22, No. 23. See the NIHR Journals Library website for further project information.

Evaluation of community-level interventions to increase early initiation of antenatal care in pregnancy: protocol for the Community REACH study, a cluster randomised controlled trial with integrated process and economic evaluations.

BACKGROUND: The provision of high-quality maternity services is a priority for reducing inequalities in health outcomes for mothers and infants. Best practice includes women having their initial antenatal appointment within the first trimester of pregnancy in order to provide screening and support for healthy lifestyles, well-being and self-care in pregnancy. Previous research has identified inequalities in access to antenatal care, yet there is little evidence on interventions to improve early initiation of antenatal care. The Community REACH trial will assess the effectiveness and cost-effectiveness of engaging communities in the co-production and delivery of an intervention that addresses this issue. METHODS/DESIGN: The study design is a matched cluster randomised controlled trial with integrated process and economic evaluations. The unit of randomisation is electoral ward. The intervention will be delivered in 10 wards; 10 comparator wards will have normal practice. The primary outcome is the proportion of pregnant women attending their antenatal booking appointment by the 12th completed week of pregnancy. This and a number of secondary outcomes will be assessed for cohorts of women (n = approximately 1450 per arm) who give birth 2-7 and 8-13 months after intervention delivery completion in the included wards, using routinely collected maternity data. Eight hospitals commissioned to provide maternity services in six NHS trusts in north and east London and Essex have been recruited to the study. These trusts will provide anonymised routine data for randomisation and outcomes analysis. The process evaluation will examine intervention implementation, acceptability, reach and possible causal pathways. The economic evaluation will use a cost-consequences analysis and decision model to evaluate the intervention. Targeted community engagement in the research process was a priority. DISCUSSION: Community REACH aims to increase early initiation of antenatal care using an intervention that is co-produced and delivered by local communities. This pragmatic cluster randomised controlled trial, with integrated process and economic evaluation, aims to rigorously assess the effectiveness of this public health intervention, which is particularly complex due to the required combination of standardisation with local flexibility. It will also answer questions about scalability and generalisability. TRIAL REGISTRATION: ISRCTN registry: registration number 63066975 . Registered on 18 August 2015.

An optimised patient information sheet did not significantly increase recruitment or retention in a falls prevention study: an embedded randomised recruitment trial.

BACKGROUND: Randomised controlled trials are generally regarded as the 'gold standard' experimental design to determine the effectiveness of an intervention. Unfortunately, many trials either fail to recruit sufficient numbers of participants, or recruitment takes longer than anticipated. The current embedded trial evaluates the effectiveness of optimised patient information sheets on recruitment of participants in a falls prevention trial. METHODS: A three-arm, embedded randomised methodology trial was conducted within the National Institute for Health Research-funded REducing Falls with ORthoses and a Multifaceted podiatry intervention (REFORM) cohort randomised controlled trial. Routine National Health Service podiatry patients over the age of 65 were randomised to receive either the control patient information sheet (PIS) for the host trial or one of two optimised versions, a bespoke user-tested PIS or a template-developed PIS. The primary outcome was the proportion of patients in each group who went on to be randomised to the host trial. RESULTS: Six thousand and nine hundred patients were randomised 1:1:1 into the embedded trial. A total of 193 (2.8%) went on to be randomised into the main REFORM trial (control n = 62, template-developed n = 68; bespoke user-tested n = 63). Information sheet allocation did not improve recruitment to the trial (odds ratios for the three pairwise comparisons: template vs control 1.10 (95% CI 0.77-1.56, p = 0.60); user-tested vs control 1.01 (95% CI 0.71-1.45, p = 0.94); and user-tested vs template 0.92 (95% CI 0.65-1.31, p = 0.65)). CONCLUSIONS: This embedded methodology trial has demonstrated limited evidence as to the benefit of using optimised information materials on recruitment and retention rates in the REFORM study. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number registry, ISRCTN68240461 . Registered on 01 July 2011.

NHS Health Check comorbidity and management: an observational matched study in primary care.

BACKGROUND: The NHS Health Check programme completed its first 5 years in 2014, identifying those at highest risk of cardiovascular disease and new comorbidities, and offering behavioural change support and treatment. AIM: To describe the coverage and impact of this programme on cardiovascular risk management and identification of new comorbidities. DESIGN AND SETTING: Observational 5-year study from April 2009 to March 2014, in 139 of 143 general practices in three clinical commissioning groups (CCGs) in east London. METHOD: A matched analysis compared comorbidity in NHS Health Check attendees and non-attendees. RESULTS: A total of 252 259 adults aged 40-74 years were eligible for an NHS Health Check and, of these, 85 122 attended in 5 years. Attendance increased from 7.3% (10 900/149 867) in 2009 to 17.0% (18 459/108 525) in 2013 to 2014, representing increasing coverage from 36.4% to 85.0%. Attendance was higher in the more deprived quintiles and among South Asians. Statins were prescribed to 11.5% of attendees and 8.2% of non-attendees. In a matched analysis, newly-diagnosed comorbidity was more likely in attendees than non-attendees, with odds ratios for new diabetes 1.30 (95% confidence interval [CI] = 1.21 to 1.39), hypertension 1.50 (95% CI = 1.43 to 1.57), and chronic kidney disease 1.83 (95% CI = 1.52 to 2.21). CONCLUSION: The NHS Health Check programme provision in these CCGs was equitable, with recent coverage of 85%. Statins were 40% more likely to be prescribed to attendees than non-attendees, providing estimated absolute benefits of public health importance. More new cases of diabetes, hypertension, and chronic kidney disease were identified among attendees than a matched group of non-attendees.