79860495 true Parents and Young Children under Extreme Stress (PYCES2): A randomised controlled efficacy trial of trauma-focused cognitive behaviour therapy for post-traumatic stress disorder (PTSD) in young children aged 3-8 years PYCES2 The primary objective of this study is to establish whether trauma-focused cognitive behavioural therapy for young children (CBT-3M) is an efficacious intervention for young children with post-traumatic stress disorder (PTSD). This question will be investigated by comparing CBT-3M to a care-as-usual (CAU) control group in the UK NHS. Secondary objectives are to gather qualitative data on children and families lived experience of the intervention, and to acquire basic demographic, cognitive and behavioural data in trial participants to assess mediators and moderators of outcome. Background and study aims Many young children who experience traumatic events such as accidents, medical emergencies, or witnessing violence may go on to develop post-traumatic stress disorder (PTSD). PTSD can cause distressing symptoms like nightmares, flashbacks, anger outbursts, and changes in behaviour or play. While there are effective treatments for older children and adults, there is currently no approved treatment in the UK for children as young as 3 years. This study aims to find out whether a new therapy, CBT-3M, can help young children with PTSD recover and improve their daily functioning. Who can participate? Children aged 3 to 8 years who have experienced a single traumatic event (such as an accident, a medical emergency, or witnessing violence) and who are diagnosed with PTSD can take part, along with a parent or caregiver. Children are not able to take part if they: 1. Are currently at risk of ongoing trauma or abuse 2. Have a serious head injury or a history of brain damage 3. Have a learning disability or another mental health condition that needs treatment first 4. Are not able to speak English with their family What does the study involve? Children will be randomly assigned to receive either CBT-3M or care-as-usual through the NHS. CBT-3M is a trauma-focused cognitive behavioural therapy delivered over 12 weekly sessions involving both the child and their parent/caregiver. It includes games, storytelling, and other activities to help the child make sense of the trauma and feel safer. Families will be assessed before, during, and after the therapy to see how well it works and what their experiences are. What are the possible benefits and risks of participating? Participants in the therapy group may benefit from symptom relief and improved coping. Risks are minimal but may include emotional discomfort when talking about the traumatic event. Support will be available throughout the study. Where is the study run from? The study is run from the Medical Research Council Cognition and Brain Sciences Unit at the University of Cambridge, in collaboration with the Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), and NHS sites in Cambridge, Norwich, and South-East London (UK). When is the study starting and how long is it expected to run for? June 2025 to March 2028 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK) Who is the main contact? Mrs Alicja Podgorski, alicja.podgorski@mrc-cbu.cam.ac.uk PTSD diagnostic status assessed using the Diagnostic Infant and Preschool Assessment (DIPA) at 3-month follow-up post-treatment 1. Co-morbid psychiatric diagnoses, assessed using the Diagnostic Infant and Preschool Assessment (DIPA) at baseline, post-treatment, and 3-month follow-up 2. PTSD symptoms, measured by the Young Child PTSD Checklist (parent-report) at baseline, mid-treatment, post-treatment, and 3-month follow-up 3. General emotional distress, measured by the Paediatric Emotional Distress Scale (PEDS) at baseline, mid-treatment, post-treatment, and 3-month follow-up 4. Parental PTSD symptoms, measured by the PTSD Checklist for DSM-5 (PCL-5) at baseline, mid-treatment, post-treatment, and 3-month follow-up 5. Parental depression symptoms, measured by the Patient Health Questionnaire (PHQ-9) at baseline, mid-treatment, post-treatment, and 3-month follow-up 6. Parental anxiety symptoms, measured by the General Anxiety Disorder-7 (GAD-7) at baseline, mid-treatment, post-treatment, and 3-month follow-up 7. Parental trauma-related beliefs and behaviours, assessed using the Parental Trauma Response Questionnaire (PTRQ) at baseline, mid-treatment, post-treatment, and 3-month follow-up 8. Child post-traumatic cognitions, measured using a 4-item developmentally adapted interview based on the Child Post-Traumatic Cognitions Inventory (CPTCI) at baseline and post-treatment 9. Child cognitive processes (decision-making under uncertainty), assessed using an explore/exploit task adapted from Kim et al. (2025) at baseline and post-treatment 10. Cognitive functions: inhibitory control (assessed using Go/No-Go), working memory (assessed using Mr. Ant), and cognitive flexibility (assessed using Card Sorting) via the Early Years Toolbox 11. Child irritability, assessed using the Affective Reactivity Index (ARI-P) at baseline and post-treatment 12. Child functioning, assessed using the Strengths and Difficulties Questionnaire (SDQ) at baseline and post-treatment 13. Treatment acceptability and experience, explored through qualitative interviews: 13.1. With parents at 3-month follow-up or earlier if they withdraw 13.2. With clinicians following CBT-3M delivery Ethics approval required East of England - Cambridge South Research Ethics Committee

Equinox House City Link

Nottingham United Kingdom NG2 4LA 26/EE/0048 10.1186/ISRCTN79860495 335868 CPMS: 59122, NIHR: 207262, PYCES2_2025 335868 59122 207262 PYCES2_2025 Multi-centre patient-level two-arm randomized controlled efficacy trial Interventional Randomised parallel trial Efficacy Quality of life Treatment 2028-03-31T00:00:00.000Z United Kingdom England MRC-Cognition and Brain Sciences Unit, University of Cambridge

15 Chaucer Rd

Cambridge England CB2 7EF Cambridgeshire and Peterborough NHS Foundation Trust

Elizabeth House Fulbourn Hospital Fulbourn

Cambridge England CB21 5EF RT1@2.16.840.1.113883.2.1.3.2.4.18.48 South London and Maudsley NHS Foundation Trust

Bethlem Royal Hospital Monks Orchard Road

Beckenham England BR3 3BX RV5@2.16.840.1.113883.2.1.3.2.4.18.48 Norfolk and Suffolk NHS Foundation Trust

Trust Headquarters County Hall Martineau Lane

Norwich NO COUNTRY SPECIFIED, assuming England England NR1 2DH Carer Patient Service user 1. Participants will be children aged 3–8 years with a principal diagnosis of PTSD, according to the developmentally sensitive algorithm validated in our background work, following a discrete single-incident or short-lived stressor (e.g., accident, witnessing or experiencing violence, medical emergency or procedure). 2. PTSD will be assessed with the Diagnostic Infant and Preschool Assessment (DIPA; see outcome measures section). 3. Children with either acute (1–6 months post-trauma) or chronic (>6 months post-trauma) PTSD will be included, as our feasibility trial data and US data indicate that CBT-3M provides benefit across this boundary. Child 3 Years 8 Years All 80 0 1. In line with the feasibility trial, victims of chronic sexual/physical abuse will not be invited into the trial given the need to involve specialist services. 2. Head trauma (Glasgow Coma Score <8) 3. Learning disability 4. Another primary psychiatric diagnosis that warrants treatment using a psychological therapy ahead of the traumatic stress response 5. Inability to speak English within the family 6. Ongoing exposure to trauma or other threats 7. History of organic brain damage 2026-07-31T00:00:00.000Z 2028-03-01T00:00:00.000Z Post-traumatic stress disorder (PTSD) in young children aged 3–8 years following a single-incident or short-term trauma such as an accident, medical emergency, or witnessed violence Mental and Behavioural Disorders Participants will be randomised using a minimisation procedure stratified by age (3–5 vs 6–8 years), sex, and baseline PTSD severity, as assessed by the Diagnostic Infant and Preschool Assessment (DIPA). The intervention group will receive CBT-3M, a trauma-focused cognitive behavioural therapy tailored for young children. It consists of 12 structured sessions with the child and parent/caregiver, including psychoeducation, coping skills, graduated exposure, trauma narrative, and cognitive restructuring. The control group will receive Care As Usual (CAU) through NHS and GP-referred services, which typically does not include trauma-focused psychological therapy for this age group. Behavioural De-identified (anonymised) individual participant data (IPD) may be made available upon reasonable request to qualified researchers. Any requests must be approved by the trial sponsor and relevant ethics committees. Data will only be shared for research purposes that align with the original aims of the study and must comply with UK data protection regulations. Requests should be submitted in writing to the Chief Investigator and will be reviewed on a case-by-case basis. Available on request

Participant information sheet Migrated from patient info sheet field

Study website Migrated from study website field

580ea31e-f083-40e9-8d1f-387abcc6a001 dba5d8c5-2650-4392-89d5-4c3eea5f5b35 797c2792-b7f2-4c96-ac69-b958e10be02d a7648026-9314-4579-99e0-b4e2262c963b Yes Alicja Podgorski https://orcid.org/0000-0002-0147-6460 Public Scientific

University of Cambridge MRC Cognition and Brain Sciences Unit 15 Chaucer Road

Cambridge United Kingdom CB2 7EF +44 (0)1223769906 alicja.podgorski@mrc-cbu.cam.ac.uk Public Tim Dalgleish https://orcid.org/0000-0002-7304-2231 Principal investigator

University of Cambridge MRC Cognition and Brain Sciences Unit 15 Chaucer Road

Cambridge United Kingdom CB2 7EF +44 (0)1223 767654 tim.dalgleish@mrc-cbu.cam.ac.uk Public Cambridgeshire and Peterborough NHS Foundation Trust Hospital/treatment centre https://ror.org/040ch0e11 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 11089633 true Improving Social Recovery in Psychosis (ISRIP): a definitive randomised controlled trial and process evaluation of Social Recovery Therapy compared to treatment as usual for people with psychosis and severe social disability ISRIP Primary Objective: 1. Determining whether Social Recovery Therapy plus Treatment as Usual (intervention) will be superior to Treatment as Usual alone (control) in improving social recovery at 15 months post-randomisation. Study Objectives: 1. Assessing whether Social Recovery Therapy plus Treatment as Usual (intervention) will be superior to Treatment as Usual alone (control) in improving social recovery at 9 months post-randomisation. 2. Evaluating mental health symptoms at 9 and 15 months post-randomisation. 3. Assessing service user-defined recovery at 9 and 15 months post-randomisation. 4. Evaluating quality of life and hope at 9 and 15 months post-randomisation. 5. Evaluating the cost-effectiveness of the intervention compared to the control at 9 and 15 months post-randomisation. 6. Explore the maintenance of intervention effects at 24 months post-randomisation. An embedded mixed-methods process evaluation will address the following aims:    1. Assess the extent to which SRT was implemented as intended, by measuring treatment fidelity, dose and reach  2. Explore patterns of uptake and adherence to SRT, with particular focus on underserved groups   3. Test hypothesised mechanisms of change of SRT   4. Explore participant, family and therapist experiences of SRT, with a particular focus on the experiences of underserved groups and any adaptations made to increase cultural sensitivity  5. Identify contextual factors that maximise intervention delivery and interact with effectiveness, to inform implementation Background and study aims Schizophrenia spectrum disorders are the mental health problems most frequently associated with poor social outcomes and the personal and economic costs are large, particularly for those from minoritised groups. Existing psychosocial interventions have small and short-term effects on social functioning, with the effects being weakest for people experiencing more severe social disability. We have conducted two early-phase randomised controlled trials of a novel intervention, social recovery therapy (SRT) with promising effects, but a definitive trial is needed to demonstrate effectiveness and confirm wider implementation. Our primary hypothesis is that in people experiencing persistent social disability in the context of a schizophrenia spectrum diagnosis, social recovery therapy plus treatment as usual (SRT+TAU) will be superior to TAU alone on the primary outcome of time spent in structured activity, measured using the Time Use Survey. Secondary outcomes will include psychotic symptoms, mood, hopefulness, and quality of life. We will also test the hypothesis that SRT will be cost-effective compared to TAU. We will collect data on intervention maintenance effects at 24 months using data from patient records on employment and education, service engagement, and relapse. Alongside the trial we will conduct a mixed-methods process evaluation to understand implementation, causal mechanisms and contextual factors which shape outcomes, with a particular focus on the experiences of underserved groups and any adaptations required to increase cultural sensitivity. Who can participate? Working age adults (18 – 65 years old) with non-affective psychosis, presenting with less than 30 hours in structured activity per week. What does the study involve? Participants who agree to take part will be asked to complete questionnaires at three timepoints. Participants allocated to the intervention group will receive social recovery therapy in addition to usual care, whilst participants allocated to the control group will receive usual care. What are the possible benefits and risks of participating? Participants will get a chance to meet with a researcher to identify meaningful activities for themselves, have regular meetings with a therapist and receive three £20 vouchers. People may feel pressured into undertaking new activities, which could result in the returning or worsening of certain psychological difficulties. Where is the study run from? 1. Norfolk and Suffolk NHS Foundation Trust (UK) 2. Cambridgeshire and Peterborough NHS Foundation Trust (UK) 3. Sussex Partnership NHS Foundation Trust (UK) 4. Pennine Care NHS Foundation Trust (UK) 5. Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust (UK) When is the study starting and how long is it expected to run for? July 2026 to December 2029 Who is funding the study? NIHR Health Technology Assessment (UK) Who is the main contact? 1. Dr Joanne Hodgekins, j.hodgekins@uea.ac.uk 2. Lauren Ooi, isrip.study@uea.ac.uk Hours per week in structured activity, assessed through the Time Use Survey at 15 months post-randomisation 1. Hours per week in structured activity assessed using the Time Use Survey at 9 months 2. Functioning assessed using Recovering Quality of Life (ReQoL), Goal-Based Outcomes, and the WHO Disability Assessment Schedule (WHO-DAS) at baseline, 9 and 15 months post-randomisation 3. Quality of life assessed using EQ-5D-5L at baseline, 9 and 15 months post-randomisation 4. Psychotic symptoms assessed using Clinical Global Impression-Schizophrenia (CGI-SCH) and Scale for the Assessment of Negative Symptoms (SANS) at baseline, 9 and 15 months post-randomisation 5. Mood assessed using Patient Health Questionnaire-9 (PHQ-9) and Generalised Anxiety Disorder-7 (GAD-7) at baseline, 9 and 15 months post-randomisation 6. Hopelessness and suicidal ideation assessed using the Beck Hopelessness Scale (BHS) at baseline, 9 and 15 months post-randomisation 7. Service engagement (contact with mental health teams) and relapse rate (number of hospitalisations) recorded at 24 months 8. Education and employment status recorded at 24 months Ethics approval required London - Bloomsbury Research Ethics Committee

Health Research Authority 2 Redman Place Stratford

London United Kingdom E20 1JQ 26/LO/0203 10.1186/ISRCTN11089633 346911 CPMS: 63757, NIHR: 169529 346911 63757 169529 Randomized controlled trial Interventional Randomised controlled trial Treatment 2029-12-31T00:00:00.000Z United Kingdom England Sussex Partnership NHS Foundation Trust

Trust Hq Swandean Arundel Road

Worthing England BN13 3EP RX2@2.16.840.1.113883.2.1.3.2.4.18.48 Norfolk and Suffolk NHS Foundation Trust

County Hall Martineau Lane

Norwich England NR1 2DH RMY@2.16.840.1.113883.2.1.3.2.4.18.48 Cambridgeshire and Peterborough NHS Foundation Trust

Elizabeth House Fulbourn Hospital Fulbourn

Cambridge England CB21 5EF RT1@2.16.840.1.113883.2.1.3.2.4.18.48 Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust

St Nicholas Hospital Jubilee Road Gosforth

Newcastle upon Tyne England NE3 3XT RX4@2.16.840.1.113883.2.1.3.2.4.18.48 Pennine Care NHS Foundation Trust

225 Old Street

Ashton-under-lyne England OL6 7SR RT2@2.16.840.1.113883.2.1.3.2.4.18.48 false 1. Diagnosis of non-affective psychosis 2. Working-age adult (18-65 years) 3. Social disability indicated by structured activity of <30 hours per week on the Time Use Survey 4. History of social impairment indicated by a score of <60 on the Global Assessment of Functioning for >6 months 5. Under the care of secondary mental health services 6. Capacity and ability to provide informed consent Mixed 18 Years 65 Years All 410 0 1. Organic aetiology indicated for psychosis (e.g., brain injury) 2. Severe learning disability that would prevent engagement with intervention or assessments 3. Current involvement in any other interventional research study 4. Immediate serious risk to self or other 2026-07-01T00:00:00.000Z 2028-01-01T00:00:00.000Z Psychosis Mental and Behavioural Disorders This study will use an assessor-blind randomised controlled trial design to compare Social Recovery Therapy plus treatment as usual (SRT + TAU) to TAU alone, with a 9-month intervention period and a 24-month follow-up period. An embedded process evaluation will inform interpretation of outcomes and provide understanding of how SRT might be applied in routine practice, with a particular focus on delivery to under-served groups. We will recruit working-age adults who have non-affective psychosis (schizophrenia spectrum diagnosis) and social disability (defined as activity levels lower than 30 hours per week) from community-based mental health services across five UK sites. Participants will be approached about the study by their clinical teams and asked if they would be interested in taking part. Following verbal consent to contact, participants will be provided with a Participant Information Sheet (PIS) by a member of the research team and asked to provide informed consent for their participation. Following a screening and baseline assessment, participants will be randomised to receive either SRT + TAU or TAU alone. SRT will be delivered by NHS-employed non-expert psychological practitioners, trained and supervised by SRT experts. The intervention period will last for 9 months, with approximately weekly to fortnightly sessions. Research assessments will be conducted by trained research assistants (RAs) at baseline, 9 months (end of treatment), and 15 months (primary follow-up). Assessment procedures have been designed to be flexible and are based on assertive outreach principles, which involves the delivery of assessments wherever most suitable for the participant. Assessments are likely to take up to 2 hours but can be split over several assessment visits. Participants will be supported by study RAs to complete outcome measures, either face-to-face or online where requested by the participant. All RAs will receive training and supervision in engaging individuals with psychosis, as well as training in completing the outcome measures. We will also provide cultural competency training to all research staff. At 24 months, data linkage with the NHS England Mental Health Services Dataset (MHSDS) will be used to collect routine data on service use and education/employment status. Participants will also be contacted by an automated text message to ask about their education and employment since the last follow-up visit. This method of data collection has been chosen to reduce attrition from in-person research visits and loss to follow-up. Information about data linkage is included in the PIS. Following the end of the intervention period, participants will be invited to take part in a qualitative interview, lasting approximately 1 hour, about their experiences of the study and the intervention. We will also invite family members to share their experiences in a separate interview and will seek specific informed consent from family members to participate in this. In addition, we will seek consent from SRT therapists to complete feedback questionnaires before and after they receive SRT training and the extent to which they expect the intervention will cause a positive change in social recovery for people with psychosis. At the end of the intervention period, SRT therapists will be invited to participate in a qualitative interview, lasting approximately 1 hour, about their experiences of delivering the intervention, with a specific focus on understanding any adaptations made for under-served groups. A separate PIS and consent form has been developed for trial therapists. Wider stakeholders from NHS mental health services (e.g., team leads, service managers) will be invited to participate in focus groups to explore their views on SRT and the potential ‘fit’ of the approach within standard care for people with psychosis. We will explore suggestions for improvements and wider perspectives on the team and service context. This will include potential barriers and facilitators of SRT implementation, including uptake, engagement, delivery feasibility and acceptability, as well as the service resource and training needs required. Behavioural Data sharing statement to be made available at a later date bfe4bcee-70d4-41f6-b167-68ed0fe54b79 b543ad10-af76-41a8-b5fe-a333235f9962 6ff44e4d-49b6-46ad-853d-6fcc6263a2a3 45129038-d2e0-45f1-a539-0b9bfb511211 No Lauren Ooi https://orcid.org/0000-0002-8312-8207 Public

Norwich Clinical Trials Unit Norwich Medical School University of East Anglia

Norwich United Kingdom NR4 7TJ - isrip.study@uea.ac.uk Public Joanne Hodgekins https://orcid.org/0000-0003-4124-854X Scientific Principal investigator

Department of Clinical Psychology and Psychological Therapies (CPPT) Norwich Medical School University of East Anglia

Norwich United Kingdom NR4 7TJ - j.hodgekins@uea.ac.uk Public Sussex Partnership NHS Foundation Trust Hospital/treatment centre https://ror.org/05fmrjg27 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 81900834 true Core belief–inclusive cognitive behavioural protocol versus treatment as usual for obsessive–compulsive disorder in NHS Talking Therapies: a feasibility study Applied with CONSORT guidelines: Primary Objective To evaluate the feasibility and acceptability of delivering a core belief–involved cognitive behavioural therapy (CBT) augmentation for adults experiencing Obsessive-Compulsive Disorder (OCD) within NHS Talking Therapies services. Feasibility will be assessed through recruitment rates from routine service pathways, participant retention across treatment and follow-up timepoints, treatment adherence and session attendance, therapist protocol fidelity, therapist-reported confidence, usability, and perceived clinical coherence of the intervention, and participant-reported acceptability, engagement, and perceived relevance of treatment. Feasibility hypotheses The CBT augmentation will demonstrate acceptable feasibility within NHS Talking Therapies, indicated by recruitment, retention, adherence, and fidelity parameters comparable to treatment as usual. Therapists delivering the augmented CBT protocol will report acceptable levels of confidence, usability, and perceived clinical coherence, indicating that the intervention can be implemented within routine clinical practice. Secondary Objective To obtain preliminary estimates of change in OCD symptom severity across treatment conditions in order to inform the design of a full powered future trial . Clinical hypotheses Participants receiving augmented CBT will show greater reductions in OCD symptom severity from baseline to post-treatment and follow-up compared with participants allocated to the waiting-list arm. There will be a difference in OCD symptom change between participants receiving augmented CBT and those receiving treatment as usual. Exploration Objectives (Mechanisms of Change) To explore whether changes in self-based core belief process are associated with changes in OCD symptom severity across the course of therapy. Mechanism hypotheses Participants receiving augmented CBT will show greater reductions in negative self-based core beliefs compared with participants receiving treatment as usual. Participants receiving augmented CBT will show greater reductions in self-ambivalence compared with participants receiving treatment as usual. Reductions in negative self-based core beliefs will be associated with reductions in OCD symptom severity across the treatment period. Acceptability and Engagement Objectives To evaluate participant engagement with the intervention and perceived relevance of the therapeutic approach. Acceptability hypotheses Participants allocated to the augmented CBT condition will demonstrate withdrawal rates comparable to or lower than those in the treatment as usual group. Participants receiving augmented CBT will report acceptable levels of engagement and perceived relevance of treatment, as reflected in post-treatment feedback and sessional measures. Background and study aims Obsessive-Compulsive Disorder (OCD) is a common mental health difficulty that can significantly affect daily life. Current psychological treatment within NHS Talking Therapies usually involves cognitive behavioural therapy (CBT), which helps individuals gradually face feared situations and reduce compulsive behaviours. Research suggests that focusing more directly on a person’s core self-beliefs (deeply held beliefs about the self) may improve therapy outcomes for some individuals. However, current OCD treatments do not consistently include structured techniques specifically targeting core self-beliefs. This study aims to investigate whether an enhanced CBT approach that explicitly addresses self-based core beliefs can be delivered within NHS Talking Therapies and whether it shows potential to improve treatment outcomes. The study also evaluates whether the enhanced approach is acceptable to both participants and therapists. This is a feasibility study, meaning the main aim is to determine whether the enhanced treatment can be delivered successfully in routine NHS services and whether it shows promise for future research. Who can participate? Adults aged 18 to 65 who are receiving treatment for Obsessive-Compulsive Disorder through NHS Talking Therapies. What does the study involve? Participants are randomly allocated (by computer) to one of three groups: A) Waiting list group (participants wait a short period before receiving treatment as usual) B) Treatment as usual (standard CBT provided within NHS Talking Therapies) C) Augmented CBT including additional techniques focusing on core self-beliefs Participants in the two therapy groups attend approximately twelve weekly therapy sessions, each lasting around 60 minutes, followed by a follow-up appointment. The waiting list group waits for a shorter period than typical NHS waiting times before beginning treatment outside of the study. Participants complete questionnaires at several time points during therapy and at follow-up. Some of these questionnaires are routinely used in NHS Talking Therapies, while others are included for research purposes. Participants may also be invited to provide feedback about their experience of therapy. The information collected helps researchers understand whether the enhanced treatment can be delivered successfully and whether it may improve treatment outcomes for OCD. What are the possible benefits and risks of participating? Participants may benefit from receiving psychological therapy for OCD. The augmented therapy may help improve understanding of self-beliefs that contribute to OCD symptoms. However, improvement cannot be guaranteed. As with all psychological therapies, discussing personal experiences and confronting feared situations may sometimes lead to temporary emotional discomfort. This level of discomfort is expected to be similar to standard psychological treatment. Therapists monitor wellbeing throughout therapy and provide support where needed. Taking part in the study helps researchers improve understanding of OCD treatment and may contribute to improving future NHS psychological therapies. Where is the study run from? The study is conducted within NHS Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) Talking Therapies services in collaboration with Anglia Ruskin University. When is the study starting and how long is it expected to run for? Recruitment is expected to begin in Spring 2026. Participation lasts for the duration of therapy (approximately 12 sessions) and includes a follow-up appointment approximately 6 months after treatment. The overall study is expected to run for the duration of the doctoral research project, until March 2028. Who is funding the study? The study forms part of a PhD research project sponsored by Anglia Ruskin University. Who is the main contact? Chief Investigator: Laura Laken, lcl121@pgr.aru.ac.uk (Laura Laken) Clinically significant recovery the Yale-Brown Obsessive Compulsive Scale Second Edition score pre-test to post-test and (for Arms B and C) follow-up Clinical recovery the Obsessive Compulsive Inventory Revised score pre-test to post-test and (for Arms B and C) follow-up Acceptability and Retention Reflections patient and research facilitating therapist qualitative feedback and study retention, end of treatment, follow up sessions, and monthly supervision of research facilitating therapists. Reliable change the Negative Core Beliefs Inventory pre-test to post-test and (for Arms B and C) follow-up Reliable change the Rosenberg Self-Esteem Scale pre-test to post-test and (for Arms B and C) follow-up Reliable change Self-Ambivalence Measure pre-test to post-test and (for Arms B and C) follow-up Ethics approval required North West - Greater Manchester Central Research Ethics Committee

2 Redman Place Stratford

London United Kingdom E20 1JQ - 10.1186/ISRCTN81900834 341182 M001155 341182 M001155 Interventional Randomized controlled trial Open (masking not used) Dose comparison Parallel Health services research Treatment Not applicable 2028-03-31T00:00:00.000Z United Kingdom England Cambridgeshire and Peterborough Mental Health Partnership Tr Hq

Elizabeth House, Fulbourn Hospital Cambridge Road Fulbourn

Cambridge England CB21 5EF RT119@2.16.840.1.113883.2.1.3.2.4.18.48 false 1. Completed referral and assessment from NHS Talking Therapies and indicated ‘Yes’ to contact for research participation. 2. OCD working diagnosis confirmed via structured clinical assessment routinely used within NHS Talking Therapies. 3. All participants must be aged 18 to 65 specifically experiencing symptoms and goals indicating Obsessive Compulsive Disorder requiring treatment with a Therapist. 4. Any prescribed medication is GP concordant and has been stable for three months, to control for psychopharmacological effects. 4. Amenable to either webcam or in-person treatment. 5. To attend individual therapy sessions at a reasonable and regular frequency e.g., weekly. 6. To complete therapy in English without the aid of translation services. 7. Comorbid affective disorders e.g., major depressive disorder, are secondary to OCD. OCD to be the clear dominant pathology and the reason for seeking treatment. Mixed 18 Years 65 Years All 131 0 1. Individuals not meeting NHS Talking Therapies suitability criteria for outpatient psychological therapy. 2. Awaiting diagnosis of learning disability. 3. Current or pending diagnosis of neurodevelopmental condition e.g., ADHD, where treatment adaptation would be required beyond the scope of the study protocol. 4. Current significant alcohol or drug misuse. 5. Simultaneously being under the care of other mental health services or on waiting list for alternative psychotherapeutic service. 2026-04-30T00:00:00.000Z 2027-12-31T00:00:00.000Z Obsessive-Compulsive Disorder (OCD) in adults receiving psychological treatment within NHS Talking Therapies services. Mental and Behavioural Disorders Participants are randomly allocated to one of three study arms: Waiting list control (A) Participants allocated to the waiting list receive no active psychological treatment for Obsessive-Compulsive Disorder during the waiting period but continue to have access to usual service support. Participants are offered treatment following completion of the waiting period in accordance with NHS Talking Therapies procedures. Treatment as usual (B) Participants receive standard exposure response prevention CBT for Obsessive-Compulsive Disorder as delivered within NHS Talking Therapies services. Treatment is delivered by qualified therapists following routine service protocols of 12 sessions, typically involving weekly individual therapy sessions. Arm C: Core belief–involved CBT (augmented intervention) Arm C retains a fundamental CBT approach with the mentioned psychometrics, same mode, frequency, duration of contact and episode. However, the difference between B and C will be the psychological application of cognitive therapy and techniques directly including core beliefs within and between all sessions. This will involve early identification of an unhealthy and a healthier alternative core belief, connection to historical predisposing and perpetuating factors, psychoeducation on core beliefs, and core belief modification interventions within and between sessions. Therapy is delivered individually by trained NHS Talking Therapies clinicians across twelve sessions, followed by a follow-up appointment (for arm B and C). Participants complete outcome measures at multiple time points across the treatment period to evaluate feasibility of repeated measurement and preliminary clinical indicators. Participants are randomly allocated to study arms using computer-generated randomisation procedures. The target sample size (n=131) was granted in the ethics approval. The sample size selected allows estimation of feasibility parameters (recruitment, retention, adherence) and provides preliminary estimates of effect size to inform a future fully powered trial. It also allows for expected attrition across repeated measurement time points. Behavioural Data sharing statement to be made available at a later date a9650678-4b80-492c-8333-1ad2189da05a 2e4a4c5d-852e-47e8-8276-283735b6e062 54b57942-0892-4e8b-a6f0-6a6fa8329a7b 9a820bc5-5521-474e-a852-50dfdffb3496 No Laura Laken https://orcid.org/0009-0004-7801-7387 Principal investigator Scientific Public

Anglia Ruskin University East Road

Cambridge United Kingdom CB1 1PT +44 07875515835 LCL121@pgr.aru.ac.uk Public Anglia Ruskin University https://ror.org/0009t4v78 Non-commercial Investigator initiated and funded National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 94157188 true A multicEntre trial to AssesS the validitY of the Kardia six-lead hand-held ECG in psychiatry (Easy ECG V1) Easy ECG V1 1. Compare the diagnostic accuracy of the K6L to the 12L for QT interval in people taking antipsychotic medication. 2. Compare the time to obtain QTc readings between the K6L and 12L – efficiency. 3. Understand the patient acceptability of the K6L compared with the 12L. 4. Using the NICE EVA as reference, determine why and how frequently it is necessary to perform a 12L after a K6L. 5. Describe the prevalence of QT prolongation in patients taking antipsychotics. 6. Understand the clinician acceptability of the K6L. Background and study aims Some medications that are prescribed for patients with mental health problems have side effects that can affect the heart. Doctors use heart tracings called ECGs to understand how the heart is working and ensure it is safe for the person to take these medications. To have a standard ECG, electrode stickers are stuck on the person's chest, wrists and ankles, who then needs to lie still whilst the ECG is recorded. Sometimes, people who need an ECG cannot have it. For example, people who are in distress may not be able to undress or lie still. Sometimes people feel uncomfortable undressing in front of others. Often, NHS clinics do not have the facilities to do ECGs, and the person's GP is asked to do it. Our work has shown that this causes delays in treatment and extra appointments. A new credit-card-sized ECG device (the Kardia 6L [K6L]) has recently been developed. To use it, the person rests two fingers on top of the device and places it so that the back touches the skin of their knee or ankle. The recordings are sent to a phone via Bluetooth. We think the K6L will help more people with mental illness get the ECGs they need. This would help improve safety for people taking medication, reduce the number of appointments and improve the experience for people. We have already shown that the K6L works well in patients seen in a cardiology service. We want to find out how well it works in people seen in mental health services. Who can participate? Patients aged 18 years and over who have been prescribed an antipsychotic medication in any setting What does the study involve? Once consented into the study, participants will first have their demographic information and relevant history recorded. This will be done by reviewing the patient records (notes) and speaking to the participant. Every participant will have their height and weight recorded. Participants will have a 12L ECG followed by a 6L ECG. The 6L should be started as soon as possible after the 12L ECG has been recorded. This time should be no longer than 2 minutes after the 12L has been recorded. The operator will be either a research assistant or a research nurse. At selected sites, a healthcare worker from the participant’s regular clinical team who has been trained to conduct ECGs will carry out the ECGs. The operator of the machines will record the time taken to conduct the 12L from the point that the participant starts to undress or the operator starts to prepare the equipment (whichever comes first). The operator will record the time taken to conduct a 6L starting from the time the operator starts to prepare the equipment. After the ECGs have been take the operator will ask the participant a two-question survey: If you were to have this procedure again with either machine, which test would you choose? What are the reasons you chose [answer from question 1]? What are the possible benefits and risks of participating? We do not anticipate any adverse events in this study. No intervention is being delivered, and data is being collected at one timepoint. Where is the study run from? Leeds Yorkshire Partnership Foundation Trust (UK) When is the study starting and how long is it expected to run for? April 2026 to April 2027 Who is funding the study? Alivecor, Inc. (USA) Who is the main contact? 1. Nazya Azam, nazya.azam@nhs.net 2. Dr George Crowther, georgecrowther@nhs.net QT interval Kardia 6L and standard 12-lead ECG baseline Old ethics approval format Approved 27/10/2025, HRA and Health and Care Research Wales (HCRW) (2 Redman Place, Stratford, London, E20 1JQ, UK; Tel: not available; approvals@hra.nhs.uk), ref: 25/YH/0173 10.1186/ISRCTN94157188 356658 CPMS: 61500 356658 61500 Non-randomized study Interventional Non randomised study Treatment 2027-04-01T00:00:00.000Z United Kingdom England Leeds and York Partnership NHS Foundation Trust

St. Marys House St. Marys Road

Leeds England LS7 3JX RGD@2.16.840.1.113883.2.1.3.2.4.18.48 Tees, Esk and Wear Valleys NHS Foundation Trust

Trust Headquarters West Park Hospital Edward Pease Way

Darlington England DL2 2TS RX3@2.16.840.1.113883.2.1.3.2.4.18.48 Kent and Medway Mental Health NHS Trust

Farm Villa Hermitage Lane

Maidstone England ME16 9PH RXY@2.16.840.1.113883.2.1.3.2.4.18.48 Essex Partnership University NHS Foundation Trust

The Lodge Lodge Approach Runwell

Wickford England SS11 7XX R1L@2.16.840.1.113883.2.1.3.2.4.18.48 Humber Teaching NHS Foundation Trust

Trust Hq Block a Willerby Hill Beverley Road Willerby

Hull England HU10 6ED RV9@2.16.840.1.113883.2.1.3.2.4.18.48 Bradford District Care NHS Foundation Trust

New Mill Victoria Road Saltaire

Shipley England BD18 3LD TAD@2.16.840.1.113883.2.1.3.2.4.18.48 Cambridgeshire and Peterborough NHS Foundation Trust

Elizabeth House Fulbourn Hospital Fulbourn

Cambridge England CB21 5EF RT1@2.16.840.1.113883.2.1.3.2.4.18.48 Surrey and Borders Partnership NHS Foundation Trust

18 Mole Business Park Randalls Road

Leatherhead England KT22 7AD RXX@2.16.840.1.113883.2.1.3.2.4.18.48 Hampshire and Isle of Wight Healthcare NHS Foundation Trust

Tatchbury Mount Hospital Calmore

Southampton England SO40 2RZ RW1@2.16.840.1.113883.2.1.3.2.4.18.48 false Any patient prescribed or due to be prescribed an antipsychotic medication in any setting (ward or outpatient) Mixed 18 Years 100 Years All 800 0 1. Aged under 18 years old 2. Patients who lack capacity and do not have a personal consultee to give advice or where the personal consultee does not think they would want to take part 2025-12-04T00:00:00.000Z 2027-04-01T00:00:00.000Z Cardiovascular and mental health Circulatory System We will conduct a multi-centre study comparing K6L vs 12L ECGs in people receiving antipsychotic therapy. There will be ten NHS sites in total. Our sites span England and Wales and serve a range of rural, urban and semi-rural communities. This will allow us to ensure participants are from a wide range of socioeconomic and ethnic backgrounds. Duration is eighteen months in total (3 months set up, 12 months data collection, 3 months analysis and write up). Recruitment will take place in any clinical area where antipsychotic treatments are prescribed (outpatient or inpatient) in eligible people. Study procedures consist of one 12L ECG and one KardiaMobile 6L ECG per participant, recorded sequentially by the same individual. The 6L should be started as soon as possible after the 12L ECG has been recorded. This time should be no longer than 2 minutes after the 12L has been recorded. Once consented into the study, participants will first have their demographic information and relevant history recorded. This will be done by reviewing the patient records (notes) and speaking to the participant. Demographic information: 1. Age 2. Gender at birth 3. Ethnicity 4. Height 5. Weight History: 1. Primary psychiatric diagnosis for which the antipsychotic is prescribed for 2. Other psychiatric diagnoses 3. Current antipsychotic treatment – type/types of antipsychotic, dose and administration route 4. Other prescribed medications that can impact QT interval 5. Cardiovascular history The 12L will be collected using a MAC 550 (GE Healthcare, WI, USA) or equivalent recorder (calibrated as per machine standards). The 6L will be collected using an Alivecor Kardiamobile 6-lead ECG machine. The operator will be either a research assistant or research nurse. At selected sites (Leeds, Hull, Tees Esk and Wear Valleys (TEWV) and Kent), a healthcare worker from the participant's regular clinical team who has been trained to conduct ECGs will carry out the ECGs. The operator of the machines will record the time taken to conduct the 12L from the point that the participant starts to undress or the operator starts to prepare the equipment (whichever comes first). The operator will also record the time taken to conduct a 6L starting from the time the operator starts to prepare the equipment. After the ECGs have been take the operator will ask the participant a two-question survey: 1. If you were to have this procedure again with either machine, which test would you choose? 2. What are the reasons you chose the [answer from question 1]? Participant survey data will be analysed to understand patient acceptability. A simple count will be used to demonstrate preference between the devices (survey question 1). Content analysis will be used to illustrate the reasons behind this decision and a list of the top 5 reasons for the preference will be created for each type of machine. Healthcare worker time to treatment and ECG quality analysis: At selected sites (Leeds, Kent, Hull and TEWV), 80 ECGs will be collected by a member of the participant's usual treating team who has been trained to use K6L and 12L ECGs. This is to test whether there is a difference in time taken to complete the ECGs and the K6L ECG quality when ECGs are completed by a researcher compared to the usual treating team (real world setting). The data recorded will be identical to the data collection set out above, except that the person conducting the ECG will be asked to indicate which ECG they prefer and why (objective 6). The ECGs will be graded by independent observers who are blinded to the patient and patient details. Noise on ECG will be described according to a noise score (NS) where NS 1 is a completely clear ECG, NS 2 is an ECG with noise but where a good interpretation was possible, NS 3 borderline ECG for noise (analysis based on RR regularity), and NS 4 is not interpretable. K6L validation: The automated QT and QTc analysis will be recorded. This data will be available to the clinical team to aid patient management. Additionally, all other automated intervals will be recorded, e.g. PR interval. Statistical analysis will be performed (Bland Altman and regression analysis) to compare the differences in these results between the 12L versus the K6L for QT, QTc and PR intervals in leads I, II, and AvL. Equivalence of the measurements using the two methods will be carried out using standard equivalence testing methods at a 5% level of significance, with 95% limits of agreement reported. Time to obtain ECG reading: Statistical analysis will be performed to compare the time taken to complete the 6- and 12-lead ECGs. Two separate analyses will be reported: 1. The difference in time when the ECGs are performed by a research assistant. 2. The difference in time when the ECGs are performed by a member of the clinical team (who has been trained to conduct ECGs). Frequency of the need to repeat ECG following K6L: From the 6L data only, using the NICE early valuation assessment criteria for when a repeat QT interval measurement using a 12-lead electrocardiogram (ECG) device is offered following a 6-lead ECG*, we will report the number and proportion of times it would be necessary to complete a 12 Lead ECG following a 6-lead ECG. *When QTc interval is > 440 in men or >470 in women. Prevalence of QT prolongation: The whole cohort will be used to demonstrate the prevalence of QT prolongation in (>440 in men, >470 in women) in people taking antipsychotics. We will also use the data to demonstrate any dose-related effects of antipsychotics on QT (total daily antipsychotic dose as an equivalent to haloperidol vs QTc), and any differences in QTc dependant on antipsychotic type or administration route. All prevalence data will be displayed as a percentage. Recruitment: Potential participants will be identified by their clinical care team, in conjunction with local site research assistants or research nurse (depending on site preference). A research assistant or research nurse (depending on site preference) at each site will recruit 80 participants from both wards and outpatient clinics. The research assistant/nurse will provide the participant information sheet and explain the study. We will work with our PPI group to ensure these materials are understandable and provide easy read versions. Furthermore, we have budgeted for services to translate patient information where necessary. It is hoped that participants will be recruited on the same day, but where necessary they will be given time to consider participation or discuss it with family and friends. Where potential participants lack capacity to consent, personal consultees will be approached on their behalf. Patients who do not wish to participate will receive treatment as usual. ECG registry: Every recruited patient will have the opportunity to opt into a long-term registry. Consent will be obtained to enable the study team to collect adverse cardiac event data and details of the psychotropic prescriptions from hospital or GP records for 10 years. Other Data sharing statement to be made available at a later date 77a68d28-9476-4e3d-9bd5-7e3e6d15a7ec 8b50210b-6e32-4731-9612-ee1882789b29 81826f35-0404-45cc-9d0b-18bac5540999 74e2c6f7-2959-4fd6-86be-20464f387187 No Nazya Azam Scientific

Leeds and York Partnership NHS Foundation Trust, 1st Floor, Main House, St Mary's House

Leeds United Kingdom LS7 3JX +44 (0)7980 958984 nazya.azam@nhs.net Public George Crowther Scientific

Liaison Psychiatry for Older People, Beckett Wing, St James's Hospital

Leeds United Kingdom LS9 7TF +44 (0)7703288239 georgecrowther@nhs.net Public Leeds and York Partnership NHS Foundation Trust Hospital/treatment centre https://ror.org/00n635c12 Non-commercial Alivecor, Inc. 11440256 true Improving quality of life and behaviour that challenges in people with mild to moderate intellectual disability through person-centred solution focused communication (ICONIC) ICONIC Current study objectives as of 16/04/2026: 1. To pilot the adapted DIALOG quality of life scale and intervention (aDIALOG+) and obtain feedback on what aspects of the intervention (including the aDIALOG scale, supporting app, training and manual) worked well or did not work well and suggestions for improvement. 2. To test the psychometric properties of the aDIALOG scale to establish whether the aDIALOG scale is a useful quality of life measure in people with learning disability, and to compare it with the original DIALOG scale in people with mental health issues. 3. To conduct a feasibility study of aDIALOG+ delivered by clinicians from community learning disability services to assess recruitment and retention of service users and clinicians. 4. To conduct a feasibility study of aDIALOG+ delivered by care workers from care homes (supported living or residential care) for people with learning disability to assess recruitment and retention of care homes, care workers and service users. _____ Previous study objectives: 1. To pilot the adapted DIALOG quality of life scale and intervention (aDIALOG+) and obtain feedback on what aspects of the intervention (including the aDIALOG scale, supporting app, training and manual) worked well or did not work well and suggestions for improvement. 2. To test the psychometric properties of the aDIALOG scale to establish whether the aDIALOG scale is a useful quality of life measure in people with learning disability. 3. To conduct a feasibility study of aDIALOG+ delivered by clinicians from community learning disability services to assess recruitment and retention of service users and clinicians. 4. To conduct a feasibility study of aDIALOG+ delivered by care workers from care homes (supported living or residential care) for people with learning disability to assess recruitment and retention of care homes, care workers and service users. Background and study aims This research is part of the ICONIC programme, which aims to improve quality of life and behaviour that challenges in people with mild to moderate learning disability through person-centred solution focused communication. DIALOG+ is an evidence based, face-to-face intervention delivered by health professionals using a tablet, which structures routine care sessions to ensure that care planning is personalised, holistic and co-produced. DIALOG+ involves collaboratively completing a quality-of-life scale and then using those ratings to have a solution focused discussion in order to set actions and improve service user satisfaction. Studies have found that it can enhance the communication between service users and those who support them, and can improve quality of life in people with mental health problems, but it has not been used in people with learning disabilities. We want to make DIALOG+ accessible and suitable for people with learning disability and to use it to help individuals think about things in their life they want to improve (e.g. leisure activities, accommodation) by using resources available to them or their carers. Our aim is to test if it improves quality of life and behaviour. Who can participate? Piloting Study: Service users will be eligible to take part if they are aged 18 or over, have mild or moderate learning disability based on service records/clinical notes, have a current history of behaviour that challenges (at least one incident of self-injurious behaviour, physical or verbal aggression, anger / frustration outbursts, or damage to property in the last 3 months), are living in any setting including the family home and supported living/ residential home, and can provide informed verbal or written consent. Psychometric Testing Study: Service users will be eligible to take part if they are aged 18 or over, have mild or moderate learning disability based on service records / clinical notes, are known to community ID services from participating NHS trusts or to voluntary groups for people with ID, and can provide informed verbal or written consent. Comparison Testing Study: Service users will be eligible to take part if they are aged between 18 and 65 years, are under the care of a community psychiatric team or currently an inpatient in a psychiatric hospital in East London NHS Foundation Trust, have a primary diagnosis of a mental health issue, and can provide informed verbal or written consent. Clinical Services Feasibility Study: Service users will be eligible to take part if they are aged 18 or over, have mild or moderate learning disability based on service records / clinical notes, have a current history of behaviour that challenges (at least one incident of self-injurious behaviour, physical or verbal aggression, anger / frustration outbursts, or damage to property in the last 3 months), are living in any setting including the family home and supported living/ residential home, and can provide informed verbal or written consent. Care Homes Feasibility Study: Service users will be eligible to take part if they are aged 18 or over, have mild or moderate learning disability based on service records / clinical notes, have a current history of behaviour that challenges (at least one incident of self-injurious behaviour, physical or verbal aggression, anger / frustration outbursts, or damage to property in the last 3 months), are residing in supported living or residential care, and can provide informed verbal or written consent. What does the study involve? Comparison Testing Study: A resident trainee, clinical studies officer or a member of the research team will arrange a face-to-face or remote (via Teams or Zoom) meeting with at least 200 service users with any mental health diagnosis (without learning disability) to complete the aDIALOG scale, along with the original DIALOG scale, and some demographic questions (e.g. gender, age, ethnicity, primary mental health diagnosis, how they receive their care and the number of years of treatment). Alternatively, service users can be sent the consent form and questionnaires to complete via email or post. Clinical Services Feasibility Study: In this study, we will be assessing whether it is feasible for clinicians to deliver an adapted version of aDIALOG+ to service users with mild or moderate learning disability who have behaviours that challenge (such as physical or verbal aggression towards others or property, anger / frustration outbursts, and self-injurious behaviour). Our aim is to establish whether it is possible to recruit 8-12 clinicians, 30 service users and 30 participant carers (if applicable) into the study. We will also examine the number of sessions of aDIALOG+ that are delivered over 6 months, the quality of the sessions, and the experiences and views of clinicians, service users and participant carers about the intervention, what worked well and what needs to be improved. We will also examine if there are any potential benefits of the intervention by looking at changes in outcome measures such as behaviour, community participation, quality of life and service use. Care Homes Feasibility Study: In this study, we will be assessing whether it is feasible for care workers to deliver an adapted version of DIALOG+ (aDIALOG+) to service users with mild or moderate learning disability who have behaviours that challenge (such as physical or verbal aggression towards others or property, anger / frustration outbursts, and self-injurious behaviour). What are the possible benefits and risks of participating? For the piloting study, service users and care workers will receive a £20 shopping voucher for participating in the interview/focus group following the 6-week intervention period to thank them for their time, and service users will also receive a £20 voucher after taking part in the psychometric testing study. For the psychometric comparison study service users will receive a £10 voucher for taking part. For the clinical services and care homes feasibility studies, service users, participant carers and care workers will receive a £20 shopping voucher for completing qualitative interviews, and service users will receive £20 after completing the baseline assessment and £20 prior to the 6-month follow-up assessments to thank them for their time. Participant carers and care workers will also receive £20 following completion of the baseline assessment and prior to the 6-month follow-up assessments. By sharing experience and views on the aDIALOG+ software, it will help us to improve it and adapt it for clinicians and care workers who use aDIALOG+ in the future. We know that using the original DIALOG+ intervention improved the quality of life of people with psychosis when they used it face to face and we are hoping we can replicate those benefits in service users with learning disability. Where is the study run from? The research is coordinated at the Unit for Adult Mental Health and Wellbeing, Queen Mary University of London. Dr Afia Ali has overall responsibility for the study and it is sponsored by East London NHS Foundation Trust. When is the study starting and how long is it expected to run for? The piloting study started in January 2026 and is expected to run for 3 months. The psychometric testing study started in July 2025 and is expected to run for 17 months. The comparison testing study started in May 2026 and is expected to run for 12 months. The clinical services and care homes feasibility studies started in May 2026 and are expected to run for 13 months. Who is funding the study? National Institute for Health and Care Research (NIHR) (UK). Who is the main contact? Dr Afia Ali (Chief Investigator) afia.ali@qmul.ac.uk / afia.ali6@nhs.net Miss Laura Miller (Programme Manager) l.miller@qmul.ac.uk / laura.miller58@nhs.net Current primary outcomes as of 16/04/2026: WP1a Piloting: 1. Acceptability of / feedback on the intervention is measured using semi-structured interviews / focus groups after 2-4 weeks. 2. Intervention implementation processes from the perspective of clinicians and care workers are assessed using the NoMAD questionnaire after 2-4 weeks. WP1b Psychometric Testing: 1. Construct and concurrent validity of the aDIALOG scale are measured using the Mini-MANS LD and the WHOQOL Disabilities module and Clinical Outcome in Routine Evaluation- Learning Disability (CORE-LD), 14 item version (measure of psychological distress) at baseline. 2. Test re-test reliability of the aDIALOG scale is measured by completing the scale at baseline and again 24 hours to 1 week later. WP1b Comparison Testing: 1. Reliability of the aDIALOG scale through measuring the internal consistency and comparing to the original DIALOG scale. 2. Validity of the aDIALOG scale measured using evenness of distribution of scores compared to the original DIALOG scale and confirmatory factor analysis. _____ Previous primary outcomes: WP1a Piloting: 1. Acceptability of / feedback on the intervention is measured using semi-structured interviews / focus groups with at 6 weeks. 2. Intervention implementation processes from the perspective of clinicians and care workers are assessed using the NoMAD questionnaire at 6 weeks. WP1b Psychometric Testing: 1. Construct and concurrent validity of the aDIALOG scale are measured using the Mini-MANS LD and the WHOQOL Disabilities module and Clinical Outcome in Routine Evaluation- Learning Disability (CORE-LD), 14 item version (measure of psychological distress) at baseline. 2. Test re-test reliability of the aDIALOG scale is measured by completing the scale at baseline and again 24 hours to 1 week later. Feasibility studies: 1. Changes in behaviour in service users is measured using the Aberrant Behaviour Checklist (ABC) – Irritability subscale at baseline and 6 months Feasibility studies: 1. Quality of life in service users is measured using the 13- item WHOQOL Disabilities module (WHOQOL-DIS) at baseline and 6 months 2. Community and Leisure participation in service users is measured using the Guernsey Community Participation and Leisure Assessment – Revised (GCPLA-R) at baseline and 6 months 3. Changes in psychological distress in service users is measured using the Learning Disability – Clinical Outcomes in Routine Evaluation, 14 item version (LD-CORE-14) at baseline and 6 months 4. Changes in the presence of psychiatric disorders in service users is measured using the Moss Psychiatric Assessment Schedule - Check (Moss-PAS Check) at baseline and 6 months 5. Changes in behaviour and functioning in service users as a result of the intervention is measured using a modified version of the Clinical Global Impressions Scale – Improvement version (CGI-I) at 6 months 6. Paid and family carer distress in participant carers is measured using the Kessler Psychological Distress Scale - K6 at baseline and 6 months 7. Changes in health-related quality of life in service users is measured using the EuroQol Five Dimensions - Learning Disability modified version of the EQ-5D-3L at baseline and 6 months. A proxy version of the EQ-5D-5L will also be completed by participant carers at baseline and 6 months. 8. Health related quality of life in participant carers is measured using the EQ-5D-5L at baseline and 6 months. 9. Health and social care contacts and medication in service users is measured using a modified version of the Client Services Receipt Inventory (CSRI) at baseline and 6 months. 10. Treatment costs of delivering the intervention are measured using staff time, room bookings and other resource use in participating clinical services and care homes. 11. Intervention implementation processes from the perspective of clinicians and care workers are assessed using the NoMAD questionnaire at 6 months. 12. Recruitment is measured using screening logs of the number of clinicians, care workers and eligible service users who were approached agreed to take part throughout the study at 6 months. 13. Retention is measured using withdrawal forms completed to record clinicians, care workers and service users who drop out of the study and the reasons why, as well as the number of participants that complete the follow-up assessment at 6 months. 14. Intervention adherence is measured using session completion data from the aDIALOG+ app at 6 months. 15. Intervention fidelity is measured using audio/video recordings of sessions, action plans from the aDIALOG+ app and completed session fidelity checklists at 6 months. 16. Acceptability of the intervention is measured using semi-structured interviews / focus groups with at 6 months. Ethics approval required South West - Cornwall & Plymouth Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 25/SW/0055 10.1186/ISRCTN11440256 349711 CPMS: 68145, NIHR: 205440 349711 68145 205440 Interventional non-randomized Interventional Non randomised study Treatment 2027-06-01T00:00:00.000Z United Kingdom England East London NHS Foundation Trust

Robert Dolan House 9 Alie Street

London England E1 8DE RWK@2.16.840.1.113883.2.1.3.2.4.18.48 Cornwall Partnership NHS Foundation Trust

Carew House Beacon Technology Park Dunmere Road

Bodmin England PL31 2QN RJ8@2.16.840.1.113883.2.1.3.2.4.18.48 North London NHS Foundation Trust

Camden Learning Disability Service 5 Pancras Square

London England N1C 4AG Cambridgeshire and Peterborough NHS Foundation Trust

Elizabeth House Fulbourn Hospital Fulbourn

Cambridge England CB21 5EF RT1@2.16.840.1.113883.2.1.3.2.4.18.48 Derbyshire Healthcare NHS Foundation Trust

Trust Headquarters Kingsway Hospital Kingsway

Derby England DE22 3LZ RXM@2.16.840.1.113883.2.1.3.2.4.18.48 Hampshire and Isle of Wight Healthcare NHS Foundation Trust

Tatchbury Mount Hospital Calmore

Southampton England SO40 2RZ RW1@2.16.840.1.113883.2.1.3.2.4.18.48 Rotherham Doncaster and South Humber NHS Foundation Trust

Woodfield House Tickhill Road

Doncaster England DN4 8QN RXE@2.16.840.1.113883.2.1.3.2.4.18.48 Livewell Southwest

Local Care Centre 200 Mount Gould Road

Plymouth England PL4 7PY NR501@2.16.840.1.113883.2.1.3.2.4.18.48 South West Yorkshire Partnership Teaching NHS Foundation Trust

Trust Headquarters Fieldhead Hospital Ouchthorpe Lane

Wakefield England WF1 3SP RXG@2.16.840.1.113883.2.1.3.2.4.18.48 Bradford District Care NHS Foundation Trust

New Mill Victoria Road Saltaire

Shipley England BD18 3LD TAD@2.16.840.1.113883.2.1.3.2.4.18.48 Norfolk Community Health and Care NHS Trust

Research Office, Ground Floor, West Pottergate Medical Centre, Earlham Road

Norwich England NR2 4BX Dane View Care Home with Nursing

165 Glenfield Road

Leicester England LE3 6DP VNC2X@2.16.840.1.113883.2.1.3.2.4.18.48 Central and North West London NHS Foundation Trust

Northwick Park Hospital, Mental Health Unit, Watford Road

Harrow England HA1 3UJ Patient Current key inclusion criteria as of 01/09/2026: WP1a: Service Users Inclusion Criteria: 1. Aged 18 years or over 2. Mild or moderate ID based on service records / clinical notes 3. Current history of behaviour that challenges (at least one incident of self-injurious behaviour, physical or verbal aggression, anger / frustration outbursts, or damage to property in the last 3 months) 4. Living in any setting including the family home and supported living/residential home 5. Can provide informed verbal or written consent WP1b Psychometric Testing: Service Users Inclusion Criteria: 1. Aged 18 years or over 2. Mild or moderate ID based on service records / clinical notes 3. Are known to community ID services from participating NHS trusts or to voluntary groups for people with ID 4. Can provide informed verbal or written consent WP1b Comparison Testing: Service Users Inclusion Criteria: 1. Aged between 18 and 65 years 2. Under the care of a community psychiatric team or currently an inpatient in a psychiatric hospital in East London NHS Foundation Trust 3. Have a primary diagnosis of a mental health issue 4. Can provide informed verbal or written consent WP2: Service Users Inclusion Criteria: 1. Aged 18 years or over 2. Mild or moderate ID based on service records / clinical notes 3. Current history of behaviour that challenges (at least one incident of self-injurious behaviour, physical or verbal aggression, anger / frustration outbursts, or damage to property in the last 3 months) 4. Living in any setting including the family home and supported living/residential home 5. Can provide informed verbal or written consent WP3: Service Users Inclusion Criteria: 1. Aged 18 years or over 2. Mild or moderate ID based on service records / clinical notes 3. Current history of behaviour that challenges (at least one incident of self-injurious behaviour, physical or verbal aggression, anger / frustration outbursts, or damage to property in the last 3 months) 4. Residing in supported living or residential care 5. Can provide informed verbal or written consent WP1a Clinicians Inclusion Criteria: 1. Aged 18 or over 2. Currently working within a community ID service, intensive support team or in a local authority or social care organisation for people with ID 3. From any profession (e.g. psychology, nursing, speech and language therapy, psychiatry, social work), with a minimum of six months experience working with people with ID 4. Consent to participation WP2 Clinicians Inclusion Criteria: 1. Aged 18 or over 2. Currently working within a community ID service, intensive support team or in a local authority or social care organisation for people with ID 3. From any profession (e.g. psychology, nursing, speech and language therapy, psychiatry, social work), with a minimum of six months experience working with people with ID 4. Consent to participation WP3 Care Workers Inclusion Criteria: 1. Aged 18 or over 2. Have worked in the care home for at least three months 3. Provide at least one day of support per week to service users 4. Consent to participation _____ Previous inclusion criteria as of 16/04/2026: WP1a: Service Users Inclusion Criteria: 1. Aged 18 years or over 2. Mild or moderate ID based on service records / clinical notes 3. Current history of behaviour that challenges (at least one incident of self-injurious behaviour, physical or verbal aggression, temper tantrums / outbursts, or damage to property in the last 3 months) 4. Living in any setting including the family home and supported living/residential home 5. Can provide informed verbal or written consent WP1b Psychometric Testing: Service Users Inclusion Criteria: 1. Aged 18 years or over 2. Mild or moderate ID based on service records / clinical notes 3. Under community ID services from the East London Foundation Trust - Updated 04/11/2025: from participating NHS trusts 4. Can provide informed verbal or written consent WP1b Comparison Testing: Service Users Inclusion Criteria: 1. Aged between 18 and 65 years 2. Living in the community and treated as out-patients by community psychiatric teams from participating NHS trusts 3. Have a primary diagnosis of a mental health issue 4. Can provide informed verbal or written consent WP2: Service Users Inclusion Criteria: 1. Aged 18 years or over 2. Mild or moderate ID based on service records / clinical notes 3. Current history of behaviour that challenges (at least one incident of self-injurious behaviour, physical or verbal aggression, temper tantrums / outbursts, or damage to property in the last 3 months) 4. Living in any setting including the family home and supported living/residential home 5. Can provide informed verbal or written consent WP3: Service Users Inclusion Criteria: 1. Aged 18 years or over 2. Mild or moderate ID based on service records / clinical notes 3. Current history of behaviour that challenges (at least one incident of self-injurious behaviour, physical or verbal aggression, temper tantrums / outbursts, or damage to property in the last 3 months) 4. Residing in supported living or residential care 5. Can provide informed verbal or written consent _____ Previous inclusion criteria: WP1a 1. Service Users Inclusion Criteria: 1. Aged 18 or over 2. Mild or moderate ID based on service records / clinical notes 3. Current history of behaviour that challenges (at least one incident of self-injurious behaviour, physical aggression or damage to property in the last 3 months) 4. Living in any setting including the family home and supported living/residential home 5. Can provide informed verbal or written consent 2. Clinicians Inclusion Criteria: 1. Aged 18 or over 2. Currently working within a community ID service, intensive support team or in a local authority or social care organisation for people with ID 3. From any profession (e.g. psychology, nursing, speech and language therapy, psychiatry, social work), grade 4 and above with a minimum of six months experience working with people with ID 4. Consent to participation 3. Care Workers Inclusion Criteria: 1. Aged 18 or over 2. Have worked in the care home for at least three months 3. Provide at least one day of support per week to service users 4. Consent to participation WP1b 1. Service Users Inclusion Criteria: 1. Aged 18 or over 2. Mild or moderate ID based on service records / clinical notes 3. Under community ID services from the East London Foundation Trust - Updated 04/11/2025: from participating NHS trusts 4. Can provide informed verbal or written consent WP2 1. Service Users Inclusion Criteria: 1. Aged 18 or over 2. Mild or moderate ID based on service records / clinical notes 3. Current history of behaviour that challenges (at least one incident of self-injurious behaviour, physical aggression or damage to property in the last 3 months) 4. Living in any setting including the family home and supported living/residential home 5. Can provide informed verbal or written consent 2. Clinicians Inclusion Criteria: 1. Aged 18 or over 2. Currently working within a community ID service, intensive support team or in a local authority or social care organisation for people with ID 3. From any profession (e.g. psychology, nursing, speech and language therapy, psychiatry, social work), grade 4 and above with a minimum of six months experience working with people with ID 4. Consent to participation 5. Have not participated in other work packages 3. Participant Carers Inclusion Criteria: 1. Aged 18 or over 2. Are paid or unpaid (e.g. family carer); if a paid carer, need to have worked with the person for at least six months and should know the person well and support the person on a regular basis 3. Consent to participation WP3 1. Service Users Inclusion Criteria: 1. Aged 18 or over 2. Mild or moderate ID based on service records / clinical notes 3. Current history of behaviour that challenges (at least one incident of self-injurious behaviour, physical aggression or damage to property in the last 3 months) 4. Residing in supported living or residential care 5. Can provide informed verbal or written consent 2. Care Homes Inclusion Criteria: 1. Supported living or residential placements for service users with ID in the participating areas 2. Service manager has agreed for the care home to take part 3. Care Workers Inclusion Criteria: 1. Aged 18 or over 2. Have worked in the care home for at least three months 3. Provide at least one day of support per week to service users 4. Consent to participation 5. Have not participated in other work packages Mixed 18 Years 100 Years All 502 472 Current key exclusion criteria as of 01/09/2026: WP1a Clinicians Exclusion Criteria: 1. Under 18 years of age 2. Not currently working within a community ID service, intensive support team or in a local authority or social care organisation for people with ID 3. Less than 6 months experience working with people with ID 4. Do not consent to participation WP1b Psychometric Testing: Service Users Exclusion Criteria: 1. Under 18 years of age 2. Severe ID based on service records/clinical notes 3. Not known to community ID services from participating NHS trusts or to voluntary groups for people with ID 4. Unable to provide informed verbal or written consent WP1b Comparison Testing: 1. Under 18 years of age and over 66 years of age 2. Do not have a primary mental health diagnosis (e.g., substance misuse disorder) 3. Unable to provide informed verbal or written consent WP2 Clinicians Exclusion Criteria: 1. Under 18 years of age 2. Not currently working within a community ID service, intensive support team or in a local authority or social care organisation for people with ID 3. Less than 6 months experience working with people with ID 4. Do not consent to participation WP3 Care Workers Exclusion Criteria: 1. Under 18 years of age 2. Have worked in the care home for less than 3 months 3. Do not provide at least one day of support per week to service users 4. Do not consent to participation _____ Previous exclusion criteria as of 16/04/2026: WP1b Psychometric Testing: Service Users Exclusion Criteria: 1. Under 18 years of age 2. Severe ID based on service records/clinical notes 3. Not under community ID services from the East London Foundation Trust - Updated 04/11/2025: from participating NHS trusts 4. Unable to provide informed verbal or written consent WP1b Comparison Testing: 1. Under 18 years of age and over 66 years of age 2. Currently in an inpatient in a psychiatric hospital 3. Do not have a primary mental health diagnosis (e.g., substance misuse disorder) 4. Unable to provide informed verbal or written consent _____ Previous exclusion criteria: WP1a 1. Service Users Exclusion Criteria: 1. Under 18 years of age 2. Severe ID based on service records / clinical notes 3. Likely to move out of borough within the next 3 months or at imminent risk of hospital admission 4. Unable to provide informed verbal or written consent 2. Clinicians Exclusion Criteria: 1. Under 18 years of age 2. Not currently working within a community ID service, intensive support team or in a local authority or social care organisation for people with ID 3. Below grade 4 and less than 6 months experience working with people with ID 4. Do not consent to participation 3. Care Workers Exclusion Criteria: 1. Under 18 years of age 2. Have worked in the care home for less than 3 months 3. Do not provide at least one day of support per week to service users 4. Do not consent to participation WP1b 1. Service Users Exclusion Criteria: 1. Under 18 years of age 2. Severe ID based on service records / clinical notes 3. Not under community ID services from the East London Foundation Trust - Updated 04/11/2025: from participating NHS trusts 4. Unable to provide informed verbal or written consent WP2 1. Service Users Exclusion Criteria: 1. Under 18 years of age 2. Severe ID based on service records / clinical notes 3. Already participating in WP3 or involved in another clinical trial 4. Likely to move out of borough within the next 6 months or at imminent risk of hospital admission 5. Unable to provide informed verbal or written consent 2. Clinicians Exclusion Criteria: 1. Under 18 years of age 2. Not currently working within a community ID service, intensive support team or in a local authority or social care organisation for people with ID 3. Below grade 4 and less than 6 months experience working with people with ID 4. Do not consent to participation 5. Have participated in other work packages 3. Participant Carers Exclusion Criteria: 1. Under 18 years of age 2. If a paid carer and have worked with the person for less than six months and/or do not know the person well and/or support the person on a regular basis 3. Do not consent to participation WP3 1. Service Users Exclusion Criteria: 1. Under 18 years of age 2. Severe ID based on service records / clinical notes 3. Already participating in WP2 or involved in another clinical trial 4. Likely to move out of the care home within the next six months or are at imminent risk of hospital admission 5. Unable to provide informed verbal or written consent 2. Care Homes Exclusion Criteria: 1. Not supported living or residential placements for service users with ID and/or not in the participating areas 2. Service manager does not agree for the care home to take part 3. Care Workers Exclusion Criteria: 1. Under 18 years of age 2. Have worked in the care home for less than 3 months 3. Do not provide at least one day of support per week to service users 4. Do not consent to participation 5. Have participated in other work packages 2025-08-07T00:00:00.000Z 2026-11-30T00:00:00.000Z Mild to moderate intellectual disability Mental and Behavioural Disorders Current interventions as of 16/04/2026: An adapted version of DIALOG+ (a brief, low-cost solution-focused intervention that improves the therapeutic effectiveness of routine clinical meetings between patients and clinicians) for individuals with learning disability will be piloted for 2-4 weeks, the adapted scale tested for psychometric properties at 2 timepoints (within 24 hours-1 week) and comparison tested with the original DIALOG scale, and delivered in clinical and care home feasibility studies for 6 months. _____ Previous interventions: An adapted version of DIALOG+ (a brief, low-cost solution-focused intervention that improves the therapeutic effectiveness of routine clinical meetings between patients and clinicians) for individuals with learning disability will be piloted for 4-6 weeks, tested for psychometric properties at 2 timepoints (within 24 hours-1 week), and delivered in clinical and care home feasibility studies for 6 months. Behavioural Data sharing statement to be made available at a later date Protocol

086586ae-3919-40ae-b565-48eaf7fd7840 5bfd6e0a-f6be-42db-af32-79e65800296e 174d80bc-3550-48b2-8785-521553bef35e bd3c8ad4-709e-4148-8736-f221f3b481aa No Protocol file 47564 ICONIC_ WP1 2 and 3 Protocol v1.0 30.05.2025.pdf 6003dfb0-844c-4af6-a553-045bcb24459d true application/pdf 651827 4568e0d65fbd906a796445e923b512a4 Protocol file ISRCTN11440256_PROTOCOL_V3.0_14Oct2025.pdf 7969177c-3c73-44d2-8686-e72b1ec0a78e true application/pdf 746942 3152c1ad486bbc76c7d41a04e951bc25 Protocol file ISRCTN11440256_WP1 2 and 3_PROTOCOL_V5.0_02Apr2026.pdf 4f2b9443-e9af-4f49-9086-51d2b8b13c3d true application/pdf 784320 096cbe3095124bcd27c3728b1f59aa94 Protocol file ISRCTN11440256 ICONIC_WP1 2 and 3 protocol v7.0 07.08.2026.pdf f4e82e02-6c9d-4771-b8bb-e7ce9f38ac7b true application/pdf 679559 508e1db2b92f3a1d7372b6369bbd9c49 Protocol file ISRCTN11440256_PROTOCOL_V8.0_16Sep2026.pdf e806e700-96ca-4eec-b82d-e3047e0cc8a3 true application/pdf 785067 5b5323785ca6ea45878d669d18fae9a0 Laura Miller https://orcid.org/0000-0001-8802-3554 Public Scientific

Unit for Adult Mental Health and Wellbeing Centre for Psychiatry and Mental Health (CPMH) Wolfson Institute of Population Health Queen Mary University of London Yvonne Carter Building, 58 Turner Street

London United Kingdom E1 2AB +44 7352 980401 l.miller@qmul.ac.uk Public Afia Ali https://orcid.org/0000-0002-0104-9370 Principal investigator

Unit for Adult Mental Health and Wellbeing Centre for Psychiatry and Mental Health (CPMH) Wolfson Institute of Population Health Queen Mary University of London Yvonne Carter Building, 58 Turner Street

London United Kingdom E1 2AB +44 7836 584017 afia.ali@qmul.ac.uk Public North East London NHS Foundation Trust Hospital/treatment centre https://ror.org/023e5m798 Non-commercial NIHR Central Commissioning Facility (CCF) 16864220 true The clinical and cost effectiveness of quetiapine for people with borderline personality disorder: A pragmatic, double-blind, placebo-controlled, randomised trial QUEST Primary objective: To test whether adding quetiapine to treatment as usual, in comparison to placebo and treatment as usual, improves the mental health of people with borderline personality disorder Secondary objectives: 1. To examine whether the addition of quetiapine improves social and occupational functioning, quality of life and reduces the incidence of suicidal behaviour in comparison to placebo and TAU 2. To compare the levels of adherence and the incidence of side-effects, including change in weight, amongst those prescribed quetiapine and those prescribed placebo. Economic Objective: To examine the cost, cost-effectiveness and cost-utility of adding quetiapine to TAU for adults with BPD in comparison to placebo and TAU. Background and study aims Borderline personality disorder (BPD) describes a collection of problems including negative feelings about self, fears of being let down, an acute sense of abandonment and rapid, distressing changes in mood. People with BPD find it difficult to maintain relationships, have high levels of mental health problems like depression and drug misuse, and high rates of self-harm and suicide. There are currently no drugs licensed for the treatment of BPD and clinicians are often unsure how best to help people with BPD. Quetiapine is the most widely prescribed antipsychotic medication for BPD in the UK despite limited evidence that it works. There is only one published trial of quetiapine for BPD treatment which found that quetiapine was more effective than a ‘dummy tablet’ (placebo) in improving symptoms of BPD. However, the trial was short with a small number of participants so a longer and larger trial of quetiapine is required to see if these promising results can be repeated. It would be a very important finding and provide evidence for use of quetiapine to treat BPD. If the result does not provide evidence of the benefits of quetiapine, then clinicians would review whether treatment with quetiapine should be continued. Who can participate? We will recruit people in contact with mental health services in the NHS in regions in England that are under-represented in mental health research. What does the study involve? In this trial, people with BPD will be allocated, by chance, to receive either placebo or quetiapine for 12-months alongside their usual treatment. We will also examine any changes in cost that result from prescribing this drug and whether any changes in costs are worthwhile in terms of improvements in outcomes. What are the possible benefits and risks of participating? Not provided at time of registration Where is the study run from? University of Liverpool (UK) When is the study starting and how long is it expected to run for? March 2025 to October 2028 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK) Who is the main contact? questtrial@liverpool.ac.uk 1. Symptoms of BPD at 12 months using the total score on the ZAN BPD from baseline to 12 months 1. Standardised Assessment of Personality Abbreviated Scale at 12 months using SAPAS at baseline and 12 months 2. Total score on the ZAN-BPD over 12 months measured at baseline, 3, 6, 9 and 12 months 3. Total score on the 21 item Beck Depression Inventory at baseline, 3, 6 and 12 months. 4. Mood Instability using the Affective Lability Scale – Short Form at baseline, 3, 6 and 12 months 5. Incidence and severity of suicidal behaviour and self-harm using the Deliberate Self-Harm Inventory at baseline, 6 and 12 months 6. Self-Reported Version of ZAN BPD at baseline, 3, 6, 9 and 12 months 7. Social functioning measured via the Work and Social Adjustment Scale (WSAS) at baseline, 6 and 12 months 8. Health-related quality of life measured using EuroQoL-5D-5L at baseline, 6 and 12 months 9. Side effects using the Antipsychotic Non-Neurological Side Effects Scale (ANNSERS) at baseline, 3, 6, 9 and 12 months 10. Medication adherence using the Brief Adherence Rating Scale (BARS) at 3, 6, 9 and 12 months 11. Use of alcohol and other drugs via ASSIST-Lite at baseline, 6 and 12 months 12. Body Weight in Kg at baseline and 12 months 13. Serious adverse events up to 12 months 14. Use of rescue medication at 6 and 12 months 15. Sleep Disturbance using PROMIS Sleep Disturbance -Short Form at baseline, 3, 6, 9 and 12 months 16. Use of health and social services using the ADSUS at baseline, 6 and 12 months Ethics approval required West Midlands - Edgbaston Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 25/WM/0052 10.1186/ISRCTN16864220 1010899 CPMS: 69443, UoL00181894 1010899 69443 UoL00181894 Interventional double blind randomized parallel group placebo controlled trial Interventional Randomised parallel trial Efficacy Safety 2028-10-31T00:00:00.000Z United Kingdom England Mersey Care NHS Foundation Trust

V7 Building Kings Business Park Kings Drive

Prescot England L34 1PJ RW4@2.16.840.1.113883.2.1.3.2.4.18.48 Cambridgeshire and Peterborough NHS Foundation Trust

Elizabeth House, Fulbourn Hospital Fulbourn

Cambridge England CB21 5EF RT1@2.16.840.1.113883.2.1.3.2.4.18.48 Birmingham and Solihull Mental Health NHS Foundation Trust

The Uffculme Centre 52 Queensbridge Road Moseley

Birmingham England B13 8QY RXT@2.16.840.1.113883.2.1.3.2.4.18.48 Fulbourn Hospital

Cambridge Road Fulbourn

Cambridge England CB21 5EF RT113@2.16.840.1.113883.2.1.3.2.4.18.48 Vale House Mental Health Resource Centre

High St

Winsford England CW7 2AS Rowan View

Maghull Health Park

Liverpool England L31 1HW RW40C@2.16.840.1.113883.2.1.3.2.4.18.48 Phoenix Service

The Barberry 25 Vincent Drive

Birmingham England B15 2FG W6D8R@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Current key inclusion criteria as of 03/10/2025: 1. Aged ≥18 years 2. Able to provide written and informed consent and agreement to comply with the requirements of the trial 3. In contact with secondary care mental health services 4. Contraception is to be used for the duration of the trial 5. Meet diagnostic criteria for borderline personality disorder using the Structured Clinical Interview for DSM-V Personality Disorders (SCID-5) 6. A ZAN-BPD total score of ≥9 at the time of randomisation 7. Ability to speak and read English Previous key inclusion criteria: 1. Aged ≥18 years 2. Able to provide written and informed consent and agreement to comply with the requirements of the trial. 3. In contact with secondary care mental health services. 4. Meet diagnostic criteria for borderline personality disorder using the Structured Clinical Interview for DSM-V Personality Disorders (SCID 5). 5. A ZAN-BPD total score of ≥9 at the time of randomisation. 6. Ability to speak and read English 7. Able to swallow IMP whole Mixed 18 Years 100 Years All 270 0 Current exclusion criteria as of 21/01/2026: 1. Prescribed an antipsychotic medication (oral or intramuscular) within two weeks of baseline assessments 2. Have a current clinical diagnosis of schizophrenia, bipolar I or bipolar II disorder 3. Pregnant, trying to conceive and/or breastfeeding 4. Women of childbearing potential who are unable or unwilling to use a highly effective method of contraception for the duration of the trial 5. Known hypersensitivity to quetiapine or to any of the excipients of the XL formulation 6. Concomitant administration of erythromycin, clarithromycin or nefazodone within 14 days 7. Concomitant administration of cytochrome P450 3A4 inhibitors, such as anti-fungal medicines: (itraconazole, ketoconazole, voriconazole, posaconazole); medicines used to treat cancer: idelalisib, tucatinib, ceritinib; medicines used to treat HIV: atazanavir, cobicistat, darunavir, fosamprenavir, lopinavir, ritonavir, saquinavir, tipranavir 8. History of QTc prolongation, including congenital long QT syndrome, severe neutropenia, agranulocytosis, history of cardiovascular disease (angina, stroke, myocardial infarction, arrythmia, congestive cardiac failure, heart hypertrophy) 9. Unable/refusal to undertake blood tests 10. Clinically significant findings that, in the opinion of the investigator, are contraindicated for inclusion in the study 11. Unable to swallow IMP whole 12. Individuals who are being investigated for or have a confirmed diagnosis of dementia (any kind) Previous exclusion criteria as of 03/10/2025: 1. Prescribed an antipsychotic medication within 2 weeks of baseline assessments 2. Have a current clinical diagnosis of schizophrenia, bipolar I or bipolar II disorder 3. Pregnant, trying to conceive and/or breastfeeding 4. Women of childbearing potential who are unable or unwilling to use a highly effective method of contraception for the duration of the trial 5. Known hypersensitivity to quetiapine or to any of the excipients of the XL formulation 6. Concomitant administration of erythromycin, clarithromycin or nefazodone within 14 days 7. Concomitant administration of cytochrome P450 3A4 inhibitors, such as anti-fungal medicines: (itraconazole, ketoconazole, voriconazole, posaconazole); medicines used to treat cancer: idelalisib, tucatinib, ceritinib; medicines used to treat HIV: atazanavir, cobicistat, darunavir, fosamprenavir, lopinavir, ritonavir, saquinavir, tipranavir 8. History of QTc prolongation, severe neutropenia, agranulocytosis, history of cardiovascular disease (angina, stroke, myocardial infarction, arrhythmia, congestive cardiac failure) 9. Unable/refusal to undertake blood tests 10. Clinically significant findings that, in the opinion of the investigator, are contraindicated for inclusion in the study 11. Unable to swallow IMP whole Previous key exclusion criteria: 1. Prescribed an antipsychotic medication within 2 weeks of baseline assessments. 2. Have a current clinical diagnosis of schizophrenia, bipolar I or bipolar II disorder. 3. Pregnant, trying to conceive and/or breastfeeding. 4. Women of childbearing potential who are unable or unwilling to use a highly effective method of contraception for the duration of the trial. 5. Known hypersensitivity to quetiapine or to any of the excipients of the XL formulation. 6. Concomitant administration of erythromycin, clarithromycin or nefazodone within 14 days. 7. Concomitant administration of cytochrome P450 3A4 inhibitors, such as anti-fungal medicines: (itraconozole, ketoconazole, voriconazole, posaconazole); medicines used to treat cancer: idelalisib, tucatinib, ceritinib; medicines used to treat HIV; atazanavir, cobicistat, darunavir, fosamprenavir, lopinavir, ritonavir, saquinavir, tipanavir. 8. History of QTc prolongation, severe neutropenia, agranulocytosis, history of cardiovascular disease (angina, stroke, myocardial infarction, arrhythmia, congestive cardiac failure) 2026-02-09T00:00:00.000Z 2027-07-31T00:00:00.000Z Borderline personality disorder Mental and Behavioural Disorders Participants will be randomised (ratio 1:1) via a secure, 24-hour, web-based randomisation system controlled centrally by the LCTC to receive either quetiapine or matched placebo. Route of administration: oral IMP: Quetiapine prolonged release tablets (overencapsulated) in 50mg and 150mg. Dose: 150mg daily. Participants will be up titrated to this regime as follows: Week 1 – 50mg daily, Week 2- 100mg daily, Week 3 and onwards: 150mg daily Higher or lower doses will be permitted according to clinical response and tolerability (minimum dose of 50mg daily and maximum dose of 750mg daily) Placebo: Overencapsulated capsules filled with lactose to match IMP, in 50mg and 150mg. Dose: Same as IMP Trial treatment duration is 12 months Drug Phase III Quetiapine fumarate Data sharing statement to be made available at a later date 59955ddb-33bd-47af-9650-461bc925bc3c 62df05ab-c214-4030-a36a-0c9018b40f4b 1a758796-ce95-460f-9ebc-573fdc47c4c3 f8e2f4f3-08ca-48aa-8362-8a1ed21aabb0 No Nadia Ismail Public Scientific

Liverpool Clinical Trials Centre, Block C, Waterhouse Building, 1-5 Brownlow Street

Liverpool United Kingdom L69 3GL - questtrial@liverpool.ac.uk Public Inti Qurashi Principal investigator

Parkbourn

Liverpool United Kingdom L31 1HW +44 151 472 4045 inti.qurashi@merseycare.nhs.uk Public University of Liverpool University/education https://ror.org/04xs57h96 Non-commercial Health Technology Assessment Programme http://dx.doi.org/10.13039/501100000664 86317609 true MELODIC: co-developing a Music therapy intervention Embedded in the Life Of Dementia Inpatient mental health Care to help manage distress MELODIC This is a complex intervention development study with an embedded feasibility study. The aims are: Aim 1: To co-develop a music therapy model (MELODIC) for mental health dementia wards. This will include: 1. A manual outlining music therapy intervention delivery 2. A handbook and resources for ward managers, staff, and relatives Aim 2: To pilot the MELODIC intervention. This will: 1. Enable refinement of the intervention 2. Determine acceptability with patients, relatives, and staff 3. Assess the feasibility of delivery, including facilitators and barriers to implementation 4. Assess adherence to the intervention 5. Establish cost parameters of delivery 6. Test potential outcome measures to inform the design of a future controlled trial Background and study aims Distress is common for people with dementia on hospital mental health wards, but music might help. There are lots of reasons why people get distressed. Sometimes it is a result of symptoms like hallucinations, and sometimes it is because the care they receive does not meet their needs. If a person with dementia is so distressed that they behave in a way that puts themselves or others at risk, they may be admitted to a hospital mental health ward. The aim of the hospital stay is to understand and treat their distress, so that they may be discharged with an appropriate support plan. This can take a long time. There is little research looking at these hospital wards, which can be very different to general hospital wards or care homes. It is hard to care for someone who is very frightened and distressed, and both staff and patients can get hurt (staff experience more physical assaults than prison officers). Calming medications (antipsychotics) are often given to a person with dementia on these wards when distressed. This is a worry because research suggests that these increase the risks of falls and death. Music therapy has helped lower distress for people with dementia living in care homes and supported staff to understand why someone might be distressed. But we do not know enough about how music therapy can help people with dementia in mental health wards. Our own research on mental health wards found that on the days the therapy took place, there were fewer assaults and staff could see a positive impact on the ward. But not all mental health wards have music therapy. People with dementia and their family members that we spoke to also found music helpful and supported the idea of having this therapy on wards. In this 18-month project, we will create a music therapy manual for mental health wards together with people with dementia, their families and staff with the aim of reducing distress and assaults. Who can participate? People who have stayed, visited family or worked on mental health dementia in the NHS in the last 5 years can take part in an interview or focus group (Stage 1). Two mental health wards in the NHS will be invited to take part and test the music therapy manual for four weeks (Stage 3). Everybody staying, visiting or working on the wards will be able to take part. What does the study involve? The study has three stages: Stage 1. Talking to people with dementia, relatives and staff with experience of mental health wards. This will help us understand how distress and assaults are currently managed and the support people need. Stage 2. Co-creating a music therapy manual with people with dementia, relatives and staff based on findings from Stage 1. Stage 3: Testing the music therapy manual over four weeks on two mental health wards, one that already has music therapy and one that has never offered this before. Once the manual is finished, we will share it with the public and look to test it on more mental health wards for people with dementia. What are the possible benefits and risks of participating? If you take part in this study you can help shape the way that music and music therapy are used on NHS mental health dementia wards. If you are staying, visiting or working on a ward where the intervention is tested you will have access to more music therapy delivered by a qualified healthcare professional. They will help work out how music can best be used to reduce distress and improve care experience for everyone on the ward. Where is the study run from? The study is led by Anglia Ruskin University and the Cambridgeshire and Peterborough NHS Foundation Trust (UK). Other supporters include Dementia UK, the University of Cambridge and the University of Hull. When is the study starting and how long is it expected to run for? June 2023 to February 2025 Who is funding the study? National Institute for Health and Care Research, Research for Patient Benefit Scheme (UK) Who is the main contact? Naomi Thompson, naomi.thompson@aru.ac.uk The feasibility of intervention delivery and the research methods will be measured by: 1. Intervention adherence measured through interventionist diaries completed during the intervention period, collected post-intervention 2. Recruitment rate recorded as the number of eligible participants who consent to participate in the study by 4 months 3. Data completeness for quantitative outcome measures across all four timepoints (4 weeks before, baseline, endpoint, 4 weeks follow-up) 4. Training needs and requirements assessed through interviews conducted post-intervention 5. Costs of intervention delivery calculated post-intervention 1. Initial impact of MELODIC for patients, staff, families and the ward measured by: 1.1. Realist interviews post-intervention 1.2. Patient standardised questionnaires (4 weeks before, baseline, endpoint, 4 weeks follow-up): 1.2.1. Distress measured by the Neuropsychiatric Inventory and the Cohen-Mansfield Agitation Inventory 1.2.2. Quality of life measured by Quality of Life in Alzheimer’s Disease 1.3. Staff standardised questionnaires (4 weeks before, baseline, endpoint, 4 weeks follow-up): 1.3.1. Job satisfaction measured by Job Satisfaction Index 1.3.2. Burnout measured by the Maslach Burnout Inventory 1.3.3. Attitudes of hope and personhood in dementia measured by the Approaches to Dementia Questionnaire 1.4. Family standardised questionnaires (4 weeks before, baseline, endpoint, 4 weeks follow-up): 1.4.1. Attitudes of hope and personhood in dementia measured by Approaches to Dementia Questionnaire 1.4.2. Mental health measured by the General Health Questionnaire 1.5. Ward level outcomes (4 weeks before, 4 weeks during, 4 weeks after intervention): psychotropic medication use; physical assaults, seclusion, mortality, restraint, staff absence, number of bank/agency staff, patient length of stay, discharge destination 2. Refinement of the MELODIC Music therapy intervention protocol Ethics approval required Yorkshire & The Humber - Bradford Leeds Research Ethics Committee

NHSBT Newcastle Blood Donor Centre

Newcastle upon Tyne United Kingdom NE2 4NQ 23/YH/0155 Faculty of Arts, Humanity and Social Sciences, Anglia Ruskin University

Anglia Ruskin University

Cambridge United Kingdom CB1 1PT ETH2223-8044 10.1186/ISRCTN86317609 323503 CPMS: 54739 323503 54739 Complex intervention development study including qualitative exploration, co-design of intervention protocol, and a non-randomized feasibility study Interventional Non randomised study Prevention Quality of life Treatment 2025-02-01T00:00:00.000Z United Kingdom England Cambridgeshire and Peterborough NHS Foundation Trust

Elizabeth House, Fulbourn Hospital Fulbourn

Cambridge United Kingdom CB21 5EF Humber Teaching NHS Foundation Trust

Trust Hq, Block A, Willerby Hill Beverley Road Willerby

Hull United Kingdom HU10 6FE RV9@2.16.840.1.113883.2.1.3.2.4.18.48 Avon and Wiltshire Mental Health Partnership NHS Trust

Bath NHS House Newbridge Hill

Bath United Kingdom BA1 3QE RVN@2.16.840.1.113883.2.1.3.2.4.18.48 Black Country Healthcare NHS Foundation Trust Hq

Delta Point Greets Green Road

West Bromwich United Kingdom B70 9PL TAJHQ@2.16.840.1.113883.2.1.3.2.4.18.48 Herefordshire and Worcestershire Health and Care NHS Trust

Unit 2 Kings Court Charles Hastings Way

Worcester United Kingdom WR5 1JR R1A@2.16.840.1.113883.2.1.3.2.4.18.48 Northumbria Healthcare NHS Foundation Trust (headquarters)

Rake Lane

North Shields United Kingdom NE29 8NH RTFHQ@2.16.840.1.113883.2.1.3.2.4.18.48 South West Yorkshire Partnership NHS Foundation Trust

Trust Headquarters Fieldhead Hospital Ouchthorpe Lane

Wakefield United Kingdom WF1 3SP RXG@2.16.840.1.113883.2.1.3.2.4.18.48 Woodlands Care Centre

Hawkins Road

Cambridge United Kingdom CB4 2RD VLVV8@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Health professional Carer Inclusion criteria for the qualitative study are: 1. Direct or indirect (through family and close friends) experience of inpatient mental health dementia wards in the last five years to capture current experiences 2. The ward was part of the NHS, with private care excluded 3. The ward came under NHS mental health provision, with wards situated within general health hospitals excluded 4. The ward was for people with dementia (sometimes called organic) only, with wards caring for people with other mental health illnesses and dementia together excluded 5. The participant must be able to speak English 6. No geographical restrictions within the UK Inclusion criteria for the feasibility study are: The mental health dementia ward will be purposively sampled. It must meet the above criteria for dementia wards. All patients, staff and families on the ward are eligible to participate. Mixed 18 Years 150 Years All 102 138 Exclusion criteria related to the setting the participant had experience of: 1. Mental health ward not in the NHS 2. Dementia ward within an acute NHS Trust 3. Dementia ward in community nursing or residential care home 2023-10-01T00:00:00.000Z 2024-12-01T00:00:00.000Z Management of distress for people with dementia on NHS mental health wards Mental and Behavioural Disorders A co-designed, standardised music therapy protocol (MELODIC) will be developed in the first 8 months of the project. This will be tested and refined through a feasibility study on two wards with differing experience of music therapy. Qualitative and quantitative data will be collected to test the feasibility of the research methods. Behavioural The datasets generated and/or analysed during the current study are not publicly available due to their confidential nature, but are available from the corresponding author on reasonable request (cimtr@aru.ac.uk). The type of data that will be shared: anonymised data. Individual demographic information will not be shared to protect anonymity due to the small dataset. Information on type of participant (staff/patient/family member) will be provided. Dates of availability: until February 2035. Whether consent from participants was required and obtained: participant consent for sharing of anonymous data for secondary analysis required and obtained. Comments on data anonymization: ID numbers will be assigned to all participants. Any ethical or legal restrictions: ethical approval has been obtained from the Health Research Authority and Anglia Ruskin University. Available on request Not expected to be made available 2025 Results article in https://doi.org/10.1002/gps.70091 (added 17/07/2025) 2025 Results article in https://doi.org/10.3389/fpsyt.2025.1618324 (added 17/07/2025) 2024 Protocol article in https://doi.org/10.1080/08098131.2024.2435869 (added 03/04/2025) Results

Study website Migrated from study website field

61c3a35d-758c-4a5c-b9e3-a12bffc93cc3 f6353f03-8b22-434c-ba9f-001dd2caa639 c62229dc-bed8-401b-9221-4bca00ecc504 bae24f17-87a0-4e13-8916-6035201859b2 79ac1c70-e50f-470d-a20e-415655ef2343 Yes Ming-Hung Hsu Scientific Principal investigator

Cambridge Institute for Music Therapy Research Anglia Ruskin University

Cambridge United Kingdom CB1 1PT +44 (0)1223 695401 ming-hung.hsu@aru.ac.uk Public Naomi Thompson Public Scientific

Cambridge Institute for Music Therapy Research Anglia Ruskin University

Cambridge United Kingdom CB1 1PT +44 (0)1223 695401 naomi.thompson@aru.ac.uk Public Anglia Ruskin University University/education https://ror.org/0009t4v78 Non-commercial Cambridgeshire and Peterborough NHS Foundation Trust Hospital/treatment centre https://ror.org/040ch0e11 Non-commercial Research for Patient Benefit Programme http://dx.doi.org/10.13039/501100009128 17687131 true Is Mindfulness for Adolescents and Carers plus treatment as usual more effective and cost-effective compared to treatment as usual alone; how does it work and for whom does it work best? A randomised controlled trial with embedded economic evaluation and study of mechanisms ATTEND The research aims to answer the following questions: PGfAR WP3 RCT: 1. Is Mindfulness for Adolescents and Carers (MAC) plus treatment as usual (TAU) more effective at producing a sustained reduction of symptoms of depression in adolescents compared to TAU? 2. Is MAC plus TAU cost-effective compared to TAU? 3. Does MAC plus TAU impact the following secondary outcomes: 3.1. For young people: 3.1.1. Anxiety 3.1.2. Quality of life 3.1.3. Ability to cope 3.1.4. Perceived quality of family relationship 3.2. For parents/carers: 3.2.1. Depression 3.2.2. Anxiety 3.2.3. Quality of life 3.2.4. Ability to cope 3.2.5. Perceived quality of family relationship PGfAR WP4 mechanisms: 4. What characteristics moderate the effect of MAC? 5. Does MAC work through its intended psychological mechanisms (such as increases in the ability to decentre and mindfulness skills)? And if yes, what are the exact pathways? 6. Do changes in process variables (such as decentring and mindfulness) transfer to influence outcomes across the young person-carer dyad? If yes, what are the exact pathways? 7. Are outcomes of the MAC intervention related to the amount of mindfulness practice that participants engage in? 8. How is the learning from the trial intervention reflected in participants' actual responses to negative mood (as assessed using second-person methods to analyse subjective reports)? 9. What are the experiences of young people and their carers with the intervention? Background and study aims In the UK about 140,000 15–19-year-olds experience depression. An estimated 35,000 young people access NHS treatment for depression, of which about 14,000 do not respond and a further 8,000 are likely to experience depression again after initial successful treatment. Teenagers who still have symptoms after treatment for low mood, depression or anxiety, or who relapse quickly, need more treatment options. These young people have a high risk of substance misuse, self-harm, school, or relationship difficulty, as well as poor adult mental and physical health. Parenting a teenager with depression is stressful and can damage family relationships. Teenagers whose parents have depression are more likely to develop mental health problems in adulthood. Mindfulness-based cognitive therapy (MBCT) combines training in mindfulness meditation with principles from cognitive therapy. It teaches skills to recognise early warning signs of depression, avoid repetitive thinking patterns that make depression more likely, and respond in ways that protect mental health. Although MBCT is recommended for adults who have experienced three or more depressive episodes, MBCT for teenagers is relatively untested. Mindfulness for Adolescents and Carers (MAC) was developed as a version of MBCT adapted to be more engaging for teenagers. MAC aims to help teenagers recover from depression and the parallel parent/carer group aims to support parents and carers to cope better. The aim of this study is to see if MAC supports recovery and prevents relapse amongst 15-18-year-olds who risk developing recurrent depression as adults. Who can participate? Young people aged between 15 and 18 who have completed at least one evidence-based treatment for anxiety or depression but are still experiencing symptoms of low mood. If a young person is eligible to participate then their parent or carer will be invited to take part in a parallel parent mindfulness group. What does the study involve? This study is run across six different parts of England: London, Devon, Sussex, East of England, Oxford and Nottingham. People who agree to take part will either be randomly assigned to take part in the Mindfulness for Adolescents and Carers (MAC) group and continue to receive their current/usual treatment, or be assigned to continue with their current/usual treatment only. MAC is mindfulness-based cognitive therapy adapted for teenagers. MAC is delivered to a group of up to 12 young people. There are eight weekly sessions, each 1 hour 30 to 45 minutes. Between MAC sessions, people will be asked to record their Mindfulness at Homepractice on the MAC App. The App will have spaces where they can select what practices they have done and how they found them. This will be shared with their therapist. The App will also automatically record usage information such as how often they open the App, which audio recordings they listen to the most and how long they listen to them for. This automatically collected information will not be shared with their therapist, but it will be used in the study’s final analysis. The researchers will invite parents/carers to attend sessions as well as this can really help them to support their child. The young people and parent/carer sessions run separately, each in their own room. However, young people can still take part in this study even if their parent/carer doesn’t want to take part themselves. Mindfulness works by helping to learn skills that can prevent low mood or depression from coming back, helping people to become more aware of how their body is feeling and the impact this can have on their emotions, and trying to help pay attention to the present moment and think about the kind of things their internal voice is saying to you. Often our mind is thinking about what will happen (the future) or what has happened (the past) and sometimes we miss what is happening right now. The present is not always as bad as we think, but even when it is, then mindfulness practices and ideas can help us find new ways of responding to difficulties. The MAC programme aims to help the young person to ‘train their mind’ so that they can choose to respond rather than react to difficulties. To do this, first we need to learn to notice when we are doing something unhelpful, and then we need to let go of it and find a different way of working with our mind. In this programme we learn to be flexible, kind and understanding with ourselves in order to take the above steps. What are the possible benefits and risks of participating? Engaging in MAC involves a commitment to the workshops and the mindfulness practice. This typically involves experiencing the full range of positive, negative and neutral experiences that are an essential part of the treatment. This is done in a supportive and constructive therapeutic contact. Participants will complete some questionnaires and discuss with researchers how they are feeling. Some of these questions are personal and sometimes people can find it upsetting to discuss these issues. This is a new treatment and is only available through taking part in the study. Where is the study run from? Cambridge and Peterborough NHS Foundation Trust and University of Cambridge (UK) When is the study starting and how long is it expected to run for? September 2021 to September 2027 Who is funding the study? National Institute for Health Research, Programme Grant for Applied Research (NIHR PGfAR) (UK) Who is the main contact? Gemma Giove-Hunt, gg434@cam.ac.uk Young people’s levels of depression measured using the Short Moods and Feelings Questionnaire (SMFQ) over the 12-month follow-up period using an Area Under the difference Curve (AUC) analysis of the fortnightly For young people: Measured at baseline, 3.5 months post-randomisation and 12 months post-randomisation: 1. Anxiety measured using the Revised Children's Anxiety and Depression Scale-25 (RCADS-25) 2. Quality of life measured using the EQ-5D-5L 3. Ability to cope with life measured using a single bespoke question 4. Parent – young people relationship quality measured using the Parent-Adolescent Relationship Scale (PARS) For parents or carers: Measured at baseline, 3.5 months post-randomisation and 12 months post-randomisation: 1. Depression measured using the Patient Health Questionnaire eight-item depression scale (PHQ-8) over the 12-month follow-up period using an Area Under the difference Curve (AUC) analysis of the fortnightly 2. Anxiety measured measured using Generalized Anxiety Disorder 7 (GAD-7) 3. Quality of Life measured using the EQ-5D-5L 4. Ability to cope with life using a single bespoke question 5. Parent – young people relationship quality measured using the PARS Old ethics approval format Approved 23/05/2024, East of England – Cambridge South Research Ethics Committee (Equinox House, City Link, Nottingham, NG2 4LA, UK; +44 (0)207 104 8084, +44 (0)207 104 8258, +44 (0)207 104 8208; cambridgesouth.rec@hra.nhs.uk), ref: 24/EE/0091 10.1186/ISRCTN17687131 341587 CPMS: 62119, NIHR: 204413 341587 62119 204413 Randomized; Interventional; Design type: Treatment, Psychological & Behavioural Interventional Randomised controlled trial Treatment 2027-09-30T00:00:00.000Z United Kingdom England CAMHS Croydon London Road

78 London Road

Croydon England CR0 2TB RV5C4@2.16.840.1.113883.2.1.3.2.4.18.48 Lambeth CAMHS (clamhs)

393 Brixton Road

London England SW9 7AW RV5JK@2.16.840.1.113883.2.1.3.2.4.18.48 CAMHS Lewisham Park

78 Lewisham Park

London England SE13 6QJ RV5KE@2.16.840.1.113883.2.1.3.2.4.18.48 CAMHS Southwark Adolescent Team

Bloomfield Clinic St. Thomas Street

London England SE1 9RT RV5YW@2.16.840.1.113883.2.1.3.2.4.18.48 South London and Maudsley NHS Foundation Trust

Bethlem Royal Hospital Monks Orchard Road

Beckenham England BR3 3BX RV5@2.16.840.1.113883.2.1.3.2.4.18.48 Children and Family Health Devon

Single Point of Access Team 1a Capital Court Bittern Road Sowton Industrial Estate

Barnstaple England EX2 7FW Livewell Southwest

Local Care Centre 200 Mount Gould Road

Plymouth England PL4 7PY NR501@2.16.840.1.113883.2.1.3.2.4.18.48 Devon Partnership NHS Trust

Wonford House Hospital Dryden Road

Exeter England EX2 5AF RWV@2.16.840.1.113883.2.1.3.2.4.18.48 Cambridge Child and Adolescent Mental Health Services

18a Trumpington Road

Cambridge England CB2 8AH Peterborough Child and Adolescent Mental Health Services

City Care Centre Thorpe Road

Peterborough England PE3 6DB Huntingdon Child and Adolescent Mental Health Services

Newtown Centre Nursery Road

Huntingdon England PE29 3RJ Sussex Partnership NHS Foundation Trust

Trust Hq Swandean Arundel Road

Worthing England BN13 3EP RX2@2.16.840.1.113883.2.1.3.2.4.18.48 Carer Patient Young people: 1. Aged 15 to 18 years old at the time of recruitment 2. Completed at least one evidence-based treatment for anxiety or depression 3. Primary problem of unresolved or relapsed depression or anxiety: not recovered sufficiently to be discharged, or who have subsequently relapsed and been re-referred for treatment of depression or anxiety 4. Readiness to engage in a group-based mindfulness-based intervention, which would include the ability to focus and participate in a group for up to 1 hour 45 minutes; capacity to think flexibly and reflect on one's own experiences; and the willingness to practice everyday mindfulness and learn formal meditation for up to 15 minutes per day. Carers: 1. A carer of a young person who has consented to take part in the study Mixed 15 Years 18 Years All 480 0 Young people: 1. Current active management required for suicidal risk, self-harm or eating disorder 2. Current psychosis or PTSD Carers: 1. A carer of a young person who has not consented to take part in the study 2024-08-21T00:00:00.000Z 2026-02-28T00:00:00.000Z Mental health Mental and Behavioural Disorders The programme grant has work packages as follows: 1. Finalise the therapist-training programme. 2. Co-produce two Apps to encourage and measure mindfulness practice. 3.1. Recruit 480 teenagers, and their parents/carers will be invited too. Half will access MAC and half will access the standard NHS treatment currently available. This will allow us to compare the differences between the two groups on depression and other outcomes. 3.2. Compare the two group’s treatment costs, with their symptoms 9 months after treatment, to assess whether MAC is value for money. 4. Find out how MAC works and who benefits the most by exploring changes in how teenagers and parents feel, think, and relate to each other. 5. Understand how best we can make MAC available across the NHS. Work packages 3 and 4 form part of an individually randomised two-arm controlled trial. The researchers will be recruiting 15–18-year-olds who, even after having a previous evidence-based treatment for depression or anxiety, continue to experience significant symptoms or have relapsed. The focus is to test the effectiveness of MAC as an intervention. This does not include the therapist training (WP1), the App for home practice (WP2), or the different care pathways or implementation (WP5 IRAS number 333973), which have their own protocols and ethics where applicable. The economic analysis will evaluate the cost and cost-effectiveness of MAC plus TAU compared to TAU alone from NHS/personal social services, education, and societal perspectives. WP4 Mechanisms: In line with guidelines on the evaluation of complex interventions (Skivington et al., 2021), the researchers will investigate treatment moderators and mediators. This WP aims to provide a more nuanced understanding of: 1. Who is likely to benefit 2. How change is achieved 3. How mechanisms of change are best facilitated Participant journey: Recruitment + eligibility: 1. The Clinical Team and the Clinical Research Network will identify potential young participants by active screening of caseloads. Research Assistants in each site will provide support by answering any eligibility queries but will not have access to identifiable information. Participants will also be recruited via practitioner referrals. Any participants who contact the study email address directly via word-of-mouth or from seeing promotional materials will be asked to provide their name, date of birth, and the city/town they live in. The relevant site’s Research Assistant with the local Clinical Team and Clinical Research Network will then screen their case notes for eligibility. One method of recruitment will be via NHS Trust research databases, each approved and operated by the relevant NHS Trust. The database will be queried to find patients who are likely to meet the study’s eligibility criteria. For patients that have specifically consented to the following (either in advance or having been approached by their primary clinical team), the Trust will provide the patient’s details to the research team and authorize the research team to view the patient’s records and to contact the patient to discuss participation in the study. Researchers will not be given identifiable information without the patient’s specific consent. Study participation itself would require the patient’s further consent. 2. Potential eligible young participants that have been identified will be provided with a short, written summary (Appendix b) in the format of a printable or email leaflet from the referring clinician, local CRN support, or clinical care team which have recruited them. 3. If a young person expresses an interest in the study, the young person (aged 16 to 18 years) or parent/carer (for a young person aged 15 years) will be asked to return a Permission to Contact Form (Appendix e) either directly to the study team or provide permission for the person who referred them to return it. 4. When a permission to contact form is received by the study team, a Research Assistant will contact the young person and parent/carer to explain more about the study and answer any questions. 5. If the young person is still interested, they will be sent the full Participant Information Sheet (PIS) and the Privacy Notice, and a time will be arranged to complete an intake assessment. 6. During the intake assessment the study will be fully explained to the young person and their parent/carer before written informed consent is obtained by the Research Assistant via REDCap. The Research Assistant will also ask the young person to complete an eligibility questionnaire. Parents/carers of eligible young participants that have consented to join will be invited to take part in the parent/carer group of the trial. Trial: The next stage is participants complete the baseline questionnaires online and they will be randomised. They then start the fortnightly completion of a short questionnaire online for 12 months. Those assigned to MAC will complete the 8-week intervention. Those assigned to TAU will continue their standard care as normal. They will all complete a set of online questionnaires at 14 weeks post-randomisation and 12 months randomisation. The researchers will thank them for their involvement and pay both the young people and parent/carers a small incentive at set stages. Behavioural Data sharing statement to be made available at a later date Protocol

Study website Migrated from study website field

5bfe2435-513e-498e-b0fc-e60e81d6f42f 775af89d-3c5c-4dc8-85f7-f62ae25a76c5 8cd5270f-55f4-4bbc-8a18-8ec36d805053 f2ca1a06-ff0f-40ba-bae6-6a02306e1c1a 127a4b25-5fc5-4f36-94b2-c141c447064b No Participant information sheet 45872_PIS_V1.4_17Jul24.pdf 248226b6-ef7b-476a-94fd-96b2ecbeab7d true application/pdf 11280779 9e074ecbaf0cdb4df3603d2c6f15657b Protocol file 45872_PROTOCOL_V1.3_20Jun24.pdf e02c2136-8e10-44ae-98bb-ebe744b1fe17 true application/pdf 3770562 d5193d7f2149ad19ec6ef3cf03e3e0d4 Tamsin Ford https://orcid.org/0000-0001-5295-4904 Principal investigator

University of Cambridge Developmental Psychiatry Douglas House 18b Trumpington Road

Cambridge United Kingdom CB2 8AH - tjf52@medschl.cam.ac.uk Public Rachel Hayes https://orcid.org/0000-0001-7525-322X Scientific

South Cloisters (room 2.05) St Luke's Campus University of Exeter

Exeter United Kingdom EX1 2LU +44 (0)1392 722978 R.A.Hayes@exeter.ac.uk Public Gemma Giove-Hunt Scientific

University of Cambridge Herchel Smith Building Forvie Site Addenbrooke’s Hospital

Cambridge United Kingdom CB2 0AH - gg434@cam.ac.uk Public Cambridgeshire and Peterborough NHS Foundation Trust Hospital/treatment centre https://ror.org/040ch0e11 Non-commercial NIHR Central Commissioning Facility (CCF) 68282588 true Clinical effectiveness of an adolescent-specific strengthening programme, compared to usual care, for ambulant adolescents with spastic cerebral palsy (ROBUST trial): a parallel group randomized controlled trial ROBUST An adolescent-specific muscle strengthening programme has superior clinical effectiveness compared to usual care for ambulant adolescents with spastic cerebral palsy. Background and study aims Cerebral palsy (CP) is caused when babies suffer brain injury around birth from a lack of oxygen in the brain. Children with CP develop stiff and weak muscles. They often have difficulty walking and moving and that makes it difficult for them to join in activities. Exercises prescribed by physiotherapists become a big part of their lives as it tries to train their muscles and help them participate in activities. When they reach adolescence and their body grows, weakness of muscles in the legs becomes more of a problem. Exercises to strengthen muscles to maintain or improve movement are often used by physiotherapists in adolescents with CP. However, there is wide variability in the strengthening exercise programmes used. Therefore, professional groups have highlighted the need for evidence-based physiotherapy exercise programmes in adolescents with CP. The aim of this study is to assess the effectiveness of a strengthening programme compared to usual care in adolescents with CP. Who can participate? Adolescents aged 12-18 years with spastic cerebral palsy What does the study involve? Participants will be randomly allocated into either the intervention (exercise programme) group or the usual NHS physiotherapy group. The intervention will involve six sessions with the physiotherapist over 16 weeks. Adolescents will receive an exercise programme which includes specific individually tailored strengthening exercises. The usual care group will receive the usual NHS physiotherapy treatment, involving one session to receive advice and guidance on their usual exercise and activity programme but does not include specific strengthening exercises. Adolescents or their parents/guardians in both groups will be required to fill out a questionnaire when entering the study and again at 6 and 12 months. Participants will also receive a clinical assessment upon entering the study and again at 6 months. What are the possible benefits and risks of participating? As with any form of exercise, adolescents may experience delayed muscle soreness on movement and/or mild altered walking (limping) for a few days after completing some of the exercises suggested by the physiotherapist. The benefit of participating is that the information from this study will be used to help treat other adolescents with CP more effectively. Where is the study run from? The study will be centrally managed by the Surgical Intervention Trials Unit (SITU), in collaboration with the Oxford Clinical Trials Unit (OCTRU) (UK) When is the study starting and how long is it expected to run for? January 2024 to February 2028 Who is funding the study? National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) Programme (UK) Who is the main contact? 1. Sally Hopewell, sally.hopewell@csm.ox.ac.uk 2. Joanna O’Mahoney, joanna.omahoney@ndorms.ox.ac.uk Functional mobility measured using the patient/parent-reported Gait Outcomes Assessment List (GOAL) questionnaire at 6 months 1. Muscle strength measured using the five time sit-to-stand test for adolescents with CP at 6 months 2. Motor function measured using the Timed Up and Go (TUG) test at 6 months 3. Functional mobility measured using the patient/parent-reported Gait Outcomes Assessment List (GOAL) questionnaire at 12 months 4. Independence measured using GOAL subdomain A at 6 and 12 months 5. Balance measured using GOAL subdomains A, B, D at 6 and 12 months 6. Pain and discomfort measured using GOAL subdomain C at 6 and 12 months 7. Health-related quality of life measured using EQ-5D-Y at 6 and 12 months 8. Educational outcomes measured using educational attendance records (days) at 6 and 12 months 9. Patient/parent exercise adherence self-reported at 6 and 12 months 10. Additional physiotherapy treatment self-reported at 6 and 12 months Old ethics approval format Approved 30/08/2023, South Central - Hampshire A Research Ethics Committee (Health Research Authority, 2 Redman Place, Stratford, London, E20 1JQ, UK; +44 (0)207 104 8388; hampshirea.rec@hra.nhs.uk), ref: 23/SC/0231 10.1186/ISRCTN68282588 325313 CPMS: 57227 325313 57227 Randomized; Interventional; Design type: Treatment, Physical, Rehabilitation Interventional Randomised controlled trial Treatment 2028-02-29T00:00:00.000Z United Kingdom England Wales University Hospitals Dorset NHS Foundation Trust

Management Offices Poole Hospital Longfleet Road

Poole England BH15 2JB R0D@2.16.840.1.113883.2.1.3.2.4.18.48 Derbyshire Healthcare NHS Foundation Trust

Trust Headquarters Kingsway Hospital Kingsway

Derby England DE22 3LZ RXM@2.16.840.1.113883.2.1.3.2.4.18.48 Gloucestershire Health and Care NHS Foundation Trust

Edward Jenner Court 1010 Pioneer Avenue Gloucester Business Park

Gloucester England GL3 4AW RTQ@2.16.840.1.113883.2.1.3.2.4.18.48 Alder Hey Children's NHS Foundation Trust

Alder Hey Hospital Eaton Road West Derby

Liverpool England L12 2AP RBS25@2.16.840.1.113883.2.1.3.2.4.18.48 Solent NHS Trust

Solent NHS Trust Headquarters Highpoint Venue Bursledon Road

Southampton England SO19 8BR R1C@2.16.840.1.113883.2.1.3.2.4.18.48 Isle of Wight NHS - Hq

St Mary's Hospital Parkhurst Road

Newport England PO30 5TG R1FHQ@2.16.840.1.113883.2.1.3.2.4.18.48 Barts Health NHS Trust

The Royal London Hospital 80 Newark Street

London England E1 2ES R1H@2.16.840.1.113883.2.1.3.2.4.18.48 St George's University Hospitals NHS Foundation Trust

St George's Hospital Blackshaw Road Tooting

London England SW17 0QT RJ7@2.16.840.1.113883.2.1.3.2.4.18.48 Leeds Community Healthcare NHS Trust

3 White Rose Office Park Millshaw Park Lane

Leeds England LS11 0DL RY6@2.16.840.1.113883.2.1.3.2.4.18.48 West Suffolk NHS Foundation Trust

West Suffolk Hospital Hardwick Lane

Bury St. Edmunds England IP33 2QZ RGR@2.16.840.1.113883.2.1.3.2.4.18.48 The Royal Wolverhampton NHS Trust

New Cross Hospital Wolverhampton Road Heath Town

Wolverhampton England WV10 0QP RL4@2.16.840.1.113883.2.1.3.2.4.18.48 Northern Care Alliance NHS Foundation Trust

Salford Royal Stott Lane

Salford England M6 8HD RM3@2.16.840.1.113883.2.1.3.2.4.18.48 Torbay and South Devon NHS Foundation Trust

Torbay Hospital Newton Road

Torquay England TQ2 7AA RA9@2.16.840.1.113883.2.1.3.2.4.18.48 Mid Cheshire Hospitals NHS Foundation Trust

Leighton Hospital Leighton

Crewe England CW1 4QJ RBT@2.16.840.1.113883.2.1.3.2.4.18.48 Whittington Health NHS Trust

Northern Health Centre, 580 Holloway Road

London England N7 6LB Oxford Health NHS Foundation Trust

NIHR Oxford Cognitive Health Clinical Research Facility, Warneford Hospital, Warneford Lane, Headington

Oxford England OX3 7JX Bedfordshire Hospitals NHS Trust

Child Development Centre, Hill Rise

Kempston England MK42 7EB Betsi Cadwaladr University Health Board

Ysbyty Glan Clwyd, Rhuddlan Road

Rhyl Wales LL18 3RF Cambridgeshire and Peterborough NHS Foundation Trust

Elizabeth House Fulbourn Hospital Fulbourn

Cambridge England CB21 5EF RT1@2.16.840.1.113883.2.1.3.2.4.18.48 Hertfordshire Community NHS Trust

Unit 1a Howard Court 14 Tewin Road

Welwyn Garden City England AL7 1BW RY4@2.16.840.1.113883.2.1.3.2.4.18.48 Kingston and Richmond NHS Foundation Trust

Galsworthy Road

Kingston upon Thames England KT2 7QB RAX@2.16.840.1.113883.2.1.3.2.4.18.48 Leicestershire Partnership NHS Trust

Room 100/110 Pen Lloyd Building County Hall Leicester Road

Leicester England LE3 8RA RT5@2.16.840.1.113883.2.1.3.2.4.18.48 Maidstone and Tunbridge Wells NHS Trust

The Maidstone Hospital Hermitage Lane

Maidstone England ME16 9QQ RWF@2.16.840.1.113883.2.1.3.2.4.18.48 North East London NHS Foundation Trust

West Wing C E M E Centre Marsh Way

Rainham England RM13 8GQ RAT@2.16.840.1.113883.2.1.3.2.4.18.48 Northampton General Hospital NHS Trust

Cliftonville

Northampton England NN1 5BD RNS@2.16.840.1.113883.2.1.3.2.4.18.48 Powys Teaching Local Health Board

Bronllys Hospital

Brecon Wales LD3 0LY 7A7@2.16.840.1.113883.2.1.3.2.4.18.48 Robert Jones & Agnes Hunt Orthopaedic Hospital

Gobowen

Oswestry England SY10 7AG R1DAC@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Free London NHS Foundation Trust

Royal Free Hospital Pond Street

London England NW3 2QG RAL@2.16.840.1.113883.2.1.3.2.4.18.48 Shropshire Community Health NHS Trust

Mount Mckinley Anchorage Avenue Shrewsbury Business Park

Shrewsbury England SY2 6FG R1D@2.16.840.1.113883.2.1.3.2.4.18.48 The Newcastle upon Tyne Hospitals NHS Foundation Trust

Freeman Hospital Freeman Road High Heaton

Newcastle upon Tyne England NE7 7DN RTD@2.16.840.1.113883.2.1.3.2.4.18.48 Wonford House

Wonford House Hospital Dryden Road

Exeter England EX2 5AF RWV62@2.16.840.1.113883.2.1.3.2.4.18.48 Chelsea and Westminster Hospital NHS Foundation Trust

Chelsea & Westminster Hospital 369 Fulham Road

London England SW10 9NH RQM@2.16.840.1.113883.2.1.3.2.4.18.48 County Durham & Darlington NHS Foundation Trust

Children’s Therapy, Children’s Centre Chester le Street Community Hospital Front Street Chester le Street

Durham England DH3 3AT Patient 1. Adolescents aged 12-18 years (i.e. from their 12th to their 18th birthday) 2. Diagnosis of spastic CP (bilateral or unilateral) Gross Motor Function Classification System (GMFCS) levels I–III 3. Willing for their community physiotherapy service and GP to be informed of their participation in the trial 4. Under 16 years of age: Participant is willing to take part in the study and has a parent/guardian who is willing and able to give informed consent for the child’s participation in the study. 5. Over 16 years of age: Participant is willing and able to give informed consent or a nominated Consultee can advise on behalf of the participant (Outside Scotland)/legal representative can consent on the participant's behalf (Scotland) Mixed 12 Years 18 Years All 334 0 1. Patient has had orthopaedic surgery of the lower limbs or selective dorsal rhizotomy in the past 12 months or planned (i.e. date confirmed) in the next 6 months 2. Patient has had lower limb botulinum toxin injections or serial casting in the past 4 months or planned (i.e. date confirmed) in the next 6 months 3. Patient is regularly performing a structured resistance exercise programme focused on resistance training as part of their usual physiotherapy routine 4. Patient is unable to comply with the assessment procedures and exercise programme with or without support from their carer 2024-01-29T00:00:00.000Z 2027-02-28T00:00:00.000Z Cerebral palsy Nervous System Diseases Cerebral palsy ROBUST is a randomised controlled trial with 1:1 allocation. Follow-up assessors will be blinded to the randomisation allocation. Participants will be identified through the Cerebral Palsy Integrated Pathway (CPIP) Network and recruited from NHS Trusts, providing care for children and young people with CP, where they will be assessed for eligibility by the clinical team, both supported by the local PI and research team in case of uncertainty. Adolescents and their parent(s) will be approached as part of their annual community physiotherapy CPIP review or other routine CP clinical care attendance. They will have the opportunity at their appointment to ask any questions they have about the study. Screening forms will be completed at each site. These will include questions on patient demographics and detail any reasons given for exclusion and non-participation. Participants will be asked to sign an assent form (for adolescents aged 12-15 years) whilst the parent/guardian will be asked to sign a consent form on behalf of their child. For those aged 16-18 years when entering the study, the young person will either be asked to sign a consent form or, if the clinician assesses the young person to be unable to provide informed consent, their parent/guardian (or other relative/friend, if applicable) will be asked to complete a consultee declaration on their behalf. Randomisation will take place once informed consent has been given, eligibility has been confirmed and baseline assessments have been made. During the baseline assessment participants, with the support of their parent/guardians will be asked to complete a baseline assessment questionnaire, which will include baseline measurements for the primary and secondary outcomes. Clinician-assessed outcomes (i.e. muscle strength and motor function) at baseline will be recorded electronically by a physiotherapist at site and before learning the outcome of the randomisation. All data will be entered into the study database (REDCap). Those randomly allocated to the progressive resistance exercise programme will receive six physiotherapy sessions over 16 weeks and will be requested to complete follow-up questionnaires via a link in an email or by paper through the post at 6 and 12 months. Clinician-assessed outcomes will be assessed at a face-to-face clinic appointment at 6 months by a blinded physiotherapist/assistant practitioner who is blind to the treatment allocation and has not been involved in the delivery of the intervention or usual care. Those randomly allocated to the usual NHS care arm will receive one session of usual care advice, with a physiotherapist/assistant practitioner. Participants allocated to this group will also be sent a link via email or a paper copy of the questionnaires to complete at 6 months and 12 months. They will also receive a blinded clinician assessment at the 6-month timepoint. Behavioural Upon completion of the trial, and with appropriate participant consent, anonymised research data will be shared with other organisations on request to the Chief Investigator Sally Hopewell (sally.hopewell@csm.ox.ac.uk) and in accordance with the data sharing policies of OCTRU, the Sponsor and funder. Requests for data (anonymised trial participant level data) will be provided at the end of the trial to external researchers who provide a methodologically sound proposal to the trial team (and who will be required to sign a data sharing access agreement with the Sponsor) and in accordance with the NIHR guidance. After the end of the trial an anonymised trial dataset will be created and stored, and may be shared with other researchers upon request. Participant consent for this is included in the informed consent form for the trial. Available on request Protocol

Participant information sheet Migrated from patient info sheet field

Study website Migrated from study website field

4871c32f-72a2-4d6d-aaed-8e4da9f09504 c5f948d1-8509-4af0-aee6-67cac8b37067 33328056-c571-4973-9832-413ad33ea716 c1a3f6e4-9d19-4ca0-ae63-283aee998b34 Yes Protocol file ISRCTN68282588 ROBUST Protocol Version 1.0_15Jun2023.pdf 620941c0-0d14-45a7-920a-60d3ebf419f2 true application/pdf 1457329 de0d44c7c572a8e50bc5533c61265382 Protocol file ISRCTN68282588_PROTOCOL_V2.0_21Nov23.pdf d16e687c-0735-422d-b96d-473aff0ef3fa true application/pdf 1338143 02d6ccf12b75c3f85e490fcc9673c154 Protocol file ISRCTN68282588_Protocol_V3.0_12Dec2024.pdf 07e2958a-5a7a-4e67-9f65-978ce192d6b7 true application/pdf 2824954 41d872d894bd8e99ae98251c6728c6ca Protocol file ISRCTN68282588_Protocol_V4.0_09Jun2025.pdf d2350a89-eec6-466c-95ed-7ee7140aaafd true application/pdf 2904521 dea8d497f72ba25291ce5bd0d31d33ca Joanna O'Mahoney Scientific

Surgical Intervention Trials Unit The Botnar Research Centre Windmill Road

Oxford United Kingdom OX3 7LD +44 (0)1865 737643 joanna.omahoney@ndorms.ox.ac.uk Public Sally Hopewell https://orcid.org/0000-0002-6881-6984 Principal investigator

University of Oxford Botnar Institute for Musculoskeletal Sciences Windmill Road

Oxford United Kingdom OX3 7LD +44 (0)1865 223458 sally.hopewell@csm.ox.ac.uk Public University of Oxford University/education https://ror.org/052gg0110 Non-commercial NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: NIHR135150 61917909 true Social cognition and functioning in Alzheimer's dementia Research Question Is impairment in theory of mind associated with decline in social functioning in people with mild Alzheimer’s disease (AD)? Objectives 1. To test whether theory of mind deficits, or those in other social cognitive domains, are associated with current and subsequent level of social behaviour and functioning in Alzheimer’s disease. 2. To establish the reliability and validity of novel approaches to the measurement of social behaviour and function in Alzheimer’s disease Background and study aims Impaired social functioning is a core feature of dementia and declines progressively through the disease course, but we do not currently understand the specific causes of this decline and have no effective treatments for social functioning. Social cognitive impairment, particularly impaired theory of mind (meaning inability to understand that other people have other thoughts and conceptualise what those thoughts might be), is a likely major cause of this decline and, if this is established, it could be a target for future interventions which aim to maintain social cognition. Is impairment in theory of mind associated with decline in social functioning in people with mild Alzheimer’s disease (AD)? Who can participate? 207 people with mild Alzheimer’s disease and 207 family/friend informants recruited from NHS memory clinics and other sources. What does the study involve? At baseline, we will assess social cognition using a detailed neuropsychological battery and will assess social functioning. At 4 and 8 months, participants will remotely rate their social functioning using a questionnaire and the full battery of testing will be repeated at 1 year follow-up. In a remote monitoring sub-study (SOCIAL-RM), up to 50 consenting participants with a mobile phone will have remote digital monitoring using a mobile phone application throughout the study duration. In a further behavioural observation sub-study (SOCIAL-BO), up to 50 consenting participants will have social behaviour assessed during a video-recorded semi-structured social interaction at baseline and 1 year follow-up. What are the possible benefits and risks of participating? Participants may not receive direct benefit from being in this study but information learned from this study may help us to improve care for people with Alzheimer’s dementia in the future. Each person with Alzheimer’s dementia will receive a £20 gift certificate as a token of our thanks for their time. There are no specific risks associated with participation. Participants may feel anxious before or tired after taking part in the tasks, but we will do everything we can to minimise or prevent this and participants will be given the opportunity to have either a short break or for the testing to be stopped if necessary. Where is the study run from? University College London (UK) When is the study starting and how long is it expected to run for? July 2022 to February 2026 Who is funding the study? Wellcome Trust (UK) Who is the main contact? a.sommerlad@ucl.ac.uk Social functioning is measured using the Social Functioning in Dementia (SF-DEM) Scale at baseline, 4 months, 8 months, 12 months 1. Social cognition including emotion recognition and theory of mind is measured using The Awareness of Social Inference Test short form at baseline and 12 months 2. Empathy is measured using the Interpersonal Reactivity Index at baseline and 12 months 3. Cognition is measured using the Addenbrooke’s Cognitive Examination at baseline and 12 months 4. Quality of life is measured using the Quality of Life in Alzheimer’s Disease scale at baseline and 12 months 5. Neuropsychiatric symptoms are measured using the Neuropsychiatric Inventory at baseline and 12 months 6. Depression is measured using the Cornell Scale for Depression in Dementia at baseline and 12 months 7. Activities of Daily living are measured using the Bristol Scale for ADLs at baseline and 12 months 8. Awareness of social behaviour is measured using the Revised Self-monitoring Scale at baseline and 12 months 9. Physical comorbidities are measured using the Charlson Comorbidity Index at baseline and 12 months Ethics approval required Wales REC 6

Health and Care Research Wales Support and Delivery Centre, Castlebridge 4, 15-19 Cowbridge Road East

Cardiff United Kingdom CF11 9AB 23/WA/0157 10.1186/ISRCTN61917909 313873 CPMS: 56436, WT 222932/Z/21/Z 313873 56436 WT 222932/Z/21/Z Observational cohort study Observational Cohort study Other 2026-02-26T00:00:00.000Z United Kingdom England Camden and Islington NHS Foundation Trust

St Pancras Hospital 4 St Pancras Way

London England NW1 0PE TAF@2.16.840.1.113883.2.1.3.2.4.18.48 Oxford Health NHS Foundation Trust

Warneford Hospital Warneford Lane Headington

Oxford England OX3 7JX RNU@2.16.840.1.113883.2.1.3.2.4.18.48 Devon Partnership NHS Trust

Wonford House Hospital Dryden Road

Exeter England EX2 5AF RWV@2.16.840.1.113883.2.1.3.2.4.18.48 Devon Partnership NHS Trust

Wonford House Hospital Dryden Road

Exeter England EX2 5AF RWV@2.16.840.1.113883.2.1.3.2.4.18.48 North East London NHS Foundation Trust

West Wing C E M E Centre Marsh Way

Rainham England RM13 8GQ RAT@2.16.840.1.113883.2.1.3.2.4.18.48 Northumbria Healthcare NHS Foundation Trust (headquarters)

Rake Lane

North Shields England NE29 8NH RTFHQ@2.16.840.1.113883.2.1.3.2.4.18.48 Herefordshire and Worcestershire Health and Care NHS Trust

Unit 2 Kings Court Charles Hastings Way

Worcester England WR5 1JR R1A@2.16.840.1.113883.2.1.3.2.4.18.48 North Staffordshire Combined Healthcare NHS Trust

Lawton House Bellringer Road Trentham

Stoke-on-trent England ST4 8HH RLY@2.16.840.1.113883.2.1.3.2.4.18.48 Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust

St Nicholas Hospital Jubilee Road Gosforth

Newcastle upon Tyne England NE3 3XT RX4@2.16.840.1.113883.2.1.3.2.4.18.48 Somerset NHS Foundation Trust

Trust Management Lydeard House Musgrove Park Hospital

Taunton England TA1 5DA RH5@2.16.840.1.113883.2.1.3.2.4.18.48 Cambridgeshire and Peterborough NHS Foundation Trust

Elizabeth House Fulbourn Hospital Fulbourn

Cambridge England CB21 5EF RT1@2.16.840.1.113883.2.1.3.2.4.18.48 Patient People with Alzheimer’s dementia: 1. Clinical diagnosis of probable Alzheimer’s disease dementia made by dementia specialist clinic. 2. Mini-mental state examination score >= 20 or Addenbrooke’s Cognitive Examination III score >= 52 (consistent with mild dementia) 3. English speaking ability sufficient to be able to complete standardised social cognition tests (TASIT-S) which are only available in the English language Additional criteria for SOCIAL-RM study: 4. Possess an Android smartphone Family/friend informant: 1. Family/friend informant must see the person with Alzheimer’s disease at least monthly to be able to report on social functioning and other symptoms. 2. English speaking to be able to complete English language questionnaires Mixed 50 Years 120 Years All 414 416 People with Alzheimer’s dementia: 1. Lack of mental capacity to consent to participate 2. Previous diagnosis of schizophrenia, severe traumatic brain injury, or autistic spectrum disorder 3. Aged under 50 years Family/friend informant 1. Lack of mental capacity to consent to participate 2. Diagnosis of dementia or other serious mental illness 3. Aged under 18 years 2023-05-01T00:00:00.000Z 2025-01-21T00:00:00.000Z Dementia Nervous System Diseases Procedures: Main Social Cognition and Functioning in Alzheimer's Dementia (SOCIAL) Study The volunteer will meet with us on two occasions – the first study visit, and then a final visit after 1 year when the tests of social cognition and behaviour will be repeated. Between these face-to-face visits, after 4 and 8 months, we will make telephone contact with the volunteer or their relative to complete a questionnaire and repeat the mobile phone monitoring for those taking part in that part of the study. As above, these visits can take place at the university building or other appropriate research site, and we will reimburse travel via taxis if needed. Or if volunteers prefer, we will visit them at their homes. Baseline: Once the consent form is signed, participants will complete a form asking about basic characteristics such as age, sex, ethnicity etc. The person with Alzheimer's dementia will then complete a series of tasks on a computer which test their ability to understand what another person might be thinking, recognise other peoples’ emotions, and empathise with their perspectives. These tasks involve either watching a short video or listening to a brief and then choosing from a list of options which test the volunteer’s understanding of what happened in the scenario. They will also complete other standard questionnaires assessing social functioning and other symptoms of dementia. These tasks will take around 60-75 minutes. Participants can have a break during this or can continue testing on a separate occasion if required. The consenting family member or friend of the person with dementia will also provide basic information about themselves and then complete with a researcher several questionnaires about the social functioning and other symptoms of the person with Alzheimer's dementia, lasting 35-45 minutes. 4 and 8 months: We will contact the family member of friend of the person with dementia by phone or email and ask them to complete a single questionnaire about social functioning lasting around 5 minutes. 1 year follow-up: We will meet again at the university or NHS site or participants home to repeat all tests conducted at baseline. SOCIAL-Behavioural Observation sub-study We will ask up to 50 of the SOCIAL study participants to also take part in this sub-study (these will be participants recruited from Camden and Islington NHS Foundation Trust or University College London for practical reasons related to video-recording interviews). We will provide a participant information sheet and ask for a separate consent form to be signed at the same time as the main SOCIAL study recruitment and consent respectively. With the volunteer’s knowledge and agreement, we will assess the quality of social behaviour by video-recording two brief (5-10minute) informal social interactions. The first will be between them and their relative, and the second will be with a study researcher. This video-recording will then be watched and rated for evidence of difficulties in social behaviour using a standard assessment scale (the Social Behaviour Observation Inventory). SOCIAL-Remote Monitoring sub-study Up to 50 participants who are recruited from Camden and Islington NHS Foundation Trust or University College London (for practical reasons related to downloading the mobile phone app) will be asked to participate in the remote monitoring sub-study. These participants may be the same or may be different from those recruited for the SOCIAL-BO sub-study). Participants will be required to have an Android smartphone. We will provide a participant information sheet and ask for a separate consent form to be signed at the same time as the main SOCIAL study recruitment and consent respectively. For consenting participants, the researcher will support themto download a mobile phone application to their mobile phone. There is nothing further required from them – we would like them to continue using their phone as they normally would and the app will run continuously on their phone to collect data for the study: - Number of phone-calls to and from their phone, the duration of the call and anonymised identity of the other phone: each telephone number will be anonymised using a code, rather than using the telephone number, which will allow the research team to count how many different telephone numbers contact or are contacted by the study participant. - Number of text messages to and from their phone, and anonymised identity - Number of contacts in phone contact list - Number of nearby Bluetooth devices and number connected to their phone - Location of phone, which is anonymised using a code - Status of the app, and battery level of phone, used to clarify any reason for problems with the data collection. The app will run in the background of the phone and not require participants to do anything active to provide data. If a participant requests that data collection is stopped, then the app can be turned off at any time by the research team and data collection will be stopped by our team after one year and we will support them to remove the app from their phone if they wish (although the app will not be collecting any information at that stage). Other The datasets generated during and/or analysed during the current study will be stored in a non-publicly available repository: Dementias Platform UK for the main SOCIAL study data (not SOCIAL-RM or SOCIAL-BO). The data is expected to become available from June 2026 for 10 years. Data will be shared by Dementias Platform UK according to their data access policy (https://portal.dementiasplatform.uk/Apply/DataAccessPolicy) to all bona fide researchers to use data for health-related research that is in the public interest. Consent will be obtained by participants for this sharing. Stored in non-publicly available repository Protocol

Main study, Person with Alzheimer’s disease

Behavioural observation substudy, Informant

Behavioural observation substudy, Person with Alzheimer’s disease

Main study, Consultee

Main study, Informant

Remote monitoring substudy, Person with Alzheimer’s disease

db613a00-c86a-4150-89ae-3535f235ce73 031a745e-70f7-4466-bf0a-5f859f6d3b95 67d6af9c-1e1b-44fa-a2e9-6a245b2e9f3d Yes Main study, Person with Alzheimer’s disease 43775 PIS PwAD_v1.0 20Mar2023.pdf 505a194e-0a0f-46d4-aab9-f45dcf8c30cd true application/pdf 176588 c9497402e33a414d958de400307c4b6a Protocol file 43775 Protocol v1.2 26May2023.pdf 87d119ea-ee23-4d36-9ea8-bd373ac4a4e5 true application/pdf 1412543 31264dd8076ee0f0497b94dcb50e19ab Main study, Informant 43775 PIS Informant_v1.1 26May2023.pdf 660605d8-a946-48ba-b1b0-3c59be3af177 true application/pdf 242831 cc598b1ad4314667352f6af46a954fe7 Main study, Consultee 43775 PIS Consultee_v1.1 26May2023.pdf 1e115edb-9ee9-439d-b6fc-8240e6e00364 true application/pdf 268137 d999e5d203e5751f2cbc951599ff85df Behavioural observation substudy, Person with Alzheimer’s disease 43775 Behavioural observation substudy PIS PwAD_v1.0 20Mar2023.pdf 0b94725c-b8e5-416f-aa1b-eeea881b54a7 true application/pdf 241747 8dbbf445ee6b98b79bd0556bbdfc39d4 Behavioural observation substudy, Informant 43775 Behavioural observation substudy PIS Informant_v1.0 20Mar2023.pdf d0dbc697-600d-491c-8ce0-7d14e8ebfb81 true application/pdf 242730 56a9697dfbaece979f0b705e143cd12b Remote monitoring substudy, Person with Alzheimer’s disease 43775 Remote monitoring substudy PIS PwAD_v1.1 26May2023.pdf a6799742-dbcf-41f0-ad68-883994c512d5 true application/pdf 244462 d4a356901bbafbb3ebf975b8d0d67740 Statistical Analysis Plan ISRCTN61917909 Analysis plan - SOCIAL Study 11.02.2026.pdf 458062ca-6aa8-4f67-8aae-141a90a9e497 true application/pdf 293804 0dc249be99867a8198eb9a20274ba038 Andrew Sommerlad https://orcid.org/0000-0002-8895-7055 Scientific Principal investigator Public

4th Floor, Maple House 149 Tottenham Court Road

London United Kingdom W1T 7NF +44 (0) 20 7679 9248 a.sommerlad@ucl.ac.uk Public University College London University/education https://ror.org/02jx3x895 Non-commercial Wellcome Trust http://dx.doi.org/10.13039/100010269