63031617 true A multi-centre, randomised controlled feasibility trial comparing virtual reality-enhanced blended care versus standard eye movement desensitization and reprocessing therapy for adults with post-traumatic stress disorder Background and study aims Post-traumatic stress disorder (PTSD) can be very distressing. A talking therapy called eye movement desensitisation and reprocessing (EMDR) is a recommended treatment, but access is often limited by how many in-person sessions clinicians can offer. This study tests whether giving patients a virtual reality (VR) headset to use at home, alongside their usual EMDR sessions, is a safe, practical and acceptable way to support their treatment. As this is a feasibility study, the main aim is to find out whether this "blended care" approach works well in practice, before a larger trial is carried out. Who can participate? Patients aged 18 years or over with a primary diagnosis of PTSD What does the study involve? Participants are randomly allocated (like flipping a coin) to one of two groups. Both groups receive six weekly sessions of standard, in-person EMDR therapy from a qualified clinician. Participants in the intervention group are additionally given a VR headset to take home for a 3-week period, during which they use it for 40-50 minutes roughly every other day to complete therapeutic exercises, with their clinician monitoring progress and adjusting the schedule as needed. All participants complete questionnaires about their PTSD, mood and anxiety symptoms at the start, middle and end of the 6-week treatment period. What are the possible benefits and risks of participating? All participants receive standard EMDR therapy, a treatment recommended by NICE guidance for PTSD. Those in the VR group may benefit from more flexible and frequent treatment, which could help them engage more with their recovery, though this has not yet been proven. Possible risks include increased emotional distress if home-based trauma processing is difficult to tolerate, mild physical discomfort (such as nausea or eye strain) from using a headset, and a small risk of minor injury during unsupervised home use. These risks are reduced through in-clinic training before home use, a maximum session length, built-in prompts to support grounding exercises, weekly clinical monitoring, and a clear crisis plan given to every participant. Where is the study run from? The study is coordinated by Reinhart (UK) and is being run from three sites in England: Avon and Wiltshire Mental Health Partnership NHS Trust (Bath), Nightingale Hospital (London) and The Soke (London). When is the study starting and how long is it expected to run for? August 2026 to April 2027 Who is funding the study? Innovate UK Who is the main contact? Dr Francis Madden, francis@reinhart.uk Feasibility adherence rate the proportion of prescribed home-use sessions successfully completed, extracted objectively via the VR software's internal logs continuously monitored over the 3-week active home-use block (assessed at week 6 end of treatment) Clinical efficacy (PTSD severity) the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition PTSD Checklist (DSM-5 PCL-5) score baseline (week 1), midpoint (week 3/VR start), and end of treatment (week 6) Clinical efficacy (comorbidities) the Patient Health Questionnaire-9 (PHQ-9) for depression and Generalized Anxiety Disorder-7 (GAD-7) for anxiety baseline (week 1), midpoint (week 3/VR start), and end of treatment (week 6) Safety profile the incidence and frequency of adverse device effects (ADEs) tracked continuously throughout the 6-week trial duration Usability/acceptability the System Usability Scale (SUS) and User Experience Questionnaire - Short Version (UEQ-S) week 6 post-treatment (intervention group only) Ethics approval required South East Scotland REC 02

Waverley Gate, 2-4 Waterloo Place

Edinburgh United Kingdom EH1 3EG 26/SS/0056 10.1186/ISRCTN63031617 365747 CPMS: 72883 365747 72883 Interventional Randomized controlled trial Open (masking not used) Active Parallel Device feasibility Health services research Treatment Not applicable 2027-04-11T00:00:00.000Z United Kingdom England Avon and Wiltshire Mental Health Partnership NHS Trust

Bath NHS House Newbridge Hill

Bath England BA1 3QE RVN@2.16.840.1.113883.2.1.3.2.4.18.48 Nightingale Hospital

11-19 Lisson Grove

London England NW1 6SH The Soke

241 Fulham Road

London England SW3 6HY false 1. Capable of giving informed consent 2. Male or female adults aged 18 years or over 3. Primary diagnosis of post-traumatic stress disorder (PTSD) (relating to single-event or multiple/complex trauma) confirmed by a clinician 4. Proficient in English (sufficient to complete assessments and engage with the therapy/software) 5. Willing to be randomised to either treatment group (Standard Care or Blended VR Care) Mixed 18 Years 999 Years All 64 0 1. Currently receiving another formal psychotherapy for PTSD or anxiety 2. Current severely dependent substance use disorder 3. Active suicidal ideation or intent, or a recent suicide attempt 4. Presence of severe mental health conditions that would interfere with participation or safety, specifically active psychosis, severe depression requiring inpatient care, or Dissociative Identity Disorder (DID) 5. Medical conditions that contraindicate EMDR therapy, such as uncontrolled seizure disorders 6. Medical conditions that contraindicate Virtual Reality use, such as severe history of motion sickness or specific visual impairments that prevent the use of the headset 7. Known inability to use or tolerate VR or AR equipment 8. Currently involved in a conflicting clinical trial for an investigational drug or device 2026-08-24T00:00:00.000Z 2027-02-28T00:00:00.000Z Post-traumatic stress disorder (PTSD) Mental and Behavioural Disorders Participants are randomised 1:1 to the intervention or control group using permuted block randomisation with varying block sizes. The randomisation sequence is managed through a secure, central online randomisation service to ensure allocation concealment. Control Group: Participants receive 6 weekly sessions of standard in-person Eye Movement Desensitization and Reprocessing (EMDR) therapy delivered by a qualified clinician Intervention Group: Participants receive standard weekly in-person EMDR therapy combined with a fixed 3-week home-use block. During this block, participants self-administer a 40–50 minute adjunctive trauma processing session every other day (targeting 3–4 sessions per week) utilising the Psylaris EMDR-VR medical device. Device Not Applicable VR EMDR Anonymised participant-level data may be made available to external researchers upon reasonable request and approval by the Trial Management Group, following publication of the primary results. The final dataset will be accessible to the Chief Investigator, the trial statistician, and the Trial Management Group. Available on request 7b5ac052-5dfc-46af-92b4-c76e7f97da90 2d2e467b-f885-4513-adb0-92ac62e9c7a4 697bfb1f-65c6-4009-b582-8f59dfba59c2 Yes Francis Madden https://orcid.org/0000-0003-2944-0934 Public Scientific Principal investigator

6 Charlton Terrace

London United Kingdom SE11 4DG +44 (0)7474589637 francis@reinhart.uk Public Reinhart Group Ltd Commercial Innovate UK http://dx.doi.org/10.13039/501100006041 13746769 true A randomised controlled trial evaluating the efficacy and mechanisms of online PeRinatal emOtional skillS groups compared to treatment as usual for women and birthing parents with borderline Personality disordER (PROSPER). PROSPER Principal objective: To determine whether online emotional skills group (ESG) sessions, in addition to standard NHS perinatal mental health care, can help to relieve symptoms of BPD in women and birthing parents who have borderline personality disorder, in comparison to standard NHS perinatal mental health care only. Secondary objectives: To determine whether ESG sessions reduce psychological distress and/or improve wellbeing, social functioning, health-related quality of life, postpartum bonding and caregiving. To determine whether ESG sessions affect the health of participants' babies. To test whether ESG sessions work by improving the regulation of emotions, tolerance of distress, mindfulness and/or the understanding of others. To explore participants' and their therapists' views and experiences of perinatal ESG sessions. Background and study aims People with a diagnosis of borderline personality disorder (BPD) often have difficult relationships, experience distressing changes in mood and are at increased risk of self-harm and suicide. Pregnancy, childbirth and becoming a parent are known as the ‘perinatal period’. During this period, the bond that forms with a baby is very important and can affect the health and later development of the baby. This period can be particularly stressful for women and birthing parents with BPD, but we do not know the best way to help people with BPD during the perinatal period. People with BPD have advised us that they would have valued more help during this very important period of their lives. The aim is to determine the efficacy of perinatal emotional skills groups (ESGs) (in addition to Current NHS care) for women and birthing parents with BPD. Who can participate? Women and birthing parents aged 18 or over who are currently pregnant (from 12 weeks’ gestation onwards) or who have given birth within the past 12 months can take part in the study. Participants will need internet access, at least conversational-level English, and to meet the DSM-5 criteria for borderline personality disorder. What does the study involve? Individuals who decide to take part in the PROSPER study will be randomly put into one of two groups. Group 1 will receive NHS current perinatal mental health care; this currently consists of assessments, care planning, and reviews delivered by staff working in perinatal community mental health teams. Group 2 will attend ESGs for 3 months. This involves attending 12 online sessions (each lasting about 2 hours) covering a range of topics, including feelings about becoming a parent and their relationship with the baby. They will also receive current NHS perinatal mental health care. Babies are welcome to be present during the sessions; there is no expectation that parents need to arrange childcare. A researcher will contact the participants three times during the first 3 months. Participants will also be contacted by the researcher at 4, 8 and 12 months. During each call, the researcher will go through several questionnaires about participants’ mental health and well-being. They will also ask about any complications participants have had since their last call. At 12 months, the researcher will also ask them for some information about their baby’s health. Each video call with the researcher will last for 30-60 minutes. With participants’ consent, the study team would like to video-record a portion of the 12-month video call they have with the researcher, so that we can look at their interactions with their baby. They will ask if participants agree to this during their 8-month follow-up call with the researcher (the call before the 12-month follow-up call); if they agree, they will ask them to sign a consent form. Some participants will also be invited to have a conversation (research ‘interview’) to understand their views on being in the study and their treatment experiences since starting the study. What are the possible benefits and risks of participating? Benefits: There is no guarantee that the study will benefit participants’ health directly; however, it will guide the study team in finding the best way to help people who are perinatal with BPD in future. All appointments for the study can be done remotely, so there is no expectation for participants to travel to see us for this study. Risks: Participants will be asked to spend time completing questionnaires across the year, which will focus on their mental health and wellbeing. If they are put into Group 2, during the Emotional Skills Groups, they will be asked to think about and discuss their feelings about becoming a parent and their relationship with the baby. These discussions will sometimes touch on sensitive matters relating to emotions and relationships. The sessions will be conducted by a clinical psychologist, working with other trained and experienced perinatal health professionals, and the well-being and safety of all those taking part will be closely monitored by an independent group of experts throughout the study. During the optional interview, participants may be asked about their experiences of the support they received for the symptoms of BPD and during pregnancy. For some people, this may cause distress. The research team will try to ensure that participants are comfortable. They can pause or stop the interview at any time with no obligation to continue. Where is the study run from? This study is sponsored by the University of Bristol; the Bristol Trials Centre (at the University of Bristol) is responsible for managing the study. When is the study starting and how long is it expected to run for? The study began in June 2025, with participant recruitment expected to start in June 2026. The study is expected to run until late 2028. Who is funding the study? The National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME), UK. Who is the main contact? Chief Investigator, Prof Paul Moran, paul.moran@bristol.ac.uk The global BPD symptom severity the total score on the Zanarini Rating Scale for Borderline Personality Disorder-Self Report (ZAN-BPD-SR) 4 months post-randomisation (end of intervention delivery) Emotional regulation, distress tolerance, mindfulness and interpersonal sensitivity, the Difficulties in Emotion Regulation Scale, Distress Tolerance Scale, Mindful Attention Awareness Scale and the Brief Symptom Inventory interpersonal sensitivity subscale, respectively, 4 months post-randomisation Psychological distress, wellbeing, social functioning, health-related quality of life and postpartum bonding CORE-10, SWEMWBS, WSAS, EQ-5D-5L & PBQ 4 months post-randomisation Global BPD symptom severity, and psychological distress, wellbeing, social functioning, health-related quality of life and postpartum bonding, ZAN-BPD-SR, and CORE-10, SWEMWBS, WSAS, EQ-5D-5L & PBQ, respectively, at 8- and 12-months post-randomisation Sensitivity the NICHD assessment 12-months post-randomisation Infant weight, height, vaccination status & referrals to safeguarding services self reporting by the participant including use of the Personal Child Health Record (PCHR) 12-months post-randomisation Treatment adherence, therapeutic alliance, and group cohesion attendance of ESG sessions, Working Alliance Inventory – Short Revised and the Group Climate Questionnaire-Short (GQS-S) 4-months post-randomisation Ethics approval required North West - Preston Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 26/NW/0022 10.1186/ISRCTN13746769 341566 CPMS: 61444, NIHR: 167051 341566 61444 167051 Interventional Randomized controlled trial Open (masking not used) Active Parallel Treatment Not applicable Treatment 2028-08-31T00:00:00.000Z United Kingdom England Leeds and York Partnership NHS Foundation Trust

St. Marys House St. Marys Road

Leeds England LS7 3JX RGD@2.16.840.1.113883.2.1.3.2.4.18.48 Mersey Care NHS Foundation Trust

V7 Building Kings Business Park Kings Drive

Prescot England L34 1PJ RW4@2.16.840.1.113883.2.1.3.2.4.18.48 Avon and Wiltshire Mental Health Partnership NHS Trust

Bath NHS House Newbridge Hill

Bath England BA1 3QE RVN@2.16.840.1.113883.2.1.3.2.4.18.48 West London NHS Trust

1 Armstrong Way

Southall England UB2 4SD RKL@2.16.840.1.113883.2.1.3.2.4.18.48 Hampshire and Isle of Wight Healthcare NHS Foundation Trust

Tatchbury Mount Hospital Calmore

Southampton England SO40 2RZ RW1@2.16.840.1.113883.2.1.3.2.4.18.48 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 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 false Participants may enter the study if ALL of the following apply: 1. Women and birthing parents aged 18 years or over who are pregnant (from week 12 gestation onwards) or within 12 months of having a live birth 2. Meet DSM-5 criteria for borderline personality disorder 3. Have internet access 4. Does not require an interpreter to facilitate clinical engagement 5. Provided informed consent for audio-recording of the ESG sessions (if allocated to the ESG group) Adult 18 Years 51 Years Female 216 0 Participants may not enter the study if ANY of the following apply: 1. Those with psychosis, bipolar disorder or substance dependence 2. Those who pose a high risk to their baby or themselves 3. Those requiring admission to a psychiatric hospital 4. Those who are already receiving psychological treatment that is focused on personality or personality disorder symptoms 2026-06-10T00:00:00.000Z 2027-08-31T00:00:00.000Z Specialty: Reproductive Health and Childbirth, Primary sub-specialty: General Obstetrics (antenatal and postnatal care, perinatal mental health); Health Category: Mental health, Reproductive health and childbirth; Disease/Condition: Mood [affective] disorders, Persons encountering health services in circumstances related to reproduction Mental and Behavioural Disorders Women and birthing parents, aged 18 years or over, meeting DSM-5 diagnostic criteria for BPD will be recruited. They will be allocated to receive emotional skills group (ESG) sessions plus standard perinatal mental health care, or standard perinatal mental health care alone, in a 1:1 ratio. Randomisation will be stratified by centre and minimised by perinatal stage and severity of BPD symptoms. The internal pilot, run across 3 sites, will establish whether sufficient numbers of eligible patients can be recruited, engage with their allocated treatment and whether sufficient primary outcome data can be obtained to robustly answer the trial questions. If the progression criteria are met, the main trial recruitment period will start at (at least) 7 sites. If the main trial proceeds, patients from the internal pilot will be included in the final analysis. All participants will be followed up for 1 year following the final randomisation within each cohort. Within each recruitment centre, potentially eligible patients will be identified from the existing caseload by the PI (or delegated member of the clinical team) for screening into the study. The PI (or delegated member of the clinical team) will introduce the study to potentially eligible patients during an in-person or remote consultation and will establish whether the patient agrees to being contacted by a member of the local research team. The PI (or delegated member of the team) will provide the patient with a copy of the participant information using a layered approach, and it will be explained that, if they agree to be contacted by a member of the local research team, then the first step involves participating in a screening interview to assess their eligibility to enter the trial. During the approach at the initial consultation, the PI (or delegated member of the clinical team) will record the relevant clinical eligibility checks on a screening CRF if the patient agrees to be contacted by the local research team, or if the patient does not wish to be contacted. Where possible, reason(s) for non-participation will be stated. A member of the local research team will arrange a time to schedule a call with the participant to explain the study in more detail, answer any questions and complete the rest of the screening assessment if the patient is interested in participating. This will include confirming the presence or absence of DSM-5 symptoms of BPD by administering the McLean Screening Instrument for Borderline Personality Disorder (MSI-BPD). The member of the local research team will inform the patient during the screening interview whether they are eligible for the study or not. Following eligibility being confirmed, if the patient would like to take part and has time to proceed, informed consent will be obtained during the initial screening call. If the patient does not have time during this first call, the member of the local research team will schedule a further call with the patient, where informed consent will be obtained. Consent will also be sought for details of the participant to be shared with the qualitative researcher so that they can be approached about taking part in an interview. Patients who are willing to participate in the trial will be asked to provide informed, written consent, either electronically (e-consent) or on paper. The baseline assessment will proceed once informed consent has been obtained. If the participant has time and it is convenient for them, the baseline assessment will take place immediately after informed consent has been obtained. If this is not convenient for the participant, a further call will be arranged in order to complete the baseline assessment with the participant. The assessment will take place online. The assessments include the Zanarini Rating Scale for Borderline Personality Disorder-Self Report (ZAN-BPD-SR), alongside measures of psychological distress (CORE-10), mental well-being (SWEMWBS), infant bonding (PBQ), social function (WSAS) and quality of life (EQ-5D-5L). The participant will complete the questionnaires verbally with the researcher and the researcher will enter the data directly into the REDCap database. Screensharing may be utilised to show the questionnaires, so that participants have time to read and digest the questions. At baseline, participants will be asked to provide socio-demographic details and additional information will be gathered on indicators of socio-economic status. Birth outcomes will be collected from the participant (e.g. birth weight, mode of delivery and whether the baby was transferred to a neonatal unit); these will be collected later if the participant has not yet given birth at the time of joining the study. After informed consent has been provided by the participant and the baseline assessment has been completed, participants will be randomised by the local research team using REDCap. Individuals will be allocated, on a 1:1 ratio, to online perinatal ESGs (in addition to usual care (UC)) or UC alone. There may be a short delay until treatment begins to allow for a sufficient number of participants to be recruited to online ESGs. Participants randomised to perinatal ESGs will attend up to two individual, preparatory sessions (60 minutes per session), followed by 12 online group intervention sessions (2 hours per session). The individual preparatory sessions involve having an opportunity to meet the facilitators and ask any questions, as well as establishing specific, individually tailored goals for the group intervention. The optimum number of participants in each group is 6-8. The ESG sessions will be audio-recorded in order to monitor how well the sessions are being delivered. Participants will be informed in the participant information leaflet that ESG sessions will be audio-recorded and will provide consent to the recording. The comparator treatment will be usual perinatal mental health care, delivered on an individual basis, in accordance with current NICE (National Institute for Health and Care Excellence) guidelines. Usual care (UC) will be delivered by staff working in perinatal community mental health teams and will comprise assessment, care planning, and reviews. UC does not routinely include access to perinatal ESGs. However, as part of UC, during a crisis, patients may be referred to a mental health crisis team, and arrangements may also be made for inpatient treatment if it is not possible to safely manage them in the community. Staff will also be able to refer participants in both groups to psychological treatments during their study participation, except psychological treatments that are focused on personality or personality disorder symptoms, because such treatments are closely related to the intervention (ESG sessions). The rationale for this is that the overarching aim of the study is to test the efficacy of ESGs. The frequency and nature of service contact and treatment associated with UC will be captured in both trial arms directly from participants. Follow-up frequencies will be calculated based on the randomisation date of the last recruited participant within each cohort. All follow-up assessments, at 4,8 and 12 months post-randomisation, will be done remotely by video call (or telephone, if preferred) with a member of the local research team. These calls will each last 30-60 minutes; participants will be asked questions about their mental health and any adverse events they have experienced since the previous assessment. At 12 months, sensitivity will be assessed via a video-recording of a portion of the call; this is so that researchers can assess the participant's interactions with their baby. The assessment is performed using the National Institute of Child Health and Human Development Sensitivity Scale (NICHD). This is optional, and participants will be asked via a consent form at the 8-month follow-up assessment whether they agree to a section of the 12-month follow-up video call being recorded for this purpose. If the participant agrees, at the beginning of the 12-month follow-up call, the local research team will again ask the participant if it is acceptable to record. The following secondary infant outcomes will also be collected at 12 months post-randomisation: weight, height and vaccination status, which will be self-reported by the participant using the Personal Child Health Record (PCHR), i.e. 'Red Book' and referrals to safeguarding services, which will be self-reported by the participant. The embedded mechanistic study will determine how any reductions in BPD severity are mediated; this will be assessed via various questionnaires in all participants during weeks 1, 6 and 12 of treatment (1st, 6th and 12th ESG sessions or the equivalent timepoint in the UC group). Questionnaires administered will be as follows: Difficulties in Emotion Regulation Scale (DERS), Distress Tolerance Scale (DTS), Mindful Attention Awareness Scale (MAAS) and the Brief Symptom Inventory (BSI) interpersonal sensitivity subscale. Additional mechanistic assessments will be carried out in only those randomised to perinatal ESGs during weeks 1, 6 and 12 of treatment measurements. Some participants will also be invited to take part in the embedded qualitative study, participants will be asked to provide verbal consent to being interviewed and these interviews will be audio-recorded. We will examine the views and experiences of both the intervention and the trial with a sample of participants, therapists and their supervisors. Interviews with ESG participants, supervisors and therapists at 4 months will examine group dynamics and the therapeutic alliance with group facilitators, and how the groups may impact the domains of emotional regulation, distress tolerance, mindfulness and interpersonal sensitivity. We will also explore patient and staff perspectives about the emerging relationship with the baby. Usual care participants will be interviewed to examine their experiences and compare them with those of intervention arm participants. We anticipate interviewing up to 30 participants, 14 therapists and 7 supervisors. Each interview will take up to one hour. A Study Within A Trial is also embedded. Given that the PROSPER trial will exclude people with Limited English Proficiency (LEP) due to the current set-up and delivery of the ESG online sessions, the aim of the SWAT is to explore the feasibility of adapting the perinatal ESG group intervention for people with symptoms of BPD who have LEP, and whether it can be tailored for people from different ethnic groups. We will use a mixed-methodology approach to address these objectives. Using detailed screening data, we will collect ethnicity and language data (where available) to explore the need for possible adapted perinatal ESGs. Qualitative methods will then be used to explore the views of perinatal people, therapists and supervisors on barriers and facilitators of setting up adapted perinatal ESG groups for people from ethnic minority groups with LEP. Individual, semi-structured interviews with the therapists and supervisors will be combined within the main qualitative realist evaluation to reduce both participant and researcher burden. Patients excluded from the trial, as deemed 'required an interpreter to facilitate clinical engagement will be approached and provided with the Summary and Main SWAT PIL. With permission via verbal consent, contact details will be passed on to the research team to arrange an interview. Participants who agree to be contacted will be approached by the GCP-trained researcher who will explain more about the interview, answer any questions, and, if they agree, arrange a convenient time via their preferred method to conduct the interview. An interpreter will be provided for interviews taking place with patients approached to take part in PROSPER who were excluded due to LEP. Interviews will be up to 60 minutes. A maximum of 20 therapists and supervisors at sites and up to 15 perinatal people from ethnic minority groups will be interviewed. Behavioural Data sharing statement to be made available at a later date

c219e95e-a4ff-4201-ab6b-26d2e285986f 7cd8ef66-623f-4025-9708-4b50f6fff8e1 4ce2a5bb-753b-4d14-ba3a-b12e206d3967 66d84590-5a1c-4b74-bb3a-751f3f08544f No Nikki Blythe https://orcid.org/0009-0002-9267-4848 Public

Trial Manager, 1-5 Whiteladies Road

Bristol United Kingdom BS8 1NU - Prosper-trial@bristol.ac.uk Public Paul Moran https://orcid.org/0000-0002-9257-8699 Principal investigator Scientific

Chief Investigator, University of Bristol, Canynge Hall, 39 Whatley Road

Bristol United Kingdom BS8 2PS +44 (0)117 455 4673 paul.moran@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 67429289 true A peer-delivered programme for mental health disclosure distress and internalised stigma (Let’s Talk) in comparison to treatment as usual in adults with psychosis: A randomised controlled trial to investigate the efficacy of a peer intervention targeted at stigma-related mechanisms Let's Talk 2 The study objective is to establish Let’s Talk’s clinical efficacy in a multisite Randomised Controlled Trial (RCT) for adults with psychosis who report moderate to severe Internalised Stigma (IS) and disclosure-related distress; and to assess whether improved measures of personal recovery are mediated via key stigma variables. The objective is to recruit 352 participants to detect a target difference of 4.5 points on the QPR. Eligible participants will be randomised to either the intervention arm (Let’s Talk + Treatment as Usual (TAU)) or the control arm (TAU alone). Participants allocated to the intervention will be offered up to 16 sessions over a four-month intervention window with up to one booster session. Outcome data will be collected at baseline, at 4-month assessment (end of treatment) and at 12-month assessment (12 months post-randomisation). The study will determine whether the treatment effect on recovery is mediated by key mechanisms targeted in the intervention: (1) reduced IS (primary mechanism), (2) reduced stigma stress (degree to which perceived stigma is exceeded by personal coping resources for stigma) and (3) reduced disclosure distress. Background and study aim People who experience psychosis often face stigma and discrimination, which can negatively affect how they consider themselves and their identities. This is referred to as ‘internalising’ stigma. This can cause serious problems with self-esteem, cause depression and anxiety, and lead to withdrawal from others, study or work. To help people with psychosis feel less troubled by ‘internalised stigma’, mental health researchers in Manchester adapted an American intervention into a new intervention called ‘Let’s Talk’. A small trial was conducted to test this intervention. Let’s Talk involved Peer Support Workers (PSWs), who also have experience of psychosis, meeting with people taking part in the trial (Peers). PSWs and Peers discussed mental health stigma, and how to talk about mental health difficulties with others. Many sessions focused on helping Peers understand how to decide whether they want to discuss their mental health difficulties with others, or not. The trial found that people were interested in taking part, that most participants offered the intervention attended the sessions, and most participants attended the research assessments. A larger trial of Let’s Talk is planned to understand more clearly how it can help improve the personal wellbeing of people who experience psychosis. In a larger trial, more participants can be included and more advanced research tests can be run to see what parts of the Let’s Talk approach are most helpful. This would help make Let’s Talk as effective as possible, and it could then be offered in NHS mental health services. Who can participate? People in four UK areas aged 16+ who meet an ICD-11 Schizophrenia or other primary psychotic disorders diagnosis (as determined by the participant’s clinical team) or are receiving care for psychosis from Early Intervention Services (EIS), or under the care of a secondary or tertiary mental health service at the point of referral to ensure provision of care. They will also report moderate to severe self-reported disclosure-related distress (scoring >3 on the disclosure distress screening item), and moderate to severe internalised stigma (scoring of ≥3 on at least one of the Internalised Stigma domains of the Semi-structured Interview Measure of Stigma (SIMS)). What does the study involve? Participants will meet with a research assistant (RA), and they will complete a range of questionnaires, including the Questionnaire about the Process of Recovery (QPR). Participants will be randomly allocated (50:50 chance) to either receive the peer-delivered Let’s Talk intervention (plus their usual mental health treatment) or receive their usual mental health care alone (TAU). Participants who are allocated to receive the Let’s Talk intervention will be offered sessions with a peer support worker over 16 weeks, which will involve completing an 8-module workbook together. Participants will meet with research assistants again at 4 and 12 months to complete the same set of questionnaires. What are the possible benefits and risks of participating? If the Let’s Talk intervention is found to improve personal recovery outcomes, this could add to the current evidence base for helpful psychological interventions and potentially benefit future mental health services for people experiencing psychosis. A potential risk is that participants may find the research assessment process distressing. Participants will be offered choices around their assessments, including the option of breaks and assessments spread across multiple occasions. Where is the study run from? The lead site is Greater Manchester Mental Health NHS Foundation Trust (GMMH). Avon and Wiltshire Mental Health Partnership NHS Trust (AWP), South London and Maudsley NHS Foundation Trust (SLaM) and North East London NHS Foundation Trust (NELFT) are also sites from which the Let’s Talk 2 study is run. When is the study starting and how long is it expected to run for? May 2025 to August 2028. The study will begin enrolling participants in November 2025 to May 2027. Overall, the study is expected to run for 40 months. Who is funding the study? National Institute for Health and Care Research (NIHR), UK. Who is the main contact? Dr Melissa Pyle, based at Greater Manchester Mental Health NHS Foundation Trust (GMMH), melissa.pyle@gmmh.nhs.uk Personal recovery will be measured using the total score on the 15-item Questionnaire about the Process of Recovery (QPR) at 4 months The following secondary outcome measures will assess relevant dimensions of psychiatric distress and quality of life at baseline, 4 and 12 months: 1. Social anxiety will be measured using the Social Interaction Anxiety Scale (SIAS) 2. Depression will be measured using the Patient Health Questionnaire-9 (PHQ-9) 3. Satisfaction in multiple life domains and in treatment aspects will be measured using the DIALOG 4. Paranoia will be measured using the revised Green et al. Paranoid Thoughts Scale (R-GPTS) 5. The presence and impact of non-auditory hallucinations will be assessed using The Psychotic Symptoms Rating Scale: Multimodal Hallucinations. This is an unpublished scale adapted from PSYRATS-AH. The proposed mechanisms of action for Let’s Talk will also be measured with the following instruments at baseline, 4 months and 12 months: 1. Experienced, perceived, and internalised stigma will be measured using the Semi-structured Interview Measure for Stigma in Psychosis (SIMS) 2. Stigma stress will be assessed by the 8-item Stigma Stress Scale (SSCI-8) 3. Disclosure distress will be measured using the single-item Distress Disclosure Index (DDI) Ethics approval required Cambridge South Research Ethics Committee

Equinox House, City Link

Nottingham United Kingdom NG2 4LA 25/EE/0718 10.1186/ISRCTN67429289 343302 CPMS: 62177, NIHR: 163493 343302 62177 163493 Randomized controlled trial Interventional Randomised controlled trial Treatment 2028-08-31T00:00:00.000Z United Kingdom Greater Manchester Mental Health NHS Foundation Trust

Prestwich Hospital Bury New Road Prestwich

Manchester England M25 3BL RXV@2.16.840.1.113883.2.1.3.2.4.18.48 Bethlem Royal Hospital

Monks Orchard Road

Beckenham England BR3 3BX Y7O8M@2.16.840.1.113883.2.1.3.2.4.18.48 North East London NHS Foundation Trust

West Wing C E M E Centre Marsh Way

Rainham England RM13 8GQ RAT@2.16.840.1.113883.2.1.3.2.4.18.48 Avon and Wiltshire Mental Health Partnership NHS Trust

Bath NHS House Newbridge Hill

Bath England BA1 3QE RVN@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Current inclusion criteria as of 03/07/2026: 1. Age 16+ years 2. Meet the ICD-11 schizophrenia or other primary psychotic disorders diagnosis (as determined by the participant’s clinical team) or be receiving care for psychosis from Early Intervention Services (EIS) to account for diagnostic uncertainty in the early stages of psychosis or be attending NHS mental health services for the treatment of psychosis. 3. Under the care of a secondary or tertiary mental health service at point of referral to ensure provision of care. 4. Able to provide written, informed consent (for ethical considerations). 5. Willing to engage in a peer support intervention. 6. Moderate to severe self-reported disclosure-related distress as determined by scoring >3 on the disclosure distress screening item. 7. Moderate to severe internalised stigma as determined by a score of >=3 on at least one of the Internalised Stigma domains of the Semi-structured Interview Measure of Stigma. Previous inclusion criteria: 1. Age 16+ years 2. Meet the ICD-11 schizophrenia or other primary psychotic disorders diagnosis (as determined by the participant’s clinical team) or be receiving care for psychosis from Early Intervention Services (EIS) to account for diagnostic uncertainty in the early stages of psychosis. 3. Under the care of a secondary or tertiary mental health service at point of referral to ensure provision of care. 4. Able to provide written, informed consent (for ethical considerations). 5. Willing to engage in a peer support intervention. 6. Moderate to severe self-reported disclosure-related distress as determined by scoring >3 on the disclosure distress screening item. 7. Moderate to severe internalised stigma as determined by a score of >=3 on at least one of the Internalised Stigma domains of the Semi-structured Interview Measure of Stigma. Mixed 16 Years 100 Years All 352 0 1. A primary diagnosis of alcohol or substance dependency, where this is clearly the cause of their psychotic symptoms. This does not exclude people who use substances or alcohol, only those with a primary diagnosis. This will be confirmed by participants' care teams. 2. A diagnosis of moderate to severe learning disability. This will be confirmed by participants' care teams. 3. An ICD-11 diagnosis of organic psychosis. This will be confirmed by participants' care teams. 4. Language barriers that are an obstacle to participation, since we are unable to provide translation of the intervention workbook or interpreters during intervention sessions. 5. Immediate risk to self or others. This will be confirmed by participants' care teams. 6. Currently receiving structured, individual psychological therapy. 2025-11-01T00:00:00.000Z 2027-05-31T00:00:00.000Z Schizophrenia, schizotypal and delusional disorders, psychosis Mental and Behavioural Disorders Design A clinical efficacy randomised controlled trial (RCT) will be conducted across 4 NHS secondary or tertiary care mental health services in the UK: Avon and Wiltshire, Greater Manchester, North East London, and South London. Participants who meet all inclusion criteria and no exclusion criteria will be randomly allocated to either Let’s Talk plus treatment as usual (TAU), or TAU alone. Participants will be randomised at the individual level via a Clinical Trials Unit (CTU)-hosted, web-based system using random permuted blocks. Randomisation will be at a 1:1 ratio, stratified by site. Outcome and mediational variables will be collected in research assessments at baseline, 4 months (end of treatment) and 12 months post-randomisation. The assessments will be conducted by raters who are blind to participant allocation. Clinical efficacy aims 1. To establish the efficacy of Let’s Talk + TAU in improving personal recovery (primary outcome) when delivered to adults with psychosis who report moderate to severe internalised stigma and disclosure-related distress compared to TAU alone. 2. To establish the efficacy of Let’s Talk + TAU on secondary outcomes of improving quality of life, reducing depression, and reducing social interaction anxiety compared to TAU alone. Clinical efficacy hypotheses 1. Let’s Talk plus TAU will result in improved measures of personal recovery at the end of treatment (4-month follow-up; primary outcome) and 12-month follow-up compared to TAU alone. 2. Let’s Talk plus TAU will result in improved quality of life at the end of treatment (4-month follow-up) and 12-month follow-up compared to TAU alone. 3. Let’s Talk plus TAU will result in a reduction in the level of depression and social interaction anxiety at the end of treatment (4-month follow-up) and 12-month follow-up. Mechanistic aims 1. To examine the extent to which Let’s Talk plus TAU impacts on measures of personal recovery via a decrease in stigma-specific processes (Internalised stigma [IS], stigma stress, and disclosure distress). Mechanistic hypotheses 1. Let’s Talk + TAU will lead to reductions in IS and stigma stress 2. The mechanisms by which Let’s Talk + TAU lead to improvements in personal recovery are due to reductions in IS, stigma stress and disclosure distress. Primary outcome The primary outcome will be the total score on the 15-item Questionnaire about the Process of Recovery (QPR) at 4-month follow-up. The QPR was developed in collaboration with patients to assess personal recovery from psychosis, containing items that were initially derived from qualitative interviews about this topic. It has excellent reliability, validity, and sensitivity to change and is nationally adopted as a PROM for evaluation of early intervention for psychosis services, forming part of the Mental Health Services Data Set. Patients consistently prioritise personal recovery over specific symptom change, and the QPR has been cited as the only measure of recovery that directly maps onto all 5 processes of the influential CHIME framework of personal recovery. Secondary outcomes Secondary outcomes will assess relevant dimensions of psychiatric distress and quality of life. 1. The Social Interaction Anxiety Scale (SIAS), a 20-item self-administered scale questionnaire, which reflects anxieties people may encounter in social situations. Items are rated on a 5-point scale from 0 (not at all) to 4 (extremely). The SIAS is a reliable and valid measure, with initial testing demonstrating high levels of internal consistency and test-retest reliability. 2. Depression will be measured using the Patient Health Questionnaire-9 (PHQ-9), a validated, nine-item, patient-reported outcome measure (PROM). The PHQ-9 is a brief self-administered scale which reflects the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, fifth edition) criteria. It classifies current symptoms on a scale of 0 (not at all) to 3 (nearly every day). 3. The DIALOG scale is a validated, 11-item, patient-reported outcome and experience measure (PROM/PREM). The DIALOG scale assesses eight life domains (mental health, physical health, job situation, accommodation, leisure, partner/family, friendship, personal safety) and three treatment aspects (medication, practical help, meetings with healthcare professionals). The items are rated on a 7-point scale from “totally dissatisfied” to “totally satisfied” with the value 4 representing a neutral “in the middle.” 4. The Psychotic Symptoms Rating Scale: Multimodal Hallucinations, an unpublished scale adapted from the PSYRATS: Auditory Hallucinations subscale for assessing the presence and impact of nonauditory hallucinations. 5. The Revised Green et al Paranoid Thoughts Scale (R-GPTS), a reliable measure of paranoia comprising two subscales to assess ideas of reference (Part A; 8 items) and ideas of persecution (Part B; 10 items), over the past month. The two subscales are designed to be treated as distinct measures and should be scored separately. A total score for each subscale is obtained by adding together the items. Items are scored on a 4-point scale from 0 (Not at all) to 4 (Totally). Mechanistic outcomes The proposed mechanisms of action for Let’s Talk will also be measured with the following instruments: 1. The Semi-structured Interview Measure for Stigma in Psychosis (SIMS), which assesses experienced, perceived, and internalised stigma. 2. Stigma stress will be assessed by the 8-item Stigma Stress Scale. 3. Disclosure-related distress will be assessed using a single item from the Disclosure Distress Scale. Assessment schedule Research assessments comprising the above measures will be completed at baseline, 4 months (end of treatment) and 12 months post-randomisation. Participants will receive £25 on completion of each research assessment as a token of appreciation for their time (£75 total). Treatment condition (Let's Talk + TAU) Let’s Talk will be delivered, in addition to TAU, on a one-to-one basis by Peer Support Workers (PSWs). A 4-month treatment window permits ≤16 sessions, with an option for 1 booster session to consolidate gains. The expectation for delivery is in-person, but the intervention can be delivered remotely via video call or telephone as a contingency. The aims of Let’s Talk are to: help participants weigh pros and cons of disclosing which vary by setting (e.g., disclosure at one’s employment has different costs and benefits than disclosure to one’s friendship network); teach relatively safe ways to disclose should the person decide to do so; help people craft stories that reflect their disclosure goals; support participants with internalised stigma and developing affirming self-beliefs. Sessions with the PSW will be structured around the Let's Talk manual and workbook, which have been refined based on qualitative feedback from participants and PSWs in the Let's Talk feasibility RCT. All participants allocated to Let’s Talk will receive a copy of the workbook. All routine or additional treatments in the comparator arm will be monitored. Comparator condition (TAU) The control condition is treatment as usual (TAU). All participants in the intervention and comparator arms are required to be under the care of a secondary or tertiary care mental health service as a condition of inclusion. In the UK, TAU for psychosis is based on the Care Programme Approach and typically includes psychiatric medication, assignment of community-based health and social care staff, care coordination, access to rehabilitative services, and outpatient care. Referrers for participants in the TAU arm will not be requested to withhold any treatment throughout the duration of the trial, and all routine or additional treatments will be monitored. Except for emergent risk issues, TAU alone will also not involve liaison between researchers and the participants’ healthcare teams. Research Assistants will identify any risks to self or others that require immediate action. All routine or additional treatments in the TAU arm will be monitored. Behavioural Data sharing statement to be made available at a later date Protocol

Migrated from study website field

86951dcc-2709-4977-93e7-386473d73385 ebf9cd3f-3712-4e66-8c43-5ffed88e1e87 930f7421-94a2-4fe9-bdd7-45895906a077 No Protocol file 48087_Protocol_V2.0_22Sept2025.pdf 6932fd62-0051-4487-9381-c93a98b39eef true application/pdf 745143 60d880bd51153d9dc2c4f27ea9cfce79 Participant information sheet 48087_PIS_V3_08Sept2025.pdf acb1f0de-12fc-4088-b5a4-262f760134b6 true application/pdf 304066 a6e5157f9f588469b3032ea140d1693a Protocol file ISRCTN67429289_Protocol_V4.0_19Mar2026.pdf 570ab5e4-3cc8-407d-bdd9-5c8af6e866b8 true application/pdf 831250 f1e9b8abf702a68f1689f7939553a448 Participant information sheet ISRCTN67429289_PIS_V4_19Mar2026.pdf 7d16f22b-6bcd-4d6f-936e-359058349b65 true application/pdf 304194 913611ee2cdba3fdb31190cc5bfb3c91 Melissa Pyle https://orcid.org/0009-0004-5337-9031 Public Scientific Principal investigator

Greater Manchester Mental Health NHS Foundation Trust The Psychosis Research Unit, R&I Central Park Hub, Building B Northampton Road

Manchester United Kingdom M40 5BP +44 (0)161 271 0084 melissa.pyle@gmmh.nhs.uk Public Greater Manchester Mental Health NHS Foundation Trust Hospital/treatment centre https://ror.org/05sb89p83 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 92005743 true Randomized controlled trial to compare clinical effectiveness and cost-effectiveness of mentalization-based treatment - trauma focused versus treatment as usual for people with probable complex post-traumatic stress disorder in mental health services in England MBT-TF The aim of this study is to conduct a randomised controlled trial (RCT) to investigate whether Mentalization-Based Treatment - Trauma Focused (MT-TF) is an effective treatment for individuals who meet threshold for diagnostic criteria for complex post-traumatic stress disorder (CPTSD) in personality disorder (PD) services compared to Treatment as Usual (TAU). Background and study aims To date, treatments that effectively address both the symptoms of complex trauma and personality difficulties that characterise complex post-traumatic stress disorder (CPTSD) are rare. The burden of CPTSD in the UK includes significant psychiatric comorbidity, chronic illness, and an elevated risk of suicide. Mentalization-Based Treatment - Trauma Focused (MT-TF) aims to directly address the impact of trauma in a complex presentation and alleviate patients' distress in tailored, inclusive, non-stigmatising and non-discriminating treatment pathways that mitigate the risk of drop out by integrating trauma processing. This study aims to compare MBT-TF with TAU for adults meeting the diagnostic criteria for CPTSD in personality disorder services. Who can participate? Males, females, individuals who do not identify as male or female, aged 18 - 65 years old, who meet PTSD criteria with sufficient knowledge of the English language. What does the study involve? Participants are randomised to MT-TF or Treatment as Usual (TAU). Participants randomised to MBT-TF will receive weekly group therapy sessions lasting 90 minutes. Treatment will involve approximately 36 group sessions and up to 5 individual supportive therapy sessions as needed over a 9-month period. Baseline data will be collected pre-randomisation. Participants will be followed up at 3, 9 and 15 months post-randomisation. What are the possible benefits and risks of participating? There is minimal risk from randomisation and treatment to the participants themselves. Both MBT-TF and TAU will be delivered by experienced professionals used to working with this client group. Those who agree to participate in the trial will be involved in a number of time-consuming interviews and assessments, which may be somewhat burdensome but do not carry specific risk. The researchers are experienced in conducting assessments and encourage regular breaks to be taken by the participant if necessary. By agreeing to take part, the participant will receive a treatment intervention that would not normally be offered. The outcomes of the evaluation could also improve the provision of interventions for other patients. Where is the study run from? North London NHS Foundation Trust is sponsoring the study and University College London is the lead. When is the study starting and how long is it expected to run for? March 2025 to June 2028 Who is funding the study? University College London (UK) Who is the main contact? 1. Dr Tobias Nolte, Tobias.NolteMD@annafreud.org 2. Prof. Patrick Luyten, p.luyten@ucl.ac.uk Symptoms of complex post-traumatic stress disorder (CPTSD) assessed by the International Trauma Questionnaire (ITQ) at baseline (T1), 3-month follow-up (T2), 9-month follow-up (T3) and 15-month follow-up (T4). 1. Diagnosis of Borderline personality disorder will be measured by the Borderline Symptom List at baseline (T1), 9-month follow-up (T3) and 15-month follow-up (T4). 2. Childhood trauma will be measured by the Childhood Trauma Questionnaire at baseline (T1) only. 3. Disturbance, impulsivity, severity of personality disorder, global functioning, social functioning, interpersonal functioning, suicide ideation and behaviour, sense of belonging, self-care, emotional distress and health related quality of life will be measured by the International Consortium for Health Outcomes Measurement Personality Disorder List at Collected at baseline (T1), 9 month follow up (T3) and 15 month follow up (T4). 4. Diagnosis of PTSD will be measured by the Clinician Administered PTSD Scale for DSM-5 at baseline (T1), 9 month follow up (T3) and 15 month follow up (T4) and Clinician Administered PTSD Scale for DSM-5 at baseline (T1), 9 month follow up (T3) and 15 month follow up (T4). 5. Levels of personality functioning will be measured by the Level of Personality Functioning Screener-Brief Form at baseline (T1), 9-month follow-up (T3) and 15-month follow-up (T4). 6. Interpersonal difficulties will be measured by the Inventory of Personal Problems at baseline (T1), 9-month follow-up (T3) and 15-month follow-up (T4). 7. Quality of life will be measured by the EQ-5D-5L at baseline (T1), 9-month follow-up (T3) and 15 month follow up (T4). 8. Dissociative experiences will be measured by the Dissociative Experiences Scale-II at baseline (T1), 3-month follow-up (T2), 9-month follow-up (T3) and 15-month follow-up (T4). 9. Psychological distress and psychiatric disorder will be measured by the Brief Symptom Inventory 18 at baseline (T1), 3-month follow-up (T2), 9-month follow-up (T3) and 15-month follow-up (T4). 10. Individual's feeling of loneliness will be measured by the UCLA Loneliness Scale Short Form at baseline (T1), 9-month follow-up (T3) and 15 month follow up (T4). 11. Trust in communicated knowledge will be measured by the Epistemic Trust, Mistrust and Credulity Questionnaire at baseline (T1), 9-month follow-up (T3) and 15-month follow-up (T4). 12. Reflective functioning will be measured by the Reflective Functioning Questionnaire at baseline (T1), 9-month follow-up (T3) and 15-month follow-up (T4) 13. Indicators of failures in mentalizing trauma and adverse relationships will be measured by the Failure to Mentalize Trauma Questionnaire at baseline (T1), 3-month follow-up (T2), 9-month follow-up (T3) and 15-month follow-up (T4). 14. Patient experiences will be measured by the Helping Alliance Questionnaire at baseline (T1) and 9-month follow-up (T3) and Client Satisfaction Questionnaire at 9-month follow-up (T3) only. 15. Feelings of shame related to experiencing traumatic events will be measured by the Trauma-Related Shame Inventory at Baseline (T1), 3-month follow-up (T2), 9-month follow-up (T3) and 15-month follow-up (T4). 16. Service use will be measured by the Adult Service Use Schedule at baseline (T1), 9-month follow-up (T3) and 15-month follow-up (T4). 17. Post-traumatic growth will be measured by the Posttraumatic Growth Inventory - Expanded at baseline (T1), 3-month follow-up (T2), 9-month follow-up (T3) and 15-month follow-up (T4). Ethics approval required London - Hampstead Research Ethics Committee

2 Redman Place

London United Kingdom E20 1JQ 25/LO/0137 10.1186/ISRCTN92005743 340141 340141 Multi-site superiority single-blind randomized controlled trial Interventional Randomised controlled trial Treatment 2028-06-01T00:00:00.000Z United Kingdom England Scotland Wales Oxleas NHS Foundation Trust

Pinewood House Pinewood PLACE

Dartford England DA2 7WG RPG@2.16.840.1.113883.2.1.3.2.4.18.48 Merseycare NHS Trust

V7 Building Kings Business Park

Prescot England L34 1PJ Y03793@2.16.840.1.113883.2.1.3.2.4.18.48 Kent and Medway NHS and Social Care Partnership Trust

Farm Villa Hermitage Lane

Maidstone England ME16 9PH RXY@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 England M25 3BL RXV@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 Avon and Wiltshire Mental Health Partnership NHS Trust

Bath NHS House Newbridge Hill

Bath England BA1 3QE RVN@2.16.840.1.113883.2.1.3.2.4.18.48 Devon Partnership NHS Trust

Wonford House Hospital Dryden Road

Exeter England EX2 5AF RWV@2.16.840.1.113883.2.1.3.2.4.18.48 South West London and St. George's Mental Health NHS trust

Springfield Hospital 61 Glenburnie Road

London England SW17 7DJ Barnet, Enfield and Haringey Mental Health NHS Trust

Trust Headquarters Block B2 St Ann's Hospital St Ann's Road

London England N15 3TH Patient 1. Aged 18-65 years 2. Meeting PTSD criteria on the ITQ in combination with at least one symptom from each Disturbances in Self-Organization (DSO) cluster, with functional impairment associated with these symptoms as assessed by the ITQ at screening equivalent to CPTSD diagnosis. 3. Scoring ≥31 on the LPFS-BF (36) at screening, which corresponds to 1.5 standard deviations above the latent mean (T score of 65), indicating at least moderate severity in terms of personality disorder features. 4. Sufficient knowledge of the English language. Mixed 18 Years 65 Years All 198 0 1. Current psychotic episode 2. Diagnosis of severe neurological disorder 2025-06-01T00:00:00.000Z 2027-12-31T00:00:00.000Z Complex post-traumatic stress disorder (CPTSD) Mental and Behavioural Disorders Participants are randomised (minimization, 1:1) to Mentalization-Based Treatment - Trauma Focused (MT-TF) or Treatment as Usual (TAU). Participants randomised to MBT-TF will receive weekly group therapy sessions lasting 90 minutes. Treatment will involve approximately 36 group sessions and up to 5 individual supportive therapy sessions as needed over a 9-month period. Participants will be followed up at 3, 9 and 15 months post-randomisation. Behavioural Not expected to be made available 67b128a6-40e4-43aa-9ebb-a13705a88e06 8ebeeebc-1f24-4f19-b164-6f4d43c1fac1 2b4b24ab-10ca-4963-92f4-75919a822f1c 74c7cb7a-e6d2-41d9-923b-bf653f66a229 33e02a5b-fde8-459a-b938-bfd0ed7cd400 No Tobias Nolte Scientific Principal investigator

North London Foundation Trust St Pancras Hospital in Camden

London United Kingdom NW1 0PE +44 (0)20 8702 3000 Tobias.NolteMD@annafreud.org Public Patrick Luyten https://orcid.org/0000-0002-1161-2817 Scientific Principal investigator

University College London 1-19 Torrington Place

London United Kingdom WC1E 7HB +44 (0)2076792000 p.luyten@ucl.ac.uk Public Elizabeth Simes https://orcid.org/0000-0003-1704-6278 Public

University College London 1-19 Torrington Place

London United Kingdom WC1E 7HB +44 (0)2076792000 e.simes@ucl.ac.uk Public Noclor Hospital/treatment centre Non-commercial University College London http://dx.doi.org/10.13039/501100000765 86317609 true MELODIC: co-developing a Music therapy intervention Embedded in the Life Of Dementia Inpatient mental health Care to help manage distress MELODIC This is a complex intervention development study with an embedded feasibility study. The aims are: Aim 1: To co-develop a music therapy model (MELODIC) for mental health dementia wards. This will include: 1. A manual outlining music therapy intervention delivery 2. A handbook and resources for ward managers, staff, and relatives Aim 2: To pilot the MELODIC intervention. This will: 1. Enable refinement of the intervention 2. Determine acceptability with patients, relatives, and staff 3. Assess the feasibility of delivery, including facilitators and barriers to implementation 4. Assess adherence to the intervention 5. Establish cost parameters of delivery 6. Test potential outcome measures to inform the design of a future controlled trial Background and study aims Distress is common for people with dementia on hospital mental health wards, but music might help. There are lots of reasons why people get distressed. Sometimes it is a result of symptoms like hallucinations, and sometimes it is because the care they receive does not meet their needs. If a person with dementia is so distressed that they behave in a way that puts themselves or others at risk, they may be admitted to a hospital mental health ward. The aim of the hospital stay is to understand and treat their distress, so that they may be discharged with an appropriate support plan. This can take a long time. There is little research looking at these hospital wards, which can be very different to general hospital wards or care homes. It is hard to care for someone who is very frightened and distressed, and both staff and patients can get hurt (staff experience more physical assaults than prison officers). Calming medications (antipsychotics) are often given to a person with dementia on these wards when distressed. This is a worry because research suggests that these increase the risks of falls and death. Music therapy has helped lower distress for people with dementia living in care homes and supported staff to understand why someone might be distressed. But we do not know enough about how music therapy can help people with dementia in mental health wards. Our own research on mental health wards found that on the days the therapy took place, there were fewer assaults and staff could see a positive impact on the ward. But not all mental health wards have music therapy. People with dementia and their family members that we spoke to also found music helpful and supported the idea of having this therapy on wards. In this 18-month project, we will create a music therapy manual for mental health wards together with people with dementia, their families and staff with the aim of reducing distress and assaults. Who can participate? People who have stayed, visited family or worked on mental health dementia in the NHS in the last 5 years can take part in an interview or focus group (Stage 1). Two mental health wards in the NHS will be invited to take part and test the music therapy manual for four weeks (Stage 3). Everybody staying, visiting or working on the wards will be able to take part. What does the study involve? The study has three stages: Stage 1. Talking to people with dementia, relatives and staff with experience of mental health wards. This will help us understand how distress and assaults are currently managed and the support people need. Stage 2. Co-creating a music therapy manual with people with dementia, relatives and staff based on findings from Stage 1. Stage 3: Testing the music therapy manual over four weeks on two mental health wards, one that already has music therapy and one that has never offered this before. Once the manual is finished, we will share it with the public and look to test it on more mental health wards for people with dementia. What are the possible benefits and risks of participating? If you take part in this study you can help shape the way that music and music therapy are used on NHS mental health dementia wards. If you are staying, visiting or working on a ward where the intervention is tested you will have access to more music therapy delivered by a qualified healthcare professional. They will help work out how music can best be used to reduce distress and improve care experience for everyone on the ward. Where is the study run from? The study is led by Anglia Ruskin University and the Cambridgeshire and Peterborough NHS Foundation Trust (UK). Other supporters include Dementia UK, the University of Cambridge and the University of Hull. When is the study starting and how long is it expected to run for? June 2023 to February 2025 Who is funding the study? National Institute for Health and Care Research, Research for Patient Benefit Scheme (UK) Who is the main contact? Naomi Thompson, naomi.thompson@aru.ac.uk The feasibility of intervention delivery and the research methods will be measured by: 1. Intervention adherence measured through interventionist diaries completed during the intervention period, collected post-intervention 2. Recruitment rate recorded as the number of eligible participants who consent to participate in the study by 4 months 3. Data completeness for quantitative outcome measures across all four timepoints (4 weeks before, baseline, endpoint, 4 weeks follow-up) 4. Training needs and requirements assessed through interviews conducted post-intervention 5. Costs of intervention delivery calculated post-intervention 1. Initial impact of MELODIC for patients, staff, families and the ward measured by: 1.1. Realist interviews post-intervention 1.2. Patient standardised questionnaires (4 weeks before, baseline, endpoint, 4 weeks follow-up): 1.2.1. Distress measured by the Neuropsychiatric Inventory and the Cohen-Mansfield Agitation Inventory 1.2.2. Quality of life measured by Quality of Life in Alzheimer’s Disease 1.3. Staff standardised questionnaires (4 weeks before, baseline, endpoint, 4 weeks follow-up): 1.3.1. Job satisfaction measured by Job Satisfaction Index 1.3.2. Burnout measured by the Maslach Burnout Inventory 1.3.3. Attitudes of hope and personhood in dementia measured by the Approaches to Dementia Questionnaire 1.4. Family standardised questionnaires (4 weeks before, baseline, endpoint, 4 weeks follow-up): 1.4.1. Attitudes of hope and personhood in dementia measured by Approaches to Dementia Questionnaire 1.4.2. Mental health measured by the General Health Questionnaire 1.5. Ward level outcomes (4 weeks before, 4 weeks during, 4 weeks after intervention): psychotropic medication use; physical assaults, seclusion, mortality, restraint, staff absence, number of bank/agency staff, patient length of stay, discharge destination 2. Refinement of the MELODIC Music therapy intervention protocol Ethics approval required Yorkshire & The Humber - Bradford Leeds Research Ethics Committee

NHSBT Newcastle Blood Donor Centre

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

Anglia Ruskin University

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

Elizabeth House, Fulbourn Hospital Fulbourn

Cambridge United Kingdom CB21 5EF Humber Teaching NHS Foundation Trust

Trust Hq, Block A, Willerby Hill Beverley Road Willerby

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

Bath NHS House Newbridge Hill

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

Delta Point Greets Green Road

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

Unit 2 Kings Court Charles Hastings Way

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

Rake Lane

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

Trust Headquarters Fieldhead Hospital Ouchthorpe Lane

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

Hawkins Road

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

Study website Migrated from study website field

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

Cambridge Institute for Music Therapy Research Anglia Ruskin University

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

Cambridge Institute for Music Therapy Research Anglia Ruskin University

Cambridge United Kingdom CB1 1PT +44 (0)1223 695401 naomi.thompson@aru.ac.uk Public Anglia Ruskin University University/education https://ror.org/0009t4v78 Non-commercial Cambridgeshire and Peterborough NHS Foundation Trust Hospital/treatment centre https://ror.org/040ch0e11 Non-commercial Research for Patient Benefit Programme http://dx.doi.org/10.13039/501100009128 79060696 true gameChange VR: a real-world waitlist randomised controlled trial for the treatment of severe agoraphobic avoidance in the context of psychosis Primary: For NHS patients diagnosed with psychosis and having severe agoraphobia, gameChange, when added to usual care, compared to usual care, will reduce agoraphobic avoidance (at six months). Secondary: 1. Compared to usual care, gameChange will reduce agoraphobic avoidance at the end of treatment (8 weeks). 2. Compared to usual care, gameChange will reduce agoraphobic distress. 3. Compared to usual care, gameChange will reduce paranoia. 4. Compared to usual care, gameChange will increase the number of social contacts outside the home. gameChange is an acceptable treatment for patients. Background and study aims This study aims to evaluate gameChange, a virtual reality (VR) treatment for people with psychosis, in real-world settings within the NHS. The goal is to help the National Institute for Health and Care Excellence (NICE) decide whether to fully recommend gameChange for use in the NHS. The project is funded by the National Institute for Health and Social Care Research (NIHR) and supported by the Office for Life Sciences (OLS) and NICE. Who can participate? The study will include individuals with psychosis who have severe fears and are often housebound. Participants will be selected from six NHS mental health trusts: Bristol, Cornwall, Humber, Manchester, Oxford, and West Midlands. What does the study involve? Participants will be divided into two groups: one group will start using gameChange immediately, while the other group will start after six months. gameChange involves using a VR headset to practice facing everyday situations with the guidance of a virtual therapist and support from mental health staff. Participants will typically have six sessions, but they can have more if needed. What are the possible benefits and risks of participating? The potential benefits include a significant reduction in fears related to everyday situations, especially for those with severe problems. This could lead to improved quality of life and greater independence. There are minimal risks, but some participants might find the VR experience challenging or uncomfortable at first. 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 2025 to October 2027. Who is funding the study? National Institute for Health and Care Research (NIHR) in the UK. Who is the main contact? Eloise Prouten: eloise.prouten@psy.ox.ac.uk Daniel Freeman: daniel.freeman@psy.ox.ac.uk Julia Jones: julia.jones@psy.ox.ac.uk Agoraphobic avoidance is measured using the Oxford Agoraphobic Avoidance (O-AS) – avoidance subscale at baseline, 8 weeks, 26 weeks. (This will be measured additionally at 34 weeks for the wait-list control group i.e. after they have received the treatment.) The primary endpoint for this outcome is 26 weeks. 1. Agoraphobic avoidance (distress level) is measured using the Oxford Agoraphobic Avoidance Scale (O-AS) – distress subscale at baseline, 8 weeks, and 26 weeks. (This will be additionally measured at 34 weeks for the control group.) 2. Paranoia is measured using the Revised Green et al Paranoid Thoughts Scale at baseline, 8 weeks, and 26 weeks. (This will be additionally measured at 34 weeks for the control group.) 3. Number of social contacts is measured using the Social Contact Assessment at baseline, 8 weeks, and 26 weeks. (This will be additionally measured at 34 weeks for the control group.) 4. Treatment acceptability is measured using the Theoretical Framework of Acceptability (TFA) at 8 weeks for the intervention group. (This will also be measured at 34 weeks for the control group after they have had the VR treatment.) 5. VR side effects will be measured using the Oxford – VR Side Effects Checklist at 8 weeks for the intervention group. (This will also be measured at 34 weeks for the control group after they have had the VR treatment.) 6. Occurrence of serious adverse events will be checked using medical notes (in addition to any patient reports) over 0-26 weeks. (Notes will also be checked for the period 26-34 weeks for the control group.) Ethics approval required Wales REC 3

Health and Care Research Wales, Castlebridge 4

Cardiff United Kingdom CF11 9AB 25/WA/0081 10.1186/ISRCTN79060696 351247 CPMS: 67294 351247 67294 Multicentre two-arm waitlist randomized controlled trial Interventional Randomised controlled trial Treatment 2027-10-01T00:00:00.000Z 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 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 Cornwall Partnership NHS Foundation Trust

Carew House Beacon Technology Park Dunmere Road

Bodmin United Kingdom PL31 2QN RJ8@2.16.840.1.113883.2.1.3.2.4.18.48 Humber Teaching NHS Foundation Trust

Trust Hq, Block A, Willerby Hill Beverley Road Willerby

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

Bath NHS House Newbridge Hill

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

Trafalgar House 47-49 King Street

Dudley United Kingdom DY2 8PS TAJ@2.16.840.1.113883.2.1.3.2.4.18.48 Patient 1. Attending NHS or commissioned Voluntary, Community and Social Enterprise (VCSE) mental health services. 2. Clinical diagnosis of schizophrenia spectrum psychosis or an affective diagnosis with psychotic symptoms 3. Severe agoraphobic avoidance as assessed by the Oxford Agoraphobic Avoidance Scale (score of 6 or above) and wanting help for that difficulty Mixed 16 Years All 200 1. Photosensitive epilepsy. 2. In forensic settings or Psychiatric Intensive Care Unit. 3. Command of spoken English inadequate for engaging in the therapy or assessments. 4. 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. 2025-05-01T00:00:00.000Z 2026-11-01T00:00:00.000Z Agoraphobic avoidance (severe) in patients with a diagnosis of psychosis Mental and Behavioural Disorders UKCA marked gameChange VR therapy. Guided provision of VR therapy for 8 weeks. Delivery supported by a mental health staff member (e.g, peer support worker, assistant psychologist, therapist). gamechange is a cognitive treatment that aims for patients to relearn safety by testing their fear expectations. Within the VR environments a virtual coach guides the person through the treatment. When first entering VR, the patient goes into the coach's virtual office and is guided in how to use VR. At the beginning of the first session, the virtual coach explains the rationale behind the treatment, and the participant selects one of the six VR scenarios. The six virtual reality scenarios are: a cafe, GP waiting room, pub, bus, street scene, and newsagent. Each scenario has five degrees of difficulty (e.g, the number and proximity of people in the social situation increases) and participants work their way through each level of difficulty. There are game type tasks within a number of the levels. The participant can choose a different scenario in each session or repeat a previous situation. gameChange is now delivered on a standalone headset. Control group The total duration of the study will be 34 weeks. The total duration of treatment will be 8 weeks. The duration of the follow up period in total will be 34 weeks, with assessments at baseline, 8 weeks, 26 weeks, and 34 weeks. After randomisation, the control group will receive their usual care until completion of the 26 week follow up. After this, they will receive gameChange VR therapy (plus treatment as usual) for up to 8 weeks. They will then complete the 34 week follow up, after which participation will be complete. Usual care is typically antipsychotic medication and regular contact with the mental health team. Treatment group The total duration of the study will be 26 weeks. The total duration of treatment will be 8 weeks. The duration of the follow-up period in total will be 26 weeks, with assessments at baseline, 8 weeks, and 26 weeks. Usual care will continue. Randomisation process Patients will be randomised once they have completed the baseline assessment to either the treatment group or the control group. Randomisation will be carried out by a member of staff unblinded to treatment allocation. An online system from Sealed Envelopes (https://www.sealedenvelope.com/), will use a permuted blocks algorithm with randomly varying block size, stratified by centre. Other Requests, accompanied by a study summary, for sharing of de-identified data will be considered by the Chief Investigator (daniel.freeman@psy.ox.ac.uk) and the team. The intent is to share data for reasonable requests. 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 2025 Protocol article in https://pubmed.ncbi.nlm.nih.gov/40819857/ (added 18/08/2025) Protocol

d9b94331-fe5c-48c6-89e7-a710dc75a597 e5d99e40-7493-4869-87e8-a2f24280fac9 4391590f-ad70-40b2-a78e-2c4465f236fd 311ef113-ca84-4e74-85de-591ebb803f5d 563de263-f8a6-4028-b2b6-2ee2223663eb Yes Daniel Freeman https://orcid.org/0000-0002-2541-2197 Public Scientific Principal investigator

Department of Experimental Psychology, University of Oxford, Radcliffe Observatory Quarter

Oxford United Kingdom OX2 6GG +44 1865223635 daniel.freeman@psy.ox.ac.uk Public Julia Jones Scientific

Department of Experimental Psychology, University of Oxford, Radcliffe Observatory Quarter

Oxford United Kingdom OX2 6GG +44 1865 281864 julia.jones@psy.ox.ac.uk Public Eloise Prouten Scientific

Department of Experimental Psychology, University of Oxford, Radcliffe Observatory Quarter

Oxford United Kingdom OX2 6GG +44 7976 467942 eloise.prouten@psy.ox.ac.uk Public University of Oxford Research organisation https://ror.org/052gg0110 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 16347322 true A feasibility trial of a skills enhancing programme for carers of people presenting with complex emotional needs and/or chronic emotion dysregulation – Carers All Require Emotional support, Resilience and Skills: the CARERS trial CARERS The aim of the study is to investigate whether a definitive trial is feasible and acceptable and to optimise the design of such a trial. Background and study aims People with complex emotional needs and/or chronic emotion dysregulation or a diagnosis of Emotionally Unstable Personality Disorder have chaotic relationships, experience highly distressing changes in mood and have urges to harm themselves and others. It is also one of the most challenging mental health conditions to live with for a carer or family member. Carers, therefore, often become overwhelmed with the needs of the person they care for. Currently, there is a lack of research into the most effective way of supporting carers of these people. ‘Family Connections’ (FC) is an intervention designed specifically for carers of people with chronic emotion dysregulation, originally developed in the US and adapted for the UK. It consists of 12, 2-hour, weekly, peer-supported group sessions delivered online, to inform carers about chronic emotion dysregulation; stress the importance of maintaining personal wellbeing; and equip carers with skills to support loved ones in crisis. However, we don't know whether FC benefits carers or the people they support, so we plan to undertake a feasibility trial. The trial will offer FC to one group of carers and another group will be offered the support currently available. We will ask carers and their loved ones if there is any improvement in their lives at the end of the intervention and after a 9-month follow-up period. We will interview carers, people with chronic emotion dysregulation and healthcare staff, to assess their views on the acceptability of the trial and the intervention. This study was initially devised by a mental health carer with lived experience of supporting a family member, a service user in NHS mental health services, with chronic emotional difficulties, including multiple suicide attempts and self-harm. The study aims to evaluate the value of such carers participating in a 12-week support and skills course. The study also aims to evaluate if improving carers' wellbeing and skills has an impact on the person they are supporting: the service user. The study is a feasibility trial to determine whether a full trial is possible, since recruitment of both carers and service users to a research trial for such an intervention has not been done before in the UK. Who can participate? Carers of people with complex emotional needs or a diagnosis of borderline personality disorder or emotionally unstable personality disorder in each of the three study sites are able to participate, along with their respective service users. What does the study involve? The study requires the carer to be randomised into one of two groups: either receiving the 12-week course immediately, or, after the end of the trial. Both sets of carers will be asked to complete a set of questionnaires before the start of the course, after completing the course, and 6 months following the end of the course. Their respective service user will also be required to complete a set of questionnaires at these time points. Some participants will also be invited to take part in a qualitative interview to find out more about their perceptions of the course and their participation in the research trial. What are the possible benefits and risks of participating? We do not envision that there are any risks to those participating in the study. The course requires that participants consider alternative ways of managing their own stress and of communicating with others. They will also learn more about the condition that their loved one is experiencing. Service Users will not be subject to any intervention themselves, so they will only encounter the time imposition of completing three sets of questionnaires, which we estimate will take 30-40 minutes each time for both carers and service users. The benefits of carer participation are assumed to include: improved sense of wellbeing and relationship with loved ones, leading to fewer harmful episodes and challenging interpersonal interactions. Where is the study run from? The study is run from the University of York. There are three study sites: Bristol, Essex and South Yorkshire/South Humberside (UK) When is the study starting and how long is it expected to run for? March 2024 to April 2026 Who is funding the study? NIHR Research for Patient Benefit programme (UK) Who is the main contact? Co-Chief Investigator Prof Martin Webber, University of York, martin.webber@york.ac.uk Co-Chief Investigator Karen Bulsara, University of York, k.bulsara@nhs.net Trial Manager Dr Elizabeth Mair, elizabeth.mair@york.ac.uk Feasibility outcome: Number of eligible carers and service users recruited within 6 months For carers: 1. Burden is measured using the Burden Assessment Scale (BAS) at baseline, 14 weeks and 40 weeks post randomisation 2. Mental wellbeing is measured using the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) at baseline, 14 weeks and 40 weeks post randomisation 3. Family relationships are measured using The Family Questionnaire (TFQ) at baseline, 14 weeks and 40 weeks post randomisation 4. Health-related quality of life is measured using the EQ-5D-5L at baseline, 14 weeks and 40 weeks post randomisation 5. Capability wellbeing is measured using the ICECAP-A at baseline, 14 weeks and 40 weeks post randomisation 6. Carer costs are measured using the Client Services Receipt Inventory at baseline, 14 weeks and 40 weeks post randomisation 7. Experiences of FC; it's impact on their lives; positive and negative aspects of the course; and potential benefits for service users measured by interview during follow-up period For service users: 1. Mental wellbeing is measured using the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) at baseline, 14 weeks and 40 weeks post randomisation 2. Social functioning is measured using Work and Social Adjustment Scale (WSAS) at baseline, 14 weeks and 40 weeks post randomisation 3. Health-related quality of life is measured using the EQ-5D-5L at baseline, 14 weeks and 40 weeks post randomisation 4. Capability wellbeing is measured using the ICECAP-A at baseline, 14 weeks and 40 weeks post randomisation 5. Service user costs are measured using the Client Services Receipt Inventory at baseline, 14 weeks and 40 weeks post randomisation Course facilitators will be interviewed about the delivery of FC; the value of the training and supervision; and the acceptability, strengths and weaknesses of the intervention during follow-up period Ethics approval required Cambridgeshire and Hertfordshire Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 24/EE/0131 10.1186/ISRCTN16347322 339642 CPMS: 62945, NIHR: 204033 339642 62945 204033 Interventional randomized controlled feasibility trial Interventional Randomised controlled trial Other 2026-04-30T00:00:00.000Z United Kingdom England Avon and Wiltshire Mental Health Partnership NHS Trust

Bath NHS House Newbridge Hill

Bath England BA1 3QE RVN@2.16.840.1.113883.2.1.3.2.4.18.48 Rotherham Doncaster and South Humber NHS Foundation Trust

Woodfield House Tickhill Road

Doncaster England DN4 8QN RXE@2.16.840.1.113883.2.1.3.2.4.18.48 Essex Partnership University NHS Foundation Trust

The Lodge Lodge Approach Runwell

Wickford England SS11 7XX R1L@2.16.840.1.113883.2.1.3.2.4.18.48 Carer Service user Potential carer participants must satisfy the following criteria to be enrolled in this study: 1. Adults aged >=18 years 2. Self- or service user-identified carer or support person. We recognise that the identification and recording of carers in patient records is not routine and we will explore the best identification mechanisms during the study 3. Willing to attend Family Connections groups 4. Willing to provide written, informed consent to take part 5. Access to PC/laptop/smartphone and good quality internet for the purpose of completing the intervention sessions as well as completing questionnaires and possible qualitative interviews online 6. Has not attended and completed Family Connections sessions previously Potential service user participants must satisfy the following criteria to be enrolled in this study: 1. Adults aged >=18 years 2. Presenting with complex emotional needs and chronic emotion dysregulation, and/or a clinical diagnosis of borderline personality disorder or emotionally unstable personality disorder 3. Competent and willing to provide written, informed consent to take part 4. Access to PC/laptop/smartphone and good quality internet for the purpose of completing questionnaires and possible qualitative interviews online Mixed 18 Years 100 Years All 96 102 Literacy levels such that the study materials are inaccessible. This will be established through discussion with the service user’s care coordinator during the eligibility assessment. Given this is a feasibility study the researchers will not have the resources to support non-English literacy/speaking participants. 2024-07-15T00:00:00.000Z 2025-03-19T00:00:00.000Z Complex emotional needs and/or chronic emotion dysregulation Mental and Behavioural Disorders We will randomise carers (and their associated service user) to either the intervention group or a control group. Carers in the intervention group will receive the 12-week ‘Family Connections’ (FC) course, which will be delivered online within their NHS Trust by a trained clinician and carer. This will be in addition to any other support they receive. Carers in the control group will continue to receive support available to them from with the NHS Trust, Local Authority or voluntary sector carer services. Service users will continue to receive care and support from their community mental health team throughout the study and this will not be affected. At the end of the FC course (14 weeks after the baseline measurements), the participants will be asked to complete the same outcome measures as they did at the beginning. A final follow-up point for participants will come at 40 weeks after the baseline measurements, when all the the participants will be asked to complete the outcome measures for a final time. Data will be assessed for completeness and analysed for indicative change over time and between the groups. We will also conduct semi-structured interviews with service users, carers and clinicians to help determine the acceptability and feasibility of the trial design. Carers and service users who decline consent for the main study will be asked whether they would like to take part in a qualitative interview about why they declined. Up to 25 carers and service users participating in the trial will be interviewed in the follow-up period (after the intervention has been delivered) to explore experiences of FC; it's impact on their lives; positive and negative aspects of the course; and potential benefits for service users. Course facilitators will be interviewed about the delivery of FC; the value of the training and supervision; and the acceptability, strengths and weaknesses of the intervention. All qualitative data will be anonymised, transcribed and then coded using qualitative analysis software. Behavioural The datasets generated during and/or analysed during the current study will be available upon request from Professor Martin Webber (martin.webber@york.ac.uk). Anonymous feasibility trial data will be available after publication of the findings for a period of ten years. It will be provided to researchers wishing to undertake secondary analysis on provision of a study protocol. It will be sent online via an encrypted file sharing server. Consent for sharing has been obtained from participants. Available on request

Study website Migrated from study website field

4dc80873-6df5-4db8-be51-a274229ceace 20f6ee98-beb4-49f8-ae81-8a64bb06fb8a d11a1ba3-bbe8-46ac-a217-f96963f1c72e b818bf6f-7f75-409f-9c79-4928c273733f 11d2df8f-27fb-4d80-9db7-4ab047fcdbba Yes Martin Webber https://orcid.org/0000-0003-3604-1376 Principal investigator

International Centre for Mental Health Social Research, School for Business and Society, University of York, Heslington

York United Kingdom YO10 5DD +44 1904 321203 martin.webber@york.ac.uk Public Karen Bulsara Principal investigator

International Centre for Mental Health Social Research, School for Business and Society, University of York, Heslington

York United Kingdom YO10 5DD - k.bulsara@nhs.net Public Elizabeth Mair https://orcid.org/0000-0001-5356-5927 Public Scientific

International Centre for Mental Health Social Research, School for Business and Society, University of York, Heslington

York United Kingdom YO10 5DD +44 1904 328810 elizabeth.mair@york.ac.uk Public University of York University/education https://ror.org/04m01e293 Non-commercial NIHR Central Commissioning Facility (CCF) 18207465 true The clinical and cost-effectiveness of behavioural therapy for interepisode bipolar symptoms (STABILISE): a feasibility study STABILISE Assessment of the acceptability and feasibility of a future trial. Background and study aims Some people with bipolar disorder experience ongoing low mood or mood swings outside of full episodes of depression or mania. This might be associated with a sense of never feeling properly “well”, or of not having extended periods of stable mood. Most of the research that has looked at psychological therapies for people with bipolar disorder has focussed on helping people recover from periods of major depression, or on reducing the chance of having another major episode. These are important issues to address, however, we do not yet have a therapy that is specifically designed to address ongoing symptoms. Researchers have been working on developing such a therapy. The long-term aim is to help the NHS to offer a treatment that can support people with bipolar disorder who would particularly like support with persisting low mood or mood swings. This study is to test out aspects of the therapy and of the research processes in preparation for being able to run a large clinical trial in future. This study cannot give the final answer on whether the therapy works in general: a larger study is needed for this. However, this small study is a necessary step towards a bigger trial. Who can participate? People with ongoing symptoms of bipolar disorder between major episodes What does the study involve? The study involves either receiving the new therapy or continuing with usual care without receiving the new therapy. This is decided at random and there is a 50% chance of receiving the therapy. Throughout the study there are several questionnaires to complete at different time points over 12 months. What are the possible benefits and risks of participating? Behavioural therapies for people with depression and for people with emotional instability have been found to be beneficial overall, and early-stage studies with people with bipolar disorder suggest that this may be a helpful approach. The researchers do not anticipate that this therapy programme will place participants at any more risk than they would face if they attended other therapeutic programmes. Where is the study run from? Exeter Clinical Trials Unit at the University of Birmingham (UK) When is the study starting and how long is it expected to run for? September 2023 to November 2026 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK) Who is the main contact? Dr Kim Wright, k.a.wright@exeter.ac.uk 1. Average recruitment rate recorded as the number of eligible participants recruited per site over 15 months to assess the feasibility of a future trial 2. Completion of the 30-week follow-up point Clinical outcome measures (completed at baseline, 14, 30 and 52-week follow-up) 1. Depression symptom severity measured using the Patient Health Questionnaire – 9 (PHQ-9) 2. The extent to which mood tends to fluctuate measured using the Affective Lability Scales (ALS) 3. Level of current mania symptoms measured using the Bech-Rafaelsen Mania Scale 4. Disorder-specific quality of life measured using Brief Quality of Life in Bipolar Disorder (QoLBD) 5. Anxiety symptoms measured using the General Anxiety Disorder Assessment – 7 (GAD-7) 6. Sense of personal recovery measured using the Bipolar Recovery Questionnaire (BRQ) 7. Life chart self-report – self-report of number and duration of depressive and manic episodes in the period since the last assessment (completed at 14, 30 and 52-week follow-up points only) 8. Health economic variables (employment, health service use, ability to perform activities of daily living) measured using the Health Economics Questionnaire (HEQ) over the past 6 months / since last contact 9. Health-related quality of life measured using EQ-5D-5L Ethics approval required East of England - Cambridge East Research Ethics Committee

2 Redman Place

London United Kingdom EC20 1JQ 24/EE/0018 10.1186/ISRCTN18207465 335983 CPMS: 60510 335983 60510 Two-arm randomized parallel controlled feasibility trial Interventional Randomised controlled trial Treatment 2026-11-30T00:00:00.000Z United Kingdom England The Accept Clinic (university of Exeter)

Mood Disorders Cent, School of Psyc University of Exeter, Perry Road Washington Singer Building

Exeter England EX4 4QG 8J414@2.16.840.1.113883.2.1.3.2.4.18.48 Avon and Wiltshire Mental Health Partnership NHS Trust

Bath NHS House Newbridge Hill

Bath England BA1 3QE RVN@2.16.840.1.113883.2.1.3.2.4.18.48 Devon Partnership NHS Trust

Wonford House Hospital Dryden Road

Exeter England EX2 5AF RWV@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Participants will be adults who: 1. Meet research diagnostic criteria for Bipolar I or II Disorder, Other Specified Bipolar Disorder or Cyclothymic Disorder 2. Do not meet the criteria for a manic or severe depressive episode 3. Have IEBS, defined as at least mild depressive symptoms (Patient Health Questionnaire [PHQ9] >=5) or above-average bipolar mood instability defined as >=1.3 on the brief Affective Lability Scale (ALS) depression-elation scale 4. Are willing to engage in psychological work addressing IEBS or its impact on functioning 5. Sufficient English to complete questionnaires without translation 6. Have completed the intake measures 7. Are registered with a General Practice within the study site catchment area Mixed 18 Years 120 Years All 60 0 1. Current substance dependence according to ICD-11 criteria (as this may interfere with the ability to engage in and use therapy; current substance abuse is not an exclusion criterion). 2. Risk of harm to self or others that cannot be safely managed in a community outpatient setting. 3. Currently engaged in another psychological therapy for bipolar disorder. 4. Participant anticipates they will be unable to regularly attend therapy sessions within the site area (e.g. planning to move out of the study area, work commitments prevent regular attendance, lengthy period of travel not mitigated by access to online therapy sessions). 2024-04-01T00:00:00.000Z 2025-06-30T00:00:00.000Z Bipolar disorder Mental and Behavioural Disorders This is a feasibility study with two arms: usual care + the new therapy, and usual care only. 60 participants will be randomised to these two arms, with half receiving each. As this is a feasibility trial the researchers will be using data from the trial to characterise usual care to refine their understanding of this for a future definitive trial. As such we do not place any restrictions on what people receive as part of usual care. This could therefore include the full range of NHS and private/third sector health assessments and interventions available to the person. Similarly, the researchers do not mandate any healthcare assessment to be part of usual care (i.e. there is not a stated minimum set of components). The intervention therapy consists of up to 20 individual, hour-long therapy sessions (plus up to two initial assessment sessions) of behavioural therapy, delivered over up to 7 months (30 weeks). This is followed by a period of consolidation whereby patients can opt to see the therapist up to 3 times up until 12 months after starting therapy. Participants will complete measures of clinical symptoms, quality of life/sense of personal recovery and use of healthcare services at four time points: study intake, 14 weeks after intake, 30 weeks after intake, and 52 weeks after intake. They will also complete additional measures at some of these time points. Further details are given below. Measures: Demographic assessment at baseline only: 1. Demographic questionnaire: age, gender, ethnicity, relationship status, highest level of education, perceived financial status, currently open to secondary care services. Measures to assess eligibility: The following measures will be completed at intake to assess participant eligibility. 1. Structured clinical interview for DSM-V (SCID-5) – at baseline only. The Hamilton Depression Rating Scale (HAM-D: Hamilton, 1960) will be used with participants who meet the criteria for a current depressive episode to establish severity (those scoring in the severe range of >=24 will not be eligible). The International Classification of Diseases, 11th revision (ICD-11) will be used to determine the presence or absence of current substance dependence. 2. Patient Health Questionnaire – 9 (PHQ-9) 3. Affective Lability Scales - short version (ALS) Clinical outcome measures (completed at baseline, 14-, 30- and 52-week follow-up): 1. PHQ-9 2. ALS 3. Bech-Rafaelsen Mania Scale (BRMS) 4. Brief Quality of Life in Bipolar Disorder (QoLBD) 5. General Anxiety Disorder Assessment – 7 (GAD-7) 6. Bipolar Recovery Questionnaire (BRQ) 7. Life chart self-report – self-report of number and duration of depressive and manic episodes in the period since the last assessment (completed at 14, 30 and 52-week follow-up points only) 8. Health Economics Questionnaire (HEQ) 9. EQ-5D-5L Process measures (completed at baseline, 14 and 30 week follow-up): 1. Positive and Negative Urgency Scales (PU & NU) 2. Behavioural Activation in Depression Scale – Short Form (BADS-SF) 3. Momentary Assessment Block (MAB: completed at baseline, 14 and 30-week follow-up points). Participants will be invited to report on their current mood and activity 5 times per day for 10 days via a purpose-built web application (momentary assessment block). These momentary assessment blocks will take place on three occasions: for 10 days following the intake assessment, for 10 days at 14 weeks post-randomisation, and for 10 days following the 30-week follow-up point. 4. Altman Scale for Rating Mania (ASRM) 5. Beck Depression Inventory (BDI) Qualitative interview: At 30 weeks (patient participants) and at the end of the trial (therapists) there will be audio-recorded qualitative interviews of approximately 60 minutes conducted by one of the research team exploring experiences of the therapy. Behavioural The datasets generated during and/or analysed during the current study will be stored in a publicly available repository. All trial data excluding personally identifiable information will be made available indefinitely. Consent from participants will be obtained for data to be stored for the purposes of other ethically approved research in the future and that data will be shared anonymously. Available on request Stored in publicly available repository 2025 Protocol article in https://pubmed.ncbi.nlm.nih.gov/40640965/ (added 11/07/2025) Protocol

4b992cb3-1872-43be-acca-6b8fc5322704 f6e525f5-d77e-4622-9311-c86e64895cd2 b61a637b-18c9-4f4c-a3ba-329ed64ec9e6 4367d472-107f-40dc-9021-f901d2fd3f19 Yes Statistical Analysis Plan ISRCTN18207465_SAP_V1.0.pdf 7aedf16a-3e42-4b9a-80b5-c3f372e688ee true application/pdf 832554 5de8e1d479465f33696feb8f501876f6 Statistical Analysis Plan ISRCTN18207465 stabilise_feasibility_sap_v1.2 24Oct2024.pdf 12a2b6d3-2821-4da4-ae0e-10cfdea773c8 true application/pdf 614215 8bc2c3ed6b17b156c0020412261fef5c Kim Wright Scientific Principal investigator

Washington Signer Labs Perry Road

Exeter United Kingdom EX44QG +44 (0)1392725227 K.A.Wright@exeter.ac.uk Public Study Team Public

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- United Kingdom - - stabilise@exeter.ac.uk Public University of Exeter University/education https://ror.org/03yghzc09 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 93974770 true Feeling Safer: a cohort study and a randomised controlled trial of a guided online programme for the treatment of persecutory delusions For patients with persistent persecutory delusions in the context of a psychosis diagnosis can Feeling Safer, added to treatment as usual, delivered by either peer support workers, graduate mental health workers, or CBT therapists, compared to treatment as usual, reduce persecutory delusions? The primary time-point is 6 months (post-therapy). This is the study hypothesis for the main randomised controlled trial (RCT) test of Feeling Safer. Background and study aims Persecutory delusions (inaccurate beliefs that others intend to harm you) (e.g. “MI5 and the police are trying to torture me” “My neighbours are out to get me and are spreading nasty gossip”) are very common in severe mental health disorders such as schizophrenia. People withdraw from everyday life. This seriously affects their mental and physical health. Existing treatments often don’t work well enough. In the UK 150,000 NHS patients experience these distressing thoughts despite treatment. This is why the Feeling Safe programme has been developed. It is the outcome of 15 years of research and clinical practice. Feeling Safe was recently tested in a clinical trial with 130 patients with persistent persecutory delusions. The treatment was delivered by clinical psychologists over 20 sessions. Half of people achieved large benefits. Another quarter made moderate gains. These results provide great cause for optimism in the treatment of delusions. The challenge now is to make Feeling Safe widely available. So, the study team have created a 6-month guided online version that users can access whenever they choose via smartphone/computer/or tablet. A range of mental health workers can support the delivery of the treatment over 6 months (both remotely and face-to-face). Six face-to-face sessions will be reserved for a key task: going out with patients into everyday situations to relearn safety. The new programme is called Feeling Safer. By providing Feeling Safe in an accessible version for use across the NHS, the aim is to achieve substantially improved outcomes for the large number of people with persecutory delusions who have not responded sufficiently to current treatment. The study team now wish to assess the effectiveness of Feeling Safer. There is an initial cohort study of Feeling Safer, and then the main clinical trial that this trial registration confirms. Who can participate? Patients (aged 16 years or older) with persecutory delusions in the context of a diagnosis of psychosis attending NHS mental health services. What does the study involve? Participants will complete a set of questionnaires at baseline. Participants will then be randomly allocated to one of four groups. Three groups will receive Feeling Safer supported by either a peer support worker, graduate mental health worker, or CBT therapist, in addition to their usual care. The fourth group will continue to receive their usual care. All groups will then complete another set of questionnaires after 3, 6 and 9 months. Whether a person has Feeling Safer will be randomly decided by a computer (rather like flipping a coin). What are the possible risks and benefits of participating? The study team hope that using Feeling Safer will help people feel safer, happier, and to be more active. The research aims to find out whether this is the case. The study team do not anticipate any major risks from taking part. People can stop using the Feeling Safer programme if they wish. If the assessments are experienced as upsetting then it is possible to reduce the number of these or stop. Where is the study run from? University of Oxford (UK) When is the study starting and how long is it expected to run for? August 2023 to May 2027 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK) (NIHR PGfAR NIHR204013) Who is the main contact? 1. Prof. Daniel Freeman, daniel.freeman@psy.ox.ac.uk 2. Dr Laina Rosebrock, laina.rosebrock@psy.ox.ac.uk Severity of persecutory delusion measured by the Psychotic Symptoms Rating Scale (PSYRATS) at baseline, 3, 6, and 9 months. The primary endpoint is 6 months. 1. Depression measured using Patient Health Questionnaire-9 (PHQ-9) at baseline, 6 and 9 months 2. Anxiety measured using Generalised Anxiety Disorder Assessment (GAD-7) at baseline, 6 and 9 months 3. Insomnia measured using the Insomnia Severity Index at baseline, 6 and 9 months 4. Agoraphobia measured using the Oxford Agoraphobic Avoidance Scale at baseline, 6 and 9 months 5. Paranoia measured using the Revised Green et al Paranoid Thoughts Scale at baseline, 6 and 9 months 6. Psychological well-being measured using the Warwick-Edinburgh Mental Well-being Scale at baseline, 6 and 9 months 7. Personal recovery measured using the Process of Recovery Questionnaire at baseline, 6 and 9 months 8. Meaningful activity measured using time budget at baseline, 6 and 9 months 9. Quality of life measured using EQ-5D-L and ReQol at baseline, 6 and 9 months Ethics approval required London - Harrow Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 23/LO/0951 10.1186/ISRCTN93974770 330744 CPMS: 57021 330744 57021 Multi-centre four-arm single-blind interventional randomized controlled trial Interventional Randomised controlled trial Treatment 2027-05-01T00:00:00.000Z United Kingdom England Oxford Health NHS Foundation Trust

Warneford Hospital Warneford Lane Headington

Oxford England OX3 7JH Berkshire Healthcare NHS Trust Headquarters

Skimped Hill Lane

Bracknell England RG12 1LH RWXHQ@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 Central and North West London NHS Foundation Trust

Trust Headquarters 350 Euston Road Regents PLACE

London England NW1 3AX RV3@2.16.840.1.113883.2.1.3.2.4.18.48 Avon and Wiltshire Mental Health Partnership NHS Trust

Bath NHS House Newbridge Hill

Bath England BA1 3QE RVN@2.16.840.1.113883.2.1.3.2.4.18.48 Coventry and Warwickshire Partnership NHS Trust

Wayside House Wilsons Lane

Coventry England CV6 6NY Greater Manchester Mental Health NHS Foundation Trust

Prestwich Hospital Bury New Road Prestwich

Manchester England M25 3BL RXV@2.16.840.1.113883.2.1.3.2.4.18.48 Pennine Care NHS Trust

225 Old Street

Ashton-under-lyne England OL6 7SR RT2HQ@2.16.840.1.113883.2.1.3.2.4.18.48 Tees, Esk & Wear Valley NHS Trust

West Park Hospital Edward Pease Way

Darlington England DL2 2TS Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust

St. Nicholas Hospital Jubilee Road Gosforth

Newcastle upon Tyne England NE3 3XT National Virtual Clinic

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- England - Patient 1. Participant is willing and able to give informed consent for participation in the trial 2. Aged 16 years or older 3. Attending NHS mental health services for the treatment of psychosis 4. Persistent (at least 3 months) persecutory delusion (as defined by Freeman & Garety, 2000), held with at least 50% conviction 5. No planned significant medication changes at the outset of participation Mixed 16 Years 100 Years All 484 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 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 2024-11-25T00:00:00.000Z 2026-11-30T00:00:00.000Z Psychosis with a current persecutory delusion Mental and Behavioural Disorders Participants will be patients (aged 16 years or older) with persecutory delusions in the context of a diagnosis of psychosis attending NHS mental health services. Participants will be randomised to one of four conditions: Feeling Safer (added to standard care) supported by peer support workers, or graduate mental health workers, or CBT therapists, or standard care. Randomisation will use a permuted blocks algorithm, with randomly varying block sizes, stratified by centre. The treatment being tested is Feeling Safer, which is a guided online programme recommended for adults (16 years or older) attending psychosis services who have a persecutory delusion. It is a cognitive-behavioural intervention, developed from Feeling Safe, and delivery is supported by a mental health staff member. The goal of the treatment is to reduce persecutory delusions. There is an introductory module providing information about the programme and animations of patient accounts. Patients then complete an assessment for the programme to provide the relevant treatment modules for them (e.g. improving sleep, increasing self-confidence, reducing worry) i.e. the intervention is personalised. The patient then works through each module before going on to the next relevant module. There are up to ten modules. Each module is broken down into many 10-20-minute sections for the person to complete. There are then tasks to complete offline. Throughout there are regular assessments, with information on progress fed back to the user. Information is conveyed by voice and text, animations, and videos. There is a diary reminder section. There is also a section for people when they are having a particularly difficult day and would not want to complete a section of a module. It is expected for patients to log in two or three times a week. Regular check-ins, typically weekly, are expected with the mental health staff member. These are conducted remotely (e.g. telephone or video call). There are in-person sessions, which are typically focussed on the staff member assisting the person in getting back into everyday activities. The level of staff support can be tailored to a patient’s needs. The staff-supported provision of Feeling Safer is provided over 6 months. Patients can still have access to the programme after this period but without the staff support. If a patient does not have a suitable device to access Feeling Safer then this is provided for them. Other Requests - accompanied by a study summary - for sharing of de-identified data will be considered by the Chief Investigator (daniel.freeman@psy.ox.ac.uk) and team. The intent is to share data for reasonable requests. 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 2025 Protocol article in https://pubmed.ncbi.nlm.nih.gov/40480660/ (added 09/06/2025) Protocol

9e627ced-597a-4622-b5bc-b033d93a89c9 c5ab658c-a284-4196-9dcd-623de09129ef 4c88e15d-51a6-4434-9133-409563339875 c826ff3b-b7a5-457b-aaf2-06a57ded7425 6b97095c-e89d-460b-ab70-848c8853948f Yes Daniel Freeman https://orcid.org/0000-0002-2541-2197 Scientific Principal investigator

University Of Oxford Department of Experimental Psychology New Radcliffe House Radcliffe Observatory Quarter Woodstock Road

Oxford United Kingdom OX2 6GG +44 (0)1865 613109 daniel.freeman@psy.ox.ac.uk Public Ariane Beckley https://orcid.org/0000-0001-6026-9616 Public

University Of Oxford Department of Experimental Psychology New Radcliffe House Radcliffe Observatory Quarter Woodstock Road

Oxford United Kingdom OX2 6GG +44 (0)7817236236 ariane.beckley@psy.ox.ac.uk Public Laina Rosebrock https://orcid.org/0000-0002-4583-8435 Scientific

New Radcliffe House Radcliffe Observatory Quarter Woodstock Road

Oxford United Kingdom OX2 6GG +44 (0)1865 618332 laina.rosebrock@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 14087654 true The feasibility and implementation of a Psychosis Risk Prediction Algorithm (P Risk) for use in primary care P Risk To determine the operationalisation and acceptability of using P Risk in real-world clinical situations Background and study aims Psychosis is a mental illness. Symptoms include hallucinations and strange, fixed thoughts, called delusions. Psychosis can be devastating for sufferers and their families and outcomes are often poor with many people becoming ill again after recovery. Only about 20% of people with psychosis are in paid employment and many have a poor quality of life. Physical health is also poorer with a life expectancy 15-20 years shorter than average. Treating psychosis costs the NHS about £2 billion per year. The best way to improve outcomes is to ensure that people who are at risk of psychosis receive specialist care quickly. However, being able to identify people at risk of psychosis has proved difficult. Most people enter specialist mental health care via their GP, but GPs report difficulties in detecting the warning signs of psychosis. Also, people do not always see the same GP when they visit their surgery and so small changes in their mental health can be missed. A computer tool, called P risk has been developed using a very large data set of GP records to teach the computer to spot who is likely to develop psychosis. P Risk has already proven to be accurate and can predict who will get psychosis about 80% of the time. However, it is not yet known if it will work in the real world on GP computers, or what patients, their families, GPs and mental health staff think about it. This information is needed before P Risk can be used in GP surgeries. This study aims to examine if it is feasible and acceptable to practitioners, patients, and carers to implement a psychosis risk prediction algorithm in primary care. Who can participate? As part of the qualitative work, we will conduct interviews with GPs, clinicians working in the Early Intervention Services, and patients (aged 18+ years old) who have consulted their GPs over the last six months for non-psychotic symptoms (e.g. depression or problems with sleep) and their carers. What does the study involve? In this study, the team will: 1) work with the company that provides software for GP computers to make sure that P Risk works on their computers 2) work out the accuracy of P Risk in clinical practice, and 3) explore practitioner, patients’ and carers’ views on how P Risk should be used in practice and how its results should be communicated between practitioners and between practitioners and patients. This information will help us develop the next stage of our work, which will investigate whether P Risk is effective at helping GPs identify people at risk of developing psychosis. What are the possible benefits and risks of participating? Whilst there are no individual benefits from taking part in the study, participants will make an important contribution to the P Risk research project. As a thank you for their time, we will offer patients and their carers an online shopping voucher. There is a small chance that some patients taking part in the interview may become distressed when talking about their own experiences. The researchers running the interviews will be trained to manage this situation if it occurs. If the researcher is concerned about the mental well-being of the patient, they will advise the patient to contact their GP or mental health clinician as soon as possible. Where is the study run from? 1. University of Bristol (UK) 2. University College London (UK) When is the study starting and how long is it expected to run for? March 2022 to March 2026 Who is funding the study? NIHR RfPB Biomedical Research Centre (UK) Who is the main contact? Sarah Sullivan, sarah.sullivan@bristol.ac.uk 1. Coded incident diagnosis of First Episode Psychosis (FEP) or an At-Risk Mental State (ARMS) recorded in primary and/or secondary care EHRs measured using medical records at one timepoint 2. Patients' and clinicians' views on the acceptability and potential value and implications of using P Risk in general practice measured using interviews with GPs and focus groups/individuals at one timepoint 1. Whether the P Risk threshold for high, medium or low is optimal 2. Calibration in two subsamples of patients measured using a coded diagnosis of psychosis at one time point: 2.1. Afro-Caribbean ethnicity 2.2 Older women (50-65 years of age)), where there is evidence that they are at increased risk Ethics approval required North West - Greater Manchester East Research Ethics Committee

3rd Floor, Barlow House 4 Minshull Street

Manchester United Kingdom M1 3DZ 22/NW/0289 10.1186/ISRCTN14087654 315320 CPMS: 53885, 2022 - 1178 version 0.8, 23.05.2023 315320 53885 2022 - 1178 version 0.8, 23.05.2023 Multi-centre observational study Observational Cross sectional study Screening 2026-03-31T00:00:00.000Z United Kingdom England Bristol, North Somerset and South Glos. CCG

17 Marlborough Street

Bristol England BS1 3NX London CCGs

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London England N1 1TH Avon and Wiltshire Mental Health Partnership NHS Trust

Bath NHS House Newbridge Hill

Bath England BA1 3QE RVN@2.16.840.1.113883.2.1.3.2.4.18.48 Barnet, Enfield and Haringey Mental Health NHS Trust

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London England N15 3TH Tavistock and Portman NHS Foundation Trust

The Tavistock Centre 120 Belsize Lane

London England NW3 5BA RNK@2.16.840.1.113883.2.1.3.2.4.18.48 Central and North West London NHS Foundation Trust

Trust Headquarters 350 Euston Road Regents PLACE

London England NW1 3AX RV3@2.16.840.1.113883.2.1.3.2.4.18.48 Camden and Islington NHS Foundation Trust

St Pancras Hospital 4 St Pancras Way

London England NW1 0PE TAF@2.16.840.1.113883.2.1.3.2.4.18.48 Carer Health professional Patient Work package 1: 1. GP practices which use EMIS clinical records software 2. All GP practices in the Bristol, North Somerset and South Gloucestershire CCG (BNSSGCCG) region use EMIS software Work package 3: GP practices which use EMIS clinical records software. Work package 4: 1. GPs from BNSSG and the London area 2. Clinicians from the Early Intervention Services within Avon and Wiltshire NHS Foundation Trust and the London area, who provide assessments for people at risk of psychosis 3. Patients who consulted their GP within the last six months for non-psychotic mental health problems 4. Patients' carers Mixed 18 Years 80 Years All 1064068 29 Work package 1: There are no participant exclusion criteria Work package 3: Any patient with an existing coded diagnosis of psychosis either in primary or secondary care EHRs or any recorded prescription for anti-psychotic medication at a dosage appropriate for psychosis Work package 4: Inability to provide informed consent 2023-03-16T00:00:00.000Z 2023-12-31T00:00:00.000Z Early Identification of people at risk of psychosis in Primary Care Services Mental and Behavioural Disorders This is a multi-centre observational study. The study aims to: i) demonstrate whether P Risk can be implemented in primary care data systems; ii) investigate the accuracy of P Risk using real-world primary care data systems; and iii) investigate the acceptability of P Risk to practitioners, patients, and carers. Study design: Work package 1: Conversion of the P Risk statistical algorithm into a code that is compatible with EMIS medical records software. The P Risk algorithm will be run on the historical EHRs of every patient over the previous 5 years to investigate any ‘bugs’ in the functioning of P Risk in EMIS software. Work package 3: Investigate the accuracy of P Risk in real-world data by calculating the sensitivity (true positives) and specificity (true negatives) of P Risk (number of diagnoses of psychosis correctly picked up by P Risk) against the gold standard of a coded psychosis diagnosis Work package 4: In-depth interviews will be held with GPs and focus groups/individual interviews will be held with those on whom it would be used and those affected by it (patients and their carers), to explore their views on the acceptability and potential value and implications of using P Risk in general practice. As P Risk may alter referrals from general practice to Early Intervention Teams (EITs), interviews will also be held with EIT staff to assess their views of P Risk, and their thoughts about GPs making referral decisions informed by P Risk and whether they would accept referrals on this basis. Other The datasets generated during and/or analysed during the current study are/will be available upon request from Paul Roy (quantitative data) (paul.roy1@nhs.net) or Daniela Strelchuk (qualitative data) (daniela.strelchuk@bristol.ac.uk). Data will become available after publishing the paper for a period of 5 years. Anonymous data will be shared with other researchers. Data will be shared via secure data transfer. Consent has been obtained from interviewees (from the qualitative work) to share the information collected anonymously with other researchers). Available on request 2026 Results article in https://doi.org/10.3399/BJGP.2025.0222 (added 03/03/2026) Results

Migrated from study website field

0d7b0529-54a3-4914-bd53-cbb04babe940 c3043691-5007-4b64-a414-9920f8cec439 30f08681-0410-4f70-98fd-aa268e99efff Yes Participant information sheet 44699_PIS_Patients_v1.7.pdf 24814fe1-23c4-4174-98f2-9ad073fc8a5b true application/pdf 137474 b0f6e6f377a937e145878134d556e40b Protocol file 44699_Protocol_v0.8_23May2023.pdf 114c81fc-8407-43a8-9d7c-0bc9c64f9a24 true application/pdf 356805 7f1c6e9de8e107346ee1ea0da2e6b6c6 Sarah Sullivan Public Scientific Principal investigator

Oakfield House Oakfield Grove

Bristol United Kingdom BS8 2BN +44 (0)117 331 0074 sarah.sullivan@bristol.ac.uk Public University of Bristol University/education https://ror.org/0524sp257 Non-commercial Research for Patient Benefit Programme http://dx.doi.org/10.13039/501100009128