Cost-effectiveness of acceptance and commitment therapy for people living with motor neuron disease, and their health-related quality of life.

BACKGROUND: Given the degenerative nature of the condition, people living with motor neuron disease (MND) experience high levels of psychological distress. The purpose of this research was to investigate the cost-effectiveness of acceptance and commitment therapy (ACT), adapted for the specific needs of this population, for improving quality of life. METHODS: A trial-based cost-utility analysis over a 9-month period was conducted comparing ACT plus usual care (n = 97) versus usual care alone (n = 94) from the perspective of the National Health Service. In the primary analysis, quality-adjusted life years (QALYs) were computed using health utilities generated from the EQ-5D-5L questionnaire. Sensitivity analyses and subgroup analyses were also carried out. RESULTS: Difference in costs was statistically significant between the two arms, driven mainly by the intervention costs. Effects measured by EQ-5D-5L were not statistically significantly different between the two arms. The incremental cost-effectiveness was above the £20,000 to £30,000 per QALY gained threshold used in the UK. However, the difference in effects was statistically significant when measured by the McGill Quality of Life-Revised (MQOL-R) questionnaire. The intervention was cost-effective in a subgroup experiencing medium deterioration in motor neuron symptoms. CONCLUSIONS: Despite the intervention being cost-ineffective in the primary analysis, the significant difference in the effects measured by MQOL-R, the low costs of the intervention, the results in the subgroup analysis, and the fact that ACT was shown to improve the quality of life for people living with MND, suggest that ACT could be incorporated into MND clinical services.

Recording harms in randomised controlled trials of behaviour change interventions: a qualitative study of UK clinical trials units and NIHR trial investigators.

BACKGROUND: Harms, also known as adverse events (AEs), are recorded and monitored in randomised controlled trials (RCTs) to ensure participants' safety. Harms are recorded poorly or inconsistently in RCTs of Behaviour Change Interventions (BCI); however, limited guidance exists on how to record harms in BCI trials. This qualitative study explored experiences and perspectives from multi-disciplinary trial experts on recording harms in BCI trials. METHODS: Data were collected through fifteen in-depth semi-structured qualitative interviews and three focus groups with thirty-two participants who work in the delivery and oversight of clinical trials. Participants included multi-disciplinary staff from eight CTUs, Chief investigators, and patient and public representatives. Interviews and focus group recordings were transcribed verbatim and thematic analysis was used to analyse the transcripts. RESULTS: Five themes were identified, namely perception and understanding of harm, proportionate reporting and plausibility, the need for a multi-disciplinary approach, language of BCI harms and complex harms for complex interventions. Participants strongly believed harms should be recorded in BCI trials; however, making decisions on "how and what to record as harms" was difficult. Recording irrelevant harms placed a high burden on trial staff and participants, drained trial resources and was perceived as for little purpose. Participants believed proportionate recording was required that focused on events with a strong plausible link to the intervention. Multi-disciplinary trial team input was essential for identifying and collecting harms; however, this was difficult in practice due to lack of knowledge on harms from BCIs, lack of input or difference in opinion. The medical language of harms was recognised as a poor fit for BCI trial harms but was familiar and established within internal processes. Future guidance on this topic would be welcomed and could include summarised literature. CONCLUSIONS: Recording harms or adverse events in behaviour change intervention trials is complex and challenging; multi-disciplinary experts in trial design and implementation welcome forthcoming guidance on this topic. Issues include the high burden of recording irrelevant harms and use of definitions originally designed for drug trials. Proportionate recording of harms focused on events with a strong plausible link to the intervention and multi-disciplinary team input into decision making are essential.

Exploring the barriers to, and importance of, participant diversity in early-phase clinical trials: an interview-based qualitative study of professionals and patient and public representatives.

OBJECTIVES: To explore the importance of, and barriers to achieving, diversity in early-phase clinical trials. DESIGN: Qualitative interviews analysed using thematic analysis. SETTING AND PARTICIPANTS: Five professionals (clinical researchers and methodologists) and three patient and public representatives (those with experience of early-phase clinical trials and/or those from ethnic minority backgrounds) were interviewed between June and August 2022. Participants were identified via their institutional web page, existing contacts or social media (eg, X, formerly known as Twitter). RESULTS: Professionals viewed that diversity is not currently considered in all early-phase clinical trials but felt that it should always be taken into account. Such trials are primarily undertaken at a small number of centres, thus limiting the populations they can access. Referrals from clinicians based in the community may increase diversity; however, those referred are often not from underserved groups. Referrals may be hindered by the extra resources required to approach and recruit underserved groups and participants often having to undertake 'self-driven' referrals. Patient and public representatives stated that diversity is important in research staff and that potential participants should be informed of the need for diversity. Those from underserved groups may require clarification regarding the potential harms of a treatment, even if these are unknown. Education may improve awareness and perception of early-phase clinical trials. We provide 14 recommendations to improve diversity in early-phase clinical trials. CONCLUSIONS: Diversity should be considered in all early-phase trials. Consideration is required regarding the extent of diversity and how it is addressed. The increased resources needed to recruit those from underserved groups may warrant funders to increase the funds to support the recruitment of such participants. The potential harms and societal benefits of the research should be presented to potential participants in a balanced but accurate way to increase transparency.

Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial.

INTRODUCTION: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. METHODS AND ANALYSIS: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs. ETHICS AND DISSEMINATION: The study was approved by the Yorkshire and Humber-Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN88667898.

Recording harms in randomized controlled trials of behavior change interventions: a scoping review and map of the evidence.

OBJECTIVES: Randomized controlled trials evaluate diverse interventions. This can include medical interventions such as drugs or surgical procedures, or behavior change interventions (BCIs) that aim to change a habit, belief, or attitude to improve health, for example, healthy eating, psychological wellbeing. Harms are often recorded poorly or inconsistently within randomized controlled trials of BCIs. This scoping review aimed to collate and describe literature on categories, definitions, and mechanisms of harms from BCIs; methods of identifying plausible harms; and recommendations for recording harms. STUDY DESIGN AND SETTING: A scoping review was conducted. Three databases (MEDLINE, PsycINFO, and CINAHL) were searched. Reference list checking and citation searching were performed. Articles were included if they discussed (1) interventions that aimed to modify behavior, (2) categories or mechanisms of harms, and (3) methods or recommendations for recording harms. All research designs were included. One reviewer reviewed titles, abstracts, and full texts; queries were checked with another reviewer. Data were extracted and synthesized descriptively by one reviewer and checked by another reviewer. A thematic map was constructed to summarize the review findings. Harms described from specific BCIs were identified, and examples were selected and summarized. RESULTS: The review included 37 articles. Nineteen of 37 articles contributed to a thematic review. Three articles described categories of harms; categories of harm included physical, psychological, group and social interactions, cultural, equity, opportunity cost, environmental, and economic. Seven articles included mechanisms or underlying factors for harms including feelings of failure leading to shame or stigma, and group interventions enabling knowledge exchange on unhealthy behaviors. Twelve articles provided recommendations for recording harms, including taking a proportionate approach by focusing on the most plausible and important harms, collecting different perspectives on whether harms had occurred (eg, caregivers and family members), and using qualitative research methods to identify harms. One article described a three-step method to identify plausible harms from an intervention, and six articles supported aspects of the method. Eighteen of 37 articles contributed to a review which collated harms arising from specific interventions, for example, a peer support intervention in inflammatory bowel disease caused distressing conversations which might lead to anxiety and confrontation with a possible negative future. CONCLUSION: BCIs can cause harm. This review identified categories and proposed mechanisms of harms, as well as methods and recommendations for identifying and recording harms in BCIs for inclusion in forthcoming recommendations.

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

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

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

Supporting physical activity through co-production in people with severe mental ill health (SPACES): protocol for a randomised controlled feasibility trial.

BACKGROUND: Severe mental ill health (SMI) includes schizophrenia, bipolar disorder and schizoaffective disorder and is associated with premature deaths when compared to people without SMI. Over 70% of those deaths are attributed to preventable health conditions, which have the potential to be positively affected by the adoption of healthy behaviours, such as physical activity. People with SMI are generally less active than those without and face unique barriers to being physically active. Physical activity interventions for those with SMI demonstrate promise, however, there are important questions remaining about the potential feasibility and acceptability of a physical activity intervention embedded within existing NHS pathways. METHOD: This is a two-arm multi-site randomised controlled feasibility trial, assessing the feasibility and acceptability of a co-produced physical activity intervention for a full-scale trial across geographically dispersed NHS mental health trusts in England. Participants will be randomly allocated via block, 1:1 randomisation, into either the intervention arm or the usual care arm. The usual care arm will continue to receive usual care throughout the trial, whilst the intervention arm will receive usual care plus the offer of a weekly, 18-week, physical activity intervention comprising walking and indoor activity sessions and community taster sessions. Another main component of the intervention includes one-to-one support. The primary outcome is to investigate the feasibility and acceptability of the intervention and to scale it up to a full-scale trial, using a short proforma provided to all intervention participants at follow-up, qualitative interviews with approximately 15 intervention participants and 5 interventions delivery staff, and data on intervention uptake, attendance, and attrition. Usual care data will also include recruitment and follow-up retention. Secondary outcome measures include physical activity and sedentary behaviours, body mass index, depression, anxiety, health-related quality of life, healthcare resource use, and adverse events. Outcome measures will be taken at baseline, three, and six-months post randomisation. DISCUSSION: This study will determine if the physical activity intervention is feasible and acceptable to both participants receiving the intervention and NHS staff who deliver it. Results will inform the design of a larger randomised controlled trial assessing the clinical and cost effectiveness of the intervention. TRIAL REGISTRATION: ISRCTN: ISRCTN83877229. Registered on 09.09.2022.

Identifying the Active Ingredients of a Computerized Speech and Language Therapy Intervention for Poststroke Aphasia: Multiple Methods Investigation Alongside a Randomized Controlled Trial.

BACKGROUND: Aphasia is a communication disorder affecting more than one-third of stroke survivors. Computerized Speech and Language Therapy (CSLT) is a complex intervention requiring computer software, speech and language therapists, volunteers, or therapy assistants, as well as self-managed practice from the person with aphasia. CSLT was found to improve word finding, a common symptom of aphasia, in a multicenter randomized controlled trial (Clinical and Cost Effectiveness of Computer Treatment for Aphasia Post Stroke [Big CACTUS]). OBJECTIVE: This study provides a detailed description of the CSLT intervention delivered in the Big CACTUS trial and identified the active ingredients of the intervention directly associated with improved word finding for people with aphasia. METHODS: We conducted a multiple methods study within the context of a randomized controlled trial. In study 1, qualitative interviews explored key informants' understanding of the CSLT intervention, how the components interacted, and how they could be measured. Qualitative data were transcribed verbatim and analyzed thematically. Qualitative findings informed the process measures collected as part of a process evaluation of the CSLT intervention delivered in the Big CACTUS trial. In study 2, quantitative analyses explored the relationship between intervention process measures (length of computer therapy access; therapists' knowledge of CSLT; degree of rationale for CSLT tailoring; and time spent using the software to practice cued confrontation naming, noncued naming, and using words in functional sentences) and change in word-finding ability over a 6-month intervention period. RESULTS: Qualitative interviews were conducted with 7 CSLT approach experts. Thematic analysis identified four overarching components of the CSLT approach: (1) the StepByStep software (version 5; Steps Consulting Ltd), (2) therapy setup: tailoring and personalizing, (3) regular independent practice, and (4) support and monitoring. Quantitative analyses included process and outcome data from 83 participants randomized to the intervention arm of the Big CACTUS trial. The process measures found to be directly associated with improved word-finding ability were therapists providing a thorough rationale for tailoring the computerized therapy exercises and the amount of time the person with aphasia spent using the computer software to practice using words in functional sentences. CONCLUSIONS: The qualitative exploration of the CSLT approach provided a detailed description of the components, theories, and mechanisms underpinning the intervention and facilitated the identification of process measures to be collected in the Big CACTUS trial. Quantitative analysis furthered our understanding of which components of the intervention are associated with clinical improvement. To optimize the benefits of using the CSLT approach for word finding, therapists are advised to pay particular attention to the active ingredients of the intervention: tailoring the therapy exercises based on the individual's specific language difficulties and encouraging people with aphasia to practice the exercises focused on saying words in functional sentences. TRIAL REGISTRATION: ISRCTN Registry ISRCTN68798818; https://www.isrctn.com/ISRCTN68798818.

Play brick therapy to aid the social skills of children and young people with autism spectrum disorder: the I-SOCIALISE cluster RCT.

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.

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.

Acceptance and Commitment Therapy for people living with motor neuron disease: an uncontrolled feasibility study.

BACKGROUND: Motor neuron disease (MND) is a fatal, progressive neurodegenerative disease that causes progressive weakening and wasting of limb, bulbar, thoracic and abdominal muscles. Clear evidence-based guidance on how psychological distress should be managed in people living with MND (plwMND) is lacking. Acceptance and Commitment Therapy (ACT) is a form of psychological therapy that may be particularly suitable for this population. However, to the authors' knowledge, no study to date has evaluated ACT for plwMND. Consequently, the primary aim of this uncontrolled feasibility study was to examine the feasibility and acceptability of ACT for improving the psychological health of plwMND. METHODS: PlwMND aged ≥ 18 years were recruited from 10 UK MND Care Centres/Clinics. Participants received up to 8 one-to-one ACT sessions, developed specifically for plwMND, plus usual care. Co-primary feasibility and acceptability outcomes were uptake (≥ 80% of the target sample [N = 28] recruited) and initial engagement with the intervention (≥ 70% completing ≥ 2 sessions). Secondary outcomes included measures of quality of life, anxiety, depression, disease-related functioning, health status and psychological flexibility in plwMND and quality of life and burden in caregivers. Outcomes were assessed at baseline and 6 months. RESULTS: Both a priori indicators of success were met: 29 plwMND (104%) were recruited and 76% (22/29) attended ≥ 2 sessions. Attrition at 6-months was higher than anticipated (8/29, 28%), but only two dropouts were due to lack of acceptability of the intervention. Acceptability was further supported by good satisfaction with therapy and session attendance. Data were possibly suggestive of small improvements in anxiety and psychological quality of life from baseline to 6 months in plwMND, despite a small but expected deterioration in disease-related functioning and health status. CONCLUSIONS: There was good evidence of acceptability and feasibility. Limitations included the lack of a control group and small sample size, which complicate interpretation of findings. A fully powered RCT to evaluate the clinical and cost-effectiveness of ACT for plwMND is underway. TRIAL REGISTRATION: The study was pre-registered with the ISRCTN Registry (ISRCTN12655391).

I-SOCIALISE: Results from a cluster randomised controlled trial investigating the social competence and isolation of children with autism taking part in LEGO® based therapy ('Play Brick Therapy') clubs in school environments.

LAY ABSTRACT: Autism is characterised by keen interests and differences in social interactions and communication. Activities that help autistic children and young people with social skills are commonly used in UK schools. LEGO® based therapy is a new activity that provides interesting and fun social opportunities for children and young people and involves building LEGO® models together. This study looked at LEGO® based therapy for the social skills of autistic children and young people in schools. It was a randomised controlled trial, meaning each school was randomly chosen (like flipping a coin) to either run LEGO® based therapy groups in school over 12 weeks and have usual support from school or other professionals, or only have usual support from school or other professionals. The effect of the LEGO® based therapy groups was measured by asking children and young people, their parents/guardians, and a teacher at school in both arms of the study to complete some questionnaires. The main objective was to see if the teacher's questionnaire answers about the children and young people's social skills changed between their first and second completions. The social skills of participants in the LEGO® based therapy groups were found to have improved in a small way when compared to usual support only. The study also found that LEGO® based therapy was not very costly for schools to run and parents/guardians and teachers said they thought it was good for their children and young people. We suggest further research into different potential benefits of LEGO® based therapy.

Physical Activity in Adults with Schizophrenia and Bipolar Disorder: A Large Cross-Sectional Survey Exploring Patterns, Preferences, Barriers, and Motivating Factors.

Adults with severe mental ill health may have specific attitudes toward physical activity. To inform intervention development, we conducted a survey to assess the physical activity patterns, preferences, barriers, and motivations of adults with severe mental ill health living in the community. Data were summarised using descriptive statistics, and logistic regressions were used to explore relationships between physical activity status and participant characteristics. Five-hundred and twenty-nine participants (58% male, mean age 49.3 years) completed the survey. Large numbers were insufficiently active and excessively sedentary. Self-reported levels of physical activity below that recommended in national guidelines were associated with professional inactivity, consumption of fewer than five portions of fruit and vegetables per day, older age, and poor mental health. Participants indicated a preference for low-intensity activities and physical activity that they can do on their own, at their own time and pace, and close to home. The most commonly endorsed source of support was social support from family and friends. Common motivations included improving mental health, physical fitness, and energy levels. However, poor mental and physical health and being too tired were also common barriers. These findings can inform the development of physical activity interventions for this group of people.

One session treatment (OST) is equivalent to multi-session cognitive behavioral therapy (CBT) in children with specific phobias (ASPECT): results from a national non-inferiority randomized controlled trial.

BACKGROUND: 5%-10% children and young people (CYP) experience specific phobias that impact daily functioning. Cognitive Behaviour Therapy (CBT) is recommended but has limitations. One Session Treatment (OST), a briefer alternative incorporating CBT principles, has demonstrated efficacy. The Alleviating Specific Phobias Experienced by Children Trial (ASPECT) investigated the non-inferiority of OST compared to multi-session CBT for treating specific phobias in CYP. METHODS: ASPECT was a pragmatic, multi-center, non-inferiority randomized controlled trial in 26 CAMHS sites, three voluntary agency services, and one university-based CYP well-being service. CYP aged 7-16 years with specific phobia were randomized to receive OST or CBT. Clinical non-inferiority and a nested cost-effectiveness evaluation was assessed 6-months post-randomization using the Behavioural Avoidance Task (BAT). Secondary outcome measures included the Anxiety Disorder Interview Schedule, Child Anxiety Impact Scale, Revised Children's Anxiety Depression Scale, goal-based outcome measure, and EQ-5DY and CHU-9D, collected blind at baseline and six-months. RESULTS: 268 CYPs were randomized to OST (n = 134) or CBT (n = 134). Mean BAT scores at 6 months were similar across groups in both intention-to-treat (ITT) and per-protocol (PP) populations (CBT: 7.1 (ITT, n = 76), 7.4 (PP, n = 57), OST: 7.4 (ITT, n = 73), 7.6 (PP, n = 56), on the standardized scale-adjusted mean difference for CBT compared to OST -0.123, 95% CI -0.449 to 0.202 (ITT), mean difference -0.204, 95% CI -0.579 to 0.171 (PP)). These findings were wholly below the standardized non-inferiority limit of 0.4, suggesting that OST is non-inferior to CBT. No between-group differences were found on secondary outcomes. OST marginally decreased mean service use costs and maintained similar mean Quality Adjusted Life Years compared to CBT. CONCLUSIONS: One Session Treatment has similar clinical effectiveness to CBT for specific phobias in CYP and may be a cost-saving alternative.

One-session treatment compared with multisession CBT in children aged 7-16 years with specific phobias: the ASPECT non-inferiority RCT.

BACKGROUND: Up to 10% of children and young people have a specific phobia that can significantly affect their mental health, development and daily functioning. Cognitive-behavioural therapy-based interventions remain the dominant treatment, but limitations to their provision warrant investigation into low-intensity alternatives. One-session treatment is one such alternative that shares cognitive-behavioural therapy principles but has a shorter treatment period. OBJECTIVE: This research investigated the non-inferiority of one-session treatment to cognitive-behavioural therapy for treating specific phobias in children and young people. The acceptability and cost-effectiveness of one-session treatment were examined. DESIGN: A pragmatic, multicentre, non-inferiority randomised controlled trial, with embedded economic and qualitative evaluations. SETTINGS: There were 26 sites, including 12 NHS trusts. PARTICIPANTS: Participants were aged 7-16 years and had a specific phobia defined in accordance with established international clinical criteria. INTERVENTIONS: Participants were randomised 1 : 1 to receive one-session treatment or usual-care cognitive-behavioural therapy, and were stratified according to age and phobia severity. Outcome assessors remained blind to treatment allocation. MAIN OUTCOME MEASURES: The primary outcome measure was the Behavioural Avoidance Task at 6 months' follow-up. Secondary outcomes included the Anxiety Disorder Interview Schedule, Child Anxiety Impact Scale, Revised Children's Anxiety and Depression Scale, a goal-based outcome measure, Child Health Utility 9D, EuroQol-5 Dimensions Youth version and resource usage. Treatment fidelity was assessed using the Cognitive Behaviour Therapy Scale for Children and Young People and the One-Session Treatment Rating Scale. RESULTS: A total of 274 participants were recruited, with 268 participants randomised to one-session treatment (n = 134) or cognitive-behavioural therapy (n = 134). A total of 197 participants contributed some data, with 149 participants in the intention-to-treat analysis and 113 in the per-protocol analysis. Mean Behavioural Avoidance Task scores at 6 months were similar across treatment groups when both intention-to-treat and per-protocol analyses were applied [cognitive-behavioural therapy: 7.1 (intention to treat), 7.4 (per protocol); one-session treatment: 7.4 (intention to treat), 7.6 (per protocol); on the standardised scale adjusted mean difference for cognitive-behavioural therapy compared with one-session treatment -0.123, 95% confidence interval -0.449 to 0.202 (intention to treat), mean difference -0.204, 95% confidence interval -0.579 to 0.171 (per protocol)]. These findings were wholly below the standardised non-inferiority limit of 0.4, which suggests that one-session treatment is non-inferior to cognitive-behavioural therapy. No between-group differences in secondary outcome measures were found. The health economics evaluation suggested that, compared with cognitive-behavioural therapy, one-session treatment marginally decreased the mean service use costs and maintained similar mean quality-adjusted life-year improvement. Nested qualitative evaluation found one-session treatment to be considered acceptable by those who received it, their parents/guardians and clinicians. No adverse events occurred as a result of phobia treatment. LIMITATIONS: The COVID-19 pandemic meant that 48 children and young people could not complete the primary outcome measure. Service waiting times resulted in some participants not starting therapy before follow-up. CONCLUSIONS: One-session treatment for specific phobia in UK-based child mental health treatment centres is as clinically effective as multisession cognitive-behavioural therapy and highly likely to be cost-saving. Future work could involve improving the implementation of one-session treatment through training and commissioning of improved care pathways. TRIAL REGISTRATION: This trial is registered as ISRCTN19883421. 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. 42. See the NIHR Journals Library website for further project information.

A phobia is an intense, ongoing fear of an everyday object or situation. The phobia causes distress and the person with the phobia avoids that object or situation. Many children and young people have phobias that affect their daily lives. Cognitive­behavioural therapy helps by changing what people do or think when they have a phobia and is the most common treatment approach. However, cognitive­behavioural therapy is expensive, takes time and is not always easy to get. Different treatments are needed to help children and young people with specific phobias. One such therapy is one-session treatment, which works in similar ways to cognitive­behavioural therapy but takes place over one main 3-hour session. Our study, called ASPECT (Alleviating Specific Phobias Experienced by Children Trial), compared these two treatments to examine whether or not one-session treatment is as effective as cognitive­behavioural therapy. Overall, 274 children and young people aged 7­16 years from 26 sites nationally helped with our research, of whom 268 received either cognitive­behavioural therapy or one-session treatment. The results at 6 months found that one-session treatment and cognitive­behavioural therapy worked as well as each other for treating phobias in children and young people. We also found evidence that one-session treatment is cheaper than cognitive­behavioural therapy. We spoke with children and young people, their parents/guardians and the therapists of the single-session treatment, and we found one-session treatment to be acceptable for their needs. Future research could explore how to make one-session treatment more easily available for children and young people with specific phobias because it can save time and money, and works just as well as cognitive­behavioural therapy.

A randomised controlled trial of acceptance and commitment therapy plus usual care compared to usual care alone for improving psychological health in people with motor neuron disease (COMMEND): study protocol.

BACKGROUND: Motor neuron disease (MND) is a rapidly progressive, fatal neurodegenerative disease that predominantly affects motor neurons from the motor cortex to the spinal cord and causes progressive wasting and weakening of bulbar, limb, abdominal and thoracic muscles. Prognosis is poor and median survival is 2-3 years following symptom onset. Psychological distress is relatively common in people living with MND. However, formal psychotherapy is not routinely part of standard care within MND Care Centres/clinics in the UK, and clear evidence-based guidance on improving the psychological health of people living with MND is lacking. Previous research suggests that Acceptance and Commitment Therapy (ACT) may be particularly suitable for people living with MND and may help improve their psychological health. AIMS: To assess the clinical and cost-effectiveness of ACT modified for MND plus usual multidisciplinary care (UC) in comparison to UC alone for improving psychological health in people living with MND. METHODS: The COMMEND trial is a multi-centre, assessor-blind, parallel, two-arm RCT with a 10-month internal pilot phase. 188 individuals aged ≥ 18 years with a diagnosis of definite, laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis, and additionally the progressive muscular atrophy and primary lateral sclerosis variants, will be recruited from approximately 14 UK-based MND Care Centres/clinics and via self-referral. Participants will be randomly allocated to receive up to eight 1:1 sessions of ACT plus UC or UC alone by an online randomisation system. Participants will complete outcome measures at baseline and at 6- and 9-months post-randomisation. The primary outcome will be quality of life at six months. Secondary outcomes will include depression, anxiety, psychological flexibility, health-related quality of life, adverse events, ALS functioning, survival at nine months, satisfaction with therapy, resource use and quality-adjusted life years. Primary analyses will be by intention to treat and data will be analysed using multi-level modelling. DISCUSSION: This trial will provide definitive evidence on the clinical and cost-effectiveness of ACT plus UC in comparison to UC alone for improving psychological health in people living with MND. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN12655391. Registered 17 July 2017, https://www.isrctn.com/ISRCTN12655391 . PROTOCOL VERSION: 3.1 (10/06/2020).

Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT.

BACKGROUND: The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared. OBJECTIVES: To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain. DESIGN: A randomised crossover trial with health economic analysis. SETTING: Twenty-one secondary care centres in the UK. PARTICIPANTS: Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0-10). INTERVENTIONS: Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded. OUTCOMES: The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory - Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0-10), Patient Global Impression of Change score at week 16 and patients' preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost-utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective. RESULTS: A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval -0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6-16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval -0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -0.002 (95% confidence interval -0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline -0.006 (95% confidence interval -0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -£113 (95% confidence interval -£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval -£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval -£13 to £398)]. LIMITATIONS: Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable. FUTURE WORK: Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief. CONCLUSIONS: The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients' preference in terms of side effects. TRIAL REGISTRATION: The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89. 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. 39. See the NIHR Journals Library website for further project information.

The number of people with diabetes is growing rapidly in the UK and is predicted to rise to over 5 million by 2025. Diabetes causes nerve damage that can lead to severe painful symptoms in the feet, legs and hands. One-quarter of all people with diabetes experience these symptoms, known as 'painful diabetic neuropathy'. Current individual medications provide only partial benefit, and in only around half of patients. The individual drugs, and their combinations, have not been compared directly against each other to see which is best. We conducted a study to see which treatment pathway would be best for patients with painful diabetic neuropathy. The study included three treatment pathways using combinations of amitriptyline, duloxetine and pregabalin. Patients received all three treatment pathways (i.e. amitriptyline treatment for 6 weeks and pregabalin added if needed for a further 10 weeks, duloxetine treatment for 6 weeks and pregabalin added if needed for a further 10 weeks and pregabalin treatment for 6 weeks and amitriptyline added if needed for a further 10 weeks); however, the order of the treatment pathways was decided at random. We compared the level of pain that participants experienced in each treatment pathway to see which worked best. On average, people said that their pain was similar after each of the three treatments and their combinations. However, two treatments in combination helped some patients with additional pain relief if they only partially responded to one. People also reported improved quality of life and sleep with the treatments, but these were similar for all the treatments. In the health economic analysis, the value for money and quality of life were similar for each pathway, and this resulted in uncertainty in the cost-effectiveness conclusions, with no one pathway being more cost-effective than the others. The treatments had different side effects, however; pregabalin appeared to make more people feel dizzy, duloxetine made more people nauseous and amitriptyline resulted in more people having a dry mouth. The pregabalin supplemented by amitriptyline pathway had the smallest number of treatment discontinuations due to side effects and may be the safest for patients.

The Journeying through Dementia psychosocial intervention versus usual care study: a single-blind, parallel group, phase 3 trial.

BACKGROUND: There is an urgent clinical need for evidence-based psychosocial interventions for people with mild dementia. We aimed to determine the clinical benefits and cost-effectiveness of Journeying through Dementia (JtD), an intervention designed to promote wellbeing and independence in people with mild dementia. METHODS: We did a single-blind, parallel group, individually randomised, phase 3 trial at 13 National Health Service sites across England. People with mild dementia (Mini-Mental State Examination score of ≥18) who lived in the community were eligible for inclusion. Patients were centrally randomly assigned (1:1) to receive the JtD intervention plus standard care (JtD group) or standard care only (standard care group). Randomisation was stratified by study site. The JtD intervention included 12 group and four one-to-one sessions, delivered in the community at each site. The primary endpoint was Dementia Related Quality of Life (DEMQOL) 8 months after randomisation, assessed according to the intention-to-treat principle. Only outcome assessors were masked to group assignment. A cost-effectiveness analysis reported cost per quality-adjusted life-year (QALY) from a UK NHS and social care perspective. The study is registered with ISRCTN, ISRCTN17993825. FINDINGS: Between Nov 30, 2016, and Aug 31, 2018, 1183 patients were screened for inclusion, of whom 480 (41%) participants were randomly assigned: 241 (50%) to the JtD group and 239 (50%) to the standard care group. Intervention adherence was very good: 165 (68%) of 241 participants in the JtD group attended at least ten of the 16 sessions. Mean DEMQOL scores at 8 months were 93·3 (SD 13·0) for the JtD group and 91·9 (SD 14·6) for the control group. Difference in means was 0·9 (95% CI -1·2 to 3·0; p=0·38) after adjustment for covariates, lower than that identified as clinically meaningful. Incremental cost per QALY ranged from £88 000 to -£205 000, suggesting that JtD was not cost-effective. Unrelated serious adverse events were reported by 40 (17%) patients in the JtD group and 35 (15%) patients in the standard care group. INTERPRETATION: In common with other studies, the JtD intervention was not proven effective. However, this complex trial successfully recruited and retained people with dementia without necessarily involving carers. Additionally, people with dementia were actively involved as participants and study advisers throughout. More research into methods of measuring small, meaningful changes in this population is needed. Questions remain regarding how services can match the complex, diverse, and individual needs of people with mild dementia, and how interventions to meet such needs can be delivered at scale. FUNDING: UK National Institute of Health Research Health Technology Assessment Programme.

Cost and effectiveness of one session treatment (OST) for children and young people with specific phobias compared to multi-session cognitive behavioural therapy (CBT): results from a randomised controlled trial.

BACKGROUND: In the UK, around 93,000 (0.8%) children and young people (CYP) are experiencing specific phobias that have a substantial impact on daily life. The current gold-standard treatment-multi-session cognitive behavioural therapy (CBT) - is effective at reducing specific phobia severity; however, CBT is time consuming, requires specialist CBT therapists, and is often at great cost and limited availability. A briefer variant of CBT called one session treatment (OST) has been found to offer similar clinical effectiveness for specific phobia as multi-session CBT. The aim of this study was to assess the cost-effectiveness of OST compared to multi-session CBT for CYP with specific phobias through the Alleviating Specific Phobias Experienced by Children Trial (ASPECT), a two-arm, pragmatic, multi-centre, non-inferiority randomised controlled trial. METHODS: CYP aged seven to 16 years with specific phobias were recruited nationally via Health and Social Care pathways, remotely randomised to the intervention group (OST) or the control group (CBT-based therapies) and analysed (n = 267). Resource use based on NHS and personal social services perspective and quality adjusted life years (QALYs) measured by EQ-5D-Y were collected at baseline and at six-month follow-up. Incremental cost-effectiveness ratio (ICER) was calculated, and non-parametric bootstrapping was conducted to capture the uncertainty around the ICER estimates. The results were presented on a cost-effectiveness acceptability curve (CEAC). A set of sensitivity analyses (including taking a societal perspective) were conducted to assess the robustness of the primary findings. RESULTS: After adjustment and bootstrapping, on average CYP in the OST group incurred less costs (incremental cost was -£302.96 (95% CI -£598.86 to -£28.61)) and maintained similar improvement in QALYs (QALYs gained 0.002 (95% CI - 0.004 to 0.008)). The CEAC shows that the probability of OST being cost-effective was over 95% across all the WTP thresholds. Results of a set of sensitivity analyses were consistent with the primary outcomes. CONCLUSION: Compared to CBT, OST produced a reduction in costs and maintained similar improvement in QALYs. Results from both primary and sensitivity analyses suggested that OST was highly likely to be cost saving. TRIAL REGISTRATION: ISRCTN19883421 (30/11/2016).

Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

An intervention to promote self-management, independence and self-efficacy in people with early-stage dementia: the Journeying through Dementia RCT.

BACKGROUND: There are few effective interventions for dementia. AIM: To determine the clinical effectiveness and cost-effectiveness of an intervention to promote self-management, independence and self-efficacy in people with early-stage dementia. OBJECTIVES: To undertake a randomised controlled trial of the Journeying through Dementia intervention compared with usual care, conduct an internal pilot testing feasibility, assess intervention delivery fidelity and undertake a qualitative exploration of participants' experiences. DESIGN: A pragmatic two-arm individually randomised trial analysed by intention to treat. PARTICIPANTS: A total of 480 people diagnosed with mild dementia, with capacity to make informed decisions, living in the community and not participating in other studies, and 350 supporters whom they identified, from 13 locations in England, took part. INTERVENTION: Those randomised to the Journeying through Dementia intervention (n = 241) were invited to take part in 12 weekly facilitated groups and four one-to-one sessions delivered in the community by secondary care staff, in addition to their usual care. The control group (n = 239) received usual care. Usual care included drug treatment, needs assessment and referral to appropriate services. Usual care at each site was recorded. MAIN OUTCOME MEASURES: The primary outcome was Dementia-Related Quality of Life score at 8 months post randomisation, with higher scores representing higher quality of life. Secondary outcomes included resource use, psychological well-being, self-management, instrumental activities of daily living and health-related quality of life. RANDOMISATION AND BLINDING: Participants were randomised in a 1 : 1 ratio. Staff conducting outcome assessments were blinded. DATA SOURCES: Outcome measures were administered in participants' homes at baseline and at 8 and 12 months post randomisation. Interviews were conducted with participants, participating carers and interventionalists. RESULTS: The mean Dementia-Related Quality of Life score at 8 months was 93.3 (standard deviation 13.0) in the intervention arm (n = 191) and 91.9 (standard deviation 14.6) in the control arm (n = 197), with a difference in means of 0.9 (95% confidence interval -1.2 to 3.0; p = 0.380) after adjustment for covariates. This effect size (0.9) was less than the 4 points defined as clinically meaningful. For other outcomes, a difference was found only for Diener's Flourishing Scale (adjusted mean difference 1.2, 95% confidence interval 0.1 to 2.3), in favour of the intervention (i.e. in a positive direction). The Journeying through Dementia intervention cost £608 more than usual care (95% confidence interval £105 to £1179) and had negligible difference in quality-adjusted life-years (-0.003, 95% confidence interval -0.044 to 0.038). Therefore, the Journeying through Dementia intervention had a mean incremental cost per quality-adjusted life-year of -£202,857 (95% confidence interval -£534,733 to £483,739); however, there is considerable uncertainty around this. Assessed fidelity was good. Interviewed participants described receiving some benefit and a minority benefited greatly. However, negative aspects were also raised by a minority. Seventeen per cent of participants in the intervention arm and 15% of participants in the control arm experienced at least one serious adverse event. None of the serious adverse events were classified as related to the intervention. LIMITATIONS: Study limitations include recruitment of an active population, delivery challenges and limitations of existing outcome measures. CONCLUSIONS: The Journeying through Dementia programme is not clinically effective, is unlikely to be cost-effective and cannot be recommended in its existing format. FUTURE WORK: Research should focus on the creation of new outcome measures to assess well-being in dementia and on using elements of the intervention, such as enabling enactment in the community. TRIAL REGISTRATION: This trial is registered as ISRCTN17993825. 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. 24. See the NIHR Journals Library website for further project information.

There are few services proven effective for people with mild dementia. We therefore explored the potential benefit of a programme called Journeying through Dementia. The content, devised in partnership with people living with dementia, aims to help affected individuals to live well and participate in life. The programme involves meeting in groups of about eight every week for 12 weeks. Each person also has four face-to-face meetings with a staff member. Carers are invited to 3 of the 12 group meetings to all individual meetings if the participant wanted this involvement. A total of 480 people with dementia and 350 carers from 13 locations in England took part. Just over half of the participants were randomly allocated to the new programme, whereas the others were not. This allowed us to compare the groups. We were interested in whether or not attending the Journeying through Dementia programme improved participants' quality of life. The results showed that it did not. We also measured participants' mood, self-management skills, positive attitudes and ability with daily living skills. Only one measure of positive psychology suggested even a small benefit. There was no difference between groups in the remaining measures. Although some individual participants described being more confident, enjoying social contact, trying new activities, feeling valued and having increased independence, overall, the programme is unlikely to be worth implementing. Certain aspects of the programme are worth implementing.