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Background Social skills interventions are commonly recommended to help children and young people with autism spectrum disorder develop social skills, but some struggle to engage in these interventions. LEGO® (LEGO System A/S, Billund, Denmark) based therapy, a group social skills intervention, aims to be more interesting and engaging. Objective To evaluate the clinical effectiveness of LEGO® based therapy on the social and emotional skills of children and young people with autism spectrum disorder in school settings compared with usual support. Secondary objectives included evaluations of cost-effectiveness, acceptability and treatment fidelity. Design A cluster randomised controlled trial randomly allocating participating schools to either LEGO® based therapy and usual support or usual support only. Setting Mainstream schools in the north of England. Participants Children and young people (aged 7–15 years) with autism spectrum disorder, their parent/guardian, an associated teacher/teaching assistant and a facilitator teacher/teaching assistant (intervention schools only). Intervention Schools randomised to the intervention arm delivered 12 weekly sessions of LEGO® based therapy, which promotes collaborative play and encourages social problem-solving in groups of three children and young people with a facilitator (trained teacher or teaching assistant). Participants received usual support from school and community services. Participants in the control arm received usual support only. Research assistants and statisticians were blind to treatment allocation. Main outcome measure The social skills subscale of the Social Skills Improvement System (SSIS), completed by the children and young people’s unblinded teacher pre randomisation and 20 weeks post randomisation. The SSIS social skills subscale measures social skills including social communication, co-operation, empathy, assertion, responsibility and self-control. Participants completed a number of other pre- and post-randomisation measures of emotional health, quality of life, loneliness, problem behaviours, academic competence, service resource utilisation and adverse events. Results A total of 250 children and young people from 98 schools were randomised: 127 to the intervention arm and 123 to the control arm. Intention-to-treat analysis of the main outcome measure showed a modest positive difference of 3.74 points (95% confidence interval –0.16 to 7.63 points, standardised effect size 0.18; p = 0.06) in favour of the intervention arm. Statistical significance increased in per-protocol analysis, with a modest positive difference (standardised effect size 0.21; p = 0.036). Cost-effectiveness of the intervention was found in reduced service use costs and a small increase in quality-adjusted life-years. Intervention fidelity and acceptability were positive. No intervention-related adverse events or effects were reported. Conclusions The primary and pre-planned sensitivity analysis of the primary outcome consistently showed a positive clinical difference, with modest standardised effect sizes of between 0.15 and 0.21. There were positive health economics and qualitative findings, corroborated by the difference between arms for the majority of secondary outcomes, which were not statistically significant but favoured the intervention arm. Post hoc additional analysis was exploratory and was not used in drawing this conclusion. Given the small positive change, LEGO® based therapy for children and young people with autism spectrum disorder in schools should be considered. Limitations The primary outcome measure was completed by an unblinded teacher (rather than by the facilitator). Future work The study team recommends future research into LEGO® based therapy, particularly in school environments. Trial registration This trial is registered as ISRCTN64852382. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 15/49/32) and is published in full in Public Health Research; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information. Plain language summary Autism spectrum disorder is characterised by difficulties with social relationships and communication, which can make it difficult to make friends. Social skills training is commonly used to help children and young people learn different social skills, but some children and young people do not enjoy these therapies. LEGO® (LEGO System A/S, Billund, Denmark) based therapy takes a new approach by focusing on making the process interesting and fun. This research investigated the effect of LEGO® based therapy groups in schools on the social and emotional abilities of children and young people with autism spectrum disorder. It was a randomised controlled trial, so each school that was taking part was randomly chosen to provide either usual support (from the school or NHS services) or 12 sessions of LEGO® based therapy with a trained school staff member as well as usual support. Children and young people played one of three roles – the ‘engineer’ (gives instructions), the ‘supplier’ (finds the pieces) or the ‘builder’ (builds the model) – and worked together. Questionnaires completed by children and young people, their parents/guardians and teachers were used to look at the intervention’s effects. The main objective was to see if there was a change in social skills measured by a teacher-completed questionnaire. Results showed that the social skills of children and young people in the LEGO® based therapy groups did improve a little. We found that the intervention is not very costly for schools to run. Many parents/guardians and teachers thought that the intervention was beneficial and that the children and young people enjoyed it. Scientific summary Background Autism spectrum disorder (ASD) is a neurodevelopmental condition currently estimated to affect 1.00–1.16% of children and young people (CYP) in the UK. Autistic CYP typically experience developmental differences in social communication and may have strong specific interests/preferences and repetitive behaviours. Impacts are often seen in social functioning, general mental health and long-term social and educational outcomes into adulthood. Social learning through friendships is an important part of a child or young person’s development. It is an area in which many autistic CYP struggle because they tend to initiate and engage in social interactions differently from typically developing peers. They may prefer solitary activities with structured rules and less co-operative play and emotional exchange, which may mean that they find social interactions more challenging. Over time, autistic CYP may feel socially isolated. A number of social interventions aim to help autistic CYP to develop these skills. CYP often find it difficult to transfer skills learnt in one context to other areas of their lives. LEGO® (LEGO System A/S, Billund, Denmark) based therapy is a group social skills intervention designed for autistic CYP to facilitate the learning and flexible practising of social skills with peers. It is designed to make social interactions interesting by using a structured and predictable toy with which CYP are often already familiar and intrinsically motivated to play. The use of LEGO® based therapy in the UK is increasing following reported potential benefits. However, the evidence base for LEGO® based therapy is limited, with only a small number of studies assessing its use for autistic CYP. Among these, only one small study used a randomised controlled trial design to compare LEGO® based therapy with a similar social skills intervention, the Social Use of Language Programme (SULP). This study had several limitations, including a small sample size and a lack of fully randomised allocation. A scoping review of the research in this area conducted in 2017 concluded that more robustly designed studies with larger sample sizes and standardised outcome measures are needed to properly evaluate the effectiveness of LEGO® based therapy in this population. Objectives Primary objective To examine the clinical effectiveness of LEGO® based therapy groups on the social and emotional competence (specifically perceived social skills) of autistic CYP in schools, compared with usual support for autistic CYP, at 20 weeks after randomisation. Secondary objectives To examine the clinical effectiveness of LEGO® based therapy groups on the perceived social isolation of autistic CYP in schools, compared with usual support for, at 20 and 52 weeks. To examine the clinical effectiveness of LEGO® based therapy groups on the academic competence of autistic CYP in schools, compared with usual support for autistic CYP, at 20 and 52 weeks. To examine the clinical effectiveness of LEGO® based therapy groups on assertion, social control, externalising and internalising in autistic CYP in the school setting, compared with usual support for autistic CYP, at 20 and 52 weeks. To examine the cost-effectiveness of LEGO® based therapy groups, compared with usual support for autistic CYP, at 52 weeks. To examine the emotional and behavioural symptoms in those receiving LEGO® based therapy, compared with usual support for autistic CYP, at 20 and 52 weeks. To determine if the impact of LEGO® based therapy is sustainable into the next academic year by comparing effectiveness on social and emotional competence (specifically perceived social skills) at 52 weeks after randomisation. To examine the acceptability of the intervention at follow-up points using a purpose-designed questionnaire and telephone interviews at 20 weeks. To examine treatment fidelity through independent observation of treatment sessions across schools and a self-report measure completed by the facilitator [i.e. a trained teacher or teaching assistant (TA)] after each session. Setting The setting was mainstream primary and secondary schools in the north of England. Participants Participants were CYP in mainstream schools between the ages of 7 and 15 years with a diagnosis of ASD, a parent or guardian of the CYP and a teacher or TA in the child or young person’s school who knew them well (i.e. an associated teacher). Another school staff member was recruited in schools allocated to the intervention arm to run the LEGO® based therapy sessions (i.e. a facilitator teacher). Participants were recruited by contact with mainstream primary and secondary schools following meetings to explain the study and confirmation of eligible CYP in their schools. Participants were included if they met study inclusion criteria and provided fully informed consent to participate. Methods The trial used a pragmatic cluster randomised controlled trial design. Remote randomisation of each school using stratified randomisation lists was provided by a blinded statistician from the Clinical Trials Research Unit, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK. All participants completed a set of baseline questionnaires. Once baseline measures were completed for all participants in a school, the school was randomly allocated to one of two trial arms. Participating CYP in schools allocated to the intervention arm received 12 sessions of LEGO® based therapy in addition to usual support from their school, their general practitioner and other professionals. In schools allocated to the control arm, participating CYP received usual support only. Training was provided for intervention school staff by members of the study team and experienced local authority members trained by experts in the field. All participants were followed up 20 and 52 weeks after their school was randomised and were asked to complete similar questionnaires to those completed at baseline and questionnaires around their health resource use. Acceptability of the interventions was assessed using a purpose-designed questionnaire and telephone interviews with parents and facilitators. Fidelity was assessed using questionnaires and video-recordings when possible. The study team ensured the involvement of patients and the public throughout the study, including a parent of an autistic child and groups such as the Young Dynamos research advisory group (Bradford District Care NHS Foundation Trust, Shipley, UK) and the National Autistic Society (London, UK) in initial study design and specific discussions throughout the study. Intervention LEGO® based therapy LEGO® based therapy is a social skills intervention designed to support CYP with social communication difficulties, such as autistic CYP, by offering playful opportunities to practise social skills. It was created by Daniel LeGoff, who observed that autistic CYP may be particularly drawn to LEGO bricks, perhaps because of their interests and strengths in systemising. In the intervention, CYP, usually in groups of three, build LEGO sets. The CYP take turns to play one of three roles: the ‘engineer’, who has the instructions and communicates them to the group; the ‘supplier’, who finds the correct bricks; and the ‘builder’, who builds the model. CYP then progress to collaborative ‘freestyle’ building, in which they build models of their own design together. Sessions aim to be CYP led, following their interests as far as possible. Many skills are practised throughout, including communication, joint attention, problem-solving, emotion regulation and compromise. The intervention uses a naturalistic play setting, meaning that CYP learn how to collaborate with others through doing, rather than through didactic teaching. Sessions are facilitated by an adult, who aims to guide the CYP rather than direct them explicitly. Adults are encouraged to allow CYP to solve their own challenges and to promote social problem-solving skills, stepping in to prompt through open questions when needed. CYP are encouraged to practise and role-play new social strategies discovered in the sessions. The adult’s role is also to praise and highlight the positive things happening in a session, using rewards such as stickers and certificates as motivation. Procedure The intervention was provided in school by teachers or TAs, termed ‘facilitators’, who were provided with a 3-hour face-to-face training session on how to deliver the intervention. Training was provided by members of the study team and experienced professionals from each recruiting site’s local authority who had been ‘trained to train’ school staff members by co-applicant Gina Gomez de la Cuesta and expert colleagues. Facilitators were also provided with a brief guide specifically designed for this study, which describes the essential elements of the intervention and how to facilitate sessions successfully. Schools were given all materials needed to run their sessions, including a range of LEGO sets with instructions and freestyle bricks, funded by the research. Groups were also given ‘brick club’ materials, including group rules, role cards (i.e. supplier, builder or engineer), free-play building ideas and a points system chart, all of which they were encouraged to use. Schools were asked to run 12 sessions of LEGO® based therapy over a 12-week period. It was recommended that sessions were run for 1 hour once per week for the 12-week period; however, multiple sessions in 1 week due to illness and time constraints were acceptable. Sessions less than 1 hour in duration were also acceptable, but facilitators were encouraged to run groups for at least 45 minutes. Fidelity Intervention fidelity was assessed via two methods: (1) completion of the self-report fidelity checklist after each session of LEGO® based therapy by all facilitators and (2) video-recording of a subset of sessions where consent to be video-recorded was obtained. Video-recordings were stratified to include sessions from three time points: early intervention sessions (sessions 1–4), mid-point intervention sessions (sessions 5–8) and later intervention sessions (sessions 9–12). The self-report fidelity checklist was designed by experts on the team and mapped onto the main components of the intervention identified in the manual and previous publications. It asked the facilitator to identify which components of the intervention had taken place. Video-recordings were completed in schools where all participating CYP, their parents/guardians and the facilitator consented to the recording. These were then independently reviewed and assessed for fidelity to the intended intervention delivery method against the fidelity checklist. Sixteen sessions were double rated to ensure rating accuracy. Results The clinical effectiveness of LEGO® based therapy for autistic CYP was analysed using intention-to-treat (ITT) analysis of the teacher-completed social skills subscale of the Social Skills Improvement System (SSIS) at 20 weeks. A total of 250 participants were consented and randomised to the trial, and the primary outcome ITT analysis comprised 217 CYP (86.8%) with complete baseline and primary outcome data, with 116 in the intervention arm (91.3%) and 101 in the control arm (82.1%). The SSIS is a behaviour rating scale widely used in national portfolio studies and has been shown to be sensitive to change. A modest positive difference on this scale of 3.74 points [95% confidence interval (CI) –0.16 to 7.63 points, p = 0.06; standardised effect size 0.18] was found for CYP in the intervention arm compared with the control arm. A per-protocol analysis, which included CYP in the intervention arm who had attended six or more intervention sessions, was also carried out and showed a slightly greater, statistically significant, difference (4.23 points, 95% CI 0.27 to 8.19 points; p = 0.036). Between-group differences in both analyses did not reach the pre-specified minimum clinically important difference (MCID) of a 9- to 10-point increase on the social skills subscale of the SSIS. The health economics analysis showed cost-effectiveness of the intervention through both reduced service use costs and a small but significant increase in quality-adjusted life years (QALYs). There was a small reduction in school-based intervention costs and intervention costs on the whole (with reduced NHS child mental health service costs) in the intervention arm compared with the control arm. Mean QALYs as reported by parents/guardians and CYP were shown to be marginally higher (by 0.03 QALYs) in the intervention arm than in the control arm. Fidelity to the intended intervention delivery method was measured via self-report and independent reviewers. Levels of self-reported fidelity were very good, with 99% of the core content of the intervention delivered and 91% of all content being reported as delivered. Levels of fidelity assessed by independent reviewers using video-recordings were good, with 83% of core content and 77% of all content being rated as delivered. Qualitative analysis showed good levels of acceptability of the intervention by CYP, parents/guardians and facilitators, with many schools continuing to run the intervention after the study ended. Discussion Limitations of the study included the fact that the primary outcome measure was completed by a teacher who did not deliver the intervention but who was not necessarily blind to the intervention. Although we obtained qualitative data from parents/carers and educators/facilitators, we had no direct impressions from the CYP themselves, although the adults consistently reported high levels of satisfaction on the part of the CYP. Analysis of the primary outcome showed modest positive improvements in social skills, although this analysis and sensitivity analyses did not show large enough changes in social skills scores for CYP in the intervention arm to reach the pre-specified MCID. However, the primary and pre-planned sensitivity analysis of the primary outcome consistently showed a positive clinical difference, with modest standardised effect sizes between 0.15 and 0.21, and there were positive health economics and qualitative findings. This is corroborated to some extent by the fact that the difference between arms for the majority of secondary outcomes, although not statistically significant, favoured the intervention arm. The post hoc additional analysis was exploratory and was not used in drawing this overall conclusion. Conclusions Given the positive findings of the health economics and qualitative analyses, and the presence of a small yet positive change in social skills, consideration should be given to LEGO® based therapy and its contribution to the social skills of autistic CYP when run in a school setting. The study team recommends future research into LEGO® based therapy, particularly when run in school environments. Additional analysis showed possible avenues for exploration, including whether or not there is a greater impact of the intervention for autistic CYP in secondary schools, or for those with less severe ASD symptomatology, and when there is more than one autistic child or young person in each therapy session. Trial registration This trial is registered as ISRCTN64852382. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 15/49/32) and is published in full in Public Health Research; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information.

Background Randomised controlled trials are designed to assess the superiority, equivalence or non-inferiority of a new health technology, but which trial design should be used is not always obvious in practice. In particular, when using equivalence or non-inferiority designs, multiple outcomes of interest may be important for the success of a trial, despite the fact that usually only a single primary outcome is used to design the trial. Benefit–risk methods are used in the regulatory clinical trial setting to assess multiple outcomes and consider the trade-off of the benefits against the risks, but are not regularly implemented in publicly funded trials. Objectives The aim of the project is to aid the design of clinical trials with multiple outcomes of interest by defining when each trial design is appropriate to use and identifying when to use benefit–risk methods to assess outcome trade-offs (qualitatively or quantitatively) in a publicly funded trial setting. Methods A range of methods was used to elicit expert opinion to answer the project objectives, including a web-based survey of relevant researchers, a rapid review of current literature and a 2-day consensus workshop of experts (in 2019). Results We created a list of 19 factors to aid researchers in selecting the most appropriate trial design, containing the following overarching sections: population, intervention, comparator, outcomes, feasibility and perspectives. Six key reasons that indicate a benefit–risk method should be considered within a trial were identified: (1) when the success of the trial depends on more than one outcome; (2) when important outcomes within the trial are in competing directions (i.e. a health technology is better for one outcome, but worse for another); (3) to allow patient preferences to be included and directly influence trial results; (4) to provide transparency on subjective recommendations from a trial; (5) to provide consistency in the approach to presenting results from a trial; and (6) to synthesise multiple outcomes into a single metric. Further information was provided to support the use of benefit–risk methods in appropriate circumstances, including the following: methods identified from the review were collated into different groupings and described to aid the selection of a method; potential implementation of methods throughout the trial process were provided and discussed (with examples); and general considerations were described for those using benefit–risk methods. Finally, a checklist of five pieces of information that should be present when reporting benefit–risk methods was defined, with two additional items specifically for reporting the results. Conclusions These recommendations will assist research teams in selecting which trial design to use and deciding whether or not a benefit–risk method could be included to ensure research questions are answered appropriately. Additional information is provided to support consistent use and clear reporting of benefit–risk methods in the future. The recommendations can also be used by funding committees to confirm that appropriate considerations of the trial design have been made. Limitations This research was limited in scope and should be considered in conjunction with other trial design methodologies to assess appropriateness. In addition, further research is needed to provide concrete information about which benefit–risk methods are best to use in publicly funded trials, along with recommendations that are specific to each method. Study registration The rapid review is registered as PROSPERO CRD42019144882. Funding Funded by the Medical Research Council UK and the National Institute for Health and Care Research as part of the Medical Research Council–National Institute for Health and Care Research Methodology Research programme. Plain language summary Randomised controlled trials are considered the best way to gather evidence about potential NHS treatments. They can be designed from different perspectives depending whether the aim is to show that a new treatment is better than, equal to or no worse than the current best available treatment. The selection of this design relates to the single most important outcome; however, often multiple outcomes can be affected by a treatment. For example, a new treatment may improve disease management but increase side effects. Patients want a treatment to work but not at the price of poor quality of life; therefore, a trade-off must be made, and the recommended treatment depends on this trade-off. Benefit–risk methods can assess the trade-off between multiple outcomes and can include patient preference. These methods could improve the way that decisions are made about treatments in the NHS, but there is currently limited research about the use of these methods in publicly funded trials. The aim of this report is to improve the design of clinical trials by helping researchers to select the most appropriate trial design and to decide when to include a benefit–risk method. The recommendations were created using the opinions of experts within the field and consisted of a survey, review of the literature and a workshop. The project created a list of 19 factors that can assist researchers to select the most appropriate trial design. Furthermore, six key areas were identified in which researchers may consider including a benefit–risk method within a trial. Finally, if a benefit–risk assessment is being used, a checklist of items has been created that identifies the information important to include in reports. This report is, however, limited in its applicability and further research should extend this work, as well as provide more detail on individual methods that are available. Scientific summary Background Randomised controlled trials (RCTs) are the gold standard of health technology evaluation. They can be designed to assess the objective of superiority, equivalence or non-inferiority; the objective is determined by the selected research question and primary outcome. However, in practice, selecting the most appropriate outcome measure and, subsequently, trial design can be difficult. In addition, some trials may have more than one outcome of importance to consider; this is particularly the case when using equivalence or non-inferiority designs, as a secondary superiority outcome is often important. This multidimensionality is not considered if the focus of a trial’s success is a single primary outcome. Benefit–risk (B–R) methods are used in the clinical trial regulatory setting to assess multiple outcomes and consider the trade-off of the benefits against the risks, but they are not regularly implemented in publicly funded UK trials. Objectives This guidance document aims to fill a knowledge gap, with a focus on publicly funded clinical trials throughout. This is undertaken by first providing recommendations on the most appropriate trial design to select and then identifying when a B–R method may be used within a trial to assess outcome trade-offs, whether this be qualitatively or quantitatively. Methods In this project, three key methodologies were used across three work packages (WPs) to elicit expert opinion on trial design and B–R methods. These were: WP1, a web-based survey of relevant researchers in the area. The survey was sent to researchers through appropriate mailing lists, as well as through known contacts and networks, for completion. WP2, a rapid review of current literature. The review built on previous reviews to find available B–R methods, but, in addition to previous work, we retrieved details on which of these could be implemented in publicly funded studies, as well as details on each method’s strengths and weaknesses. WP3, a 2-day expert consensus workshop. Results from the survey and the review were presented to a group of experts (n = 15) who had been contacted because of their knowledge of and interest in the area. The nominal group technique was used to select items for inclusion in checklists. Open discussions, supported by the presented findings, were used to gain opinions on reasons for including B–R methods within a trial. Open discussions were thematically analysed to identify the key points discussed and support the results of the checklists. Results To aid researchers in selecting an appropriate trial design, a list of 19 factors to consider was created. This list relates to six different sections: population, intervention, comparator, outcomes, feasibility and perspectives. Each factor is described in detail and the list of factors is used in conjunction with examples of trial designs to explain why a particular design might be chosen. Once the appropriate trial design has been selected, considering a B–R method may be justified if one of six key reasons is present: The success of the trial depends on more than one outcome. Important outcomes within the trial are in competing directions (i.e. a health technology is anticipated to be better on one outcome but worse on another). To allow patient preferences to be included and directly influence trial results. To provide transparency on subjective recommendations from a trial. To provide consistency in the approach to presenting results from a trial. To synthesise multiple outcomes into a single metric. In particular, the first reason (considering multiple outcomes) is often applicable to equivalence and non-inferiority trials, in which success also depends on the superiority of a secondary outcome; a description of this was flagged as important in the consensus workshop. Owing to the range of B–R methods available, difficulties arise when discussing a globally recommended B–R assessment. To aid with this, the 92 methods that were identified from the literature review as potentially suitable for use in publicly funded RCTs were categorised into seven groups. The first group was an overarching framework that provided structure for a B–R assessment from start to finish. The most basic group, the second group, was the use of a narrative summary of the benefits and risks; although this is not an official method, it was considered important to provide such a summary at the end of a trial. The next two groups comprised a summary table with a specific structure to contain all relevant information, before moving on to methods that can quantitatively trade off multiple outcomes. The final three groups related to preference elicitation from stakeholders, uncertainty estimation and visualisations. Importantly, these groupings show that quantitative methods are not always necessary or appropriate. However, this should not negate the need for a summary or narrative discussion of subjective interpretations. As it could be argued that favourable and unfavourable outcomes are present in all RCTs, a narrative summary of the benefits and risks would add value to the reports of all publicly funded trials. It is noted that some methods require additional data to be collected, so the need for these added resources and expenses should be considered on a case-by-case basis. To provide some clarity on this, the methods groups were linked with different stages of the RCT, from design through to conclusion and dissemination. Group discussions identified the difficulty of additional work during the trial design stage, which is something that this breakdown of the methods at different stages hopes to address. Finally, when a B–R method has been deemed important to use, whether that be a narrative summary or a quantitative trade-off method, the reporting should be transparent and consistent. A checklist of items to include when reporting the trial design in applications or protocols was created, as was a separate checklist for reporting the trial findings. There are five pieces of information that are recommended when reporting the trial design: a heading of ‘benefit–risk’ explicit use of the term ‘benefit–risk’ a plan for B–R assessment the anticipated benefits and risks discussion of the B–R balance with patient representatives. Two further items are recommended when reporting the results of the trial: a summary table of benefits and risks reporting of quality-adjusted life-years in terms of B–R. Conclusions The advice and recommendations provided in this report aim to improve the selection of a trial design, understanding of B–R methods and when it is appropriate to include them and how to effectively report the use of the methods. This guidance is aimed at researchers designing publicly funded RCTs, such as those by the National Institute for Health and Care Research or the Medical Research Council, as well as those on the funding panels. Using these recommendations will improve the design of RCTs, as well as the clarity and consistency of reporting the benefits and risks associated with the health technologies being evaluated. Further research should focus on providing more detail on each of the different B–R methods and recommendations on how they can be fully integrated in publicly funded clinical trials. Practical barriers to this implementation could be assessed to ensure that the information presented in this report can be used most effectively. Study registration This study is registered as PROSPERO CRD42019144882. Funding Funded by the Medical Research Council UK and the National Institute for Health and Care Research as part of the Medical Research Council–National Institute for Health and Care Research Methodology Research programme.

Abstract Background Knowledge mobilisation is a term used in healthcare research to describe the process of generating, sharing and using evidence. ‘Co’approaches, such as co-production, co-design and co-creation, have been proposed as a way of overcoming the knowledge to practice gap. There is a need to understand why researchers choose to adopt these approaches, how they achieve knowledge mobilisation in the management of health conditions, and the extent to which knowledge mobilisation is accomplished. Methods Studies that explicitly used the terms co-production, co-design or co-creation to mobilise knowledge in the management of health conditions were included. Web of Science, EMBASE via OvidSP, MEDLINE via OvidSP and CINHAL via EBSCO databases were searched up to April 2021. Quality assessment was carried out using the Joanna Briggs Institute qualitative quality assessment checklist. Pluye and Hong’s seven steps for mixed studies reviews were followed. Data were synthesised using thematic synthesis. Results Twenty four international studies were included. These were qualitative studies, case studies and study protocols. Key aspects of ‘co’approaches were bringing people together as active and equal partners, valuing all types of knowledge, using creative approaches to understand and solve problems, and using iterative prototyping techniques. Authors articulated mechanisms of action that included developing a shared understanding, identifying and meeting needs, giving everyone a voice and sense of ownership, and creating trust and confidence. They believed these mechanisms could produce interventions that were relevant and acceptable to stakeholders, more useable and more likely to be implemented in healthcare. Varied activities were used to promote these mechanisms such as interviews and creative workshops. There appeared to be a lack of robust evaluation of the interventions produced so little evidence in this review that ‘co’approaches improved the management of health conditions. Conclusion Those using ‘co’approaches believed that they could achieve knowledge mobilisation through a number of mechanisms, but there was no evidence that these led to improved health. The framework of key aspects and mechanisms of ‘co’approaches developed here may help researchers to meet the principles of these approaches. There is a need for robust evaluation to identify whether ‘co’approaches produce improved health outcomes. Trial Registration PROSPERO CRD42020187463 .

Background: Corticosteroids are a mainstay of the treatment of moderately severe relapses of ulcerative colitis, yet almost 50% of patients do not respond fully to these and risk prolonged steroid use and side effects. There is a lack of clarity about the definitions of steroid resistance, the optimum choice of treatment, and patient and health-care professional treatment preferences. Objectives: The overall aim of this research was to understand how steroid-resistant ulcerative colitis is managed in adult secondary care and how current practice compares with patient and health-care professional preferences. Design: A mixed-methods study, including an online survey, qualitative interviews and discrete choice experiments. Setting: NHS inflammatory bowel disease services in the UK. Participants: Adults with ulcerative colitis and health-care professionals treating inflammatory bowel disease. Results: We carried out a survey of health-care professionals (n = 168), qualitative interviews with health-care professionals (n = 20) and patients (n = 33), discrete choice experiments with health-care professionals (n = 116) and patients (n = 115), and a multistakeholder workshop (n = 9). The interviews with and survey of health-care professionals showed that most health-care professionals define steroid resistance as an incomplete response to 40 mg per day of prednisolone after 2 weeks. The survey also found that anti-tumour necrosis factor drugs (particularly infliximab) are the most frequently offered drugs across most steroid-resistant (and steroid-dependent) patient scenarios, but they are less frequently offered to thiopurine-naive patients. Patient interviews identified several factors influencing their treatment choices, including effectiveness of treatment, recommendations from health-care professionals, route of administration and side effects. Over time, depending on the severity and duration of symptoms and, crucially, as medical treatment options become exhausted, patients are willing to try alternative treatments and, eventually, to undergo surgery. The discrete choice experiments found that the probability of remission and of side effects strongly influences the treatment choices of both patients and health-care professionals. Patients are less likely to choose a treatment that takes longer to improve symptoms. Health-care professionals are willing to make difficult compromises by tolerating greater safety risks in exchange for therapeutic benefits. The treatments ranked most positively by patients were infliximab and tofacitinib (each preferred by 38% of patients), and the predicted probability of uptake by health-care professionals was greatest for infliximab (62%). Limitations: The survey and the discrete choice experiments with patients and health-care professionals are limited by their relatively small sample sizes. The qualitative studies are subject to selection bias. The timing of the different substudies, both before and during the COVID-19 pandemic, is a potential limitation. Conclusions: We have identified factors influencing treatment decisions for steroid-resistant ulcerative colitis and the characteristics to consider when choosing treatments to evaluate in future randomised controlled trials. The findings may be used to improve discussions between patients and health-care professionals when they review treatment options for steroid-resistant ulcerative colitis. Future work: This research highlights the need for consensus work to establish an agreed definition of steroid resistance in ulcerative colitis and a greater understanding of the optimal use of tofacitinib and surgery for this patient group. A randomised controlled trial comparing infliximab with tofacitinib is also recommended. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 41. See the NIHR Journals Library website for further project information.

Abstract Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised. This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process. The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text. The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits. In order to encourage its wide dissemination this article is freely accessible on the BMJ and Trials journal websites. “To maximise the benefit to society, you need to not just do research but do it well” Douglas G Altman

Abstract Background Adequate reporting of adaptive designs (ADs) maximises their potential benefits in the conduct of clinical trials. Transparent reporting can help address some obstacles and concerns relating to the use of ADs. Currently, there are deficiencies in the reporting of AD trials. To overcome this, we have developed a consensus-driven extension to the CONSORT statement for randomised trials using an AD. This paper describes the processes and methods used to develop this extension rather than detailed explanation of the guideline. Methods We developed the guideline in seven overlapping stages:1)Building on prior research to inform the need for a guideline;2)A scoping literature review to inform future stages;3)Drafting the first checklist version involving an External Expert Panel;4)A two-round Delphi process involving international, multidisciplinary, and cross-sector key stakeholders;5)A consensus meeting to advise which reporting items to retain through voting, and to discuss the structure of what to include in the supporting explanation and elaboration (E&E) document;6)Refining and finalising the checklist; and7)Writing-up and dissemination of the E&E document. The CONSORT Executive Group oversaw the entire development process. Results Delphi survey response rates were 94/143 (66%), 114/156 (73%), and 79/143 (55%) in rounds 1, 2, and across both rounds, respectively. Twenty-seven delegates from Europe, the USA, and Asia attended the consensus meeting. The main checklist has seven new and nine modified items and six unchanged items with expanded E&E text to clarify further considerations for ADs. The abstract checklist has one new and one modified item together with an unchanged item with expanded E&E text. The E&E document will describe the scope of the guideline, the definition of an AD, and some types of ADs and trial adaptations and explain each reporting item in detail including case studies. Conclusions We hope that making the development processes, methods, and all supporting information that aided decision-making transparent will enhance the acceptability and quick uptake of the guideline. This will also help other groups when developing similar CONSORT extensions. The guideline is applicable to all randomised trials with an AD and contains minimum reporting requirements.

Abstract Background People with type 1 diabetes who attend structured education training in self-management using flexible intensive therapy achieve improved blood glucose control and experience fewer episodes of severe hypoglycaemia. However, many struggle to sustain these improvements over time. To inform the design of more effective follow-up support we undertook a review of qualitative studies which have identified factors that influence and inform participants’ self-management behaviours after attending structured education and their need for support to sustain improvements in glycaemic control. Methods We undertook a meta-ethnography of relevant qualitative studies, identified using systematic search methods. Studies were included which focused on participants’ experiences of self-managing type 1 diabetes after attending structured education which incorporated training in flexible intensive insulin therapy. A line of argument approach was used to synthesise the findings. Results The search identified 18 papers from six studies. The studies included were judged to be of high methodological quality. The line of argument synthesis developed the Follow-Up Support for Effective type 1 Diabetes self-management (FUSED) model. This model outlines the challenges participants encounter in maintaining diabetes self-management practices after attending structured education, and describes how participants try to address these barriers by adapting, simplifying or personalising the self-management approaches they have learned. To help participants maintain the skills taught during courses, the FUSED model presents ten recommendations abstracted from the included papers to provide a logic model for a programme of individualised and responsive follow-up support. Conclusions This meta-ethnography highlights how providing skills training using structured education to people with type 1 diabetes does not necessarily result in participants adopting and sustaining recommended changes in behaviour. To help people sustain diabetes self-management skills after attending structured education, it is recommended that support be provided over the longer-term by appropriately trained healthcare professionals which is responsive to individuals’ needs. Although developed to inform support for people with type 1 diabetes, the FUSED model provides a framework that could also be applied to support individuals with other long term conditions which require complex self-management skills to be learned and sustained over time. Trial registration PROSPERO registration: CRD42017067961.

Introduction The successful treatment of type 1 diabetes (T1D) requires those affected to employ insulin therapy to maintain their blood glucose levels as close to normal to avoid complications in the long-term. The Dose Adjustment For Normal Eating (DAFNE) intervention is a group education course designed to help adults with T1D develop and sustain the complex self-management skills needed to adjust insulin in everyday life. It leads to improved glucose levels in the short term (manifest by falls in glycated haemoglobin, HbA1c), reduced rates of hypoglycaemia and sustained improvements in quality of life but overall glucose levels remain well above national targets. The DAFNEplus intervention is a development of DAFNE designed to incorporate behavioural change techniques, technology and longer-term structured support from healthcare professionals (HCPs).Methods and analysis A pragmatic cluster randomised controlled trial in adults with T1D, delivered in diabetes centres in National Health Service secondary care hospitals in the UK. Centres will be randomised on a 1:1 basis to standard DAFNE or DAFNEplus. Primary clinical outcome is the change in HbA1c and the primary endpoint is HbA1c at 12 months, in those entering the trial with HbA1c >7.5% (58 mmol/mol), and HbA1c at 6 months is the secondary endpoint. Sample size is 662 participants (approximately 47 per centre); 92% power to detect a 0.5% difference in the primary outcome of HbA1c between treatment groups. The trial also measures rates of hypoglycaemia, psychological outcomes, an economic evaluation and process evaluation.Ethics and dissemination Ethics approval was granted by South West-Exeter Research Ethics Committee (REC ref: 18/SW/0100) on 14 May 2018. The results of the trial will be published in a National Institute for Health Research monograph and relevant high-impact journals.Trial registration number ISRCTN42908016.

Abstract Background Randomised controlled trials (RCTs) of complex interventions often begin with a pilot phase to test the proposed methods and refine the intervention before it is trialled. Although the Medical Research Council (MRC) recommends regular communication between the practitioners delivering the intervention and the researchers evaluating it during the pilot phase, there is a lack of practical guidance about how to undertake this aspect of pre-trial work. This paper describes a novel structured process for collaborative working, which we developed to iteratively refine a complex intervention prior to an RCT. We also describe an in-built qualitative study to learn lessons about how this approach could be used by future study teams. Methods This work forms part of a broader research programme to develop and trial a complex intervention for people with type 1 diabetes, called DAFNEplus. The intervention is being piloted in three National Health Service (NHS) diabetes centres in two waves, with refinements being incrementally implemented between each wave in response to real-time, collective learning (combining practitioner experience, process evaluation data and patient and public involvement via an advisory group). A structured ‘Collaborative Working Group’ (CWG) process, comprising monthly teleconferences and four strategically timed face-to-face meetings, is being used to identify and respond systematically to emerging implementation challenges and research findings. The group involves 25 members of the study team, including the multi-disciplinary practitioners delivering the intervention, the research teams conducting the process evaluation, the study manager and Chief Investigator. An in-built qualitative study comprising documentary analysis of meeting materials, discourse analysis of meeting transcripts, reflexive note taking, and thematic analysis of focus groups and interviews with CWG members is being undertaken to explore how the CWG works and how its processes and procedures might be improved. Discussion The CWG process offers a potential model for collaborative working in future pre-trial pilot phases and intervention development studies that operationalises MRC guidance to progressively develop a complex intervention and foster shared ownership through genuine collaboration. The findings from the qualitative study will provide insight into how to best support collaborative working to achieve optimal intervention design.

During the Ebola outbreak in 2014-2015 in Sierra Leone, residual clinical specimens and accompanying data were collected from routine diagnostic testing in Public Health England (PHE) led laboratories. Most of the samples with all the accompanying data were transferred to PHE laboratories in the UK for curation by PHE. The remainder have been kept securely in Sierra Leone. The biobank holds approximately 9955 samples of which 1108 tested positive for Ebola virus. Researchers from the UK and overseas, from academia, government other research organisations and commercial companies can submit proposals to the biobank to access and use the samples. The Ministry of Health and Sanitation in Sierra Leone (MOHS) retains ownership of the data and materials and is working with PHE and other researchers to develop and conduct a series of research projects that will inform future healthcare and public health strategies relating to Ebola. The Ebola Biobank Governance Group (EBGG) was established to guarantee equality of access to the biobank for the most scientifically valuable research including by researchers from low and middle-income countries. Ensuring benefit to the people of Sierra Leone is an over-arching principle for decisions of the EBGG. Four ongoing research collaborations are based on the first wave of biobank proposals approved by EBGG. Whilst the biobank is a valuable resource its completeness and sample quality are consistent with the outbreak conditions under which they were collected.

Background: There is currently insufficient evidence for the clinical effectiveness and cost-effectiveness of psychological therapies for post-stroke depression. Objective: To evaluate the feasibility of undertaking a definitive trial to evaluate the clinical effectiveness and cost-effectiveness of behavioural activation (BA) compared with usual stroke care for treating post-stroke depression. Design: Parallel-group, feasibility, multicentre, randomised controlled trial with nested qualitative research and a health economic evaluation. Setting: Acute and community stroke services in three sites in England. Participants: Community-dwelling adults 3 months to 5 years post stroke who are depressed, as determined by the Patient Health Questionnaire-9 (PHQ-9) or the Visual Analogue Mood Scales ‘Sad’ item. Exclusions: patients who are blind and/or deaf, have dementia, are unable to communicate in English, do not have mental capacity to consent, are receiving treatment for depression at the time of stroke onset or are currently receiving psychological intervention. Randomisation and blinding: Participants were randomised (1 : 1 ratio) to BA or usual stroke care. Randomisation was conducted using a computer-generated list with random permuted blocks of varying sizes, stratified by site. Participants and therapists were aware of the allocation, but outcome assessors were blind. Interventions: The intervention arm received up to 15 sessions of BA over 4 months. BA aims to improve mood by increasing people’s level of enjoyable or valued activities. The control arm received usual care only. Main outcome measures: Primary feasibility outcomes concerned feasibility of recruitment to the main trial, acceptability of research procedures and measures, appropriateness of baseline and outcome measures, retention of participants and potential value of conducting the definitive trial. Secondary feasibility outcomes concerned the delivery of the intervention. The primary clinical outcome 6 months post randomisation was the PHQ-9. Secondary clinical outcomes were Stroke Aphasic Depression Questionnaire – Hospital version, Nottingham Leisure Questionnaire, Nottingham Extended Activities of Daily Living, Carer Strain Index, EuroQol-5 Dimensions, five-level version and health-care resource use questionnaire. Results: Forty-eight participants were recruited in 27 centre-months of recruitment, at a recruitment rate of 1.8 participants per centre per month. The 25 participants randomised to receive BA attended a mean of 8.5 therapy sessions [standard deviation (SD) 4.4 therapy sessions]; 23 participants were allocated to usual care. Outcome assessments were completed by 39 (81%) participants (BA, n = 18; usual care, n = 21). Mean PHQ-9 scores at 6-month follow-up were 10.1 points (SD 6.9 points) and 14.4 points (SD 5.1 points) in the BA and control groups, respectively, a difference of –3.8 (95% confidence interval –6.9 to –0.6) after adjusting for baseline PHQ-9 score and centre, representing a reduction in depression in the BA arm. Therapy was delivered as intended. BA was acceptable to participants, carers and therapists. Value-of-information analysis indicates that the benefits of conducting a definitive trial would be likely to outweigh the costs. It is estimated that a sample size of between 580 and 623 participants would be needed for a definitive trial. Limitations: Target recruitment was not achieved, although we identified methods to improve recruitment. Conclusions: The Behavioural Activation Therapy for Depression after Stroke trial was feasible with regard to the majority of outcomes. The outstanding issue is whether or not a sufficient number of participants could be recruited within a reasonable time frame for a definitive trial. Future work is required to identify whether or not there are sufficient sites that are able to deliver the services required for a definitive trial. Trial registration: Current Controlled Trials ISRCTN12715175. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 47. See the NIHR Journals Library website for further project information.

During the Ebola outbreak in 2014-2015 in Sierra Leone, residual clinical specimens and accompanying data were collected from routine diagnostic testing in Public Health England (PHE) led laboratories. Most of the samples with all the accompanying data were transferred to PHE laboratories in the UK for curation by PHE. The remainder have been kept securely in Sierra Leone. The biobank holds approximately 9955 samples of which 1108 tested positive for Ebola virus. Researchers from the UK and overseas, from academia, government other research organisations and commercial companies can submit proposals to the biobank to access and use the samples. The Ministry of Health and Sanitation in Sierra Leone (MOHS) retains ownership of the data and materials and is working with PHE and other researchers to develop and conduct a series of research projects that will inform future healthcare and public health strategies relating to Ebola. The Ebola Biobank Governance Group (EBGG) was established to guarantee equality of access to the biobank for the most scientifically valuable research including by researchers from low and middle-income countries. Ensuring benefit to the people of Sierra Leone is an over-arching principle for decisions of the EBGG. Four ongoing research collaborations are based on the first wave of biobank proposals approved by EBGG. Whilst the biobank is a valuable resource its completeness and sample quality are consistent with the outbreak conditions under which they were collected.