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Background Dupuytren’s contracture is caused by nodules and cords which pull the fingers towards the palm of the hand. Treatments include limited fasciectomy surgery, collagenase injection and needle fasciotomy. There is limited evidence comparing limited fasciectomy with collagenase injection. Objectives To compare whether collagenase injection is not inferior to limited fasciectomy when treating Dupuytren’s contracture. Design Pragmatic, two-arm, unblinded, randomised controlled non-inferiority trial with a cost-effectiveness evaluation and nested qualitative and photographic substudies. Setting Thirty-one National Health Service hospitals in England and Scotland. Participants Patients with Dupuytren’s contracture of ≥ 30 degrees who had not received previous treatment in the same digit. Interventions Collagenase injection with manipulation 1–7 days later was compared with limited fasciectomy. Main outcome measures The primary outcome was the Patient Evaluation Measure score, with 1 year after treatment serving as the primary end point. A difference of 6 points in the primary end point was used as the non-inferiority margin. Secondary outcomes included: Unité Rhumatologique des Affections de la Main scale; Michigan Hand Outcomes Questionnaire; recurrence; extension deficit and total active movement; further care/re-intervention; complications; quality-adjusted life-year; resource use; and time to function recovery. Randomisation and blinding Online central randomisation, stratified by the most affected joint, and with variable block sizes allocates participants 1 : 1 to collagenase or limited fasciectomy. Participants and clinicians were not blind to treatment allocation. Results Between 31 July 2017 and 28 September 2021, 672 participants were recruited (n = 336 per group), of which 599 participants contributed to the primary outcome analysis (n = 285 limited fasciectomy; n = 314 collagenase). At 1 year (primary end point) there was little evidence to support rejection of the hypothesis that collagenase is inferior to limited fasciectomy. The difference in Patient Evaluation Measure score at 1 year was 5.95 (95% confidence interval 3.12 to 8.77; p = 0.49), increasing to 7.18 (95% confidence interval 4.18 to 10.88) at 2 years. The collagenase group had more complications (n = 267, 0.82 per participant) than the limited fasciectomy group (n = 177, 0.60 per participant), but limited fasciectomy participants had a greater proportion of ‘moderate’/‘severe’ complications (5% vs. 2%). At least 54 participants (15.7%) had contracture recurrence and there was weak evidence suggesting that collagenase participants recurred more often than limited fasciectomy participants (odds ratio 1.39, 95% confidence interval 0.74 to 2.63). At 1 year, collagenase had an insignificantly worse quality-adjusted life-year gain (−0.003, 95% confidence interval −0.006 to 0.0004) and a significant cost saving (−£1090, 95% confidence interval −£1139 to −£1042) than limited fasciectomy with the probability of collagenase being cost-effective exceeding 99% at willingness to pay thresholds of £20,000–£30,000 per quality-adjusted life-year. At 2 years, collagenase was both significantly less effective (−0.048, 95% confidence interval −0.055 to −0.040) and less costly (−£1212, 95% confidence interval −£1276 to −£1147). The probability of collagenase being cost-effective was 72% at the £20,000 threshold but limited fasciectomy became the optimal treatment at thresholds over £25,488. The Markov model found the probability of collagenase being cost-effective at the lifetime horizon dropped below 22% at thresholds over £20,000. Semistructured qualitative interviews found that those treated with collagenase considered the outcome to be acceptable, though not perfect. The photography substudy found poor agreement between goniometry and both participant and clinician taken photographs, even after accounting for systematic differences from each method. Limitations Impacts of the COVID-19 pandemic resulted in longer waits for Dupuytren’s contracture treatment, meaning some participants could not be followed up for 2 years. This resulted in potential underestimation of Dupuytren’s contracture recurrence and/or re-intervention rates, which may particularly have impacted the clinical effectiveness and long-term Markov model findings. Conclusions Among adults with Dupuytren’s contracture, collagenase delivered in an outpatient setting is less effective but more cost-saving than limited fasciectomy. Further research is required to establish the longer-term implications of both treatments. Future work Recurrence and re-intervention usually occur after 1 year, and therefore follow-up to 5 years or more could resolve whether the differences observed in the Dupuytren’s interventions surgery versus collagenase trial to 2 years worsen. Study registration Current Controlled Trials ISRCTN18254597. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/102/04) and is published in full in Health Technology Assessment; Vol. 28, No. 78. See the NIHR Funding and Awards website for further award information. Plain language summary Dupuytren’s contracture happens when fibrous tissue builds up and over time bends the finger(s) into the palm, causing problems with hand function. To treat this, surgery is usually used to straighten the finger. A less intrusive alternative is an injection (collagenase), which softens the tissue after which the finger is moved to straighten it. The Dupuytren's interventions surgery versus collagenase trial recruited 672 patients who were equally and randomly assigned to have either surgery or collagenase injection. The study assessed whether the injection was as good and as safe as surgery at straightening the finger and how long the finger remained straightened. For up to 2 years after treatment, the participant’s hand function and general health were assessed. Some participants provided photographs to monitor changes to the finger, and some were asked about their experiences of Dupuytren’s contracture and treatments. We found: Hand health improved following both treatments. Initially, the injection treatment improved hand health more than surgery. However, by 1 year, surgery improved hand health more than the injection treatment. Recovery of hand function was quicker for participants who received the injection; however, they were more likely to need further treatment (i.e. further care and/or re-intervention). Participants said that the less positive longer-term outcome was acceptable for a better treatment experience. For both treatments, interviews found that participants were happy with the hand improvement they experienced at 3 months after treatment. More than half of participants had no complications, moderate or severe complications were rare, and participants who had surgery had more of these. The injection was cheaper but less effective than surgery at 1 year and was considered good value for money. However, by 2 years surgery became the better option due to its greater improvement in health benefits. Participant-taken photographs can help monitor Dupuytren’s contracture but do not give the same results as measurements taken in a clinic. Scientific summary Background Dupuytren’s disease affects over 2 million UK adults. Cords pull the fingers down towards the palm. This interferes with hand function and dexterity, impacting on quality of life. Current treatments to remove, dissolve or break the cords include surgical correction [limited fasciectomy (LF)], collagenase injection (an enzyme injected into the cord), and percutaneous needle fasciotomy (a needle is used to puncture, weaken and cut the cord). None of these treatments cure the tendency to develop Dupuytren’s contracture (DC) and so the cords and contracture can recur over time. Collagenase has some benefits over LF surgery including shorter recovery and no dependence on operating theatre availability for delivery of the intervention. There is, however, limited robust evidence comparing surgical correction and collagenase injection in terms of clinical effectiveness, cost-effectiveness, and in terms of patient’s experiences and preferences. Objectives The primary objective was to compare whether collagenase injection is not inferior to LF in the treatment of DC. Secondary objectives included investigation of recurrence at 1 and 2 years after treatment and cost-effectiveness. A qualitative substudy explored patients’ views of collagenase and LF, and a photography substudy investigated whether measurements of extension and flexion made on photographs taken by patients reflect goniometric measurements to assess recurrence. Methods Design The Dupytren's interventions surgery vs collagenase (DISC) trial was a multicentre, pragmatic, parallel two-arm randomised controlled non-inferiority trial with a cost-effectiveness evaluation, and nested qualitative and photography substudies. Participants were randomised on an equal basis to receive either of the two treatment options via a remote randomisation service. Randomisation was blocked, with randomly varying block sizes, and stratified by reference (worst-affected) joint [metacarpophalangeal (MCP) joint or proximal interphalangeal (PIP) joint]. Participants were followed up at 3 months, 6 months, 1 year and 2 years after treatment. Data collection included joint measurements and photography at baseline, and all follow-up time points. Setting Trial recruitment was undertaken in 31 NHS hand units across England and Scotland between June 2017 and September 2021. Participants Patients aged 18 years and over with a discrete, palpable Dupuytren’s cord causing contracture of ≥ 30 degrees and who were appropriate for both study treatments, were eligible for inclusion. Patients were excluded if they had severe contractures (> 135 degrees); had received treatment to the study digit; had other pre-existing disorders affecting hand function; had contraindications to collagenase; had a coagulation disorder; were female and pregnant or breastfeeding; had participated in a study involving another investigational medicinal product within 12 weeks or had another disease or disorder which would put them at risk if participating. Interventions The intervention was collagenase Clostridium histolyticum injection, supplied through routine NHS stocks. Collagenase was injected as three aliquots at set anatomical points in line with the current approved summary of product characteristics. After an interval of 1–7 days, participants returned to the clinic, where under local anaesthetic the cord was snapped to correct the contracture. The control group received LF surgery to remove the diseased nodules and cord to correct the contracture. Participants were followed up at routine wound check appointments following intervention. Outcomes The primary outcome was the Patient Evaluation Measure (PEM) score (0–100 with higher scores indicating worse outcome) at 1 year after treatment. The PEM was also completed at 3 months, 6 months and 2 years after treatment. Secondary outcomes included the Unité Rhumatologique des Affections de la Main (URAM) scale, Michigan Hand Outcomes Questionnaire (MHQ), recurrence, extension deficit and total active movement, complications, further treatments (including further care and/or re-intervention), health-related quality of life [EuroQol-5 Dimensions, five-level version (EQ-5D-5L)], resource use, time to recovery of function (using a single assessment numeric evaluation measure) and overall hand assessment. All outcomes were collected at 3 months, 6 months, 1 year and 2 years. The PEM was also recollected immediately prior to treatment delivery, and the time to recover function and quality of life were also collected at 2 and 6 weeks after treatment. Outcomes were collected primarily in hospital clinics, with some participants being followed up for postal, telephone, or video data collection during the COVID-19 pandemic. The qualitative substudy explored participants experiences of DC and treatments. The photography substudy explored the agreement between measurements obtained using a goniometer and photographs taken by participants at home, to determine whether the two methods of measurement might feasibly be used interchangeably. Results Clinical effectiveness In total 672 participants (64.6%) were recruited and randomised; 336 to receive collagenase injection and 336 to receive LF. Baseline characteristics were similar across groups. Of the 672 randomised participants, 621 (92.4%) received treatment as part of the trial. Cross-over was limited: one participant (0.3%) allocated to collagenase received LF; seven participants allocated to LF received collagenase (2.1%). On average participants received collagenase by 12.1 weeks [standard deviation (SD) 13.7] and LF in 17.7 weeks (SD 16.5) after randomisation. Most participants (n = 315, 95.2%) had just one digit treated. No participants required an unplanned inpatient admission following treatment and 62.0% (n = 201) collagenase participants and 78.3% (n = 224) LF participants had full correction following treatment. At 1 year (primary time-point) the difference in PEM scores showed that collagenase was inferior to LF; difference 5.95 [95% confidence interval (CI) 3.12 to 8.77; p = 0.49]. The benefit of LF over collagenase continued to increase to 2 years (7.18, 95% CI 4.18 to 10.88; p = 0.82). There were no material changes in these results for any of the sensitivity or additional analyses undertaken. The primary analysis therefore shows that there is little evidence to support rejection of the hypothesis that collagenase is inferior to LF at 1 and 2 years post treatment. Indeed, the observed data are highly compatible with LF being superior to collagenase with regard to the primary outcome measure at both these time points. Patient Evaluation Measure overall assessment scores corresponded with the primary outcome analyses and participants in both groups reported positive experiences of treatment. The estimated difference in URAM scores followed those of PEM, increasing in favour of LF over time from 3 months (0.82, 95% CI −0.21 to 1.84; p = 0.12) to 5.37 (95% CI 3.85 to 6.88; p ≤ 0.00005) at 2 years. At 1 year MHQ scores were higher (better) in the LF group (1 year: −4.69, 95% CI −7.27 to −2.12; p = 0.0004) and this continued at 2 years (2 years: −6.71, 95% CI −9.60 to −3.82; p ≤ 0.00005). Return to function was better in the short term for the collagenase group (week 2: 14.93, 95% CI 11.66 to 18.19; p ≤ 0.00005; 6 weeks: 5.00, 95% CI 2.29 to 7.70; p = 0.003) but by 1 year function was superior after LF (−4.93, 95% CI −7.63 to −2.22; p = 0.0004). At 1 year participants who received LF were more likely to respond as being ‘cured’ or ‘much better’ than participants who received collagenase [odds ratio (OR) 3.01, 95% 2.15 to 4.23; p ≤ 0.00005]. Passive extension deficit was similar between the groups at baseline (mean: 45.8°; SD 17.0). Following collagenase treatment, extension deficit seemed to be worse at all time points ranging from a difference of 5.73° (95% CI 2.88 to 8.59; p = 0.0001) at 3 months to 10.10° (95% CI 6.46 to 13.73; p ≤ 0.00005) at 1 year and increasing again up to 2 years. Results when imputed data were included were similar. Increases in reference joint passive range of movement (RoM) were similar between the two groups following treatment. However, from 6 months there was strong evidence that collagenase resulted in poorer passive RoM (−7.42°, 95% CI −11.54 to −3.29; p = 0.0004) and this difference increased further over time. Measurements of active extension deficit were similar between the two groups at baseline (mean: 51.9°, SD 16.1). Like passive extension deficit, active extension deficit was worse following collagenase treatment at all time points, ranging from a difference at 3 months of 5.57° (95% CI 3.02 to 8.12; p ≤ 0.00005) to 11.52° (95% CI 8.13 to 14.91; p

Abstract Background There is increasing interest in the capacity of adaptive designs to improve the efficiency of clinical trials. However, relatively little work has investigated how economic considerations – including the costs of the trial – might inform the design and conduct of adaptive clinical trials. Methods We apply a recently published Bayesian model of a value-based sequential clinical trial to data from the ‘Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis’ (HERO) trial. Using parameters estimated from the trial data, including the cost of running the trial, and using multiple imputation to estimate the accumulating cost-effectiveness signal in the presence of missing data, we assess when the trial would have stopped had the value-based model been used. We used re-sampling methods to compare the design’s operating characteristics with those of a conventional fixed length design. Results In contrast to the findings of the only other published retrospective application of this model, the equivocal nature of the cost-effectiveness signal from the HERO trial means that the design would have stopped the trial close to, or at, its maximum planned sample size, with limited additional value delivered via savings in research expenditure. Conclusion Evidence from the two retrospective applications of this design suggests that, when the cost-effectiveness signal in a clinical trial is unambiguous, the Bayesian value-adaptive design can stop the trial before it reaches its maximum sample size, potentially saving research costs when compared with the alternative fixed sample size design. However, when the cost-effectiveness signal is equivocal, the design is expected to run to, or close to, the maximum sample size and deliver limited savings in research costs.

Abstract Background A number of children experience difficulties with social communication and this has long-term deleterious effects on their mental health, social development and education. The E-PLAYS-2 study will test an intervention (‘E-PLAYS’) aimed at supporting such children. E-PLAYS uses a dyadic computer game to develop collaborative and communication skills. Preliminary studies by the authors show that E-PLAYS can produce improvements in children with social communication difficulties on communication test scores and observed collaborative behaviours. The study described here is a definitive trial to test the effectiveness and cost-effectiveness of E-PLAYS delivered by teaching assistants in schools. Methods The aim of the E-PLAYS-2 trial is to establish the effectiveness and cost-effectiveness of care as usual plus the E-PLAYS programme, delivered in primary schools, compared to care as usual. Cluster-randomisation will take place at school level to avoid contamination. The E-PLAYS intervention will be delivered by schools’ teaching assistants. Teachers will select suitable children (ages 5–7 years old) from their schools using guidelines provided by the research team. Assessments will include blinded language measures and observations (conducted by the research team), non-blinded teacher-reported measures of peer relations and classroom behaviour and parent-reported use of resources and quality of life. A process evaluation will also include interviews with parents, children and teaching assistants, observations of intervention delivery and a survey of care as usual. The primary analysis will compare pragmatic language scores for children who received the E-PLAYS intervention versus those who did not at 40 weeks post-randomisation. Secondary analyses will assess cost-effectiveness and a mixed methods process evaluation will provide richer data on the delivery of E-PLAYS. Discussion The aim of this study is to undertake a final, definitive test of the effectiveness of E-PLAYS when delivered by teaching assistants within schools. The use of technology in game form is a novel approach in an area where there are currently few available interventions. Should E-PLAYS prove to be effective at the end of this trial, we believe it is likely to be welcomed by schools, parents and children. Trial registration ISRCTN 17561417, registration date 19th December 2022. Protocol version: v1.1 19th June 2023.

Background Differences in the way autistic children experience the world can contribute to anxiety and stress. Carol Gray’s Social Stories™ are a highly personalised intervention to support children by providing social information about specific situations in an individual story. Objectives This randomised controlled trial aimed to establish whether Social Stories are clinically effective and cost-effective in improving social responsiveness and social and emotional health in children on the autism spectrum in schools. Design A multisite pragmatic cluster randomised controlled trial comparing Social Stories with care as usual. Setting Eighty-seven schools (clusters) across Yorkshire and the Humber. Participants Two hundred and forty-nine children were randomised via a bespoke system hosted at York Trials Unit (129 Social Stories and 120 care as usual). Recruitment was completed in May 2021. Participants were children aged 4–11 years with a diagnosis of autism, alongside teachers, interventionists and caregivers. Recruitment was via schools, NHS trusts, support groups and local publicity. Intervention The intervention included training for educational professionals and caregivers covering psychoeducation and implementation of Social Stories. Stories were written around contextualised goals around the child’s need for social information. Interventionists read the Social Story™ with the child at least six times over 4 weeks during school. Main outcome measure The primary outcome was the Social Responsiveness Scale-2 completed by teachers at 6 months (the primary end point), which measures social awareness, cognition, communication and behaviour. Data were collected from caregivers and educational professionals at 6 weeks and 6 months through questionnaires. Blinding of participants was not possible. Results At 6 months, the estimated difference in expected teacher-reported Social Responsiveness Scale-2 T-score (the primary end point) was −1.61 (95% confidence interval −4.18 to 0.96, p = 0.220), slightly favouring the intervention group. The estimated differences for the parent-reported secondary outcomes at 6 months were small and generally favoured the control group except the measure of children’s quality-adjusted life-year (+ 0.001, 95% confidence interval −0.032 to 0.035) and parental stress (−1.49, 95% confidence interval −5.43 to 2.46, p = 0.460), which favoured the intervention group. Children in the intervention group met their individual goals more frequently than children who received usual care alone (0.97 confidence interval 0.21 to 1.73, p = 0.012). The intervention is likely to save small costs (−£191 per child, 95% confidence interval −767.7 to 337.7) and maintain a similar quality of life compared to usual care. The probability of Social Stories being a preferred option is 75% if the society is willing to pay £20,000 per quality-adjusted life-year gained. Limitations include considerable disruptions during the coronavirus disease 2019 pandemic. Conclusion Social Stories are used in schools and represent a low-cost intervention. There is no clinically evident impact on social responsiveness, anxiety and/or depression, parental stress or general health. Benefits were observed for specific behavioural goals as assessed by the teacher, and Social Stories may serve as a useful tool for facilitating dialogue between children and school staff to address specific behavioural challenges. Usage should be at the school’s discretion. Future work Given the uncertainty of the results in light of coronavirus disease 2019, further work to establish the impact of Social Stories is merited. Trial registration This trial is registered as ISRCTN11634810. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/111/91) and is published in full in Health Technology Assessment; Vol. 28, No. 39. See the NIHR Funding and Awards website for further award information. Plain language summary Autism affects the way children experience the world, and some children find social situations stressful. We wanted to know whether Social Stories™, developed by Carol Gray, helped children with their social skills and behaviour in school and whether they offered value for money. A randomised controlled trial design was used, which gave schools an equal chance of being asked to deliver Social Stories or to continue providing care as usual. Two hundred and forty-nine children from 87 schools took part and we trained school staff and parents to write and deliver Social Stories. We agreed with teachers and parents, what each child needed help with and wrote stories with this in mind. Trained staff read the Social Story with the child at least six times over 4 weeks. Follow-up information was collected from parents and school staff at the start of the study, after 6 weeks and 6 months. After 6 months, teachers completed a questionnaire called the Social Responsiveness Scale-2 which measures the child’s social skills. Using these measures, the results suggest that Social Stories do not lead to any significant changes in social skills, mental health, parent stress, general health or quality of life but children in schools allocated to Social Stories met their goal more frequently and incurred less costs than children who did not. Parents and educational professionals found the Social Stories intervention and training beneficial. Based on our findings, Social Stories do not appear to improve general social skills in primary-aged autistic children. Benefits were observed for specific goals, and school-based costs were reduced. Scientific summary Sections of this summary have been adapted from the trial protocol by Wright et al. (Wright B, Teige C, Watson J, Hodkinson R, Marshall D, Varley D, et al. Autism Spectrum Social Stories In Schools Trial 2 (ASSSIST2): study protocol for a randomised controlled trial analysing clinical and cost effectiveness of Social Stories™ in primary schools. BMC Psychol 2020;8:60. https://doi.org/10.1186/s40359-020-00427-z). This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article unless otherwise stated. Background Children on the autism spectrum experience a higher prevalence of mental health problems than typically developing children, including anxiety and low mood. Many children on the autism spectrum struggle to manage social anxiety and feelings of frustration, which can lead to behaviours that challenge them. The International Society for Autism Research (INSAR) has highlighted that more research evaluating early interventions for children on the autism spectrum is needed to ensure practitioners and policy-makers have robust data on intervention effectiveness and implementation to secure optimal outcomes for children. One intervention that attempts to alleviate social difficulties while not being intrusive, time-consuming or requiring extensive involvement from experts is Carol Gray’s Social Stories™. Social Stories are a highly personalised intervention aiming to share accurate, meaningful information about a particular goal or topic that the child needs help with in a positive and reassuring way. Social Stories can be written and delivered by both parents and professionals in a range of settings and represent a less time-consuming and intrusive intervention than alternatives. Previous studies examining the use of Social Stories have yielded mostly positive results but have largely been single-case studies with a lack of evidence from randomised controlled trials (RCTs). Despite the lack of rigorous evidence, numerous schools and families are already accessing Social Stories training and delivering the intervention with children and therefore a fully powered trial is timely. Schools have limited resources and limited access to specialist practitioner interventions, and therefore it is important that interventions such as Social Stories undergo robust evaluation. If they are found to be clinically effective and cost-effective, they can be delivered within schools on a day-to-day basis. Objectives The aim was to assess whether Social Stories alongside care as usual is clinically effective and cost-effective in improving child social impairment, reducing anxiety and improving social and emotional health in children on the autism spectrum in primary and special educational needs (SEN) schools when compared with care as usual alone. Primary objective The primary objective of the study was to establish whether Social Stories can improve social responsiveness in children on the autism spectrum in primary schools across Yorkshire and the Humber, when compared to children who have received care as usual only. Social responsiveness can be broadly defined as social awareness, social cognition, social communication, social motivation and mannerisms. Secondary objectives The secondary objectives of this trial were: to investigate whether Social Stories can reduce behaviours that challenge children on the autism spectrum in primary schools to investigate whether Social Stories can improve social and emotional health in children on the autism spectrum in primary schools to assess the cost effectiveness of Social Stories to examine the effects of Social Stories delivered in the classroom on general measures of health-related quality of life to examine whether Social Stories improve classroom attendance to assess sustainability of Social Stories in an educational setting across a 6-month period to examine any changes in parental stress to examine any associations between treatment preference and outcomes to examine how elements of session delivery (e.g. session frequency, length and any associated problems/adverse events) are associated with outcomes. Methods This trial was a multisite pragmatic cluster RCT comparing Social Stories and care as usual with a control group receiving care as usual alone. Care as usual is defined as the existing support routinely provided for a child with autism spectrum condition (ASC) from educational and health services such as specialist autism teacher teams, mental health teams or other associated professionals. The trial included an internal pilot, economic evaluation and a nested process evaluation. Setting The Social Stories intervention was primarily delivered within educational settings by educational professionals. Educational settings included both mainstream primary schools and SEN schools. Parents/caregivers were invited to receive Social Stories training and had the option of also delivering the intervention within the home. Participants Inclusion criteria The child was aged 4–11 years at the time of recruitment. The child attended a participating primary or SEN school within Yorkshire and the Humber. The child has a clinical diagnosis of ASC and daily challenging behaviour. Parents/guardians of the child were able to self-complete the English language outcome measures (with assistance if necessary). Exclusion criteria The school had used Social Stories for any pupil in the current or preceding school term. The child or interventionist teacher had taken part in the previous Social Stories feasibility study (ASSSIST-1). Schools that have taken part were not excluded. Where families were recruited but the child’s school was unwilling or unable to participate, families were notified by a telephone call and/or an e-mail. Where children were confirmed eligible and consent had been taken from all relevant parties, baseline questionnaires were distributed to parents/carers and educational professionals. A school was considered ‘ready to randomise’ once all consent forms and baseline questionnaires had been received by the trial team. Interventions Children in the intervention arm of the trial received the Social Stories intervention in addition to their care as usual. The Social Stories intervention was delivered by a trained educational professional (the interventionist) who was employed within each school allocated to the intervention arm. The interventionist varied between the schools [e.g. a teacher, teaching assistant (TA) or Special Educational Needs Coordinator (SENCO)] but was most typically a TA. A core aspect of the intervention was to first agree a goal around which the story would be set. The goal was typically a behavioural challenge the child was struggling with, for example, sharing with their teacher how they were feeling. This goal was agreed during a collaborative ‘goal-setting meeting’ attended by the child’s teacher, a parent/caregiver, a member of the research team and sometimes the child’s TA. Occasionally, the children themselves were able to feed into the goal-setting process if deemed appropriate. The intervention is designed to provide social information to the child, and so the goal sought to reflect this. In this way, many goals sought to reduce the child’s anxiety or frustration by equipping them with information or providing reassurance around appropriate behaviours within a given circumstance. We assessed goal attainment in terms of how frequently a child was able to implement the desired behaviours, for example, if a goal for a particular child was to use calming strategies when they were upset, we asked teachers to rate how often a child was able to do this. Interventionists were trained by members of the research team, who had received training via a cascade model overseen by child psychiatrist, Professor Barry Wright. The training of interventionists included some psychoeducation around the differences in children on the autism spectrum to facilitate understanding around what factors may be driving the observed behaviours associated with the behavioural goal. Training also provided key information on the design and implementation of Social Stories, with materials based on those developed in the preceding feasibility study with the support of Carol Gray and a Social Stories manual produced by Professor Barry Wright and a Clinical Psychologist with expertise in autism. During the training session, interventionists constructed a Social Story. Parents/guardians were also invited to attend these sessions. Following training, all Social Stories were assessed against a fidelity checklist by a member of the research team to ensure they conformed to the 10 established criteria central to Carol Gray’s Social Stories. They were then delivered to children in the intervention arm by the interventionist at least six times over a 4-week period. Sample size The primary outcome was that the teacher completed the Social Responsiveness Scale, Second Edition (SRS-2) T-score at 6 months. Within the pilot data, outcomes were measured at 6 and 16 weeks. The correlation between baseline and 6 weeks [r = 0.67, 95% confidence interval (CI) 0.44 to 0.80] was lower than that at 16 weeks (r = 0.83, 95% CI 0.68 to 0.91) for the pilot data. To be conservative, the lower 95% confidence limit was chosen for the lowest correlation between baseline and follow-up that we observed within our pilot data (r = 0.44). Assuming a difference of 3 points, standard deviation (SD) = 7, 5% alpha, 90% power, average cluster size 1.35, intracluster correlation coefficient (ICC) = 0.34, correlation = 0.44 and 25% attrition, a total sample size of 278 was required. Support was gained from the trial steering committee and funder to stop recruitment with 249 children, which we modelled would still retain at least 80% power under a variety of different scenarios. Randomisation Randomisation was completed by unblinded members of the trial team via a bespoke trial management system. Stratified blocked randomisation was used to allocate school clusters, with randomly varying block sizes (4, 6 and 8), stratification by school type (SEN school or mainstream school) and the number of participating children within a school (≤ 5 or > 5 participating children). There were no stipulations regarding the minimum number of participants per school cluster (i.e. any school with ≥ 1 eligible/consented child with available baseline data was eligible for randomisation). Main outcome measure The primary outcome of the trial was the SRS-2 at 6 months post randomisation, as reported by the child’s teacher. This was also collected at 6 weeks post randomisation. The SRS-2 identifies the presence and severity of social difficulty within the autism spectrum condition and consists of 65 questions. For each question, the person completing the form picks a score from 1 to 4 (1 = not true, 2 = sometimes true, 3 = often true, 4 = almost always true) that best describes the child’s behaviour. A T-score is calculated based on the sex of the child and the person completing the form (teacher). Economic evaluation The primary analysis for the economic evaluation was a within-trial cost-utility analysis conducted from a societal perspective. Combining costs and quality-adjusted life-years (QALYs), an incremental cost-effectiveness ratio (ICER) of cost per QALY was calculated and evaluated against the willingness-to-pay threshold of £20,000–30,000 per QALY gained to assess the cost effectiveness of Social Stories compared to usual care. Regression models on an intention-to-treat basis were used to compare mean costs and QALYs. To take uncertainty into consideration, a non-parametric bootstrap resampling method was used to produce CIs around the cost and QALY differences and ICER. The following sensitivity analyses were conducted to test assumptions made in the primary analysis: a complete case analysis; a sensitivity analysis from the UK NHS and personal social services (PSS) perspective; and a sensitivity analysis from the joint perspectives of the NHS/PSS and education perspectives to representative a global public sector perspective. Process evaluation The process evaluation was cross-sectional and longitudinal, encompassing all aspects of the Social Stories intervention. The aim of the process evaluation was to assess the fidelity of the programme, consider the views of various stakeholders and identify barriers and facilitators to successful implementation. We aimed to achieve this through a combination of data collection techniques, including interviews, focus groups, questionnaires, surveys and diaries (session logs). Statistical analyses For the primary outcome, differences in expected SRS-2 scores were estimated using a linear mixed-effect covariance pattern model with both post-randomisation time points (6 weeks and 6 months) included as outcomes and fixed effects for treatment group, time point and their interaction. Further fixed effects were included for the following cluster and participant-level baseline covariates: school SEN status (binary, SEN/non-SEN), number of consented children attending school (binary, ≤ 5/> 5), baseline score (linear term), age at randomisation (linear term) and sex (binary, female/male). Dependence between participants within a cluster was modelled using school cluster-level random intercepts, and dependence between repeated measurements within participants was modelled using an unstructured correlation matrix for the residual errors. Similar models were used to analyse the secondary outcomes. Results The primary analysis included all 249 randomised children. After 6 months, a reduction of 1.61 points was found on the SRS-2 in children on the autism spectrum in the intervention group (95% CI −4.18 to 0.96; p = 0.220). No statistically significant differences were found in overall symptoms of anxiety and/or depression, parental stress or general health. Children in the intervention group met their individual goals more frequently than children who received usual care alone, and this difference was statistically significant (0.97, CI 0.21 to 1.73; p = 0.012). The primary analysis was conducted under the principles of intention to treat. Coronavirus disease 2019 (COVID-19) impacted upon delivery in schools and school routines, and only 62.8% of the sample is known to have received the intervention as per protocol. Sensitivity analyses suggested that there may be a dose effect with improved clinical effects in those receiving the intervention as per protocol compared to those with fewer sessions. The economic evaluation showed that, compared to usual care, Social Stories slightly decreased the service use costs over the 6-month period by £191 (95% CI −337.7 to 767.7) per child and maintained similar QALYs. If society is willing to pay £20,000 for extra QALY gained, then the probability of Social Stories being a dominant and preferred option is 75%. The results of both primary and sensitivity analyses, which considered costs derived from various perspectives, are consistent but limited to the given data within the short study time frame, number of missing data and disruption of COVID-19. The qualitative results suggest parents and educational professionals found the Social Stories training and intervention beneficial. Limitations include considerable disruptions during the COVID-19 pandemic. Conclusion We found no impact of Social Stories on autistic children’s overall social responsiveness skills. There was some evidence that Social Stories are well supported by parents and teachers, and it may be effective at addressing a wider set of individual goals and could reduce costs. Based on the evidence generated through this trial, we cannot recommend Social Stories for the purposes of improving social skills, anxiety and/or depression, parental stress, general health and quality of life in autistic children. The COVID-19 pandemic had a large impact on schools during this trial, and sensitivity analyses suggested that poor compliance may have reduced the effectiveness of the intervention and that effects were better in those receiving Social Stories as per protocol. We did not find any negative effects, and Social Stories are already frequently used in schools to support autistic children and represent a low-cost and potentially cost-saving intervention. Despite limited evident impact on global social skills, based on the data elicited through the process evaluation, it appears that Social Stories may serve as a useful tool for facilitating dialogue between children and school staff to better understand the needs of autistic children, and usage should be at the school’s discretion. Trial registration This trial was registered as ISRCTN11634810. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/111/91) and is published in full in Health Technology Assessment; Vol. 28, No. 39. See the NIHR Funding and Awards website for further award information.

Background One in 57 children are diagnosed with autism in the UK, and the estimated cost for supporting these children in education is substantial. Social Stories™ is a promising and widely used intervention for supporting children with autism in schools and families. It is believed that Social Stories™ can provide meaningful social information to children that can improve social understanding and may reduce anxiety. However, no economic evaluation of Social Stories has been conducted. Aims To assess the cost-effectiveness of Social Stories through Autism Spectrum Social Stories in Schools Trial 2, a multi-site, pragmatic, cluster-randomised controlled trial. Method Children with autism who were aged 4–11 years were recruited and randomised (N = 249). Costs measured from the societal perspective and quality-adjusted life-years (QALYs) measured by the EQ-5D-Y-3L proxy were collected at baseline and at 6-month follow-up for primary analysis. The incremental cost-effectiveness ratio was calculated, and the uncertainty around incremental cost-effectiveness ratios was captured by non-parametric bootstrapping. Sensitivity analyses were performed to evaluate the robustness of the primary findings. Results Social Stories is likely to result in a small cost savings (–£191 per child, 95% CI −767.7 to 337.7) and maintain similar QALY improvements compared with usual care. The probability of Social Stories being a preferred option is 75% if society is willing to pay £20 000 per QALY gained. The sensitivity analysis results aligned with the main study outcomes. Conclusions Compared with usual care, Social Stories did not lead to an increase in costs and maintained similar QALY improvements for primary-aged children with autism.

Introduction Smoking during pregnancy is harmful to unborn babies, infants and women. Nicotine replacement therapy (NRT) is offered as the usual stop-smoking support in the UK. However, this is often used in insufficient doses, intermittently or for too short a time to be effective. This randomised controlled trial (RCT) explores whether a bespoke intervention, delivered in pregnancy, improves adherence to NRT and is effective and cost-effective for promoting smoking cessation.Methods and analysis A two-arm parallel-group RCT was conducted for pregnant women aged ≥16 years and who smoke ≥1 daily cigarette (pre-pregnancy smoked ≥5) and who agree to use NRT in an attempt to quit. Recruitment is from antenatal care settings and via social media adverts. Participants are randomised using blocked randomisation with varying block sizes, stratified by gestational age (

Abstract Background Evaluating the effectiveness of early years parenting interventions provides evidence to improve the development and wellbeing of children. This protocol paper describes a study to explore the feasibility of evaluating the Incredible Years Toddler early life intervention programme, which is offered to parents of 1–3-year-olds via the Better Start Bradford programme. The study aims to use a Trial within a Cohort Study (TwiCS) design that randomly selects individuals participating in a cohort to be offered an intervention. The TwiCS information and consent process is person-centred and aims to replicate real-world practice whereby only those who are offered the intervention are given information about the intervention. The cohort is the Born in Bradford’s Better Start (BiBBS) cohort, an interventional birth cohort recruiting expectant parents in three areas of Bradford, UK. The study will assess the feasibility of TwiCS procedures, staged consent, and intervention take-up. Methods We will conduct a feasibility TwiCS to test study procedures. We aim to establish the following: (1) whether TwiCS methodology can be implemented to create control and intervention arms, whilst documenting any incidences of contamination within the cohort; (2) whether satisfactory rates of intervention uptake are achieved among participants allocated to the intervention; and (3) whether satisfactory rates of retention of participants in the intervention can be achieved. A Red Amber Green (RAG) rating system has been applied to support the feasibility assessment of each objective: to be rated red (not achieved), amber (partly achieved), and green (achieved). Eligible participants in the BiBBS cohort will be individually randomised 1:1 to the intervention or control arms, with stratification by child age (1 or 2 years old at the time of randomisation) and ethnicity (White British, South Asian, or other). BiBBS researchers will seek consent from participants randomised to the intervention to pass their contact details onto Incredible Years’ delivery agents. Discussion This feasibility study will inform the utility of the TwiCs approach within an experimental birth cohort to evaluate interventions for infants, toddlers, and their families. Trial registration The study was prospectively registered on ISRCTN (ISRCTN16150114).

Introduction Secondhand smoke (SHS) exposure is a major cause of premature death and disease, especially among children. Children in economically developing countries are particularly affected as smoke-free laws are typically only partially implemented and private homes and cars remain a key source of SHS exposure. Currently, firm conclusions cannot be drawn from the available evidence on the effectiveness of non-legislative interventions designed to protect children from SHS exposure. Following the success of two feasibility studies and a pilot trial, we plan to evaluate a school-based approach to protect children from SHS exposure in Bangladesh and Pakistan—countries with a strong commitment to smoke-free environments but with high levels of SHS exposure in children. We will conduct a two-arm cluster randomised controlled trial in Bangladesh and Pakistan to assess the effectiveness and cost effectiveness of a school-based smoke-free intervention (SFI) in reducing children’s exposure to SHS and the frequency and severity of respiratory symptoms.Methods and analysis We plan to recruit 68 randomly selected schools from two cities—Dhaka in Bangladesh and Karachi in Pakistan. From each school, we will recruit approximately 40 students in a year (9–12 years old) with a total of 2720 children. Half of the schools will be randomly allocated to the intervention arm receiving SFI and the other half will receive usual education. Salivary cotinine concentration—a highly sensitive and specific biomarker of SHS exposure—is the primary outcome, which will be measured at month 3 post-randomisation. Secondary outcomes will include frequency and severity of respiratory symptoms, healthcare contacts, school absenteeism, smoking uptake and quality of life. Embedded economic and process evaluations will also be conducted.Ethics and dissemination The trial has received ethics approval from the Research Governance Committee at the University of York. Approvals have also been obtained from Bangladesh Medical Research Council and Pakistan Health Research Council. If SFI is found effective, we will use a variety of channels to share our findings with both academic and non-academic audiences. We will work with the education departments in Bangladesh and Pakistan and advocate for including SFI within the curriculum.Trial registration number ISRCTN28878365

Abstract Background Dupuytren’s contracture is a fibro-proliferative disease of the hands affecting over 2 million UK adults, particularly the white, male population. Surgery is the traditional treatment; however, recent studies have indicated that an alternative to surgery—collagenase clostridium histolyticum (collagenase)—is better than a placebo in the treatment of Dupuytren’s contracture. There is however no robust randomised controlled trial that provides a definitive answer on the clinical effectiveness of collagenase compared with limited fasciectomy surgery. Dupuytren’s intervention surgery vs collagenase trial (DISC) trial was therefore designed to fill this evidence gap. Methods/design The DISC trial is a multi-centre pragmatic two-arm parallel-group, randomised controlled trial. Participants will be assigned 1:1 to receive either collagenase injection or surgery (limited fasciectomy). We aim to recruit 710 adult participants with Dupuytren’s contracture. Potential participants will be identified in primary and secondary care, screened by a delegated clinician and if eligible and consenting, baseline data will be collected and randomisation completed. The primary outcome will be the self-reported patient evaluation measure assessed 1 year after treatment. Secondary outcome measures include the Unité Rhumatologique des Affections de la Main Scale, the Michigan Hand Questionnaire, EQ-5D-5L, resource use, further procedures, complications, recurrence, total active movement and extension deficit, and time to return to function. Given the limited evidence comparing recurrence rates following collagenase injection and limited fasciectomy, and the importance of a return to function as soon as possible for patients, the associated measures for each will be prioritised to allow treatment effectiveness in the context of these key elements to be assessed. An economic evaluation will assess the cost-effectiveness of treatments, and a qualitative sub-study will assess participants’ experiences and preferences of the treatments. Discussion The DISC trial is the first randomised controlled trial, to our knowledge, to investigate the clinical and cost-effectiveness of collagenase compared to limited fasciectomy surgery for patients with Dupuytren’s contracture. Trial registration Clinical.Trials.gov ISRCTN18254597 . Registered on April 11, 2017.

Aims: A pilon fracture is a severe ankle joint injury caused by high-energy trauma, typically affecting men of working age. Although relatively uncommon (5% to 7% of all tibial fractures), this injury causes among the worst functional and health outcomes of any skeletal injury, with a high risk of serious complications and long-term disability, and with devastating consequences on patients’ quality of life and financial prospects. Robust evidence to guide treatment is currently lacking. This study aims to evaluate the clinical and cost-effectiveness of two surgical interventions that are most commonly used to treat pilon fractures. Methods: A randomized controlled trial (RCT) of 334 adult patients diagnosed with a closed type C pilon fracture will be conducted. Internal locking plate fixation will be compared with external frame fixation. The primary outcome and endpoint will be the Disability Rating Index (a patient self-reported assessment of physical disability) at 12 months. This will also be measured at baseline, three, six, and 24 months after randomization. Secondary outcomes include the Olerud and Molander Ankle Score (OMAS), the five-level EuroQol five-dimenison score (EQ-5D-5L), complications (including bone healing), resource use, work impact, and patient treatment preference. The acceptability of the treatments and study design to patients and health care professionals will be explored through qualitative methods. Discussion: The two treatments being compared are the most commonly used for this injury, however there is uncertainty over which is most clinically and cost-effective. The Articular Pilon Fracture (ACTIVE) Trial is a sufficiently powered and rigorously designed study to inform clinical decisions for the treatment of adults with this injury. Cite this article: Bone Jt Open 2021;2(3):150–163.

Abstract Background This article reports the results from a feasibility study of an intervention (‘E-PLAYS’) aimed at supporting children who experience difficulties with social communication. E-PLAYS is based around a dyadic computer game, which aims to develop collaborative and communication skills. A pilot study found that when E-PLAYS was delivered by researchers, improvements on communication test scores and on collaborative behaviours were observed. The aim of this study was to ascertain the feasibility of running a full-scale trial to test the effectiveness of E-PLAYS in a National Health Service (NHS) setting with delivery by speech and language therapists and teaching assistants. Methods The study was a two-arm feasibility cluster-randomised controlled trial of the E-PLAYS intervention with a treatment as usual control arm. Data relating to recruitment and retention, treatment fidelity, acceptability to participants, suitability of outcomes and feasibility of collecting health economic measures and of determining cost-effectiveness were collected. Speech and language therapists selected suitable children (ages 4–7 years old) from their caseload. E-PLAYS intervention (experimental group) was then delivered by teaching assistants overseen by speech and language therapists. The control group received usual care. Assessments included blinded language measures and observations, non-blinded teacher-reported measures of peer relations and classroom behaviour and non-blinded parent-reported use of health and education resources and quality of life. Results Planned recruitment was for 70 children, in the event, 50 children were recruited which was sufficient for feasibility purposes. E-PLAYS was very highly rated by children, teaching assistants and speech and language therapists and treatment fidelity did not pose any issues. We were able to collect health economic data which suggests that E-PLAYS would be a low-cost intervention. Conclusion Based on recruitment, retention and adherence rates and our outcome measures, a full-scale randomised controlled trial estimated appears feasible and warranted to assess the effectiveness of E-PLAYS for use by the NHS and schools. Trial registration ISRCTN 14818949 (retrospectively registered).

Abstract Background A number of children experience difficulties with social communication and this has long-term deleterious effects on their mental health, social development and education. The proposal presented in this article describes a feasibility study for a trial to test an intervention (‘E-PLAYS’) aimed at supporting children with social communication impairments. E-PLAYS harnesses technology in the form of a novel computer game in order to develop collaborative and communication skills. Preliminary studies by the authors show that when E-PLAYS was administered by the research team, children with social communication impairments showed improvements on communication test scores and on observed collaborative behaviours. The study described here is a pragmatic trial to test the application of E-PLAYS delivered by NHS speech and language therapists together with schools. Methods This protocol outlines a two-arm feasibility cluster-randomised controlled trial of the E-PLAYS intervention with treatment as usual control arm, with randomisation at the level of the speech and language therapist. The aim of this study is to ascertain whether it will be feasible to progress to running a full-scale definitive trial to test the effectiveness of E-PLAYS in an NHS setting. Data relating to recruitment and retention, the appropriateness of outcomes and the acceptability of E-PLAYS to participants will be collected. Speech and language therapists will select suitable children (ages 4–7 years old) from their caseloads and deliver either the E-PLAYS intervention (experimental group) or treatment as usual (control group). Assessments will include blinded language measures and observations, non-blinded teacher-reported measures of peer relations and classroom behaviour and parent-reported use of resources and quality of life. There will also be a qualitative process evaluation. Discussion The findings of this study will inform the decision as to whether to progress to a full-scale definitive randomised controlled trial to test the effectiveness of E-PLAYS when delivered by speech and language therapists and teaching assistants within schools. The use of technology in game form is a novel approach in an area where there are currently few available interventions. Trial registration ISRCTN 14818949 (retrospectively registered).

Background: Research outcome data is commonly collected using postal questionnaires; however, poor response can introduce bias and reduce statistical power. Text messaging is simple, cost-effective, and can be customised to the individual. Personalised, reminder text messages may improve response rates. Methods: A two-arm, parallel group ‘Study within a Trial’ (SWAT) was embedded within the Occupational Therapist Intervention Study (OTIS), a randomised controlled trial of a home assessment for falls prevention in older people. OTIS participants who provided a mobile phone number were randomly allocated (1:1) to receive either a personalised text message (Title, Surname, plus York Trials Unit (YTU) text) or the standard YTU text alone, prior to receiving their four-month post-randomisation follow-up postal questionnaire. The primary outcome measure was the proportion of participants who returned the questionnaire. Secondary outcomes were: time to response, completeness of response, requirement of a reminder letter, and cost-effectiveness. Binary data were compared using logistic regression and time to response by Cox proportional hazards regression. Results: A total of 403 participants were randomised: 201 to the personalised text and 202 to the standard text. Of the 283 participants included in the final analysis, 278 (98.2%) returned their questionnaire; 136 (97.8%) for the personalised text versus 142 (98.6%) for the standard text (adjusted odds ratio 0.64, 95% CI 0.10 to 3.88, p=0.63). The median time to response was nine days in both groups. In total, 271 (97.5%) participants returned a complete questionnaire; 133 (97.8%) in the personalised text versus 138 (97.2%) for the standard text. In total, 21 reminder letters were sent. The additional cost of personalised text messages was £0.04 per participant retained. Conclusions: Personalised texts were not superior to standard texts in any outcome assessed in our study. Further SWATs are needed to perform a meta-analysis and obtain more evidence. Registration: ISRCTN22202133; SWAT 35.