62906561 true A co-produced mental imagery intervention to reduce anxiety in people with mild to moderate intellectual disabilities (Co-MAID): a feasibility study Co-MAID feasibility Primary Objective: To investigate the feasibility of implementing a novel anxiety intervention with 40 patients and up to 20 carers Secondary Objectives: 1. Train 15 intellectual disabilities clinicians (e.g. clinical psychologists, learning disability nurses, psychiatrists, occupational therapists) working within specialist intellectual disabilities and mainstream mental health services to deliver Co-MAID and assess fidelity to the treatment. 2. Implement the manualised intervention in NHS services to determine the acceptability of delivering/receiving the intervention for patients, supporters, and clinicians, respectively. 3. Determine treatment adherence and fidelity. 4. Describe factors that facilitate or challenge the implementation of the intervention through NHS services. 5. Further refine the intervention logic model. 6. Determine feasibility of participant recruitment and retention rates. 7. Assess the feasibility of collecting proposed outcome measures for a definitive trial. 8. Assess the acceptability of randomization for participants, supporters and therapists. 9. Assess the acceptability of linking data between patients and their supporters in a future trial. Background and study aims People with intellectual disabilities have difficulties with their thinking, communication, and completing everyday tasks. Many people with intellectual disabilities are also anxious. This can stop them from going out and seriously affect their relationships. There are talking therapies that help anxious people. However, because people with intellectual disabilities have difficulties with thinking and communication, these therapies cannot be used without being adapted. We have worked with people with intellectual disabilities and their families to adapt the ideas behind talking therapy in a new way by using mental images for those with mild to moderate intellectual disabilities. This new therapy is called 'Co-MAID'. Mental images are the pictures we have in our heads. It is easier for people with intellectual disabilities to change their mental images than their verbal thoughts, to help them feel less anxious. Co-MAID teaches people different ways to change upsetting mental images over 9-12 individual, weekly, hour-long sessions with a therapist. Participants are encouraged to involve a supporter to attend therapy sessions and help with homework. People with intellectual disabilities say that Co-MAID is easy to understand and use. The research aims to: (a) To develop a Co-MAID training package, (b) To check whether Co-MAID can be run in the NHS, (c) To see if a larger study to test whether Co-MAID works is possible. Who can participate? 40 adults (aged 18+ years), with mild to moderate intellectual disabilities and clinical anxiety levels. Participants in the intervention arm may also have a carer involved (up to 20 carers). Five therapists, 10 patients, and 10 supporters will be recruited for the process evaluation. What does the study involve? Adults with mild to moderate intellectual disabilities will be allocated to receive the Co-MAID intervention and treatment-as-usual, or only treatment-as-usual. Co-MAID will be delivered by trained therapists over 9-12 sessions. Participants will complete outcome measures at baseline and follow-up. After the intervention study, people with intellectual disabilities, therapists and supporters will participate in interviews to evaluate Co-MAID feasibility. What are the possible benefits and risks of participating? Participants will receive £15 and reimbursed travel expenses for taking part in the intervention study. Participants may receive a novel anxiety intervention which may be provided to them more quickly than treatment-as-usual. Staff trained in the intervention will have new skills and receive additional training and supervision. There is a risk that participants may find some component of the intervention aversive. However, people with intellectual disabilities and stakeholders have been involved throughout the development and initial testing of this intervention and no aversive experiences have yet been experienced. Risk of distress will be mitigated through the intervention being delivered by an experienced healthcare professional familiar with working with people with intellectual disabilities who has received training in the intervention and will receive ongoing supervision throughout delivery. Where is the study run from? Participants will receive the intervention and complete outcome measures in a clinical or residential setting. The study is being run across five NHS trusts in central and southern England. When is the study starting and how long is it expected to run for? October 2026 to December 2027. Who is funding the study? National Institute for Health and Care Research (NIHR), UK. Who is the main contact? Dr Olivia Hewitt, olivia.hewitt@oxfordhealth.nhs.uk. Anxiety the Adapted General Anxiety Disorder-7 (GAD-7) baseline and follow-up (20 weeks after randomization) Anxiety the Glasgow Anxiety Scale for people with intellectual disabilities (GAS-ID) baseline and follow-up (20 weeks after randomization) Depression the Adapted Patient Health Questionnaire-9 (PHQ-9) baseline and follow-up (20 weeks after randomization) Quality of life the European Quality of Life 5 Dimensions 3 Level version (EQ-5D-3L) baseline and follow-up (20 weeks after randomization) Mental imagery the Mental Imagery Questionnaire for people with intellectual disabilities (MIQ-ID) baseline and follow-up (20 weeks after randomization) Resource use the Client Service Receipt Inventory (CSRI) baseline and follow-up (20 weeks after randomization) Ethics approval required North West - Liverpool Central Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 26/NW/0187 10.1186/ISRCTN62906561 349099 CPMS: 64636, NIHR: 208933 349099 64636 208933 Interventional Randomized controlled trial Blinded (masking used) Active Parallel Treatment Not applicable Treatment 2027-12-01T00:00:00.000Z United Kingdom England Berkshire Healthcare NHS Foundation Trust

London House London Road

Bracknell England RG12 2UT RWX@2.16.840.1.113883.2.1.3.2.4.18.48 Tatchbury Mount Hospital

Calmore

Southampton England SO40 2RZ Hertfordshire Partnership University NHS Foundation Trust

The Colonnades Beaconsfield Close

Hatfield England AL10 8YE RWR@2.16.840.1.113883.2.1.3.2.4.18.48 Northamptonshire Healthcare NHS Foundation Trust

St Marys Hospital 77 London Road

Kettering England NN15 7PW RP1@2.16.840.1.113883.2.1.3.2.4.18.48 Littlemore Mental Health Centre

Sandford Road Littlemore

Oxford England OX4 4XN RNU30@2.16.840.1.113883.2.1.3.2.4.18.48 false 1. Mild to moderate ID diagnosis confirmed by case note review 2. Existing diagnosis of an anxiety disorder confirmed or initially made at screening 3. Capacity to give informed consent to participate in accordance with the Mental Capacity Act (2005) Mixed 18 Years 120 Years All 40 0 1. Currently receiving another psychological therapy 2. Actively suicidal, experiencing hallucinations or delusions 3. Severe or profound intellectual disability diagnosis 2026-10-01T00:00:00.000Z 2027-05-03T00:00:00.000Z Anxiety in people with mild to moderate intellectual disabilities Mental and Behavioural Disorders Design This study aims to test the feasibility of delivering the Co-MIAD intervention in NHS settings. We are testing this out with 40 adults who have mild to moderate intellectual disabilities and anxiety. We will recruit these people from 5 NHS Trusts. Half will be randomly allocated to receive treatment as usual for anxiety (TAU), and half will receive TAU plus the Co-MAID intervention. This feasibility study is being conducted in advance of a full clinical trial of the intervention. Therefore, we are modelling a number of processes such as collecting information about resources for health economic analysis, and randomisation to allow us to investigate the acceptability of this for participants and therapists. Participants may have a supporter to attend sessions with them and help with any between-session tasks, although this is not mandatory. We will train 15 therapists across the 5 NHS trusts to deliver the Co-MAID intervention. We will capture information about the therapist, such as demographic information, professional background, years of experience etc. Randomisation Patients will be randomised using block randomisation on a 1:1 basis to either the intervention or comparator arm. The randomisation list will be produced in advance and will use a block size of 4. Randomisation will be conducted using R version 4.4.1 (2024-06-14) and the ‘blockrand’ package. The study team will communicate the outcome of randomisation for each participant to the site PI. They will then pass on this information to the participant and therapist. How will participants be recruited? All participants will be recruited through NHS services. Clinicians working in the service will identify people who meet the eligibility criteria (having a mild to moderate intellectual disability and anxiety disorder) by checking waiting lists for the service, discussion with other clinicians, searching electronic patient records and checking referrals coming into the service. Any potentially eligible participants (and their supporter if applicable) will be contacted by clinicians in the service and provided with brief information about the study in an accessible format (this study advert will be co-designed by the CDG). Participants and/or supporters can then contact the study team via two routes: (a) Participants (and supporters) tell clinicians that they want their contact details passed to the study team when asked. The study team will receive the details from clinicians and then contact the participants (and supporters). (b) Participants (and supporters) contact the study team directly using the contact information they were provided. Once they have contacted the study team, a research assistant from the study team (or site R&D) will complete screening to determine eligibility and gather informed consent. Timetable Broadly, Phase 1 involves developing project resources alongside our Co-Design Group (CDG), which will take place during months 1-6. These include a therapist's manual, a training package for therapists, a person's workbook, and fidelity checklists. Recruitment of 40 participants will take place in months 7-12, with the intervention being delivered in months 7-15. Process evaluation (including interviews with participants, supporters and therapists) will be conducted in months 12-19. Dissemination, report writing and feedback to funders will occur in months 19-21. Therefore, for participants taking part in the study, their involvement will last for about 6 months in order to screen them for eligibility, collect baseline data, randomise them and deliver the intervention (if applicable) and collect follow-up data 20 weeks post-randomisation. Data collection Data will be gathered from participants at three time points: (1) screening, (2) baseline assessment within 4-weeks of randomisation, and (3) follow-up assessment within 20-weeks of randomisation. The questionnaires that will be administered at these time points include a measure of anxiety (primary outcome measure) and may also include secondary measures such as (a) anxiety diagnosis, (b) symptoms of depression, (c) challenging behaviour, (d) quality of life, (e) wellbeing, and (f) mental imagery. Several potential outcome measures appropriate for this population will be presented to the Co-Design Group, who will make a recommendation to the study team about which measures should be included. Data will be collected by members of the research team, except for the therapists' rated fidelity checklist, which will be completed by therapists themselves and returned to the study team. We will carry out semi-structured interviews with 10 patients, 10 supporters, and 5 therapists to understand what people thought about the intervention and to understand the facilitators and barriers to delivering this intervention in NHS settings. These interviews will be held online or in the person's home or community setting, depending on personal preference. The interviews will be carried out by the research assistant. Data analysis We will recruit up to 40 patients (20 in each treatment arm), and up to 20 supporters. Five therapists will take part in process evaluation interviews. As this is a feasibility study, and the purpose is to provide estimates of key parameters to inform a future pilot trial rather than to power the current study to detect statistically significant differences, a formal a priori power calculation will not be conducted. Descriptive statistics will be reported for the study. Interviews will be audio-recorded, transcribed and analysed using Template Analysis. PPI Input The proposed research focuses on a feasibility study into Co-MAID. Co-MAID has been co-designed with people with intellectual disability and their family members, along with wider stakeholders. A group of 6-8 people with mild or moderate intellectual disability and their family members have formed our PPI group throughout our research and will continue to guide this feasibility study. PPI has been central to the design and preliminary testing of Co-MAID in NHS settings and disseminating findings from prior research stages. The involvement of a PPI co-applicant, Chrissy Marsh, has been central to this application. CM brings a wealth of expertise as the mother of a person with intellectual disability, and through her previous expertise as a teacher within a special educational school. The decision to apply for a feasibility study was made in collaboration with PPI members, and they have provided extensive feedback and support for this proposal. The research team has met with a PPI group regularly (every 6 weeks) over the past 14 months to develop the current application. This group is very familiar with the Co-MAID intervention, and some members of the PPI group have provided input into the project over the past 6 years (since the original inception of the idea for this intervention). Input from this group has included the development and refinement of the plain English summary, refining the research design, structuring the process evaluation (including the topics to be covered in qualitative interviews), designing and planning the input from the Co-Design Group, and feeding into guidance around membership of this group. PPI input has shaped and developed ideas around dissemination, including the use of a dissemination matrix to ensure the needs of all stakeholders will be addressed, and advocating for various innovative and creative methods of dissemination. Without the consistent support from our PPI partners, this research simply would not have been possible, and we continue to rely on their collaboration at each stage of our work. Behavioural Data sharing statement to be made available at a later date

056951c8-7556-47c5-ae1c-de13dc4e894e 2132027b-d8e5-4c96-bb4b-017c6729efcf 0f458c2e-04cc-46b2-a631-18e76c419578 No Olivia Hewitt https://orcid.org/0000-0002-6393-2388 Principal investigator Scientific Public

Oxford Health NHS Foundation Trust House 2, Slade House, Horspath Driftway, Headington

Oxford United Kingdom OX3 7JH +44 07775 540151 olivia.hewitt@oxfordhealth.nhs.uk Public Oxford Health NHS Foundation Trust Hospital/treatment centre https://ror.org/04c8bjx39 Commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 82078351 true Experiences of feeling exceptional: finding meaning and balance in everyday life - a proof-of-concept multiple baseline single case experimental design series testing the feasibility, acceptability, and potential clinical benefits of treating harmful grandiose delusions EOFE To establish a preliminary indication of the clinical effectiveness and acceptability of a novel intervention to reduce harmful grandiose delusions in patients with psychosis attending NHS mental health services. Feedback from this study will be used to refine the therapy in preparation for a subsequent pilot RCT. Background and study aims Experiences of Feeling Exceptional (often called grandiose delusions by mental health services) are false beliefs about having special powers, mission, wealth or identity. They are experienced by one in three patients diagnosed with severe mental health problems. These beliefs can be very meaningful but they can also come at a cost. For example: - Stephen believed he had superpowers. He crashed his car at speed to try to demonstrate his abilities. - Sophie believed that she was God. She stepped off heights as she expected to fly. - Max believed he was an undercover special forces agent. He tried to conduct arrests and got into fights believing that he had back up from other agents. Current talking therapies and medications do not work well enough for many patients with experiences of feeling exceptional. A new understanding of why these experiences persist for a person has been developed and this has been used to develop the first talking therapy specifically for the treatment of harmful experiences of feeling exceptional. The therapy aims to help people find a personally meaningful focus in life but that comes with fewer costs. The current study will conduct the very first test of this therapy. It will assess the acceptability of the therapy for patients, and provide initial evidence concerning whether the therapy is helpful. Who can participate? Adults aged 16+ years who are receiving care from Oxford Health NHS Foundation Trust’s mental health services for the treatment of affective or non-affective psychosis may be eligible to participate. Participants must have held a persistent experience of feeling exceptional for at least 3 months and be able to give informed consent. What does the study involve? Participants will all receive the talking therapy which will be delivered by a psychologist over 16 weekly one-to-one sessions. Before therapy begins, there will be a baseline (waiting) period of 4 to 6 weeks during which participants will complete brief weekly assessments. The length of this baseline period is randomly assigned. This helps researchers understand whether any changes are due to the therapy rather than the passage of time. Participants will complete the brief weekly measures throughout both the baseline and therapy phases. In addition there will be four more detailed assessment points: at the start of the baseline period, end of the baseline period (just before therapy begins), midway through therapy, and at the end of therapy. There will also be a short follow-up assessment after therapy ends. Participants will also be invited to take part in interview to share their experiences of therapy. What are the possible benefits and risks of participating? At present, since the therapy has not been evaluated before, ther eis no way to say that taking part in the study will benefit participants. It is hoped however that the therapy will help people to be able to live a meaningful and purposeful life whilst reducing difficulties associated with their experience of feeling exceptional. The therapy is not currently available outside of the study, and all participants will receive the therapy. No major risks are anticipate any from taking part. The new therapy has been designed to minimise any risks. However, the research team will check whether there are any potential problems over the course of this research study. Everyone will have the research assessments, and if these are experienced as upsetting then it is possible to reduce the length of these or for the person to withdraw. In addition to having the support of the study therapist, participants will continue to have their usual contact with their NHS care team throughout their time in the study who can offer support if participants experience distress. Where is the study run from? The study is being run within Oxford Health NHS Foundation Trust, and led by a research team based in the Department of Experimental Psychology, at the University of Oxford. When is the study starting and how long is it expected to run for? The study is expected to begin recruitment in May 2026 and will run for approximately 13 months including recruitment, therapy delivery, and follow-up. Who is funding the study? The National Institute for Health and Care Research (NIHR), UK. Who is the main contact? Dr Louise Isham (Clinical Psychologist), louise.isham@oxfordhealth.nhs.uk Grandiose delusion severity the Psychotic Symptom Rating Scale - Delusions subscale (PSYRATS delusions) the start of baseline, the end of baseline, the mid therapy, and the end of therapy Grandiosity severity Specific Psychotic Symptom Rating Scale - Grandiosity Subscale (SPEQ-G) the start of baseline, the end of baseline, the mid therapy, and the end of therapy Grandiose delusion conviction a 0-100% Visual Analogue Scale (VAS) weekly timepoints throughout baseline and therapy phases and at two-week follow-up after therapy completion Repetitive thinking about the grandiose delusions the Thinking about Experiences of Feeling Exceptional Questionnaire (TEEQ) the start of baseline, the end of baseline, the mid therapy, and the end of therapy Immersion Behaviours Immersion Behaviours Questionnaire the start of baseline, the end of baseline, the mid therapy, and the end of therapy Meaning in Grandiose Delusions the Grandiosity Meaning Measure (gram) and Grandiosity Meaning Measure - Sources (grams) the start of baseline, the end of baseline, the mid therapy, and the end of therapy Anomalous experiences the Specific Psychotic Experiences Questionnaire - anomalous experiences (SPEQ-AE) the start of baseline, the end of baseline, the mid therapy, and the end of therapy Mania the Internal State Scale the start of baseline, the end of baseline, the mid therapy, and the end of therapy Subjective harm from grandiose delusions the Subjective Harm from Experiences of Feeling Exceptional Questionnaire (SHEEQ) the start of baseline, the end of baseline, the mid therapy, and the end of therapy Brief idiographic measures (single item visual analogue scales) for repetitive thinking, immersion behaviours, meaning from grandiose delusions, anomalous experiences, mania, and subjective harm the Brief single-item visual analogue scales weekly timepoints throughout baseline and intervention phases and at two-week follow-up after the intervention has finished Depression the Patient Health Questionnaire-9 (PHQ-9) the start of baseline, the end of baseline, the mid therapy, and the end of therapy Anxiety the Generalized Anxiety Disorder-7 (GAD-7) the start of baseline, the end of baseline, the mid therapy, and the end of therapy Paranoia the Revised Green et al Paranoid Thought Scale (RGPTS) the start of baseline, the end of baseline, the mid therapy, and the end of therapy Patient satisfaction an Adapted Client Satisfaction Questionnaire the end of therapy Number of patients completing a dose of therapy (8 sessions is considered a dose of therapy) study data collection the end of therapy Participants' experience of therapy qualitative interviews a two-week follow up after the end of therapy Ethics approval required East of England - Cambridge East Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom EC20 1JQ 26/EE/0015 10.1186/ISRCTN82078351 344160 CPMS: 62659 344160 62659 Interventional N/A: single arm study Open (masking not used) Uncontrolled Single Treatment Not applicable 2027-07-14T00:00:00.000Z United Kingdom England Oxford Health NHS Foundation Trust

Littlemore Mental Health Centre Sandford Road Littlemore

Oxford England OX4 4XN RNU@2.16.840.1.113883.2.1.3.2.4.18.48 false 1. Participant is willing and able to give informed consent for participation in the study 2. Aged 16 years or older 3. Attending NHS mental health services for the treatment of affective or non-affective psychosis 4. Persistent (at least 3 months) grandiose delusion (as defined by the Schedules for Clinical Assessment in Neuropsychiatry), held with at least 60% conviction 5. No planned significant medication changes at the outset of participation Mixed 16 Years 110 Years All 9 0 1. A primary diagnosis of another mental health condition (e.g. substance use disorder) that would be the first clinical priority to treat 2. Current engagement in any other intensive individual psychological therapy or a significant change in medication 3. In forensic settings or Psychiatric Intensive Care Unit (PICU) 4. Command of spoken English inadequate for engaging in the therapy 5. Significant learning difficulties that would prevent the completion of assessments or the therapy 6. A participant may also not enter the trial if there is another factor (for example, current active suicidal plans that need to be the focus of intervention), which, in the judgement of the investigator, would preclude the participant from providing informed consent or from safely engaging with the trial procedures. Reason for exclusion will be recorded 2026-07-06T00:00:00.000Z 2027-02-14T00:00:00.000Z Treating persistent harmful grandiose delusions in patients attending NHS mental health services for the treatment of affective or non-affective psychosis. Mental and Behavioural Disorders The intervention is a psychological therapy designed to precisely target the key mechanisms which drive grandiose delusions and reduce associated harm. Central to the therapy is helping patients find alternative sources of meaning in their lives so that the grandiose delusions can fade. The therapy will be provided in up to 16 sessions. The intervention will be delivered by a mental health staff member (e.g. clinical psychologist, counselling psychologist, or CBT therapist) in up to sixteen one-hour one-to-one sessions over 16 weeks. Behavioural Not expected to be made available Protocol

d61fa88c-891e-4b29-a197-a1f943f27221 79bbc29d-a7fa-439d-a256-2bb5e24ee3a0 25fdf95f-8cd0-4ddd-adba-20bb0d7ef13c No Protocol file 49819_Protocol_V1.2_06May2026.pdf 4e591a2a-fce2-4028-af15-85acd9a8d02b true application/pdf 627143 ba15d38b18e51e6e68527eeacc9c7e06 Louise Isham https://orcid.org/0000-0003-1752-5236 Principal investigator Scientific Public

Department of Experimental Psychology University of Oxford The Life and Mind Building South Parks Road

Oxford United Kingdom OX1 3EL +44 01865 283804 louise.isham@psy.ox.ac.uk Public University of Oxford https://ror.org/052gg0110 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 34358183 true Improving Postpartum Outcomes of Severe mental Illnesses in Ethnically diverse mothers (POSIE) POSIE WP2: To gather and understand the lived experience of mothers who have experienced postpartum SMI through photovoice WP3: To co-design a postpartum SMI care pathway system using insight to improve care experiences Background and study aims People from ethnic minority backgrounds experience poorer outcomes in perinatal mental health care, including higher rates of severe mental illness after childbirth and poorer access to appropriate support. These inequalities can have serious consequences for mothers, babies, and families. This study aims to understand why these inequalities occur and how care can be improved. The study focuses on severe mental illnesses that occur during the first year after birth, such as postpartum psychosis, bipolar disorder, severe depression, and other serious mental health conditions. This stage of the study focuses on Work Package 2 (WP2) and Work Package 3 (WP3): WP2 aims to understand the experiences of people who have received care for postpartum severe mental illness by using a creative research method called Photovoice, where participants share photographs, drawings, and stories about their experiences. WP3 aims to bring together people with lived experience, carers, and professionals to use the findings from WP2 and co-design a culturally safe care pathway that could improve future services and reduce inequalities in care. Who can participate? WP2: 1. Adults aged 18 years or over. 2. People who have experienced postpartum severe mental illness and received care within the last five years from a range of ethnic and social backgrounds. WP3: 1. People who have experienced postpartum severe mental illness. 2. Family members, carers, or supporters of someone who has experienced postpartum severe mental illness. 3. Health and social care professionals, voluntary sector staff, policy makers, and other stakeholders involved in perinatal mental health care. What does the study involve? WP2 involves photovoice workshops where participants will share their experiences of postpartum severe mental illness using photographs. WP3 will review findings from earlier parts of the study and discuss the experiences of care to co-design a novel culturally safe care pathway to be implemented in NHS sites nationally. What are the possible benefits and risks of participating? Participants will have the opportunity to share their experiences and help improve future mental health services. The study may contribute to more equitable, culturally safe, and effective care for people affected by postpartum severe mental illness. Some participants may find it rewarding to contribute to research and service improvement. However, it can be upsetting or emotionally difficult to discuss experiences of mental illness and complete confidentiality in group settings cannot be guaranteed. Where is the study run from? The study is coordinated by the University of Oxford, Department of Psychiatry, and is being conducted in collaboration with NHS organisations, universities, charities, and community partners across England (UK) When is the study starting and how long is it expected to run for? September 2025 to November 2028 Who is funding the study? The study is funded by the National Institute for Health and Care Research (NIHR) through its Health and Social Care Delivery Research (HSDR) Programme (UK) Who is the main contact? Prof. Kamaldeep Bhui, kam.bhui@psych.ox.ac.uk Lived experiences, barriers, facilitators, vulnerabilities, and opportunities for improving care for people with postpartum severe mental illness (PP-SMI), thematic analysis of three photovoice workshops over 3 weeks the four study sites (Oxford, London, Sheffield and Lancashire) WP3: positive and negative experiences of the resources from WP1&2, priority setting meetings of 4–6 people the four study sites Development of a culturally safe co-designed postpartum severe mental illness care pathway and implementation plan, two in-person half-day co-design workshops over 2 months each of the four study sites There are no secondary outcomes Ethics approval required Bromley REC

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- United Kingdom - 26/LO/0304 10.1186/ISRCTN34358183 342441 CPMS: 61810, NIHR: 167329 342441 61810 167329 Non-randomized study Interventional Non randomised study Other 2028-11-30T00:00:00.000Z United Kingdom England Oxford Health NHS Foundation Trust

Littlemore Mental Health Centre Sandford Road Littlemore

Oxford England OX4 4XN RNU@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 Sheffield Health Social Care NHS Foundation Trust

Centre Court Atlas Way

Sheffield England S4 7QQ Lancashire and South Cumbria NHS Foundation Trust

Sceptre Point Sceptre Way Walton Summit

Preston England PR5 6AW RW4@2.16.840.1.113883.2.1.3.2.4.18.48 false 1. Aged 18 years or older 2. Able to communicate sufficiently in English or via approved interpretation support to participate meaningfully 3. Willing to take part in the relevant study activities for the work package 4. Have lived experience of receiving care for perinatal severe mental illness (SMI) within the preceding 5 years (from 12 weeks pregnant to up to a year after pregnancy) 5. Willing and able to participate in photovoice workshops (online or in person), including taking or selecting photographs and engaging in group discussion Mixed 18 Years 100 Years All 380 0 1. Individuals who do not have the capacity to provide informed consent 2026-09-01T00:00:00.000Z 2028-11-30T00:00:00.000Z Perinatal severe mental illness Mental and Behavioural Disorders WP2: Exploring patient priorities for postpartum SMI treatment and outcomes Sample size: 60 mothers with experience of postpartum SMI Recruitment: via NHS Trusts and community organisations Procedure: In each site, we will arrange for three consecutive photovoice workshops to be held in a hybrid model of online and carefully chosen creative environments for accessibility and comfort to facilitate discussion. Patients may bring a carer, a family member, friend, or confidante for support. This accompanying person may wish to remain during the workshops, as preferred by the participant, and so we will gather carer views also within the interpretive narratives. The first workshop of between 2 and 3 hours will introduce the research and explain that we are interested in understanding: 1. Experiences and perceptions around postpartum severe mental illness. 2. The causes and complexities of care. 3. Their experiences of care and recommendations. We will provide support and arrange comfort breaks and tailor the process to individual needs. Participants will be given disposable cameras, notebooks and asked to drop them in a central location local to them a week after the workshop. If they choose the online option they may prefer to use their phones and send the images to a project email address, or they can use their own phone even for face to face workshops. In some instances, participants may wish to use existing photographs which they feel reflect their care experiences. As set out, other creative materials will all be considered within the overall process. In the second and third workshops, participants will be presented with their digitised images and guided through reflections to generate narratives and captions for a minimum of 3-5 chosen images (total of 180-300 items). The second workshop will be a session of at least 2 hours, any time within a 6-8 hour time window, and will occur 2 weeks after the first workshop, and a third workshop will be held a week after the second. These times are flexible and can be adjusted around each participant. Prompt questions will be used to elicit their experiences (adapted from Hergenrather, 2009): Describe what you see in this photo and how it makes you feel. Why did you take a photo of this? What does this photo tell us about you? How can it provide opportunities to improve understanding about your illness and life experiences? Do you have suggestions for improving your care? In your care experiences, what helped and what did not work? How can inequalities arise and be reduced? The third workshop will be a group discussion; there will be no topic guide, but the conversation will be generated by which of their images participants wish to share with the rest of the group. The discussion will be facilitated by the research team, and participants will be encouraged to consider two questions: 1. What made a positive difference to your experience? 2. What could have been done differently? All workshops will be co-facilitated with a peer researcher. WP3: Co-design a care pathway to address inequalities in postpartum SMI treatment Sample size: 16 key stakeholders for priority-setting meetings, 80 key stakeholders for co-design days. Recruitment: via NHS Trusts and WP2 contacts and community settings Procedure: The richly contextualised narrative accounts of life-worlds and care experiences of participants from WP2 and WP1 data (CPRD data analysis) will be summarised, using visual and textual materials, to inform co-production of a culturally inclusive care pathway. In a series of priority-setting meetings (3-6 of these) with small groups (3-6 per group), we will review the photovoice outputs to conceptualise ‘touch points’ that characterise positive and negative experiences of patients with a view to generating consensus about the priorities for service improvement (participants). We understand that trust and relationship building are important for a successful co-design process, so we hope to involve the same core participants throughout the events and activities which comprise both of these key co-design phases. For this core group, we will seek to recruit people with lived experience of postpartum severe mental illness, in addition to those involved in priority setting. We aim to ensure there are at least 10 and up to 20 patients, 10 carers, and 25 professional stakeholders. The purpose is to represent multiple intersectional experiences by identity (age, gender, sexuality, neurodivergence) and place characteristics (rural, semi-rural, urban). We will pay these core participants for their time in attending events and participating in co-design activities. Our research staff, including peer researchers, will prioritise relationship building and attending to different needs and preferences of those attending workshops in order to make them a success and a good experience for participants. We will discuss and agree ground rules at the outset of the process, drawn from existing principles of good practice for co-design and user involvement. We will base the process around a series of group meetings. Depending on the composition and preferences of the group, we will consider face-to-face and online as alternatives. WP4: Evaluate the implementation of a postpartum SMI care pathway Sample size: via NHS Trust Recruitment: 5 professionals from each site and 40 mothers who received the intervention at each site. Procedure: The local teams will implement the newly developed care pathways from WP3 with around 40 mothers over 6-9 months at each study site, as well as two additional sites not involved in co-development, to learn about the role of co-design in the adoption of interventions. We will conduct the NoMAD survey before and after implementation and supplement this with interviews at each site to better understand barriers and facilitators to implementation and explore intervention fidelity. WP5: Developing guidance, dissemination and impact Sample size: 40 key stakeholders Recruitment: via NHS Trusts and Community Organisations Procedure: Key stakeholders (people with lived experience, charitable organisations, NHS leaders, healthcare professionals and policymakers) will be convened for a consensus workshop. They will be provided with the culturally inclusive care pathway for postpartum SMI, a proposed implementation strategy and a summary of the implementation evaluation. The workshop will aim to identify the following: 1. Key changes required to existing pathways; 2. the additional resources and expertise used to support the development and revision of existing pathways; 3. the training of staff to support and iterate the pathway over time whilst retaining the ethos and values base; 4. the type and nature of resources required. Behavioural Data sharing statement to be made available at a later date 3057f22a-1a59-4b1b-8ef1-bb3c1f676ec2 69424a9d-cd31-4887-835d-18706dd0f538 0462766f-094d-43e6-83eb-fa6c116d5e15 08989c08-59ba-4c97-b798-1aed64b0505e a6733cbb-51dc-456f-ac8c-8a27c578d602 No Harsimran Sansoy Scientific Public

Department of Psychiatry, University of Oxford, Warneford Hospital

Oxford United Kingdom OX3 7JX - harsimran.sansoy@psych.ox.ac.uk Public Kamaldeep Bhui Principal investigator

Warneford Hospital, Warneford Ln, Headington

Oxford United Kingdom OX3 7JX - kam.bhui@psych.ox.ac.uk Public Roisin Mooney Scientific Public

Warneford Hospital, Warneford Ln, Headington

Oxford United Kingdom OX3 7JX - roisin.mooney@psych.ox.ac.uk Public University of Oxford Hospital/treatment centre https://ror.org/052gg0110 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 74790966 true Randomised parallel trial comparing the efficacy of focused cognitive behavioural therapy versus treatment as usual for obsessive compulsive disorder The primary aim of the present study is to address the following question: Is there a difference in how much participants' OCD symptoms improve between individuals with OCD who receive focused CBT from trained psychological wellbeing practitioners (PWPs) compared to those who receive treatment as usual (TAU) at two NHS Talking Therapies services? The secondary research question is as follows: Is there a difference in how much participants' general mental health improves (anxiety, depression, and general functioning) between individuals with OCD treated with focused CBT compared to TAU? Background and study aims Obsessive compulsive disorder (OCD) is a severe mental health condition that affects around 2.3% of the population. OCD can cause high levels of distress, make it harder for people to cope in their day-to-day lives, and lead to significant healthcare costs. People with OCD repeatedly experience unwanted and distressing thoughts/images (known as obsessions) and engage in repetitive behaviours (known as compulsions) to reduce their anxiety, which leads to significant distress. Individuals with OCD rarely get better on their own, indicating the need for effective treatments. The cognitive model of OCD suggests that intrusive thoughts are common to everyone, but in OCD they are appraised as highly threatening and personally significant. Individuals with OCD tend to overestimate responsibility for preventing harm, leading to intense anxiety. Compulsive behaviours are used to neutralise perceived danger and responsibility, but these safety-seeking behaviours prevent learning that the feared outcome would not occur, thereby maintaining OCD symptoms. NICE Guidelines recommend cognitive behavioural therapy (CBT) as the first-line treatment for OCD. Numerous research papers support the use of CBT, with clinical studies indicating that CBT is more effective than no intervention (waitlist control) and drug interventions. Despite the availability of effective treatments, symptoms often go untreated for several years, with only a minority of obsessional patients receiving appropriate CBT. National Health Service Talking Therapies (NHSTT) services (formerly known as Improving Access to Psychological Therapies (IAPT)) were developed to address health inequalities and increase access to evidence-based psychological interventions in line with NICE recommendations. Through a stepped-care model, patients with ‘mild to moderate’ OCD symptoms are initially offered with Step Two (low-intensity) interventions (computerised (c)CBT) or guided self-help (GSH), while patients with ‘severe’ OCD are offered Step Three (high-intensity) interventions. NHSTT services currently report reliable improvement rates of 53%, with recovery rates likely to be around 30%, which is significantly lower than those reported clinical studies. This study aims to improve OCD recovery rates by training Psychological Wellbeing Practitioners (PWPs) in two NHSTT services to deliver a new low-intensity intervention for OCD, termed ‘focused CBT’. The focused CBT sessions are supported by workbook modules, with treatment involving the development of a shared understanding of their OCD difficulties and the introduction of cognitive and behavioural strategies aimed at addressing factors maintaining OCD symptoms. The secondary aim of the study is to compare groups on general mental health outcomes (anxiety, depression, and general functioning). Who can participate? Qualified psychological wellbeing practitioners (PWPs) working at the two participating NHSTT services. Adult patients aged 18 years and over with OCD as their main problem accepted in two NHSTT services. What does the study involve? Invites for participation will be sent to the PWPs from the service leads. Therapists will express their interest in the trial and provide informed consent via an online form before being randomly allocated (by chance) to deliver either treatment as usual (TAU) or focused CBT. Those in the focused CBT condition will receive training on how to deliver this treatment. Patient referrals to the services will be assessed using their standard triage and assessment procedures, where a main problem description is identified by the assessing clinician. Participants (people with OCD as their main difficulty) will be allocated to a treatment condition randomly (by chance) and have treatment sessions with PWPs. Random allocation will be completed on a 1:1 ratio in blocks of four using an online system such as Sealed Envelope. What are the possible benefits and risks of participating? The present study may help to improve OCD recovery rates in local NHSTT and psychological treatment for OCD. This could significantly impact the lives of patients accessing NHSTT for OCD.The present trial is not anticipated to cause any harm, with all participants receiving an active intervention (focused CBT or TAU). Services will manage risk (e.g. safeguarding and self-harm concerns) according to standard NHS talking therapy policies. In line with routine clinical care, clinical treatment notes will be recorded on participants’ electronic NHS care records, and consent forms will be uploaded. Where is the study run from? This study is being conducted at two NHS Talking Therapy services. When is the study starting and how long is it expected to run for? June 2026 to September 2027. Who is funding the study? Oxford NIHR Biomedical Research Centre, UK. Who is the main contact? 1. Roberta McGuinness, roberta.mcguinness@newc.ox.ac.uk 2. Professor Paul Salkovskis, paul.salkovskis@hmc.ox.ac.uk 3. Dr Saarim Aslam, saarim.aslam@psy.ox.ac.uk Severity of OCD symptoms the Obsessive Compulsive Inventory (OCI) assessment and every intervention session Severity of depression symptoms the Patient Health Questionnaire (PHQ-9) assessment and every intervention session Severity of anxiety symptoms the Generalised Anxiety Disorder (GAD-7) Questionnaire assessment and every intervention session General functioning the Work and Social Adjustment Scale (WSAS) assessment and every intervention session Ethics approval required London - Riverside Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 26/LO/0107 10.1186/ISRCTN74790966 357922 357922 Interventional Randomized controlled trial Open (masking not used) Active Parallel Treatment Not applicable 2027-09-27T00:00:00.000Z United Kingdom England Oxford Health NHS Foundation Trust

Littlemore Mental Health Centre Sandford Road Littlemore

Oxford England OX4 4XN false 1. Aged 18+ 2. Any gender 3. Problem descriptor of OCD both at triage and confirmed at first assessment with their therapist 4. Clinical level OCD symptoms on OCI total and/or subscales 5. Sufficient understanding of English to complete questionnaires and workbooks Mixed 18 Years 120 Years All 68 0 Pre-enrolment exclusion criteria as set by services will be the following: 1. Lack of capacity to consent 2. Alcohol or substance misuse that would impact therapy and which the individual is unwilling to reduce Trial exclusion criteria will be: 1. Acute suicide or safeguarding risk that cannot be managed 2. Current enrolment in another research study 3. Introduction or altered dose of antidepressant or anti-anxiety medication within the past month 4. Presence of a long-term health condition as their main problem 5. Inability to access study materials (e.g. no access to the internet) 2026-06-01T00:00:00.000Z 2027-06-27T00:00:00.000Z Patients with a primary problem descriptor of obsessive compulsive disorder as identified at triage and confirmed at first assessment with therapist. Mental and Behavioural Disorders The present randomised control trial aims to compare the efficacy of focused CBT with treatment as usual for OCD at two NHS Talking Therapy services . Focused CBT draws on the methodology outlined by Clark et al. (1999), Aslam et al. (2025), and Johnsen et al. (2025). Focused CBT sessions are supported by workbook modules, with treatment involving the development of a shared understanding of patients' OCD difficulties and the introduction of cognitive and behavioural strategies aimed at addressing factors maintaining OCD symptoms. Treatment will involve six to eight 30-minute sessions delivered online or face-to-face by psychological wellbeing practitioners. Treatment as usual at the services includes Guided Self-Help (GSH) and/or computerised CBT (cCBT). Interventions at both services can be delivered via phone, face-to-face, or MS Teams, depending on the individual’s preference. Both GSH and cCBT are classified as low- intensity, Step Two interventions. GSH involves a treatment planning session lasting up to 45 minutes, followed by six to eight 30-minute sessions with a PWP. Self-help materials are provided between sessions, with treatment focusing on psychoeducation and cognitive and behavioural skills. Meanwhile, cCBT is an online intervention delivered via the ‘SilverCloud’ platform. An initial ‘set-up’ call, lasting up to 20 minutes, is offered to explain the OCD programme. Patients then access the programme online, working through modules independently. Throughout the programme, patients are offered up to six online reviews, lasting up to 15 minutes each. Patients will be randomly allocated (using sampling without replacement) to either the intervention (focused CBT) or TAU (cCBT or GSH) condition on a 1:1 ratio in blocks of four using an online system called ‘Sealed Envelope’. A central randomisation system will be used to ensure allocation concealment, with an independent member of the research team not involved in the consent process, assigning participants to their treatment conditions. Clinical teams will be informed of the participant’s intervention condition, with services assigning therapists randomised to the condition. It will not be possible to blind therapists or participants to the intervention. Behavioural Not expected to be made available 3b8a317d-6c2d-490b-a9e0-757c3a77ae90 deda7b5b-b516-4d55-b5f4-b35601dad4fa daa73349-03f4-4d3e-889d-adc07f698a5c 5f74323f-d143-43d4-9939-00f059046972 79b3d64c-73dc-4a4b-932b-8de1e3f990af No Roberta McGuinness Principal investigator

Isis Education Centre, Warneford Hospital, Headington

Oxford United Kingdom OX3 7JX +44 (0)7919886360 roberta.mcguinness@newc.ox.ac.uk Public Saarim Aslam Scientific Public

Isis Education Centre, Warneford Hospital, Headington

Oxford United Kingdom OX3 7JX +44 (0)7919819678 saarim.aslam@oxfordhealth.nhs.uk Public Paul Salkovskis Scientific

Isis Education Centre, Warneford Hospital, Headington

Oxford United Kingdom OX3 7JX +44 (0)1865226369 paul.salkovskis@hmc.ox.ac.uk Public Oxford Health NHS Foundation Trust https://ror.org/04c8bjx39 Non-commercial NIHR Oxford Biomedical Research Centre http://dx.doi.org/10.13039/501100013373 37191564 true A feasibility study of a virtual reality café for people with eating disorders The aim of this study is to establish whether it is feasible to recruit, retain and follow-up participants with eating disorders to receive our newly developed virtual reality (VR) café intervention in addition to their normal treatment. We will also assess the feasibility of collecting outcome data and assess the completeness of these data. We will assess: 1. Recruitment: the number and proportion of patients who are potentially eligible, approached for consent, and consent to participate (routes via which participants were approached or contacted the relevant NHS research team will be documented) 2. Retention: the number and proportion of participants completing the study 3. Demographic, diagnosis and service use data on the individuals we recruit and what other treatment they receive 4. The numbers of sessions of VR completed, and the pattern of use of the VR intervention 5. The acceptability of the intervention, including via qualitative interviews 6. Any adverse experiences in relation to the VR intervention We will collect both qualitative and quantitative data from participants, parents of younger participants, and clinicians, as well as attempting to collect demographic and qualitative data from potential participants who decide not to participate. We will also passively collect eye-tracking data to enable us to have a more detailed understanding of what participants attend to within the VR environment. Background and study aims Eating disorders are serious mental health conditions. Many people with eating disorders find social eating settings, like cafes and restaurants, challenging. This can affect their life and can make recovery more difficult. The aim of this study is to find out whether it is possible to offer a new kind of treatment in the NHS to help people with eating disorders who find places like cafes difficult. The treatment we are inviting people to try out is a virtual reality (VR) café, where people with eating disorders can practise situations they find difficult, like ordering food or interacting with café staff, in a safe and controlled way. The treatment has been developed with people who have current and past experience of eating disorders and clinicians who are experienced in treating eating disorders. We want to find out whether people will take part in a study like this, whether they will stay in the study until it ends, and whether they find the VR café useful. Who can participate? People aged 14-25 years who are currently receiving treatment for any eating disorder in one of two participating NHS trusts can participate What does the study involve? The study involves attending up to six 1-hour sessions using the VR café, with support from a trained clinician. People who take part will attend these sessions as well as carrying on with their usual treatment for their eating disorder. VR café sessions will take place where participants usually see their eating disorder team or at their NHS mental health trust’s research base. We’ll collect information about how many people agree to take part, how many people complete the VR sessions, and how useful people find the VR café. Participants will be asked to complete some questionnaires before they start VR sessions, at the end of their first VR session, 6 weeks after their first VR session, and 3 months after their first VR session. We’ll also collect information about how people engage with the VR environments, and some types of information from health records to help us understand which people try out the VR café. To find out more about people’s experiences of participating, we’ll interview some of the young people who try out the VR café, some of their parents/carers, and some of the clinicians who support people using the treatment. We’ll also interview some of the people who didn’t want to take part in the study to understand why this might be. What are the possible benefits and risks of participating? As this is the first time the VR café has been used in the NHS, we don’t know whether everybody will benefit, but participants may find the treatment helpful for practising challenges related to going into and ordering food and drink in social eating environments such as cafés. Some people can experience motion sickness while using a VR headset. We believe that this risk is very small because participants will be seated while using the VR café. Some participants might also find reflecting on their experience of having an eating disorder distressing or find trying out the treatment challenging. Clinicians will support participants at all times during their use of the VR café, and participants can choose to take off the VR headset or stop VR café sessions altogether at any time. Where is the study run from? University of Bristol (UK) When is the study starting and how long is it expected to run for? June 2026 to October 2027 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK) Who is the main contact? Dr Helen Bould, Helen.Bould@bristol.ac.uk Feasibility of recruitment and retention will be measured by assessing the number of potentially eligible patients in the clinical settings during the study period, the number of patients approached to participate via each recruitment route during the study period, the number of participants consenting to participate during the study period, the number of potential participants declining to participate (and reasons given) during the study period, and the number of participants who consent to participate who remain in the trial at 3-month follow-up. The Feasibility of Assessment Battery will be measured by assessing the number of participants completing all measures at baseline and the number of participants completing all measures at the end of session 1 and at 6-week and 3-month follow-ups. Feasibility of the intervention will be measured by: 1. Documenting which clinician delivers the intervention (patient’s own clinician or a member of the NHS research team with experience of working in mental health) during the study period 2. Assessing VR engagement metrics, including: 2.1. Participant goal-setting re which scenarios they want to try and how many times they want to try it, captured at the end of the study period 2.2. Number (and which) VR sessions are completed, captured at the end of the study period 2.3. Time spent using VR, captured at the end of the study period 2.4. How often scenarios are repeated, captured at the end of the study period 2.5. Whether participants and clinicians think further sessions would have been useful for each participant, captured at the end of the study period Fidelity to the treatment will be measured by asking both the participant and the clinician to complete a brief measure, documenting whether they (1) set goals in relation to the VR scenario they would try, (2) tried one or more VR scenarios, and (3) discussed the experience of completing the scenario and reviewed their goals, completed at the end of each VR session. 1. Acceptability of the VR intervention to participants, through the proxy measures above, as well as by questions on satisfaction, perceived burden, ease of use and likelihood of recommending to others, collected 6 weeks after the first VR session. 2. Any adverse reactions to VR (e.g., motion sickness; stopping a session due to distress), collected during the study period. Questionnaire measures: 1. Anxiety and avoidance in relation to cafes will be measured using a bespoke questionnaire at baseline, end of VR session 1, 6 weeks after the first session, and at the 3-month follow-up 2. Self-efficacy in relation to cafes will be measured using a bespoke questionnaire at baseline, end of VR session 1, 6 weeks after the first session, and at the 3-month follow-up 3. Behaviours in relation to visiting cafés will be measured using a bespoke questionnaire at baseline, end of VR session 1, 6 weeks after the first session, and at the 3-month follow-up 4. Eating disorder symptoms will be measured by the Eating Disorder Examination Questionnaire (EDEQ) at baseline, 6 weeks after the first session, and at the 3-month follow-up 5. Symptoms of Avoidant/Restrictive Food Intake Disorder (ARFID) will be measured by the Short ARFID questionnaire at baseline, 6 weeks after the first session, and at the 3-month follow-up 6. Impact of having an eating disorder on life will be measured by the Clinical Impairment Assessment (CIA) at baseline, 6 weeks after the first session, and at the 3-month follow-up 7. General anxiety will be measured by the General Anxiety Disorder-7 (GAD-7) (18-25 year olds) or Revised Children’s Anxiety and Depression Scale (RCADS) (14-17 year olds) at baseline, 6 weeks after the first session, and at the 3-month follow-up 8. Depression will be measured by the Patient Health Questionnaire-9 (PHQ-9) (18-25 year olds) or Revised Children’s Anxiety and Depression Scale (RCADS) (14-17 year olds) at baseline, 6 weeks after the first session, and at the 3-month follow-up 9. VR side effects will be measured by the Simulator Sickness Questionnaire (SSQ) at baseline and at the end of each VR session 10. Sense of presence/place illusion will be measured at the end of the first VR session Service use measures: Service use measures will be gathered from electronic health records encompassing the study period until the 3-month follow-up: 1. Recorded diagnosis, comorbidities and prescribed medication 2. Nature of “treatment as usual” being received 3. Number and timing of clinical contacts within the eating disorders team, by professional group, before and after consenting to study participation 4. Number and timing of clinical contacts within the mental health trust, by professional group before and after consenting to study participation 5. BMI/% weight for height at the point of (1) starting treatment, (2) joining the study and (3) at 3-month follow-up (to help inform whether, for those for whom weight restoration is part of treatment, there is an optimum time during weight restoration to engage in this treatment) 6. Number of GP contacts during study participation 7. Number of contacts with other health professionals during study participation 8. Number of A&E contacts during study participation 9. Duration of admission [for inpatients] before and after consenting to study participation 10. Legal status of admission [for inpatients] before and after consenting to study participation VR headset measures: 1. Head, hand and eye-tracking data will be collected via VR headsets in all VR sessions during the study period Qualitative data collection: 1. Qualitative interviews will be conducted with a subset of trial participants, decliners, parents/carers, and clinicians during the study period Ethics approval required West of Scotland REC 5

West of Scotland Research Ethics Service Level 2, Administration Building Gartnavel Royal Hospital 1055 Great Western Road

Glasgow United Kingdom G12 0XH 25/WS/0200 10.1186/ISRCTN37191564 362410 CPMS: 70226, NIHR: 302271 362410 70226 302271 Non-randomized study Interventional Non randomised study Treatment 2027-10-30T00:00:00.000Z United Kingdom England 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 Oxford Health NHS Foundation Trust

Littlemore Mental Health Centre Sandford Road Littlemore

Oxford England OX4 4XN RNU@2.16.840.1.113883.2.1.3.2.4.18.48 false 1. Aged 14-25 years, with any eating disorder 2. Find social eating challenging 3. Currently accessing treatment for an eating disorder in a participating NHS mental health service 4. People aged 16 years or older who consent to participate 5. People aged 14-15 years old who assent to participate and for whom someone with parental responsibility consents to their participation. Mixed 14 Years 25 Years All 30 0 1. People who lack capacity to consent to participate as assessed during the consent process 2. People who are not able to travel to VR Cafe sessions 3. People who are not fluent in spoken English 4. Members of the project Patient and Public Involvement (PPI) group 2026-06-01T00:00:00.000Z 2027-05-29T00:00:00.000Z Eating disorders Mental and Behavioural Disorders The VR intervention will involve sessions of up to 1 hour in length, in which the participant will use the VR café scenarios with support from the clinician. The clinician will work with the participant to plan, support and debrief from the VR café intervention. The intervention can be delivered either by the participant’s own clinician within the Eating Disorder team (if they have been trained to do so) or by a member of the relevant NHS research team with experience of working in mental health, according to clinician availability and participant preference. Behavioural The datasets generated during and/or analysed during the current study will be stored in a publicly available repository (https://data.bris.ac.uk/data). Anonymised VR usage data, questionnaire data, and qualitative data will be made available (restricted access) to bona fide researchers on request. The data will become available after the study ends, data analysis is complete, and reports have been written. Participants’ consent will be obtained for data sharing and all shared data will be anonymised. Stored in publicly available repository Protocol

4f74db27-c62b-4b23-a22f-a61426f1d7c5 4d427d67-4dfd-42c9-a07b-777642aba698 dca05b50-9a7d-44c4-8210-f723553e751a a4ed2e15-34db-45c5-a099-fd4e8098dc15 81cf8ed2-8f31-4415-a620-8bf9ff680aa3 Yes Protocol file 49310_PROTOCOL_V1.1_07Jan2026.pdf 1ea02766-37a8-4430-bd5b-ff239b4a2403 true application/pdf 1259052 e9919400e0d5897d7fadb3f2c45661fb Laura Chapman Public

Bristol Medical School University of Bristol Canynge Hall 39 Whatley Road

Bristol United Kingdom BS8 2PS - laura.chapman@bristol.ac.uk Public Helen Bould https://orcid.org/0000-0001-8163-3210 Principal investigator Scientific

Bristol Medical School University of Bristol Canynge Hall 39 Whatley Road

Bristol United Kingdom BS8 2PS +44 (0)1174553864 Helen.Bould@bristol.ac.uk Public Laura Chapman Public

Bristol Medical School University of Bristol Canynge Hall 39 Whatley Road

Bristol United Kingdom BS8 2PS - vr-eatingdisorders-project@bristol.ac.uk Public University of Bristol Hospital/treatment centre https://ror.org/0524sp257 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 43471225 true Improving talking therapies treatment of panic disorder: a randomised parallel trial 1. Can we replicate previous study findings with a new, larger sample? That is, a difference in the clinical outcome of panic severity between individuals with panic disorder who receive focused CBT compared to those who receive Step Two Treatment As Usual (TAU). 2. Is there a difference in the clinical outcomes of depression, anxiety and one’s daily functioning between individuals with panic disorder who receive focused CBT compared to those who receive Step Two Treatment As Usual (TAU) on a larger scale? 3. Does agoraphobic avoidance and panic cognitions improve in line with panic outcomes and do they predict outcomes in panic severity? Background and study aims Panic disorder is often treated in NHS talking therapies services by psychological well-being practitioners (PWPs) at Step Two, also known as 'low intensity'. There is a need to improve recovery rates for panic disorder nationally in NHS talking therapies services. A previous pre-registered trial the authors conducted (now published) found a more specific psychological treatment for panic disorder (known as Focused CBT) was more effective than the current treatment as usual for panic disorder in NHS Talking Therapies services. Therefore, this study is being conducted to build on the previous research to examine if these same effects can be observed on a larger scale. The research also aims to examine if focused CBT can result in further improvements on panic and agoraphobic specific measures including fearful panic thoughts and agoraphobic avoidance. Who can participate? Individuals who are 18+ years of age, of any sex and where panic disorder with or without agoraphobia is the main problem. What does the study involve? People with panic disorder at the NHS talking therapies service are asked if they would like to take part in the study. If so, they will be randomly placed (determined by chance) into either the 'focused CBT' treatment or the current treatment provided for panic disorder at the NHS talking therapies services. Participants will then receive the treatment they have been randomly allocated to. The symptoms and severity of the participant's panic, depression, anxiety and the participant's daily functioning are measured before they start treatment, during each treatment session and at the end of treatment. Panic fearful thoughts and agoraphobic avoidance are measured before treatment begins, mid-way through treatment and at the end of treatment. What are the possible benefits and risks of participating? Taking part could help improve the current psychological treatment for panic disorder with or without agoraphobia. It could also help with wider implementation of this focused CBT if deemed more effective. In addition, it would also mean participants will obtain psychological treatment for panic disorder with or without agoraphobia which may help with their difficulties with panic. The research team do not anticipate any risk associated with taking part. Where is the study run from? Oxford Health NHS Foundation Trust (UK) When is the study starting and how long is it expected to run for? February 2026 - December 2027 Who is funding the study? Biomedical Research Centre NIHR - Oxford Health NHS Foundation Trust (UK) Who is the main contact? 1. Dr Saarim Aslam, saarim.aslam@psy.ox.ac.uk 2. Professor Paul Salkovskis, paul.salkovskis@hmc.ox.ac.uk Panic symptom severity Panic Disorder Severity Scale (PDSS) pre treatment, at each treatment session and end of treatment. Depression PHQ-9 pre treatment, at each treatment session and end of treatment Anxiety GAD-7 pre treatment, at each treatment session and end of treatment Work and social adjustment scale Work and Social Adjustment Scale (WSAS) pre treatment, at each treatment session and end of treatment Agoraphobia Modified Agoraphobic Cognitions Questionnaire pre, mid and end of treatment Mobility Mobility Inventory pre, mid and end of treatment Ethics approval required South West - Cornwall & Plymouth Research Ethics Committee

2 Redman Place Stratford

London United Kingdom E20 1JQ 25/SW/0156 10.1186/ISRCTN43471225 363155 363155 Interventional Randomized controlled trial Open (masking not used) Active Parallel Treatment Not applicable 2027-12-31T00:00:00.000Z United Kingdom England Oxford Health NHS Foundation Trust

Littlemore Mental Health Centre Sandford Road Littlemore

Oxford England OX4 4XN RNU@2.16.840.1.113883.2.1.3.2.4.18.48 false 1. Age 18+ 2. English speaking and able to complete questionnaires and workbooks in English 3. Any gender 4. The presence of recurrent panic attacks whereby some are unexpected 5. Panic disorder with or without agoraphobia is the main problem as identified in the problem descriptor Mixed 18 Years 110 Years All 94 0 1. Panic is not the primary difficulty 2. Individual does not have capacity to consent 3.Those with long term physical health conditions 4. Those who are involved in another research project 5. Risk/safeguarding cannot be managed 6. Substance/alcohol use that would impact on therapy and individual unwilling to work to reduce this use 7. Inability to access materials, for example, technology barriers 2026-02-20T00:00:00.000Z 2027-08-31T00:00:00.000Z Panic disorder with or without agoraphobia Mental and Behavioural Disorders 1. Focused CBT: This will involve six-eight sessions, delivered by Qualified Psychological Wellbeing Practitioners (PWPs). Participants randomly allocated to this treatment will receive workbook modules to complete which will introduce each session's topic. They will be required to complete the workbook modules before each session as these workbooks will be used by the PWPs with the participants during the treatment sessions. The workbook modules and treatment sessions will use cognitive behavioural therapy (CBT) techniques tailored to panic disorder to help participants with their panic symptoms. 2. Treatment as usual has two different treatments which are currently provided by the NHS Talking Therapies Services taking part. These are (i) Guided Self Help (GSH) and (ii) computerised CBT (cCBT). GSH involves a consultation with a PWP followed by six-eight treatment sessions whereby the participant will be guided through different skills and techniques to help with the panic symptoms and difficulties. They are also given workbooks to complete prior to the sessions. cCBT is delivered on an online platform which involves seven modules teaching participants skills to help with their panic symptoms and involves online reviews by a PWP. Random allocation: Participants will be randomly allocated to either focused CBT or treatment as usual. Randomisation is being stratified by site and using blocked randomisation. The tool used will be an online randomisation tool such as ‘Sealed Envelope’. If participants are randomly allocated to treatment as usual, they will follow normal NHS Talking Therapies service procedures for allocation to either cCBT or GSH which involves a discussion of these options with the participant and an agreement between the participant and clinician of which is the most suitable option for them. This is the normal procedure for TAU in these services. Administration: Focused CBT is administered face-to-face or online via MS Teams. Both cCBT and GSH are administered either face to face, online via MS Teams or by telephone. This is based on participant preference and clinical need. Duration: Focused CBT intervention is a total of 6-8 weeks which is dependent upon the individual's panic presentation. Treatment as usual which is both Guided Self Help and Computerised CBT is also for 6-8 weeks. There is no follow up for this study. Behavioural Not expected to be made available 8b698d3e-349e-4fc1-a9b9-a404d756191e 9aa72daa-f64c-455b-8a80-bf45a7706d41 ebf30a83-dffa-403b-92c3-43e0f33f09c2 8ea2387c-3608-412b-b152-73c6d77c6bde No Saarim Aslam https://orcid.org/0000-0001-7488-904X Public Scientific Principal investigator

University of Oxford, Department of Experimental Psychology Oxford Health NHS Foundation Trust Isis Education Centre Warneford Hospital

Oxford United Kingdom OX3 7JX +44 (0)7919819678 saarim.aslam@psy.ox.ac.uk Public Paul Salkovskis https://orcid.org/0000-0002-2951-2283 Public Scientific

The Oxford Institute of Clinical Psychology Training and Research University of Oxford, Department of Experimental Psychology Oxford Health NHS Foundation Trust Isis Education Centre Warneford Hospital

Oxford United Kingdom OX3 7JX +44 (0)1865 226 369 paul.salkovskis@hmc.ox.ac.uk Public Oxford Health NHS Foundation Trust https://ror.org/04c8bjx39 Non-commercial NIHR Oxford Biomedical Research Centre http://dx.doi.org/10.13039/501100013373 23087950 true Systematic Assessment of the Medical Utility of Radiology Artificial Intelligence (SAMURAI) in Fracture Detection SAMURAI-Fracture Primary Objective: To evaluate whether implementation of an AI fracture detection tool reduces the proportion of patients having unnecessary NHS healthcare contacts as a result of incorrect diagnoses, i.e. false positive/negative conclusions. Secondary Objectives: To assess the technical performance of an AI fracture detection tool, and its impact on clinician experience, overall patient care experience and service provision. Background and study aims Broken bones (fractures) are commonly misdiagnosed in emergency departments, which can lead to patients experiencing delayed recovery, prolonged pain, and unnecessary follow-up visits to the NHS. In the UK, around 3.7 to 8.7% of suspected fractures are misdiagnosed, primarily because busy emergency staff incorrectly interpret X-rays. This can also lead to patients without fractures being incorrectly told they have a broken bone, resulting in unnecessary treatments. This study aims to test whether using artificial intelligence (AI) software to help clinicians identify fractures on X-rays can reduce these diagnostic errors and improve patient care. The AI tool automatically analyses X-ray images and highlights areas where fractures might be present, helping doctors and nurses make more accurate diagnoses. Who can participate? Anyone aged 2 years or older who attends an emergency department or minor injuries unit and has an X-ray taken for a suspected fracture can be included in this study. This includes both children and adults. Patients cannot participate if they are under 2 years old, need X-rays for suspected child abuse, or require imaging of the skull, facial bones, teeth, or neck spine. Children under 18 with suspected lower back fractures are also excluded. Patients can opt out by using the national NHS data opt-out system or by completing an opt-out form displayed in the emergency department. What does the study involve? The study will run across several NHS hospitals and minor injuries units in the Thames Valley region. During the 6-month study period, AI software will be installed at each site. The AI tool will alternate between being switched on and off each month, so doctors sometimes have access to the AI assistance and sometimes do not. Most patients will simply receive their normal emergency care. The study team will collect information from medical records to see whether the AI reduces misdiagnoses and unnecessary follow-up appointments. No additional X-rays or tests are needed. A small number of patients (30 at each hospital) will be asked if they are willing to be contacted one month after their visit to complete a short questionnaire about their experience. Staff at participating hospitals will also be invited to complete questionnaires about their experience using the AI tool. What are the possible benefits and risks of participating? The AI tool may help clinicians detect fractures more accurately, which could mean patients receive the right treatment more quickly and have fewer unnecessary follow-up visits. Patients might also experience less pain and recover more quickly if their fracture is correctly identified early on. For patients without fractures, there may be less chance of being incorrectly diagnosed and receiving unnecessary treatment. The study involves minimal risk to patients. The AI software is a support tool only and does not replace the doctor's judgement. Clinicians will still make the final decision about diagnosis and treatment. The main risk is that the AI might occasionally make errors, but the study team will carefully monitor the tool's performance to ensure it is working safely. There are no physical risks as patients receive standard care with no additional procedures. Where is the study run from? The study is run from Oxford University Hospitals NHS Foundation Trust, with the main coordination happening at Headley Way, Oxford OX3 9DU. The study will take place across four hospital trusts in the Thames Valley region: 1. Oxford University Hospitals (John Radcliffe Hospital and Horton General Hospital emergency departments) 2. Oxford Health NHS Foundation Trust (minor injuries units) 3. Royal Berkshire NHS Foundation Trust (Royal Berkshire Hospital emergency department and associated minor injuries units) 4. Buckinghamshire Healthcare NHS Trust (Stoke Mandeville Hospital emergency department and associated minor injuries units) When is the study starting and how long is it expected to run for? The study is expected to start in December 2025 and run until December 2026, lasting approximately 12 months in total. Patient recruitment will take place over a six-month period from December 2025 to July 2026. Who is funding the study? The study is funded by Radiobotics, the company that manufactures the AI fracture detection software being tested. Who is the main contact? Prof. Alex Novak, Alex.Novak@ouh.nhs.uk Unnecessary NHS contacts measured via electronic patient record audit of composite endpoints (phone consultations, repeat ED attendances, additional imaging, GP consultations, late fracture clinic referrals, inappropriate early clinical use, unnecessary imaging, immobilization, and sick leave) compared between periods when AI system is active ("On") versus inactive ("Off") throughout the entire 6-month study period (December 2025 – May 2026), with comparison occurring monthly during the alternating On/Off periods. Patient Impact: 1. False negative fracture detection rate measured by comparison of AI algorithm output versus final radiology report at each X-ray during AI "On" periods (December 2025 – May 2026) 2. False positive fracture detection rate measured by comparison of AI algorithm output versus final radiology report at each X-ray during AI "On" periods (December 2025 – May 2026) 3. Number of inappropriate interventions (unnecessary treatments/referrals) measured via electronic patient record audit comparing AI "On" versus AI "Off" periods throughout the 6-month study period 4. Patient-reported outcomes measured using the EQ-5D questionnaire at 1 month post-initial ED/MIU presentation (December 2025 – May 2026) Clinician Impact: 1. Clinician satisfaction and confidence with the AI tool measured using a 5-point Likert scale questionnaire at baseline (December 2025) and 6 months (May 2026) Service Impact: 1. Number of patients referred to Fracture Clinic from ED/MIU measured via electronic patient record and RIS audit comparing AI "On" versus AI "Off" periods throughout the 6-month study period 2. Number of patients admitted to hospital with suspected fractures measured via electronic patient record audit comparing AI "On" versus AI "Off" periods throughout the 6-month study period 3. Number of patients recalled to ED due to missed fractures (false negatives) measured via electronic patient record audit comparing AI "On" versus AI "Off" periods throughout the 6-month study period 4. Number of unplanned reattendances for the same injury measured via electronic patient record audit comparing AI "On" versus AI "Off" periods throughout the 6-month study period 5. Length of Stay (LoS) in ED/MIU for patients with suspected fractures (measured in minutes from registration to discharge) via electronic patient record audit comparing AI "On" versus AI "Off" periods at each patient visit throughout the 6-month study period Technical Performance: 1. Sensitivity and specificity of the AI algorithm measured by comparison of algorithm output to final radiology report as gold standard at each X-ray during AI "On" periods (December 2025 – May 2026) 2. Sensitivity and specificity by subgroup (anatomical region, fracture type, patient demographics, age, ethnicity, and comorbidities) measured by comparison of algorithm output to final radiology report by subgroup during AI "On" periods (December 2025 – May 2026) 3. Number of X-rays rejected or not processed by the AI algorithm (among those within intended use) measured via comparison of vendor algorithm processing logs versus hospital EPR/RIS imaging requests throughout the AI "On" periods (December 2025 – May 2026) Ethics approval required UK Health Research Authority

2 Redman Place, Stratford

London United Kingdom E20 1JQ 357391 Joint Research Office, Oxford University Hospitals NHS Foundation Trust

Second Floor, OUH Cowley Unipart House Business Centre, Garsington Road

Oxford United Kingdom OX4 2PG PID18979-SI001 South Central – Oxford C Research Ethics Committee

Oxford University Hospitals NHS Foundation Trust Unipart House Business Centre, Garsington Road

Oxford United Kingdom OX4 2PG 25/SC/0252 10.1186/ISRCTN23087950 348658 CPMS: 64480 348658 64480 Prospective cluster randomized cross over trial (ABAB/BABA) Interventional Cluster randomised trial Diagnostic 2026-12-31T00:00:00.000Z United Kingdom England Oxford University Hospitals NHS Foundation Trust

John Radcliffe Hospital Headley Way Headington

Oxford England OX3 9DU RTH@2.16.840.1.113883.2.1.3.2.4.18.48 Oxford Health NHS Foundation Trust

Littlemore Mental Health Centre Sandford Road Littlemore

Oxford England OX4 4XN RNU@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Berkshire NHS Foundation Trust

Royal Berkshire Hospital London Road

Reading England RG1 5AN RHW@2.16.840.1.113883.2.1.3.2.4.18.48 Buckinghamshire Healthcare NHS Trust

Amersham Hospital Whielden Street

Amersham England HP7 0JD RXQ@2.16.840.1.113883.2.1.3.2.4.18.48 Patient All patients undergoing X-Rays in ED or MIU for a suspected fracture will be eligible for inclusion Mixed 2 Years 100 Years All 45000 0 1. Patients under 2 years old 2. Skeletal survey conducted to assess for non-accidental injury 3. Skull, facial bone, dental, and cervical spine X-rays 4. Thoracolumbar spine X-rays in patients under 18 years old 5. Patient has opted out of data sharing on the National Data Opt-Out 6. Patient completes the opt out questionnaire displayed on posters in the waiting room 2026-02-24T00:00:00.000Z 2026-07-30T00:00:00.000Z Patients undergoing X-ray for suspected fracture in the emergency department or minor injuries unit Injury, Occupational Diseases, Poisoning The trial will involve installing a MHRA- and CE-approved AI fracture detection software at each site for 6 months. Clinicians will be able to view AI annotated images to aid in diagnosis when reviewing X-rays for suspected fracture. Sites will be randomly assigned to begin the trial with the AI algorithm either active ("On") or inactive ("Off") during the first month. Thereafter, the algorithm status will alternate each month (“AI On” and “AI Off”) for the remaining 5 months. This crossover design ensures that each site experiences both conditions multiple times, allowing within-site comparisons of outcomes under AI-assisted versus standard practice. This study will be conducted across four sites, divided into three clusters: Cluster 1: Oxford University Hospitals NHS Foundation Trust: John Radcliffe Hospital ED (Level 1 ED) Horton General Hospital ED (Level 1 ED) Oxford Health Trust: MIUs (Level 3 EDs) Cluster 2: Royal Berkshire NHS Foundation Trust: Royal Berkshire Hospital ED (Level 1 ED) Associated MIUs (Level 3 ED) Cluster 3: Buckinghamshire Healthcare NHS Trust: Stoke Mandeville Hospital ED (Level 1 ED) Associated MIUs (Level 3 ED) All patients undergoing an X-ray for suspected fracture will be eligible for the study. Dedicated research teams at each site will extract data from Electronic Patient Records and share the anonymised data with the central trial team for evaluation of primary and secondary outcomes. We will gather feedback from patients and clinical staff through electronic surveys at each site. These sites will allow for sufficient patient heterogeneity (socioeconomic, geographical, population, ethnicity) as per the INCLUDE guidance to ensure that our results are generalisable to the wider UK population. Device Not Applicable RBFracture The datasets generated during and/or analysed during the current study will be available upon request to Prof. Alex Novak, Chief Investigator, alex.novak@ouh.nhs.uk. Type of data to be shared: Anonymised imaging data (X-ray images processed by RBFracture™ algorithm) and associated anonymised demographic, clinical, and outcome metadata Timing of availability: Data will become available upon publication of the primary results manuscript, anticipated within 12 months of study completion Duration of availability: Data will be made available for a minimum of 5 years post-publication Access criteria and sharing mechanism: Access will be restricted to bona fide researchers undertaking research aligned with the study objectives. Requests will be reviewed by the study steering group. Data will be shared via secure transfer mechanisms compliant with UK GDPR and NHS information governance requirements Participants' consent for data sharing: Participants were not explicitly consented to data sharing, however, the use of routine clinical data via EPR/RIS and an opt-out consent model supports secondary use for research aligned with the original study purpose Data anonymisation: All data will be fully anonymised with the removal of identifiable information; re-identification will not be possible Ethical and legal restrictions: Data sharing will comply with UK GDPR, NHS information governance protocols, and ethical approval conditions. No ethical restrictions are anticipated beyond these standard requirements Additional comments: This dataset of ~45,000 fracture cases will support future post-market surveillance, algorithm validation studies, comparative evaluations of fracture-detection AI tools, and health economic analyses. Available on request 2026 Protocol article in https://pubmed.ncbi.nlm.nih.gov/42629153/ (added 25/08/2026) Protocol

33be037d-4f13-43e1-9453-de95088336c4 ad31c802-1b41-4577-bab1-4d7cbb5aaa72 f9aeff56-2a4b-4bbc-9352-2c83c0e3d883 Yes Alex Novak https://orcid.org/0000-0002-5880-8235 Public Scientific Principal investigator

Headley Way Headington

Oxford United Kingdom OX3 9DU +44 (0)1865 231550 Alex.Novak@ouh.nhs.uk Public Oxford University Hospitals NHS Trust Hospital/treatment centre https://ror.org/03h2bh287 Non-commercial Radiobotics 34863912 true Enhancing the quality of interactions between parents with psychosis and their young children: a feasibility randomised controlled trial of video feedback EMBRACE The primary objective is to assess the feasibility and acceptability of conducting a randomised controlled trial of a brief video feedback intervention (Video Interaction Guidance [VIG]), versus usual care, in parents with a psychotic disorder who are a caregiver of a child aged 2-36 months. The secondary objective is to collect data on pre-post changes on the following clinical outcomes: 1. Parent-child interaction 2. Parental mental health 3. Parenting stress 4. Child social and emotional wellbeing for participants receiving VIG versus participants receiving usual care. Background and study aims Psychosis is a severe mental health problem characterised by unusual sensory experiences and distressing beliefs, difficulties with motivation, and mood problems. Many patients with psychosis are parents, and their symptoms can impact on their ability to tune into their child’s communication and respond sensitively. This impacts on the parent’s and child’s wellbeing and increases the risk of future child mental health problems. There are no interventions supported by research to help this group of parents to interact with their children. We plan to evaluate an approach called video feedback. It involves the therapist and parent watching brief videotaped interactions between the parent and child, to help parents notice moments of positive interaction where they respond sensitively to their child’s communication. This approach helps parents to build on their strengths. While we know that video feedback works with other parent groups, we do not know whether it helps parents with psychosis. Before carrying out a trial to test video feedback with this patient group, this study will pilot the intervention and study procedures to determine if a larger trial is feasible. Who can participate? People aged 16-65 years with a diagnosed psychotic disorder, who are under the care of an NHS mental health team, and who have caregiving responsibilities for a child aged 2-48 months. What does the study involve? People taking part in the study will be divided into two groups. A computer will decide at random if participants are in group 1 (video feedback) or group 2 (treatment as usual), and there is a 50% chance of being put in either group. Those in the video feedback group will receive eight 1-hour video feedback sessions with a trained therapist in their home or the clinic, spaced every 1-2 weeks. The therapist will video the parent and their child playing for a few minutes during some visits. In other visits, the parent will watch short clips from these videos that show positive moments of the parent and their child together, and parents will be asked about what is going well in the videos. Everyone taking part will continue to receive their usual mental health treatment and support in the team. Everyone who takes part will be asked to meet with a research assistant at the beginning of the study, after 4 months and after 7 months. This research assistant does not know which group participants are in. During these research meetings, participants will be asked to complete questionnaires about their mental health, stress, wellbeing of their child, sources of support, and quality of life. The research assistant will also take a brief film clip of the parent and child playing together. At the end of the study some participants will be invited to take part in an interview with a member of the research team to talk about their experiences of the study. The researchers will also interview the therapists about their experience of delivering video feedback, and survey other health practitioners in the recruiting teams to explore their views of the intervention and study. What are the possible benefits and risks of participating? It is not possible at this stage to say whether taking part will be of benefit to participants. We know from other research studies that parents have found video feedback helpful to build on their strengths and increase their parenting confidence. The information we get from this study will help us to improve the support offered to parents with psychosis in the future. The risks of taking part are likely to be small. The research assessments involve parents talking about their mental health and their children, which they may find upsetting. Parents randomised to receive video feedback would need to put some time aside for these appointments. Some people can feel self-conscious watching clips of themselves and can worry whether others will judge them. The therapists are specially trained to help people deal with these feelings if they arise. Where is the study run from? Oxford Health NHS Foundation Trust and Leicestershire Partnership NHS Trust (UK) When is the study starting and how long is it expected to run for? March 2026 to March 2028 Who is funding the study? National Institute for Health Research (NIHR) (UK) Who is the main contact? Dr Louise Johns, louise.johns@oxfordhealth.nhs.uk The primary outcome measures relate to the feasibility and acceptability of the trial procedures and intervention. The primary efficacy outcome is parent-child interaction (parental responsiveness), assessed using video clips coded using the Emotional Availability (EA) Scales by trained independent raters, at baseline, 16 weeks, and 28 weeks. The video clips of parents and infants up to 15 months will also be rated on the CARE-index by a trained independent rater at baseline, 16 weeks and 28 weeks. Feasibility parameters measured at baseline, 16 and 28 weeks: 1. Number of patients eligible, approached, and consented to participate 2. Number recruited, recruitment rate, and proportion of mothers and fathers recruited 3. Range and average number of sessions attended 4. Proportion of participants completing all planned intervention sessions 5. Number of participants who withdraw from the study and when they withdraw 6. Any adverse effects of participating in the study 7. Acceptability of the intervention, assessed qualitatively post-intervention 8. Reasons for participants not completing the intervention as planned, assessed qualitatively post-intervention 9. Number of participants who complete the outcome measures at each time point and the completeness of their data, and acceptability of the measures assessed qualitatively post-intervention 1. Parent-child interaction is assessed using video clips coded on the Emotional Availability (EA) Scales by trained independent raters at baseline, 16 weeks, and 28 weeks. Video clips of parents and infants up to 15 months are also coded by independent raters on the CARE-index at baseline, 16 weeks, and 28 weeks. 2. Parental mental health is measured using the Depression, Anxiety and Stress Scale at baseline, 16 and 28 weeks 3. Parenting stress is measured using the Parental Stress Scale at baseline, 16 and 28 weeks 4. Social and emotional wellbeing of children is assessed using the parent-reported Ages and Stages Questionnaire: Social and Emotional at baseline, 16 and 28 weeks 5. Health and social care use by the parent and child is assessed using the Client Service Receipt Inventory (CSRI), adapted for this patient group, at baseline and 28 weeks 6. Parental quality of life is measured using the EQ-5D-5L at baseline, 16 and 28 weeks 7. NHS treatments and service use are extracted from the electronic patient record at baseline and 28 weeks Old ethics approval format Approved 17/10/2025, North of Scotland Research Ethics Committee 2 (North of Scotland Research Ethics Service, Summerfield House, 2 Eday Road, Aberdeen, AB15 6RE, UK; +44 (0)1224 558458; gram.nosres@nhs.scot), ref: 25/NS/0120 10.1186/ISRCTN34863912 345724 CPMS: 63188, NIHR: 207967 345724 63188 207967 Interventional Randomized controlled trial Blinded (masking used) Active Single Treatment Not applicable Treatment 2027-12-31T00:00:00.000Z United Kingdom England Slade Site

Horspath Driftway Headington

Oxford England OX3 7JH RNUHE@2.16.840.1.113883.2.1.3.2.4.18.48 Warneford Hospital

Warneford Lane Headington

Oxford England OX3 7JX RNU33@2.16.840.1.113883.2.1.3.2.4.18.48 Whiteleaf Centre

Bierton Road

Aylesbury England HP20 1EG RNUGP@2.16.840.1.113883.2.1.3.2.4.18.48 Leicestershire Partnership NHS Trust Mental Health Services

George Hine House Gipsy Lane Humberstone

Leicester England LE5 0TD RT502@2.16.840.1.113883.2.1.3.2.4.18.48 Merlyn Vaz Health and Social Care Centre

1 Spinney Hill Road

Leicester England LE5 3GH RT5NQ@2.16.840.1.113883.2.1.3.2.4.18.48 Patient false Current inclusion criteria as of 20/07/2026: Parent: 1. Patient of mental health services (at the time of referral to the trial) 2. A clinical diagnosis of schizophrenia spectrum psychosis (non-affective psychosis) (ICD 10 codes F20–29) or bipolar disorder (F31) with psychotic symptoms (affective psychosis) 3. Caregiving responsibilities for child aged 2-48 months 4. Able to speak English or, if not, willing to involve an interpreter to engage in the trial 5. Willing and able to give informed consent Child: 1. Aged between 2 and 48 months at the time of the parent's referral to the trial 2. In regular contact with the participating parent 3. The child’s parent or legal guardian has provided informed consent for their participation in the study procedures Parent qualitative study: 1. Consent to have interviews audio recorded 2. Participation in the study (n = 5); randomised to the intervention arm and having received at least one cycle of VIG (n = 10) Clinician qualitative study: 1. Consent to have interviews audio recorded 2. Experience of either delivering VIG to study participants, or referring a parent to the study, or working with parents with psychosis and young children in the recruiting Trusts Previous inclusion criteria: Parent: 1. Patient of mental health services (at the time of referral to the trial) 2. A clinical diagnosis of schizophrenia spectrum psychosis (non-affective psychosis) (ICD 10 codes F20–29) or bipolar disorder (F31) with psychotic symptoms (affective psychosis) 3. Caregiving responsibilities for child aged 2-36 months 4. Able to speak English or, if not, willing to involve an interpreter to engage in the trial 5. Willing and able to give informed consent Child: 1. Aged between 2 and 36 months at the time of the parent's referral to the trial 2. In regular contact with the participating parent 3. The child’s parent or legal guardian has provided informed consent for their participation in the study procedures Parent qualitative study: 1. Consent to have interviews audio recorded 2. Participation in the study (n = 5); randomised to the intervention arm and having received at least one cycle of VIG (n = 10) Clinician qualitative study: 1. Consent to have interviews audio recorded 2. Experience of either delivering VIG to study participants, or referring a parent to the study, or working with parents with psychosis and young children in the recruiting Trusts Adult All 40 0 Parent: 1. A co-parent is participating in the trial 2. The parent is engaged in another parenting intervention 3. The eligible parent has psychotic symptoms or cognitive difficulties or substance misuse problems that are sufficiently severe to prevent them engaging with the intervention or completing study measures 4. Contact between the parent and child is not permitted by social services 5. Any other factor (for example, current active suicidal plans) which, in the judgement of the investigator, would preclude the participant from providing informed consent or from safely engaging with the trial procedures. Child: 1. Contact with the participating parent is prohibited by social services or a court order 2. The child is already enrolled in another parenting study 3. A sibling is participating in the trial 2026-03-03T00:00:00.000Z 2027-08-01T00:00:00.000Z Psychosis Mental and Behavioural Disorders Video Interaction Guidance (VIG): VIG is a brief, strengths-based video feedback intervention that uses videotaped interactions of the parent and child to enhance parental responsiveness to the child’s cues. The VIG therapist films parent-child interactions for 5 minutes and then edits the footage to produce three short video clips (up to 30 seconds) of successful interaction that link to the parent’s goals. In the subsequent ‘shared review’ session, the parent and VIG therapist review the selected clips together. Seeing the videos with the therapist allows the parent to build on moments of positive interaction with their child. One cycle of VIG involves filming (session 1), editing (between sessions), and reviewing video clips (session 2). Parents will receive an introductory session, 3 cycles of VIG (one cycle = two sessions, over 2-3 weeks), and a review session. The intervention will be delivered over 8-10 weeks. Sessions last 45-60 minutes and are delivered in the parent’s home or the clinic. Usual Care: All participants will continue to receive usual care from their treating team. Usual care includes care-coordination, psychiatric review, medication, psychological therapy, family therapy and carer support (for the patient’s caregivers), physical health monitoring, peer support, and, in perinatal teams, parenting skills support. We will not ask referrers or clinicians to withhold any treatment offered as part of usual care in either trial arm. Behavioural The datasets generated during and/or analysed during the current study will be available upon reasonable request from Dr Louise Johns (louise.johns@oxfordhealth.nhs.uk). De-identified data will be made available to external researchers subject to the constraints of the consent under which data were collected, with an appropriate data sharing agreement, and after publication of the main study report. Available on request aaf7a521-011a-4a6f-981c-4713a637b8ee 8c0efb40-c810-410f-aeeb-abb174948d36 4598c0db-93b7-4227-8d22-deab6e13e115 Yes Louise Johns https://orcid.org/0000-0003-3355-3202 Scientific

Oxford Early Intervention Service John Sharich House, Slade Site Horspath Driftway

Oxford United Kingdom OX3 7JH - louise.johns@oxfordhealth.nhs.uk Public Oxford Health NHS Foundation Trust Hospital/treatment centre https://ror.org/04c8bjx39 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 59554792 true The efficacy of xanomeline-trospium in treating cognitive impairment in psychosis: A randomised, double-blind active-controlled clinical trial FOCUS Primary objectives: To compare the overall change in cognitive performance between patients who have been treated for 6 weeks with xanomeline-trospium versus a D2 antagonist. Secondary objectives: 1. To compare improvement on measures of symptoms, functioning and side effects between patients who have been treated for 6 weeks with xanomeline-trospium versus D2 antagonist. 2. To compare the longer-term effects of treatment with xanomeline-trospium compared to a D2 antagonist. 3. To determine the change in biomarkers that occur following treatment with xanomeline-trospium compared to a D2 antagonist. 4. To assess if baseline biomarkers predict symptomatic improvement following treatment with xanomeline-trospium and D2 antagonists. Background and study aims Psychosis is a mental health condition where people may experience symptoms such as hearing voices or experiencing beliefs or perceptions that others may not have. Many people with psychosis also have difficulties with concentration, memory, and other thinking skills - these are called cognitive symptoms. Current treatments for psychosis work by blocking dopamine D2 receptors in the brain. These medicines can help with hallucinations and delusions but do not usually improve cognitive symptoms. Xanomeline–trospium is a new treatment being tested that works differently from standard antipsychotics, by activating muscarinic receptors rather than blocking dopamine receptors. This study will compare xanomeline–trospium with two commonly used antipsychotics (risperidone and lurasidone) to find out which is more effective at improving cognitive symptoms in people with early psychosis. Who can participate? Adults with early psychosis who are considering changing their current medication can take part. A separate group of healthy volunteers will also take part to provide comparison data, but they will complete assessments only and will not receive study medication. What does the study involve? Participants with early psychosis will be randomly assigned (like flipping a coin) to take either xanomeline–trospium or one of the two standard antipsychotics (risperidone or lurasidone) for 6 weeks. Neither participants nor the research team will know which treatment has been given until the end of this phase. During the 6-week treatment period, participants will attend visits at the start (baseline), at 3 weeks, and at 6 weeks. At these visits, they will complete tests to assess memory and thinking, and assessments of symptoms, daily functioning, and quality of life. At some visits, they will also have brain scans and give blood samples. After 6 weeks, participants will be told which treatment they received, and if they were receiving xanomeline-trospium, they can decide whether they would like to continue in the study for another year in an open-label setting. If they choose to continue with the study, there will be an additional visit after one year, and three three-monthly safety calls. What are the possible benefits and risks of participating? Participation will help researchers assess whether xanomeline-trospium helps thinking, memory, and other symptoms of psychosis, more than standard antipsychotics. The information collected will help develop better treatments for psychosis. Participants will receive reimbursement for their time and to cover travel expenses. Like all medicines, the study drugs can cause side effects. Xanomeline–trospium can cause nausea, vomiting, sweating, and constipation. Risperidone and lurasidone can cause movement problems, weight gain, drowsiness, and hormonal changes. Although these are the most common side effects, all medicines can also have other side effects, which will be monitored throughout the trial. Some of the assessments may feel mentally or emotionally demanding and giving blood samples and the brain scans may be uncomfortable. The brain scans are optional, so participants can choose not to take part in this part of the study. Where is the study run from? There will be a study site at the University of Oxford, Oxford (UK) in collaboration with Oxford Health NHS Foundation Trust, and at King’s College London, London (UK) in collaboration with South London and Maudsley (SLaM) NHS Foundation Trust (UK) When is the study starting and how long is it expected to run for? November 2025 to August 2030 Who is funding the study? The Wellcome Trust (UK) Who is the main contact? 1. Dr Robert McCutcheon, robert.mccutcheon@psych.ox.ac.uk 2. Dr Bodyl Brand, Michael Sinden or Lucy Cureton, focus@psych.ox.ac.uk Cognitive performance measured using the CANTAB composite score from baseline (Visit 2) to 6 weeks post-baseline (Visit 4) 1. Psychosis symptom severity measured using the Positive and Negative Syndrome Scale (PANSS) total and subscale scores from baseline (Visit 2) to 3- and 6-weeks post-baseline (Visit 3 and Visit 4) 2. Functional capacity measured using the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) from baseline to week 6 3. Individual cognitive domains of the CANTAB measured using individual CANTAB tests from baseline to 6 weeks post-baseline 4. Global clinical severity measured using the Clinical Global Impression – Severity/Improvement scale (CGI-S/I) from baseline to 3- and 6-weeks post-baseline 5. Patient-rated global severity measured using the Patient Global Impression – Severity/Improvement scale (PGI-S/I) from baseline to 3- and 6-weeks post-baseline (Visit 3), and 6 weeks post-baseline (Visit 4) 6. Negative symptom severity measured using the Brief Negative Symptom Scale (BNSS), from baseline, to 3- and 6-weeks post-baseline 7. Subjective cognitive functioning measured using the Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS), from baseline (Visit 2) to 3- and 6-weeks post-baseline 8. Depression symptoms measured using the Calgary Depression Scale for Schizophrenia (CDSS) from baseline to 3- and 6-weeks post-baseline 9. Subjective well-being measured using the Subjective Well-being under Neuroleptics (SWN) scale from baseline (Visit 2) to 3- and 6-weeks post-baseline 10. Work and social adjustment measured using the Work and Social Adjustment Scale (WSAS), from baseline (Visit 2) to 3- and 6-weeks post-baseline 11. Daily functioning measured using the Specific Level of Functioning Scale (SLOF) and the Social and Occupational Functioning Assessment Scale (SOFAS) from baseline (Visit 2) to 6 weeks post-baseline (Visit 4) 12. Quality of life measured using the Recovering Quality of Life scale (ReQoL), from baseline (Visit 2) to 6 weeks post-baseline (Visit 4) 13. Treatment acceptability assessed using the Theoretical Framework of Acceptability – Treatment Acceptability Scale (TFA-TAS), from baseline to 3- and 6-weeks post-baseline 14. Side effects monitored using the Glasgow Antipsychotic Side-Effect Scale (GASS) supplemented with five items from the UKU Side Effect Rating Scale (UKUSERS) at baseline (Visit 2), 3 weeks post-baseline (Visit 3), and 6 weeks post-baseline (Visit 4) Follow-up phase (participants in follow-up only): Longer-term effects of treatment measured assessing the change in PANSS, VRFCAT, CANTAB (composite and subtests), CGI-S, CGI-I, PGI-S, PGI-I, BNSS, SSTICS, CDSS, TFA-TAS, SWN, WSAS, SLOF, SOFAS, and ReQoL scores from baseline to 58 weeks post-baseline (Visit 5) Biomarkers: Biomarkers (MRI, MEG, and blood-based measures) assessed at baseline (Visit 2), 6 weeks post-baseline (Visit 4), and 58 weeks post-baseline (Visit 5) Ethics approval required South West - Central Bristol Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 25/SW/0096 10.1186/ISRCTN59554792 1010141 18770 1010141 18770 Double-blind randomized controlled parallel-group trial Interventional Randomised controlled trial Efficacy Safety 2030-08-31T00:00:00.000Z United Kingdom England Warneford Hospital

Warneford Lane Headington

Oxford England OX3 7JX RNU33@2.16.840.1.113883.2.1.3.2.4.18.48 Kings College Hospital

Mapother House De Crespigny Park Denmark Hill

London England SE5 8AB NV178@2.16.840.1.113883.2.1.3.2.4.18.48 Healthy volunteer Patient General inclusion criteria: 1. Individuals aged 18 to 55 years, willing and able to provide written informed consent 2. In the Investigator’s opinion, is able and willing to comply with all trial requirements 3. Able to understand and communicate in English 4. Body mass index ≥18 and ≤40 kg/m2 Additional inclusion criteria for early psychosis participants: 1. The participant meets DSM-5 criteria for schizophrenia, schizoaffective disorder, or schizophreniform disorder, as confirmed through the Mini International Neuropsychiatric Interview (MINI). 2. The participant has previously been treated with an antipsychotic. 3. The participant is within 10 years of first experiencing psychosis. 4. The participant is wishing to either commence an antipsychotic (if not currently receiving treatment), or switch from their current antipsychotic treatment and this is clinically indicated. 5. Attitude to antipsychotic medication is rated 4 or more on the Kemp Clinician Rating Scale (CRS). 6. Participants of childbearing potential (*) and male participants (assigned sex at birth) whose partner is of childbearing potential must confirm that they are using effective contraception, or that their partner is using effective contraception throughout the trial, in accordance with the requirements outlined in the protocol**. 7. The participant is willing to allow their General Practitioner and consultant, if appropriate, to be notified of participation in the trial. Additional inclusion criteria for control participants: 1. No diagnosis of psychiatric disorder other than previous episode(s) of depression or anxiety. 2. The participant is willing and able to undergo MRI/MEG scans. *A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. ** Methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include: 1) combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral; intravaginal; transdermal); 2) progestogen-only hormonal contraception associated with inhibition of ovulation (oral; injectable; implantable); 3) intrauterine device (IUD); 4) intrauterine hormone-releasing system (IUS); 5) bilateral tubal occlusion; 6) vasectomised partner; 7) sexual abstinence (abstinence should only be used as a contraceptive method if it is in line with the subjects’ usual and preferred lifestyle. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an acceptable method of contraception). The participant agrees to use an acceptable method of contraception for the full duration of the trial and for 30 days after any trial drug administration, unless surgically sterile or postmenopausal. Adult 18 Years 55 Years All 180 0 General exclusion criteria: 1. Pregnancy or breastfeeding. 2. The participant has a current diagnosis of ‘Substance or medication induced psychotic disorder’ or ‘Psychotic disorder due to another medical condition’ as determined through the MINI. 3. Current active suicidal ideation within the last 2 weeks, defined as a score of 1 or higher on CDSS question 8, followed by an assessment by the treating clinician who determines it is not safe for the patient to participate in the trial* 4. Meeting DSM-V criteria for substance use disorder, except for nicotine (mild, moderate, and severe allowed) well as alcohol or cannabis abuse (mild allowed). 5. Positive urine drug screen, except for cannabis provided that cannabis abuse (moderate or severe) or dependency has been ruled out, as determined through the MINI. 6. Participant has participated in another clinical trial in which the participant received an experimental or investigational drug or agent within 2 months before Visit 1. Participants who have participated in Type A studies (e.g. trials of standard and within-label treatments including antipsychotic medication) or non-CTIMP studies (e.g. studies of exercise therapy) must have completed the intervention but may be included if permitted by the protocol of the other trial. 7. The participant refuses any mandatory safety checks during the trial, specifically, refusal of: assessment of suicidality, pregnancy test (early psychosis participants of child-bearing potential only); safety blood test (early psychosis participants only); reporting of Adverse Events (AEs) (early psychosis participants only). 8. Any other significant factor which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant’s ability to participate in the trial. Additional exclusion criteria for early psychosis participants: 1. The participant meets modified Andreasen criteria for symptomatic remission AND displays no cognitive deficits at the screening visit. 2. Known hepatic impairment (mild, moderate or severe) and/or transaminase elevations levels exceeding the upper limit of normal 3 times or more and bilirubin greater than 2 times the upper limit of normal. 3. Abnormal ECG results at screening (QTC ≥450 ms for males and ≥460 ms for females) 4. In addition to abnormal transaminase levels and eGRF levels any other lab values that, based on the investigator’s assessment, may deem the participant unsuitable for inclusion. 5. Known renal dysfunction and/or estimated glomerular filtration rate (eGRF) level below 60 ml/min/1.73 m2. 6. History or high risk of urinary retention, angioedema, gastric retention, or narrow-angle glaucoma. 7. History of serious constipation requiring treatment in the last 6 months 8. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the investigator, would jeopardise the safety of the subject or the validity of the study results. 9. Experienced any adverse effects related to trospium chloride previously, or allergy to any component of trospium chloride tablets 10. Contraindication to treatment with lurasidone AND risperidone. If the participant has a contraindication to just one of these medications, they can still participate in the trial. In that case, if allocated to the standard antipsychotic arm, they will use the medication for which they do not have a contraindication. 2025-11-01T00:00:00.000Z 2029-06-30T00:00:00.000Z Schizophrenia, schizoaffective disorder, or schizophreniform disorder Mental and Behavioural Disorders Early psychosis participants are randomised in a 1:1 ratio in this Phase III trial to receive either xanomeline–trospium or a dopamine D2 antagonist (risperidone or lurasidone). Randomisation is stratified by site, baseline cognition status, and biological sex, and is performed centrally using the University of Oxford’s secure online Sortition randomisation system with randomly permuted block sizes to ensure allocation concealment. Arm 1 – Xanomeline–trospium Administered orally as capsules containing xanomeline tartrate and trospium chloride drug beads. Dosing is initiated at 50 mg/20 mg twice daily for the first 2 days, increased to 100 mg/20 mg twice daily for days 3–7, then titrated to 125 mg/30 mg twice daily from day 8 (week 2). Participants unable to tolerate the highest dose may reduce to 100 mg/20 mg twice daily. Xanomeline–trospium is administered for 6 weeks during the double-blind phase. Participants may choose to continue in a 52-week single-blind extension, during which xanomeline–trospium is prescribed and managed as part of trial procedures at the end-of-double-blind dose, with adjustments as needed for safety and tolerability. Arm 2 – Dopamine D2 antagonist (risperidone or lurasidone) Allocation to risperidone or lurasidone is based on prior treatment history and clinical contraindications. Risperidone: Initiated at 1 mg twice daily for the first 2 days, followed by 2 mg twice daily for the remainder of week 1 (days 3 to 7). On day 8 (week 2), the dose will be increased to 3 mg twice daily, unless the participant experienced adverse events from their previous dose. Participants who increased to 3 mg twice daily have the option to return to 2 mg twice daily, depending on tolerability, until day 21. Lurasidone: Initiated at 37 mg twice daily for the first 2 days, followed by 55.5 mg twice daily for the remainder of week 1 (days 3 to 7). On day 8 (week 2), the dose will be increased to 74 mg twice daily, unless the participant experienced adverse events from their previous dose. Participants who increased to 74 mg twice daily have the option to return to 55.5 mg twice daily, depending on tolerability, until day 21. All medication is taken twice daily for 6 weeks during the double-blind treatment phase. Participants may continue for a further 52 weeks in a single-blind extension. In this extension, those in arm 1 will continue to receive trial medication provided by the trial, while those in arm 2 will have their medication prescribed and managed as per usual care by their clinical team. Follow-up After the screening visit and the baseline visit, follow-up visits and assessments occur at 3 weeks, 6 weeks, and 58 weeks for those in the extension, with additional safety calls as specified in the protocol. Drug Phase III Xanomeline tartrate, trospium chloride, risperidone, lurasidone Not expected to be made available ab43c0e8-1490-4ab9-97d1-6402eb9e975f 2e0de0c8-2f96-44ae-ba7f-0fd550f117a9 5fd14951-4f85-488d-ba60-9171d7aa9c62 7458f712-665c-41a4-99d4-3553e7958291 ebd66e26-0924-4ba7-8d27-dc2c978756a2 No Robert McCutcheon Scientific Principal investigator

Department of Psychiatry University of Oxford

Oxford United Kingdom OX3 7JX +44 (0)1865 618200 robert.mccutcheon@psych.ox.ac.uk Public Bodyl Brand Scientific

Warneford Hospital Warneford Lane Headington

Oxford United Kingdom OX3 7JX - focus@psych.ox.ac.uk Public Michael Sinden Public

Trial Manager Primary Care Clinical Trials Unit Nuffield Department of Primary Care Health Sciences Gibson Building Radcliffe Observatory Quarter Woodstock Road

Oxford United Kingdom OX2 6GG - FOCUS@psych.ox.ac.uk Public University of Oxford University/education https://ror.org/052gg0110 Non-commercial Wellcome Trust http://dx.doi.org/10.13039/100010269 17122014 true REal world internet COgnitiVE theRapy for Social Anxiety Disorder (RECOVER-SAD) RECOVER-SAD Primary objective: To compare the effectiveness of iCT-SAD to treatment as usual (TAU) in reducing self-reported social anxiety Secondary Objectives: 1. To compare iCT-SAD to TAU on the binary outcomes commonly reported by NHS TT services (reliable improvement and reliable recovery) 2. To compare the effectiveness of iCT-SAD to TAU in reducing symptoms of depression and general anxiety, reducing interference with life due to mental health problems, and improving quality of life 3. To compare changes in employment status/ benefits of iCT-SAD to TAU 4. To compare the therapist time needed and cost-effectiveness of iCT-SAD to TAU Process analyses: 1. To compare the credibility, working alliance, acceptability and treatment satisfaction of iCT-SAD to TAU 2. To compare changes in unhelpful cognitions, safety behaviours and avoidance of iCT-SAD to TAU 3. To explore patient and therapist experience with iCT-SAD Background and study aims Social anxiety disorder (SAD) is a common and distressing mental health problem that can persist for many years and hold people back in life. Cognitive therapy based on the Clark & Wells (1995) model helps people recover and rebuild their lives. Clinical trials have shown it is more effective than alternative treatments (Clark et al, 2003, 2006; Ingul, Aune, & Nordahl, 2013; Mörtberg, Clark, Sundin, & Åberg Wistedt, 2007; Stangier, Heidenreich, Peitz, Lauterbach, & Clark, 2003: Stangier, Schramm, Heidenreich, Berger, & Clark, 2011; Leichsenring et al., 2013; Nordahl et al., 2016). However, many people cannot access the treatment due to shortage of therapists or because they are unable to attend clinic-based therapy during working hours. To overcome these problems, the group who developed cognitive therapy for SAD created an internet version. Instead of attending weekly 90-minute therapy sessions in a clinic, patients learn how to overcome their difficulties by working through an engaging and media-rich internet programme they can access from home at any time. A therapist supports them through the programme, but sessions are by video link or phone and much shorter than usual, as people have already learned many of the lessons of therapy from their online study. Preliminary research shows many patients find the internet cognitive therapy acceptable (Clark, et al, 2023). So far, the reported outcomes are at least as good (often better) than those seen with traditionally delivered therapy in NHS services. These promising findings led the National Institute for Care and Clinical Excellence (NICE) to recommend the internet programme for use in the NHS while further data is being collected to unambiguously assess its value NICE (2023a). NHS resources are limited and need to be spent wisely. NICE (2023b) therefore wishes to know how the internet therapy compares with clinic-based treatment when delivered by NHS staff to people with similarly disabling conditions. This randomized controlled trial will answer NICE’s question. People who are seeking treatment for SAD in six NHS Talking Therapy services and are willing to participate will receive internet cognitive therapy or usual NHS treatment. Comparisons between the treatments will look at how many people recover, how their symptoms and quality of life change, the therapist time needed to deliver the treatments, cost-effectiveness, how satisfied patients and therapists are with the internet treatments and how they describe their experience. Who can participate? 1. People with social anxiety disorder who receive treatment at one of the participating NHS Talking Therapies (NHS TT) services and agree to participate in the study 2. About 20 therapists from participating NHS TT services who will deliver the internet-assisted treatment. What does the study involve? Participating patients will be allocated by chance to receive either the iCT-SAD treatment programme supported by a NHS TT therapist or treatment as usual (TAU) with an NHS TT therapist. It also involves completing questionnaires about their symptoms, thoughts, ways of coping, and quality of life at initial assessment and 22, 44 and 66 weeks after allocation (and at the end of treatment if this is later than 22 weeks). They also rate once how credible they find the treatment they receive, and how satisfied they are with the treatment and with working with their therapist. Some will be invited to attend an interview about their experience with iCT-SAD. Participating therapists will be trained to guide and support patients during the iCT-SAD treatment programme. They will then treat patients with social anxiety participating in the trial. At the end of the study they will complete a questionnaire on their experience with delivering the treatment. Some therapists will be invited to attend an interview about their experience with iCT-SAD. What are the possible benefits and risks of participating? All participants will receive a psychological treatment for their social anxiety disorder that has been shown to be effective. The NHS therapists who deliver the treatments have received training and have regular supervision. As with any psychological treatment, it cannot be guaranteed that every participant will benefit. Undertaking treatment for social anxiety disorder can be challenging. Treatment encourages participants to reflect on their difficulties to understand how social anxiety works and supports them in tackling situations that they may have previously avoided. While doing this may temporarily increase distress, facing these challenges is an important step towards overcoming social anxiety disorder. Treatment will be personalised for each patient. Where is the study run from? University of Oxford (UK) When is the study starting and how long is it expected to run for? March 2024 to December 2028 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK). Who is the main contact? Dr Donna Winston, donna.winston@psy.ox.ac.uk 1. Social anxiety symptoms measured with the Social Phobia Inventory (SPIN) completed at baseline, 22 weeks, 44 weeks and 66 weeks post-randomisation, and actual end of treatment if different from 22 weeks. 1. Reliable improvement and reliable recovery as defined in NHS TT manual based on cut-offs on the Social Phobia Inventory (SPIN) and Patient Health Questionnaire (PHQ-9) completed at 22 weeks after randomisation, and actual end of treatment if different from 22 weeks. 2. Depression symptoms measured with the Patient Health Questionnaire PHQ-9 completed at baseline, 22 weeks, 44 weeks and 66 weeks, and actual end of treatment if different from 22 weeks. 3. Anxiety symptoms measured with the Generalised Anxiety Disorder Questionnaire (GAD-7) completed at baseline, 22 weeks, 44 weeks and 66 weeks, and actual end of treatment if different from 22 weeks. 4. Interference with life due to mental health difficulties as measured with the Work and Social Adjustment Scale (WSAS) completed at baseline, 22 weeks, 44 weeks and 66 weeks, and actual end of treatment if different from 22 weeks. 5. Changes in employment and benefits status measured by patient demographics questionnaire at baseline, 22 weeks, 44 weeks and 66 weeks, and actual end of treatment if different from 22 weeks 6. Quality of life measured by the Recovering Quality of Life (ReQoL) at baseline, 22 weeks, 44 weeks and 66 weeks, and actual end of treatment if different from 22 weeks. 7. Therapist time involved in iCT-SAD and TAU as measured by number of sessions and their duration. 8. Cost effectiveness of iCT-SAD and TAU as measured by EuroQol EQ-5D-5L, Client Service Receipt Inventory, and iMTA Productivity Cost Questionnaire completed at baseline, 22 weeks, 44 weeks, 66 weeks, and actual end of treatment if different from 22 weeks. Process measures: 9. Treatment acceptability and patient satisfaction with treatment assessed with the NHS TT Patient Experience Questionnaire (PEQ), Acceptability Scale and interviews with some iCT-SAD patients at the end of treatment. 10. Credibility of treatment measured with the Borkovec and Nau Credibility scale after the second session with therapist. 11. Quality of therapeutic relationship as measured with the Working Alliance Scale completed by patients and therapists after the second session with therapist. 12. Changes in unhelpful cognitions, safety behaviours, and avoidance as measured by the Social Cognitions Questionnaire, Social Behaviour Questionnaire, Social Attitudes Questionnaire-short, Liebowitz Social Anxiety Scale, and Social Summary Scale at baseline, 22 weeks, 44 weeks, 66 weeks, and actual end of treatment if different from 22 weeks. User experience with iCT-SAD: 13. Therapists’ experience with delivering iCT-SAD assessed with the Therapist Experience Questionnaire and, for some, interview at end of study. 14. Patients’ experience assessed through ratings of helpfulness and free comments provided at the end of each module and, for some, interview at end of study. Ethics approval required London Bloomsbury Ethics Committee

85 Tottenham Ct Road

London United Kingdom W1T 4TQ REC ref: 25/LO/0574 10.1186/ISRCTN17122014 352935 CPMS: 67316 352935 67316 Interventional multisite randomized controlled trial Interventional Randomised controlled trial Treatment 2028-12-31T00:00:00.000Z United Kingdom England Oxford Health NHS Foundation Trust

Littlemore Mental Health Centre Sandford Road Littlemore

Oxford United Kingdom OX4 4XN RNU@2.16.840.1.113883.2.1.3.2.4.18.48 Hertfordshire Partnership University NHS Foundation Trust

The Colonnades Beaconsfield Close

Hatfield United Kingdom AL10 8YE RWR@2.16.840.1.113883.2.1.3.2.4.18.48 Greater Manchester Mental Health NHS Foundation Trust

Prestwich Hospital Bury New Road Prestwich

Manchester United Kingdom M25 3BL RXV@2.16.840.1.113883.2.1.3.2.4.18.48 Homerton Healthcare NHS Foundation Trust

Homerton Row

London United Kingdom E9 6SR RQX@2.16.840.1.113883.2.1.3.2.4.18.48 Health professional Patient Patients: 1. Social Anxiety Disorder is the main psychological problem, and the patient's priority to work on in therapy 2. Any gender, aged 18 years or above with no upper age limit. 3. Willingness to be allocated by chance to either iCT-SAD or NHS TT non-digital psychological treatment as usual (TAU) 4. Able to read and write in English 5. Access to the internet at home (or another safe location) and availability of tablet or laptop/computer, access to a mobile phone that can receive text messages Clinicians: 1. High Intensity CBT therapist or Psychological Well-Being practitioner working within a participating NHS TT service 2. Trained in the delivery of iCT-SAD 3. Willing to participate 4. Clinical capacity and managerial approval to participate Adult 18 Years All 240 Patients: 1. Social Anxiety Inventory (SPIN) score below clinical caseness ( < 19) 2. Acute suicide risk 3. Substance dependence Clinicians: 1. No exclusion criteria 2025-11-24T00:00:00.000Z 2027-03-31T00:00:00.000Z Social anxiety disorder Mental and Behavioural Disorders Participants will be allocated by chance using an online randomisation system (SealedEnvelope) to one of two treatments. - Half of the participants will receive a therapist-assisted internet version of cognitive therapy for social anxiety disorder. Cognitive therapy for social anxiety disorder based on the Clark & Wells model (1995) is recommended by NICE (2013) and international treatment guidance. It is usually delivered in one-to-one sessions. A therapist-assisted internet-delivered version (iCT-SAD) has been found to be efficacious and acceptable to patients. Patients are guided through the online treatment programme by a NHS CBT therapist. Patients work through the therapy modules of iCT-SAD on a secure website, as well as completing treatment-related tasks and activities as part of their daily routine. The therapist releases the modules that are relevant to the individual patient and supports them through messages and video or phone calls. Treatment will be usually be delivered over a period of 3 to 5 months. After treatment and discharge from the service, participants will complete follow-up questionnaires at 44 and 66 weeks after randomisation. - The other half of participants will receive treatment as usual in NHS Talking Therapies services, which usually involves one-to-one video or in-person sessions of an evidence-based psychological treatment for social anxiety disorder with a NHS CBT therapist. Treatment will be usually be delivered over a period of 3 to 5 months. After treatment and discharge from the service, participants will complete follow-up questionnaires at 44 and 66 weeks after randomisation. Behavioural The data sharing plans for the current study are unknown and will be made available at a later date Data sharing statement to be made available at a later date 8f7582b6-64f2-4eda-8fa7-85d29d0843c2 910c64ae-e81f-42b8-8a91-fe02591aeaf8 06a34647-b098-488f-b267-8699625d1d4d de2be7fb-feea-419e-b96b-4e98f17ecf93 No Donna Winston https://orcid.org/0000-0001-6517-6240 Public

Oxford Centre for Anxiety Disorders and Trauma (OxCADAT) Department of Experimental Psychology University of Oxford Life and Mind Building South Parks Rd

Oxford United Kingdom OX1 3EL +44 1865281382 donna.winston@psy.ox.ac.uk Public Anke Ehlers https://orcid.org/0000-0002-8742-0192 Scientific Principal investigator

Oxford Centre for Anxiety Disorders and Trauma (OxCADAT) Department of Experimental Psychology University of Oxford Life and Mind Building South Parks Rd

Oxford United Kingdom OX1 3EL +44 (0)1865618600 anke.ehlers@psy.ox.ac.uk Public University of Oxford University/education https://ror.org/052gg0110 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272