16804705 true Indoor Versus OutdooR group psychological therapy for older adults in NHS inpatient settings; a feasibility study of a pragmatic, cluster randomized controlled trial (RCT) IVOR This is a small-scale pilot study designed to assess whether a larger trial would be feasible. The study compares indoor and outdoor group psychological therapy for older adults receiving NHS inpatient care. It will assess how practical and acceptable it is to deliver the two approaches and whether the study procedures are manageable. The findings will help determine whether and how a larger trial could be conducted in the future. Background and study aims People who spend time outdoors may experience benefits to their mental health and wellbeing, such as reduced stress and improved mood. However, psychological therapy in NHS hospitals is usually delivered indoors. There is some evidence that providing psychological therapy outdoors may help people feel better and become more engaged with therapy, but there is not yet enough research to know whether this is practical and beneficial for older adults receiving care in NHS hospitals. This study will compare group psychological therapy delivered indoors with the same type of therapy delivered outdoors for older adults staying in NHS hospital wards. The study will help us understand whether outdoor psychological therapy is practical and acceptable for patients and staff. It will also help us decide whether a larger study should be carried out in the future. Who can participate? People who are currently receiving care on dementia and frailty inpatient wards at Birmingham and Solihull Mental Health NHS Foundation Trust may be able to take part. Participants will need to have been invited to attend group psychological therapy and be able to give informed consent to take part in the research. Staff involved in delivering or supporting the therapy may also be invited to provide their views about delivering psychological therapy outdoors. What does the study involve? Participants who agree to take part will attend group psychological therapy as part of their usual care. The therapy will be delivered either indoors or outdoors. The ward will be assigned to either the indoor or outdoor therapy group, meaning that participants on the same ward will receive the same type of therapy. Participants will not individually choose whether their therapy is delivered indoors or outdoors. Participants will be asked to complete questionnaires about their wellbeing and their experience of the therapy. These questionnaires will be completed before the therapy, after the therapy, and again approximately 3 months later. The study will also collect information about how many people agree to take part, whether participants attend the therapy sessions, and whether the therapy can be delivered as planned. Staff will be asked about their experience of delivering therapy outdoors. What are the possible benefits and risks of participating? Benefits: This study will help us to consider the feasibility of delivering outdoor psychological therapy. Whilst there may be no immediate benefits to participants, the aim is to improve care for future patients on the ward. Risks: Some of the disadvantages of taking part are that participants may find it time consuming to complete the questionnaires and that they will not be able to choose where the group psychological therapy is conducted (indoors or outdoors) as it is randomly allocated. For participants who receive outdoor group psychological therapy, they may be exposed to adverse weather conditions, they may find it more difficult to walk to the venue, and there may be less privacy. Taking part is voluntary, and participants can choose not to take part or withdraw from the research without this affecting their usual care. Where is the study run from? The study is sponsored by the University of Birmingham and is delivered at Birmingham and Solihull Mental Health NHS Foundation Trust. It will take place on dementia and frailty inpatient wards within the Trust, including the Juniper Centre and Reservoir Court. When is the study starting and how long is it expected to run for? The study started recruitment in May 2026 and the study will end in January 2027. Who is funding the study? Investigator initiated and funded. Who is the main contact? Dr Stephanie Howarth Principal Investigator s.l.howarth@bham.ac.uk Recruitment rates Number and proportion of eligible participants recruited to the study, measured against the target recruitment of 16–24 participants. Recruitment rate will be calculated as the number of participants consenting to take part divided by the number of eligible participants approached/invited, expressed as a percentage. The number recruited per week will also be recorded from the start of participant recruitment until the end of the recruitment period (approximately 16 weeks). Acceptability of intervention Acceptability of Intervention Measure post-intervention Ethics approval required Seasonal REC

2 Redman Place Stratford

London United Kingdom E20 1JQ 26/LO/0064 10.1186/ISRCTN16804705 362658 362658 Interventional Randomized controlled trial Open (masking not used) Active Parallel Treatment Feasibility of outdoor group psychological therapy Not applicable 2027-01-01T00:00:00.000Z United Kingdom England Birmingham and Solihull Mental Health NHS Foundation Trust

The Uffculme Centre 52 Queensbridge Road Moseley

Birmingham England B13 8QY RXT@2.16.840.1.113883.2.1.3.2.4.18.48 false Participants (service users) will be eligible to take part in the study if: 1. They are aged 18 years or above 2. They are currently receiving care from inpatient services at the Juniper Centre or Reservoir Court, Birmingham and Solihull NHS Foundation Trust 3. They are due to take part in a therapy group, such as Stressbusters 4. They have read the Participant Information Sheet and had the opportunity to speak to a researcher and ask any questions they may have about the study 5. There are no concerns about their capacity to provide informed consent to take part in the study 6. They provide informed consent by completing the Informed Consent Form Participants (staff) will be eligible to take part in the study if: 1. They are currently working in inpatient settings at the Juniper Centre or Reservoir Court, Birmingham and Solihull NHS Foundation Trust 2. They facilitate or co-facilitate groups, such as Stressbusters 3. They have read the Participant Information Sheet and had the opportunity to speak to a researcher and ask any questions they may have about the study 4. They provide informed consent by completing the Informed Consent Form Mixed 18 Years 120 Years All 24 0 Participants (service users) will be excluded from the study if: 1. They are not currently receiving inpatient care from the Juniper Centre or Reservoir Court, Birmingham and Solihull NHS Foundation Trust 2. They are not due to take part in a therapy group, such as Stressbusters 3. They are unable to understand the Participant Information Sheet or do not have the opportunity to speak with a researcher about the study 4. There are concerns about their capacity to provide informed consent to take part in the study 5. They do not provide informed consent by completing the Informed Consent Form Participants (staff) will be excluded from the study if: 1. They are not currently working in inpatient settings at the Juniper Centre or Reservoir Court 2. They do not facilitate or co-facilitate groups such as Stressbusters 3. They are unable to understand the Participant Information Sheet or do not have the opportunity to speak with a researcher about the study 4. They do not provide informed consent by completing the Informed Consent Form 2026-05-28T00:00:00.000Z 2026-09-17T00:00:00.000Z Psychological therapy for psychological distress in adults and older adults receiving inpatient mental health care for a range of mental health conditions and/or dementia Mental and Behavioural Disorders Intervention arm – outdoor Stressbusters group: Older adult inpatients due to attend the routinely offered Stressbusters therapy group will receive five weekly, one-hour group psychological therapy sessions delivered in an outdoor space on the ward. Each session focuses on one of the five senses (sight, hearing, taste, touch and smell) and provides strategies to reduce stress, using activities such as smelling lavender, looking at calming images or listening to uplifting music. Comparator arm – indoor Stressbusters group: Older adult inpatients will receive the same five weekly, one-hour Stressbusters group sessions, but delivered indoors. The content, frequency and duration of the therapy will be the same as in the outdoor arm, with the setting being the main difference between the two groups. Participants will be grouped according to the ward on which they are receiving inpatient care. Each ward-based group (cluster) will be randomly allocated to either the indoor or outdoor intervention. The study aims to recruit 16–24 participants across the four wards. Participants will complete questionnaires before and after the five-week intervention and at three-month follow-up. Brief feedback will also be collected after each session. Staff delivering the groups will complete questionnaires about their experience of delivering the therapy in the allocated setting. The study will assess the feasibility of recruitment, attendance and outcome measurement, as well as the acceptability and practicality of delivering Stressbusters indoors or outdoors. Randomisation Participants will be randomised by cluster according to the ward on which they are receiving inpatient care. Each cluster will comprise between 1 and 8 participants and will be randomised in a 1:1 ratio to receive the Stressbusters psychological therapy either indoors or outdoors. Block randomisation will be used to allocate clusters to the two study arms. An independent researcher, who is not involved in delivering the therapy, will conduct the randomisation using an Excel spreadsheet. Following randomisation, the researcher will inform the relevant therapy staff and service user participants whether the upcoming Stressbusters group will be delivered indoors or outdoors. The group will then be delivered in the allocated setting. Behavioural Not expected to be made available Protocol

0ed03880-a2d5-49e4-a6d9-03fa53e15d13 219fe7a6-e1c0-45b4-8338-30f536557b58 92656118-54cf-4bcf-b068-f88abfd36fc4 8d6af225-90e4-4a42-b9c6-f5fe3fd13343 dce9aedd-281c-4e28-bb73-288c21115807 No Participant information sheet 50104 Participant Information Sheet (Service User) v1.0 01Aug2025.pdf 45394494-5e85-478f-8d1c-39937f5b12cd true application/pdf 146239 3af1c3a85d45ec9bb5612e67209e5c80 Protocol file 50104 Protocol v1.0 01Aug2025.pdf b55bee6e-57bc-4e53-a6be-a2e75c5c94b5 true application/pdf 573139 ad91998e7c5c05128b5ab8bf78e050e9 Stephanie Howarth Principal investigator

University of Birmingham 52 Pritchatts Road, Edgbaston

Birmingham United Kingdom B15 2TT +44 121 414 3344 s.l.howarth@bham.ac.uk Public Anna Amiry https://orcid.org/0000-0002-0912-3387 Public

School of Psychology University of Birmingham 52 Pritchatts Road, Edgbaston

Birmingham United Kingdom B15 2TT +44 121 414 3344 axa2572@student.bham.ac.uk Public Carl Krynicki https://orcid.org/0000-0003-0943-5142 Scientific

School of Psychology University of Birmingham 52 Pritchatts Road, Edgbaston

Birmingham United Kingdom B15 2TT +44 121 414 3344 c.krynicki@bham.ac.uk Public University of Birmingham https://ror.org/03angcq70 Non-commercial Investigator initiated and funded 61299413 true Effectiveness and public health impact of SELFIE, a transdiagnostic, blended ecological momentary intervention for improving self-esteem in young people exposed to childhood adversity: a hybrid effectiveness-implementation study in 6 European countries European SELFIE trial The overarching aim of the hybrid effectiveness-implementation study is to assess the 1) effectiveness and 2) public health impact of SELFIE, a transdiagnostic, blended ecological momentary intervention for improving self-esteem, in young people exposed to childhood adversity in a hybrid effectiveness-implementation study in 6 European countries (Estonia, Germany, Italy, the Netherlands, Spain, and UK) and 7 clinical investigation sites. The trial has two objectives: 1. Translate, adapt and implement SELFIE in a participatory implementation study with stakeholder groups, namely clinicians and young people, in line with prevailing ethical and regulatory requirements in 6 European countries. 2. Examine a) Reach (i.e., user participation, feasibility, acceptability), b) clinical Effectiveness (defined as the interaction of efficacy × implementation in real-world care settings), c) Adoption (proportion of users and clinicians having used SELFIE in routine care settings), d) Implementation (defined as delivery of SELFIE as intended in routine care) and e) Maintenance (defined as intended continuation of intervention usage) in a multi-country RCT, which, consistent with the RE-AIM framework, will provide the basis for establishing the public health impact and sustainability of implementation of SELFIE. Background and study aims This study is about helping young people who have faced difficult experiences in childhood and now struggle with low self-esteem and mental health. The aim is to see if a program called SELFIE can boost self-esteem and improve mental well-being over time. Who can participate? Young people aged 14 to 25 who have a history of childhood adversity, are currently feeling distressed, and report low self-esteem can take part. Participants will be recruited from Germany, the UK, the Netherlands, Italy, Spain, and Estonia. What does the study involve? Participants will fill in questionnaires and keep a digital mood diary at four points over 12 months. Some participants will be randomly chosen to try the SELFIE training, which lasts six weeks. This includes activities on an app and three sessions with a mental health professional. Others will continue with their usual care. Random selection helps make sure results are fair. What are the possible benefits and risks of participating? Taking part may help improve mental health, self-esteem, and overall well-being. There are no known health risks linked to the study. Where is the study run from? The study is sponsored by the Central Institute of Mental Health in Germany. When is the study starting and how long is it expected to run for? Recruitment starts in January 2026 and ends in July 2027. Who is funding the study? The study is funded by the Central Institute of Mental Health in Germany. Who is the main contact? If you have questions, please contact Anita Schick at anita.schick@zi-mannheim.de. General psychopathology at 6-month follow-up assessed by the revised Symptom Checklist (SCL-90-R; Derogatis (1977)). A total score will be calculated. The following secondary outcomes will be assessed based on self-rated measures (to establish Effectiveness) at 3-month (t1), 6-month (t2), and 12-month follow-up (t3): 1. Well-being assessed with the Mylife tracker (Kwan et al., 2018) and the WEMWEBS (Tennant et al., 2007) 2. Self-esteem assessed with the Rosenberg Self-Esteem Scale (RSES; Schmitt and Allik, 2005) and the Self-Esteem Rating Scale (SERS; Lecomte et al., 2006) 3. Resilience assessed by the CD-RISC (Connor and Davidson, 2003) 4. Social functioning assessed with the WSAS (Jassi et al., 2020) 5. Quality of life assessed with the WHOQOL-BREF (Kwan and Rickwood, 2015; WHOQOL Group, 1998) 6. Psychological distress assessed with CORE-10 (Barkham et al., 2013) 7. Depression assessed by PHQ-9 (Kroenke et al., 2001) 8. Anxiety assessed using the GAD-7 (Spitzer et al., 2006) 9. Service attachment measured with the Service Attachment Questionnaire (SAQ; Goodwin et al., 2003) 10. User-led and co-created outcome measures developed by young people Secondary outcomes to assess Reach, Adoption, Implementation, and Maintenance: 11. Reach assessed by the number of individuals consenting to, participating in, and dropping out during the intervention period at 3-month follow-up 12. Adoption assessed using a checklist for usage of key components of the SELFIE intervention at 3-month follow-up 13. Implementation assessed by the extent to which SELFIE components are delivered as intended, using a checklist at 3-month follow-up 14. Maintenance assessed by the intended continuation of using the EMI components of SELFIE at 6-month and 12-month follow-up Ethics approval required Ethics committee II of Heidelberg University

Theodor-Kutzer-Ufer 1-3

Mannheim Germany 68167 2025-430 MF 10.1186/ISRCTN61299413 364308 101156514, 2025-01-SELFIE 364308 101156514 2025-01-SELFIE Parallel-group assessor- and analyst-blind multi-country interventional randomized controlled trial Interventional Randomised controlled trial Prevention Treatment 2028-07-31T00:00:00.000Z United Kingdom England Estonia Germany Italy Netherlands Spain Birmingham and Solihull Mental Health NHS Foundation Trust

Forward Thinking Birmingham, 5th Floor, 1 Printing House St

Birmingham England B4 6DF Central Institute of Mental Health

J 5

Mannheim Germany 68159 University Maastricht

MHeNS / FHML Vijverdalseweg 1

Maastricht Netherlands 6226 Amsterdam UMC

DE BOELELAAN 1117

Amsterdam Netherlands 1081 Provincia Lombardo Veneta - Ordine Ospedaliero Di San Giovanni Di Dio- Fatebenefratelli

IRCCS Centro San Giovanni di Dio Fatebenefratelli Via Pilastroni 4

Brescia Italy 25121 Hospital General Universitario Gregorio Marañón

Instituto de Psiquiatría y Salud Mental Hospital Gregorio Marañón Calle Ibiza 43

Madrid Spain 28009 Mittetulundusuhing Peaasjad

Maneeži tn 3

Tallinn Estonia 10111 Patient Service user false 1. Aged 14-25 years 2. Presence of clinically meaningful psychological distress opera-tionalized as a score of >10 on the CORE-10 or a GSI score > 0.52 on the SCL-90-R 3. Exposure to childhood adversity, broadly defined (physical, sex-ual or emotional abuse, emotional or physical neglect, peer bullying or parental conflict operationalized (Reininghaus et al. 2024)) 4. Self-esteem below average measured with the Rosenberg Self-Esteem Scale (RSES; (Schmitt and Allik 2005)) 5. Willingness to participate 6. Ability to give informed consent, and for minors: parental consent Mixed 14 Years 25 Years All 448 0 1. Insufficient command of the principal country language: English, Estonian, German, Italian, Spanish or Dutch, 2. Mental health symptoms are due to an organic cause, 3. Meeting criteria for a clinical diagnosis of intellectual disability (ICD-10 F70-F79) or with a disorder of psychological development (ICD-10 F80-89) that are sufficiently severe to impair a person's ability to provide informed consent 4. Inability to use a smartphone 5. Individuals with acute risk to themselves or others. 2026-01-01T00:00:00.000Z 2027-07-31T00:00:00.000Z Mental health problems Mental and Behavioural Disorders SELFIE intervention In this hybrid effectiveness-implementation study, a parallel-group, assessor- and analyst-blind, multi-country RCT will be conducted, in which participants will be randomly allocated using a 1:1 ratio to one of two conditions: (a) the experimental condition, in which participants receive SELFIE in addition to Care-As-Usual (CAU) or (b) the control condition, in which participants are provided with CAU, with a nested process evaluation and an economic evaluation. Participants allocated to the experimental condition will have access to the SELFIE intervention, i.e. a guided self-help intervention and a medical device according to EU MDR 2017/745 consisting of three face-to-face sessions (on-site or online), delivered by trained mental health professionals, three e-mail contacts, and an Ecological Momentary Intervention (EMI) administered through a smartphone-based app for adaptive real-time and real-world transfer of the intervention components to daily life over a course of 6 weeks. We will assess outcomes at 4 points in time: at baseline, at 3-month follow-up, 6-month follow-up and 12-month follow-up. Thus, the duration of study participation for individual participants is 12 months. Randomization will be conducted using a concealed sequence generated by the trial statistician with stratification for study site and gender. The allocation list will be implemented in the electronic case report form. Behavioural The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request Available on request

213ba4db-6dd0-45a3-afe1-c010b00c9f2f a4431ce0-3ee5-44fd-b6e7-4796cd7f4248 0c7de1d6-a13d-4e05-b422-7b8e8e319f5b e3a9b163-04ad-4bda-98a7-4f77025e0718 1655fcd2-c48e-4da4-b2bd-59133e81f778 Yes Ulrich Reininghaus https://orcid.org/0000-0002-9227-5436 Scientific

Central Institute of Mental Health J5 68159 Mannheim

Mannheim Germany 68159 +4962117031930 ulrich.reininghaus@zi-mannheim.de Public Anita Schick https://orcid.org/0000-0002-2043-0353 Public Scientific

Central Institute of Mental Health J5 68159 Mannheim

Mannheim Germany 68159 +4962117031941 anita.schick@zi-mannheim.de Public Frederike Schirmbeck Principal investigator

Central Institute of Mental Health J5 68159 Mannheim

Mannheim Germany 68159 +062117037404 frederike.schirmbeck@zi-mannheim.de Public Central Institute of Mental Health Research organisation Non-commercial European Union 87426672 true Developing EVIdence for AntidepreSsant ChoicE to Treat Depression in Huntington’s Disease DEVISE-HD The primary objective is to determine the feasibility of a blinded, placebo-controlled trial of antidepressants in people with HD This feasibility trial has three five secondary objectives: 1. Determine the minimal clinically important difference (MCID), ceiling and floor effects for established measures of depression in HD, to inform outcome selection for a future efficacy trial 2. Determine potential effect sizes in outcome of interest to inform power calculations for a future efficacy trial 3. Determine if there are differences on clinical and fluid biomarkers of disease progression with antidepressant treatment 4. Determine the percentage of participants who are registered in ENROLL 5. Determine the percentage of participants who are registered in HDClarity Background and study aims Huntington’s Disease (HD) is a condition that causes problems with movement and thinking, which get worse over time. Many people with HD also experience depression, which affects their quality of life and ability to do everyday activities. Treating depression well could help people with HD and their families feel better and may reduce the need for expensive healthcare. However, depression in HD may be different from depression in people without HD, so it is not clear how well antidepressants work for people with HD. This study aims to find out if a larger trial of antidepressants for depression in HD is possible and what is the best way to measure depression in people with HD. Who can participate? Adults who have Huntington’s Disease and report mild or moderate symptoms of depression to their doctor may be able to take part. What does the study involve? Participants are randomly assigned to receive either a common antidepressant (Sertraline) or a dummy pill (placebo) for 6 months. They have assessments of depression and other HD symptoms at the start of the study and again after 6 months. The study also collects blood and a small sample of the fluid around the brain (using a lumbar puncture) to see if antidepressant treatment changes certain substances linked to inflammation. The study also looks at how many people are willing to join and stay in the study, and which depression measures work best. What are the possible benefits and risks of participating? Taking part may help researchers learn more about how to treat depression in HD, which could benefit participants and others in the future. Participants may or may not notice an improvement in their own symptoms. Risks include possible side effects from the medication, and discomfort or risks from blood tests and lumbar puncture. All procedures are explained and carried out by experienced staff. Where is the study run from? Cardiff University (UK) When is the study starting and how long is it expected to run for? The study is expected to start soon and runs for about 6 months for each participant. Who is funding the study? Health and Care Research Wales (UK) Who is the main contact? Duncan.Mclauchlan@wales.nhs.uk DEVISEHD@cardiff.ac.uk Feasibility outcomes measured at 6 months post recruitment: 1. Recruitment 2. Retention 3. Data completeness 4. Medication adherence 1. Depression severity is measured using the Montgomery Asberg Depression Rating Scale (MADRS) at baseline, 8 weeks, and 6 months post randomisation 2. Depressive symptoms are measured using the Beck Depression Inventory-II (BDI-II) at baseline, 8 weeks, and 6 months post randomisation 3. Depressive symptoms are measured using the Patient Health Questionnaire-9 (PHQ-9) at baseline, 8 weeks, and 6 months post randomisation 4. Problem behaviours are measured using the Problem Behaviour Assessment at baseline, 8 weeks, and 6 months post randomisation 5. Suicidal ideation and behaviour are measured using the Columbia Suicide Severity Rating Scale (C-SSRS) at baseline, 8 weeks, and 6 months post randomisation 6. Disability is measured using the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) at baseline, 8 weeks, and 6 months post randomisation 7. Perceived social support is measured using the MOS Social Support Survey at baseline, 8 weeks, and 6 months post randomisation 8. Clinical progression of Huntington’s Disease is measured using the critical Unified Huntington’s Disease Rating Scale (cUHDRS) at baseline and 6 months 9. Motor function is measured using the motor assessment component of the cUHDRS at baseline and 6 months 10. Functional ability is measured using the functional assessment component of the cUHDRS at baseline and 6 months 11. Cognitive function, including association between visual association and memory/thought processing and cognitive inhibition, is measured using the cognitive assessment components of the cUHDRS at baseline and 6 months Ethics approval required Wales REC 5,

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

Cardiff United Kingdom CF 11 9AB - 10.1186/ISRCTN87426672 1010717 02-TC-24-024 1010717 02-TC-24-024 Double-blind randomized controlled feasibility trial Interventional Randomised controlled trial Efficacy Treatment 2027-10-31T00:00:00.000Z United Kingdom England Wales Cardiff and Vale NHS Trust

Cardigan House University Hospital of Wales Heath Park

Cardiff Wales CF14 4XW RWM@2.16.840.1.113883.2.1.3.2.4.18.48 Birmingham and Solihull Mental Health NHS Foundation Trust

The Uffculme Centre 52 Queensbridge Road Moseley

Birmingham England B13 8QY RXT@2.16.840.1.113883.2.1.3.2.4.18.48 Betsi Cadwaladr University Lhb Colwyn Bay Office

Princes Park Princes Drive

Colwyn Bay Wales LL29 8PL 7A1YB@2.16.840.1.113883.2.1.3.2.4.18.48 Patient 1. Adult participants (age ≥ 18), with a confirmed positive genetic test of HD 2. Presenting with a new episode of depression, defined by patient report of low mood and PBAs depressed mood item (i.e. not experiencing depressive symptoms for at least 4 months before the new episode) 3. Presenting with depressive symptomatology defined by patient report of low mood and PBAs depressed mood item score >1 for both severity and frequency Mixed 18 Years 100 Years All 40 0 1. Currently taking an antidepressant medication or have taken antidepressants in the last six months (for any indication) 2. A previous reaction and/or contraindication to sertraline, and/or Sertraline found to be ineffective 3. Any brain illness/injury, other than HD that, or medication in the opinion of the principal investigator, is likely to contribute to depressive symptoms 4. Any participant with severe depression (PBAs severity >3) or suicidal ideation (due to higher risk of deterioration and suicide in this group). 5. Not able to give informed consent 2026-03-30T00:00:00.000Z 2027-04-30T00:00:00.000Z Antidepressant treatment for depression in individuals with a confirmed genetic diagnosis of Huntington's Disease. Mental and Behavioural Disorders Randomisation will take place online through a bespoke system built for the trial to maintain the blind. Participants will be randomised to receive either 50mg of sertraline or Placebo daily for 6 months. Participants will take the IMP orally. Total follow up duration is 6 months for both arms. Drug Phase IV Sertraline The datasets generated and/or analysed during the current study will be available upon request from the trial manager by emailing DEVISEHD@cardiff.ac.uk Available on request Protocol

Migrated from study website field

a1443cac-6bf6-4f96-be31-85485f8c31a0 c7cbd86f-7b3b-4eba-b93b-fa0a7d362981 dd7b5bcc-e01d-4e62-a164-42ff8629cb98 6303e0c0-5fb3-47dd-b953-758e24aa9f60 Yes Protocol file ISRCTN87426672 DEVISE-HD protocol V1.0 28.01.2026.pdf 3ca830d8-6504-4faa-8f92-879eed73bda3 true application/pdf 1191666 0d4c2ee19e8409646c501cb7a68250a6 Participant information sheet ISRCTN87426672 8 week Reminder Information Sheet V1 20Apr2026.pdf 6091f6cc-41d4-46fe-a7ee-9f9c70a8b367 true application/pdf 293577 46462cea8af12dd890935752a3088b40 Participant information sheet ISRCTN87426672 End of Trial Information Sheet V1 11May2026.pdf e75d2cc5-efd2-46e6-b3a6-841c44284186 true application/pdf 288326 d7824f30c1414d87749faa79dce496a1 Participant information sheet ISRCTN87426672 6 month Reminder Information Sheet V1 20Apr2026.pdf bf9d9b45-68f6-45bf-ae48-9e3e8507563e true application/pdf 291399 66d49123733f05691bf9b24517afc8b1 Participant information sheet ISRCTN87426672 Dose Escalation information sheet V1 11May2026.pdf 2e745b03-4025-4226-8aa3-dbd845eb74a1 true application/pdf 328868 d071341d06bede804e77d05192fdaaff Participant information sheet ISRCTN87426672_PIS_V4.1_27Apr2026.pdf 803513f5-37ab-4afc-b50e-e1511836cdfb true application/pdf 410759 81df05c0005c254d5b2a74f880fe658d Participant information sheet ISRCTN87426672 Pictorial PIS V3 13Mar2026.pdf bf377ed9-0f04-482b-8baa-519b433cc5bf true application/pdf 544459 baf8aade9892af107a6d5bf83daa914c Participant information sheet ISRCTN87426672 Study Partner IS V3 13Mar2026.pdf e72d9e55-13b4-4146-b2b8-300f7048ab7c true application/pdf 315364 c82e95509cfebddc4b02d876b6f0624e Protocol file ISRCTN87426672 Protocol V2.2 13May2026.pdf e000b30d-7ffc-412a-8736-48cb97a01f0a true application/pdf 1197250 8cfca92f61943b86660b4188fde427d2 Other files ISRCTN87426672 Participant Consent Form V1.2 13Jul2026.pdf 08e18e78-569b-4fb3-ab5d-0b082753b0a7 true application/pdf 367647 78cc4e3d5b8c6518bdd682304f10166c Other files ISRCTN87426672 Study Partner Consent Form V1 06Nov2025.pdf 511860fd-67a5-407e-b674-696fa0ab5629 true application/pdf 333739 4bf68d8d97a19ee86b110f1c065cdea0 Duncan McLauchlan https://orcid.org/0000-0002-5356-5019 Scientific Principal investigator

University Hospital of Wales (UHW) Heath Park

Cardiff United Kingdom CF14 4XW +44 7791461685 Duncan.Mclauchlan@wales.nhs.uk Public Paula Foscarini-Craggs https://orcid.org/0000-0001-9511-696X Public

Centre for Trials Research School of Medicine College of Biomedical & Life Sciences Cardiff University

Cardiff United Kingdom CF14 4YS +44 29 206 87522 DEVISEHD@cardiff.ac.uk Public Cardiff University University/education https://ror.org/03kk7td41 Non-commercial Health and Care Research Wales http://dx.doi.org/10.13039/100012068 29596999 true A peer-led group programme for people with severe mental illness to reduce risk of cardiovascular disease (PEGASUS): A feasibility evaluation study PEGASUS feasibility study The aim of this research is to feasibility test a trained peer-supported group clinic intervention for people with SMI who have increased risk of CVD. Building on development work, evidence from a systematic review and an experience-based co-design process leading to the development of a co-produced peer-supported group clinic intervention, the objectives of this study are: 1. To establish the feasibility of the intervention for future evaluation in a randomised controlled trial (RCT), specifically: 1.1. Establish the feasibility of recruitment and retention strategies for the main trial 1.2. Assess the acceptability of, and retention to the planned intervention for individuals with SMI and elevated CVD risk 1.3. Determine the feasibility of collecting primary and secondary outcome data for the main trial 2. Estimate the location (proportion) and variability (confidence intervals) of the primary outcome to refine the power calculations for the main trial 3. To refine the content and delivery strategies for the intervention 4. To determine the best method of evaluating intervention implementation and fidelity Background and study aims People living with severe mental illness (SMI), such as schizophrenia or bipolar disorder, often have poorer physical health and can die 15–20 years earlier than the general population. One of the main causes of early death is heart disease. This risk is even higher for people from Black, Asian and minority ethnic communities. The PEGASUS study is testing a new group programme designed to help people with SMI reduce their risk of heart disease. The programme includes support with healthy eating, physical activity, and managing health goals, and is co-led by peer support workers (people with lived experience of mental health difficulties) and healthcare professionals. Who can participate? Adults who have a diagnosis of severe mental illness and also an elevated risk of cardiovascular disease may be able to take part. What does the study involve? Participants will be invited to join a group of 8–12 people for 10 sessions over 6 months. Each session lasts 2 hours and is led by a peer support worker and a healthcare professional. The sessions focus on different aspects of health and wellbeing. Participants will also have an individual ‘onboarding’ session before the group starts, four one-to-one sessions with a peer worker during the programme, and a reunion session after the programme ends. The study will also involve completing questionnaires and health checks at the beginning, middle, and end of the programme. Some participants may be invited to take part in an interview or focus group to share their views on the programme. What are the possible benefits and risks of participating? Taking part may help participants improve their physical health, feel more confident about managing their health, and feel more socially connected. There are no major risks, but some people may find it difficult to talk about their health or take part in group sessions. Support will be available throughout. Where is the study run from? City St George’s, University of London (UK) When is the study starting and how long is it expected to run for? August 2025 to September 2026 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK) Who is the main contact? Dr Bethan Hatherall, bethan.hatherall@citystgeorges.ac.uk Jessica Catchpole, jessica.catchpole@citystgeorges.ac.uk Acceptability of intervention and study delivery as assessed by focus group/interviews at 3 and 6-months. 1. Participant recruitment and retention rate is measured using study records at baseline, 3 months, and 6 months 2. Waist circumference is measured using tape measurement at baseline, 3 months, and 6 months 3. Hip circumference is measured using tape measurement at baseline, 3 months, and 6 months 4. Body mass index (BMI) is measured using height and weight measurements at baseline, 3 months, and 6 months 5. Triglycerides are measured using fasting blood sample at baseline, 3 months, and 6 months 6. HDL-cholesterol is measured using fasting blood sample at baseline, 3 months, and 6 months 7. LDL-cholesterol is measured using fasting blood sample at baseline, 3 months, and 6 months 8. Total cholesterol is measured using fasting blood sample at baseline, 3 months, and 6 months 9. HbA1c is measured using blood sample at baseline, 3 months, and 6 months 10. Blood pressure is measured using automated sphygmomanometer at baseline, 3 months, and 6 months 11. Psychiatric symptoms are measured using the Modified Colorado Symptom Index at baseline, 3 months, and 6 months 12. Dietary behaviour is measured using the Dietary Instrument for Nutrition Education (DINE) adapted by IMPaCT at baseline, 3 months, and 6 months 13. Physical activity is measured using the International Physical Activity Questionnaire - Short Form (IPAQ-SF) at baseline, 3 months, and 6 months 14. Tobacco, cigarette, and betel nut or paan use is measured using self-report questionnaire at baseline, 3 months, and 6 months 15. Alcohol consumption is measured using the Alcohol Use Disorders Identification Test - Consumption (AUDIT-C) at baseline, 3 months, and 6 months 16. Health-related quality of life is measured using the EQ-5D-5L at baseline, 3 months, and 6 months 17. Depression is measured using the Patient Health Questionnaire-9 (PHQ-9) at baseline, 3 months, and 6 months 18. Self-efficacy is measured using the Generalised Self-Efficacy Scale at baseline, 3 months, and 6 months 19. Social network is measured using the Lubben Social Network Scale at baseline, 3 months, and 6 months 20. Therapeutic relationship is measured using the Scale to Assess the Therapeutic Relationship (STAR) at baseline, 3 months, and 6 months 21. Progress towards achievement of personalised lifestyle goals is measured using the Goal-Based Outcome Tool at baseline, 3 months, and 6 months 22. Health and social care service use is measured using the DIAMONDS Service Use Survey at baseline, 3 months, and 6 months 23. Physical activity levels are measured using one-week accelerometer wear at baseline, 3 months, and 6 months Ethics approval required Wales Research Ethics Committee 7

2 Redman Place, Stratford

London United Kingdom E20 1JQ 24/WA/0289 10.1186/ISRCTN29596999 326517 CPMS: 59641, NIHR: 204418 326517 59641 204418 Interventional non-randomized Interventional Non randomised study Treatment 2026-09-01T00:00:00.000Z United Kingdom England East London NHS Foundation Trust

Robert Dolan House 9 Alie Street

London England E1 8DE RWK@2.16.840.1.113883.2.1.3.2.4.18.48 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 Birmingham and Solihull Mental Health NHS Foundation Trust

Unit 1 50 Summer Hill Road

Birmingham England B1 3RB South West London and St George's Mental Health NHS Trust

Springfield Hospital 61 Glenburnie Road

London England SW17 7DJ Patient Current key inclusion criteria as of 18/12/2025: Service users participants will: 1. Be aged 18 to 75 years 2. Have capacity to consent to participate in research 3. Currently on the caseload of mental health services in community settings or on GP/ ICS severe mental illness (SMI) list 4. Current primary diagnosis of schizophrenia-spectrum disorders (ICD-10 diagnoses F20–29) or bipolar disorder (F31) or in Early Intervention for Psychosis Services (EIPS) with formal diagnosis of psychosis (ICD-10 diagnoses of F29) or an aforementioned diagnosis. 5. If on psychotropic medication, on stable dose for 90 days (N.B. This refers specifically to either adding or changing to a new antipsychotic medication, but not applies to dosage adjustment of a pre-existing antipsychotic medication.) 6. Enhanced CVD risk as indicated by any one of: i) Obesity defined as: waist circumference over 102cm in men (or >90cm in non-white men) or over 88cm in women (or >80cm in non-white women) or BMI≥25 kg/m2 (or ≥23 kg/m2 in non-white people) ii) Hypertension defined as: blood pressure over 130/85 mmHg or documented hypertension on medication iii) Dyslipidaemia defined as: fasting triglyceride level over 1.7mmol/l or total cholesterol ≥5.0 mmol/L or on medication for hyperlipidaemia (e.g. statin) or high-density lipoprotein (HDL) cholesterol level less than 0.9mmol/l (men)/1mmol/l (women) iv) Hyperglycaemia defined as: HbA1c > 37 mmol/mol (5.5%) or fasting plasma glucose level ≥5.6 mmol/l or documented Type-2 diabetes (T2D) 7. If on treatment for T2D, hypertension or hyperlipidaemia, on stable dose medication for at least 90 days Intervention staff: 1. Peer (support) workers and registered mental health nurses (or other healthcare professionals or practitioners with appropriate training) 2. Based at one of the participating sites/Trusts 3. Have been trained and engaged with the PEGASUS programme to deliver (co-facilitate) the PEGASUS intervention for the purposes of this study _____ Previous key inclusion criteria: Service users participants will: 1. Be aged 18 to 75 years 2. Have capacity to consent to participate in research 3. Service Involvement: 3.1 Currently on the caseload of mental health services in community settings 3.2 Or on GP/ICS severe mental illness (SMI) list 4. Diagnosis: 4.1 Current primary diagnosis of schizophrenia-spectrum disorders (ICD-10 diagnoses F20–29) 4.2 Or bipolar disorder (F31) 4.3 Or in Early Intervention for Psychosis Services (EIPS) with formal diagnosis of the above conditions 5. If on psychotropic medication, must be on a stable dose for 90 days 6. Enhanced Cardiovascular Disease (CVD) Risk as indicated by metabolic syndrome (NCEP ATP III definition), confirmed at screening by any three of the following: 6.1 Waist circumference over 102 cm (men) or 88 cm (women) 6.2 Blood pressure over 130/85 mmHg or documented hypertension on medication 6.3 Fasting triglyceride level over 1.7 mmol/l 6.4 HDL cholesterol level less than 0.9 mmol/l (men), 1 mmol/l (women) 6.5 HbA1c > 37 mmol/mol (5.5%) or documented Type-2 diabetes (T2D) and on medication 6.6 If on treatment for T2D, hypertension or hyperlipidaemia, must be on stable dose medication for at least 90 days Intervention staff: 1. Peer (support) workers and registered mental health nurses (or other healthcare professionals or practitioners with appropriate training) 2. Based at one of the five sites/Trusts 3. Have been trained and engaged with the PEGASUS programme to deliver (co-facilitate) the PEGASUS intervention for the purposes of this study Mixed 18 Years 75 Years All 40 18 Current key exclusion criteria as of 18/12/2025: Service users who: 1. Are currently admitted to acute psychiatric care (i.e. inpatient admission or current referral to a Crisis & Home Treatment Team) 2. Have a primary diagnosis of alcohol or substance misuse 3. Are awaiting/going through assessment with EIPS but without formal diagnosis 4. Have a diagnosis of an organic mental health disorder (e.g. dementia) 5. Are currently in receipt of a highly structured and/ or multi-goal healthy lifestyle intervention (e.g. an intervention that combines structured diet and exercise goals, or a highly structured research-based intervention such as DIAMONDS or PRIMROSE-A). Note: referral to single goal lifestyle support, as typically provided in the voluntary-sector or as online NHS advice, is considered as part of care as usual and will be assessed in both trial groups 6. Blood pressure or hyperlipidaemia managed outside of primary care 7. Type 1 diabetes Intervention staff: Peer (Support) Workers, registered mental health nurses or other healthcare professionals or practitioners who are not trained for nor delivering the PEGASUS intervention for the purposes of this study. _____ Previous key exclusion criteria: Service users who: 1. Are currently admitted to acute psychiatric care (i.e. inpatient admission or current referral to a Crisis & Home Treatment Team) 2. Have a primary diagnosis of alcohol or substance misuse 3. Are awaiting/going through assessment with EIPS but without formal diagnosis 4. Have a diagnosis of an organic mental health disorder (e.g. dementia) 5. Are currently in receipt of a highly structured and/ or multi-goal healthy lifestyle intervention (e.g. an intervention that combines structured diet and exercise goals, or a highly structured research-based intervention such as DIAMONDS or PRIMROSE-A). Note: referral to single goal lifestyle support, as typically provided in the voluntary-sector or as online NHS advice, is considered as part of care as usual and will be assessed in both trial groups 6. HbA1c > 86 mmol/mol 7. Blood pressure or hyperlipidaemia managed outside of primary care 8. Type 1 diabetes Intervention staff: Peer (Support) Workers, registered mental health nurses or other healthcare professionals or practitioners who are not trained for nor delivering the PEGASUS intervention for the purposes of this study. 2025-08-01T00:00:00.000Z 2026-03-31T00:00:00.000Z Severe mental illness and metabolic syndrome Mental and Behavioural Disorders The PEGASUS intervention is a therapeutic group programme for people with severe mental illness at risk of cardiovascular disease and has been co-produced by peer workers, clinicians, and most importantly people with lived experience. The programme consists of 10 group sessions over the course of 6 months. The duration of each session is 2 hours. Each session consists of the same group of 8-12 people and the same two facilitators; a mental health peer support worker (someone who has lived experience of mental health difficulties and is using such experience in their work to support others) and a health care professional (this might be a nurse, dietician or occupational therapist). Each session will have a focus on different aspects of health and wellbeing that our previous research has identified as important to people with SMI and cardiovascular disease risk. Participants are also offered an ‘onboarding’ session with one of the facilitators in advance of the first group session, and 4 additional one-to-one sessions with the peer support worker over the course of the programme. A reunion session will be offered within 3 months of the programme finishing. Behavioural The datasets generated during and/or analysed during the current study are/will be available upon request from the Study Team, in accordance with the policies and conditions set out by the ethical or legal restrictions. bethan.hatherall@citystgeorges.ac.uk Jessica.catchpole@citystgeorges.ac.uk Available on request Protocol

Study website Migrated from study website field

0e508769-419b-4e62-b5e9-991a81efdbff ae64e40b-031b-4cfc-9124-f96ef3755d99 799204df-3a73-4022-9e5d-6eb2f8ce94e3 33193943-4046-42ed-b670-18d3e783ab7b Yes Participant information sheet 47785 PIS PEGASUS feasibility study v1.1 15Oct24.pdf 9ac28dec-d594-4119-88d4-c9a0e16b2087 true application/pdf 241085 fdee9d5c0d31e98315ac818ffbc7b4a2 Protocol file ISRCTN29596999 Feasibility study protocol_V2.3_2025Nov20 (1).pdf 922d756d-cd07-4750-bd30-244630aef9a1 true application/pdf 714096 9943e25311a4a518b90678655bd1a259 Bethan Hatherall https://orcid.org/0000-0001-8114-9648 Public Scientific

School of Health and Medical Sciences, City St George's University of London, Northampton Square

London United Kingdom EC1V 0HB - bethan.Hatherall@citystgeorges.ac.uk Public Jessica Catchpole https://orcid.org/0000-0001-7901-1797 Public Scientific

(Lived Experience Researcher), School of Health and Medical Sciences, City St George's University of London, Northampton Square

London United Kingdom EC1V 0HB +44(0)7423 637934 Jessica.catchpole@citystgeorges.ac.uk Public City, University of London University/education https://ror.org/04489at23 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 16864220 true The clinical and cost effectiveness of quetiapine for people with borderline personality disorder: A pragmatic, double-blind, placebo-controlled, randomised trial QUEST Primary objective: To test whether adding quetiapine to treatment as usual, in comparison to placebo and treatment as usual, improves the mental health of people with borderline personality disorder Secondary objectives: 1. To examine whether the addition of quetiapine improves social and occupational functioning, quality of life and reduces the incidence of suicidal behaviour in comparison to placebo and TAU 2. To compare the levels of adherence and the incidence of side-effects, including change in weight, amongst those prescribed quetiapine and those prescribed placebo. Economic Objective: To examine the cost, cost-effectiveness and cost-utility of adding quetiapine to TAU for adults with BPD in comparison to placebo and TAU. Background and study aims Borderline personality disorder (BPD) describes a collection of problems including negative feelings about self, fears of being let down, an acute sense of abandonment and rapid, distressing changes in mood. People with BPD find it difficult to maintain relationships, have high levels of mental health problems like depression and drug misuse, and high rates of self-harm and suicide. There are currently no drugs licensed for the treatment of BPD and clinicians are often unsure how best to help people with BPD. Quetiapine is the most widely prescribed antipsychotic medication for BPD in the UK despite limited evidence that it works. There is only one published trial of quetiapine for BPD treatment which found that quetiapine was more effective than a ‘dummy tablet’ (placebo) in improving symptoms of BPD. However, the trial was short with a small number of participants so a longer and larger trial of quetiapine is required to see if these promising results can be repeated. It would be a very important finding and provide evidence for use of quetiapine to treat BPD. If the result does not provide evidence of the benefits of quetiapine, then clinicians would review whether treatment with quetiapine should be continued. Who can participate? We will recruit people in contact with mental health services in the NHS in regions in England that are under-represented in mental health research. What does the study involve? In this trial, people with BPD will be allocated, by chance, to receive either placebo or quetiapine for 12-months alongside their usual treatment. We will also examine any changes in cost that result from prescribing this drug and whether any changes in costs are worthwhile in terms of improvements in outcomes. What are the possible benefits and risks of participating? Not provided at time of registration Where is the study run from? University of Liverpool (UK) When is the study starting and how long is it expected to run for? March 2025 to October 2028 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK) Who is the main contact? questtrial@liverpool.ac.uk 1. Symptoms of BPD at 12 months using the total score on the ZAN BPD from baseline to 12 months 1. Standardised Assessment of Personality Abbreviated Scale at 12 months using SAPAS at baseline and 12 months 2. Total score on the ZAN-BPD over 12 months measured at baseline, 3, 6, 9 and 12 months 3. Total score on the 21 item Beck Depression Inventory at baseline, 3, 6 and 12 months. 4. Mood Instability using the Affective Lability Scale – Short Form at baseline, 3, 6 and 12 months 5. Incidence and severity of suicidal behaviour and self-harm using the Deliberate Self-Harm Inventory at baseline, 6 and 12 months 6. Self-Reported Version of ZAN BPD at baseline, 3, 6, 9 and 12 months 7. Social functioning measured via the Work and Social Adjustment Scale (WSAS) at baseline, 6 and 12 months 8. Health-related quality of life measured using EuroQoL-5D-5L at baseline, 6 and 12 months 9. Side effects using the Antipsychotic Non-Neurological Side Effects Scale (ANNSERS) at baseline, 3, 6, 9 and 12 months 10. Medication adherence using the Brief Adherence Rating Scale (BARS) at 3, 6, 9 and 12 months 11. Use of alcohol and other drugs via ASSIST-Lite at baseline, 6 and 12 months 12. Body Weight in Kg at baseline and 12 months 13. Serious adverse events up to 12 months 14. Use of rescue medication at 6 and 12 months 15. Sleep Disturbance using PROMIS Sleep Disturbance -Short Form at baseline, 3, 6, 9 and 12 months 16. Use of health and social services using the ADSUS at baseline, 6 and 12 months Ethics approval required West Midlands - Edgbaston Research Ethics Committee

2 Redman Place, Stratford

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

V7 Building Kings Business Park Kings Drive

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

Elizabeth House, Fulbourn Hospital Fulbourn

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

The Uffculme Centre 52 Queensbridge Road Moseley

Birmingham England B13 8QY RXT@2.16.840.1.113883.2.1.3.2.4.18.48 Fulbourn Hospital

Cambridge Road Fulbourn

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

High St

Winsford England CW7 2AS Rowan View

Maghull Health Park

Liverpool England L31 1HW RW40C@2.16.840.1.113883.2.1.3.2.4.18.48 Phoenix Service

The Barberry 25 Vincent Drive

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

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

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

Parkbourn

Liverpool United Kingdom L31 1HW +44 151 472 4045 inti.qurashi@merseycare.nhs.uk Public University of Liverpool University/education https://ror.org/04xs57h96 Non-commercial Health Technology Assessment Programme http://dx.doi.org/10.13039/501100000664 10517405 true Co-Stars: a feasibility evaluation of a co-produced mental health literacy training package to reduce mental health inequities for Black youth in underserved communities Co-Stars A tiered Mental Health Literacy (MHL) package designed to promote equitable mental health care access and improved outcomes for Black youth in underserved communities is feasible, acceptable, and cost-effective. Background and study aims Severe mental illnesses like psychosis, a mental health problem that can change how people see the world, can cause a lot of distress for a person, and have a big impact on their lives. Psychosis impacts vulnerable groups unfairly, including people from minority ethnic backgrounds, and those from social and financial hardship. In the UK, people from Black ethnic backgrounds are more likely than White British people to experience psychosis for the first time and have negative experiences accessing mental health support. The reasons for this are complex but include racism, discrimination, mental health stigma, and lack of awareness of what the symptoms and outcomes of mental illness are (mental health literacy). Mental health literacy (MHL) more broadly refers to having the right knowledge about mental illness, how to look after your mental health, and knowing where to get the right support. It can help people access the right treatments at an earlier stage to help them stay well and have a good recovery. However, interventions designed to improve MHL do not take into consideration the needs and experiences of different cultural groups. As noted in the Black community, these needs and experiences may be responsible for some of the disparities seen, which is a critical missing component in our public health approach to improving mental health. Several things promote fairer access to mental health care, incuding: 1) improving understanding within Black communities about symptoms of mental illness and where to access timely support; 2) improving education for mental health professionals around the challenges that Black people face; and, 3) ensuring everyone is treated fairly, offered a choice that respects cultural needs, and given timely access to treatments. This study aims to conduct a test run to see if a tiered MHL program is practical, acceptable, and cost-effective. This program expects to improve access to mental health care and outcomes for underserved groups. Who can participate? Individuals aged 18-65 years from Black ethnic backgrounds attending community settings. Staff members at Forward Thinking Birmingham (FTB) or Early Intervention Services (EIS) of NHS Trust. Participants in concept mapping workshops, including various stakeholders. Regional mental health experts who are involved in surveys and interviews. Patients, providers, and commissioners exploring the program's early impacts. What does the study involve? Work package 1 If participants agree to take part in work package 1, the study package they are invited to will last for a maximum of 4 months. Different community settings will be selected and split into groups, and depending on the group, participants will be asked to either participate in the MHL (MHL) Training delivered in person or learn about MHL from written leaflets and posters. The group allocation for each community setting will be randomly assigned. All participants in the study will be asked to complete a set of questionnaires before and three weeks after the training. These questionnaires will assess the community’s attitudes towards mental illness, intended and reported stigmatising behaviours, desire for social distance from someone with a mental illness, mental health knowledge, and help-seeking attitudes. The in-person training will be delivered by young people from the Black African and Black Caribbean communities with lived experience. This training will last about 1.5 hours and will be held in person in the community, at an accessible local venue. During this meeting, a member of the research team from the University of Birmingham will also be present to observe the training and take notes. By attending this training, participants will play an important role in helping assess the acceptability of the MHL training and in better understanding the barriers and enablers to access care, which will, in turn, support the future implementation strategy. Participants may also be invited to participate in a focus group or one-on-one interview, during which a member of the research team will ask questions about whether the training was helpful, appropriate, and capable of improving mental health outcomes for Black people. A focus group discussion will last approximately 1.5 to 2 hours, while a one-on-one interview will last about 1 hour. Work package 2 If participants agree to take part in work package 2, the study package they are invited to will last for a maximum of 4 months. Approximately every 4 weeks, a certified e-learning module will be implemented for a new NHS team or Trust. The timing of when each team will receive the training will be randomly allocated. When a team is allocated, everyone in the team will be asked to complete a 20-minute certified e-learning module. This e-learning is informed by lived experience and aims to raise awareness of sociocultural diversities, cultural barriers, multicultural knowledge, and sensitivity and responsiveness to patients from Black ethno-racial backgrounds. All participants will be asked to fill out a set of questionnaires before the e-learning and three weeks after the e-learning modules. These questionnaires will assess demographic characteristics such as age, gender, ethnicity, and job role, as well as the feasibility, acceptability, and fidelity of the implementation of this research. Additionally, they will evaluate mental health knowledge, attitudes, skills, and competencies when working with minoritised groups. By completing this e-learning module, participants will play an important role in helping assess the acceptability of the package and in better understanding the barriers and enablers to provide care, which will, in turn, support the future implementation strategy. Participants may also be invited to participate in a group discussion or one-on-one interview, during which a member of the research team will ask questions about whether the training was helpful, appropriate, and capable of improving mental health outcomes for Black people. A focus group discussion will last approximately 1.5 to 2 hours, while a one-on-one interview will last about 1 hour and will take place in the respective NHS Trust. Please note that the group discussion or one-on-one interview will be audio-recorded using a secure encrypted recording device to help document the process and transcribed to ensure accuracy, but participants' anonymity will be protected throughout. These audio recordings will be securely shared with a third-party transcription service for the purposes of deriving verbatim text from recorded conversations. This service will be bound by a confidentiality agreement, and the third-party transcription service will destroy all audio recordings upon verification of the accuracy of transcripts. However, the research team will retain the audio recordings and store the data safely. Participants' anonymity will be protected throughout. What are the possible benefits and risks of participating? While significant risks are not anticipated, participants may experience emotional distress or discomfort during the interviews, especially if sensitive topics are discussed. If this occurs, participants can request to pause or stop the interview and may seek additional support. Additionally, there are risks related to data protection, which we will mitigate by following strict confidentiality protocols and data security measures. However, it is possible that sharing accounts of lived experience or related topics may cause distress. Should it be identified during the study that participants are at risk of harm to themselves or others, local safeguarding procedures will be followed, and confidentiality may be breached by informing a member of their direct healthcare team. Where is the study run from? This study is run by the Institute of Mental Health at the University of Birmingham in two settings. Work Package 1 will be run in 8 community sites in Birmingham and Black Country, while Work Package 2 will be run in the Forward-Thinking Birmingham of the Birmingham Women and Children NHS Foundation Trust, Early Intervention Services of the Black Country Healthcare NHS Foundation Trust, and Birmingham and Solihull Mental Health NHS Foundation Trust. When is the study starting and how long is it expected to run for? October 2023 to April 2026 Who is funding the study? UK Research and Innovation (UKRI) Who is the main contact? Dr Sian Lowri Griffiths, University of Birmingham, s.l.griffiths@bham.ac.uk WP1 Outcome: Feasibility outcomes include the proportion of consenting clusters, percentage of training uptake and completion of pre- and post-outcome measures, as well as the acceptability of the intervention and assessment of the barriers and enablers. WP2 Outcome: Feasibility process outcomes will include the percentage of training uptake across staff and service teams in addition to the acceptability evaluation (detailed in WP1). The secondary outcome is the assessment of the training outcome of the California Brief Multicultural Competence Scale, which assesses mental health staff knowledge, attitudes, skills, and competencies when working with minoritised groups. The secondary outcome is the assessment of key training outcomes: 1. Knowledge measured using the Mental Health Knowledge Scale (MAKS) 2. Illness attributions and stigma measured using the Reported and Intended Behaviour Scale (RIBS) – Intended Behaviour Subscale to assess intended and reported stigmatising behaviours and desire for social distance from someone with a mental illness and the Community Attitudes towards Mental Illness (CAMI) scale 3. Help-seeking attitudes and efficacy - General Help-Seeking Questionnaire Ethics approval required East of Scotland Research Ethics Service (EoSRES)

Tayside Medical Science Centre Residency, Block Level 3, George Pirie Way, Ninewells Hospital and Medical School

Dundee United Kingdom DD1 9SY 24/ES/0030 10.1186/ISRCTN10517405 333999 RG_23-166 333999 RG_23-166 A pilot open-labelled pragmatic cluster-randomised controlled trial and a pilot stepped-wedge cluster randomised trial Interventional Cluster randomised trial Other 2026-04-30T00:00:00.000Z United Kingdom England Birmingham Women's and Children's NHS Foundation Trust

Steelhouse Lane

Birmingham England B4 6NH RQ3@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 England DY2 8PS TAJ@2.16.840.1.113883.2.1.3.2.4.18.48 Edgbaston Community Centre

40 Woodview Dr

Birmingham England B15 2HU GB20240611-01@2.16.840.1.113883.2.1.3.8.2.14 Birmingham and Solihull Mental Health NHS Foundation Trust

The Uffculme Centre 52 Queensbridge Road Moseley

Birmingham England B13 8QY RXT@2.16.840.1.113883.2.1.3.2.4.18.48 Health professional Population WP1: 1. Participants attending the community settings (e.g. Black majority churches, youth centres, community centres, youth residential settings) and 2. Black Ethnicity 3. Aged 18-65 years WP2: 1. All staff who have the potential for direct encounter with patients and working in either Forward Thinking Birmingham (FTB) or Early Intervention Services (EIS) 2. This would include, but is not confined to, psychiatrists, psychologists, community psychiatric nurses, occupational therapists, support workers, paramedics, and social workers. WP3: 1. Concept mapping workshop: Patients, research team, mental health service providers, and policymakers. 2. Modified Delphi survey and semi-structured interviews: Regional mental health experts 3. Exploring the early impacts of co-stars: Patients, providers, and commissioners. 4. All participants in WP3, who did not take part in WP1 or WP2, will be 18 years or older and capable of giving consent in accordance with the Mental Capacity Act 2005. WP4: This package will include the participants of WP1 and WP2. Mixed 18 Years 65 Years All 300 0 Unable to understand verbal explanations or written information given in English or to demonstrate capacity to consent. 2025-03-10T00:00:00.000Z 2026-04-20T00:00:00.000Z Mental health literacy Mental and Behavioural Disorders This is a single study with four cross-cutting work packages. The overarching aim of this feasibility study (or external pilot) is to conduct a pilot evaluation assessing the feasibility, acceptability, and cost-effectiveness of a tiered Mental Health Literacy (MHL) package. This MHL package is designed to promote equitable mental health care access and improved outcomes for Black youth in underserved communities. All four work packages (WPs) in this study are well aligned with this overarching aim, although each employs a study design specific to its specific objective. WP 3 and WP 4 are designed to explore the system-wide impact of the intervention using realist-informed participatory systems mapping and novel epidemiological analyses to examine downstream effects of the interventions delivered in WP 1 and WP2, such as improved care access for Black ethno-racial groups within the intervention areas. WP 4 includes a cost-effectiveness evaluation of these interventions. Consequently, these packages will run simultaneously, with the same recruitment start and end dates for all packages. WP1: A pilot cluster randomised controlled trial of lived experience-led mental health literacy training in community settings Aims & Objectives: The aim is to assess the feasibility and acceptability of the MHL intervention delivered to underserved communities and to assess the barriers and enablers to support the future implementation strategy/trial. Design: This is a pilot open-labelled, pragmatic, cluster-randomised controlled trial (CRT) implemented within a specific underserved community in Birmingham. The study will adhere to the CRT consort extension and procedure set out by the Birmingham Clinical Trials Unit to ensure transparency and quality of reporting. A mixed methods realist approach will be adopted for the process evaluation. Method: Recruitment of clusters and implementation of the intervention will occur over a 6-month timeframe (months 4-9). Participants within the cluster will be consented and asked to complete pre-/post outcome measures. Structured observations assessing the fidelity of intervention delivery will be conducted, as well as two focus groups and semi-structured interviews with participants within the control and intervention arms, as well as young people delivering the training. Setting: The target is 2 constituencies in the West region of Birmingham; a region with the highest proportion of Black African and Black Caribbean individuals in Birmingham (19% compared with 9% and 3.5% in Birmingham and the UK, respectively), with over half of the West region population living in the top 10% decile for deprivation, meaning that these communities are likely exposed to a multitude of social risk factors for development of severe mental illness. Unit of randomisation: Community settings include places of worship (e.g., Black majority churches), youth centres, community centres, and youth residential settings. These will be randomised as clusters and allocated on a 1:1 basis to receive the intervention or control. Clusters will be stratified by setting type to prevent imbalances in treatment groups. By design, concealing treatment allocation is not possible for this study. Population: Participants (aged 18-65 years) attending the community settings. Researchers will assess eligibility and obtain written consent before collecting the baseline measures. Individuals unable to provide informed consent due to cognitive impairment will be ineligible to take part. Participants will receive a £25 shopping voucher in respect of their time. A maximum variation sampling method will be used to identify participants for the process evaluation. Intervention: The intervention is the lived experience-led MHL training. The training will be delivered by young people of the Black African and Black Caribbean diaspora, lasting approximately 1.5 hours and will cover: 1) symptoms and signs of mental illness (including SMI); 2) how to distinguish mental health symptoms from normal behaviours; 3) attitudes and beliefs about people with mental illness; 4) advice on how to manage wellbeing; and finally, 5) information about local services and help-seeking. The intervention will be reported using TIDIER. Control: Written MHL material (information leaflets and posters) placed within the community setting. Before these materials are placed in the community setting, participants will be invited to complete baseline measures and then re-approached after 3-weeks to collect follow-up measures. Sample size: The study will recruit 120 participants from approximately 8 randomised clusters. Formal power calculations are not necessary as no hypothesis testing for trial effectiveness is being evaluated. A sample of 120 (with ~60 per arm), meets sample size recommendations for pilot and feasibility studies and is sufficient to provide precision of feasibility parameters and estimates of study summary measures for a definitive trial. Twenty participants in total will be recruited for focus groups (3 groups of 5 diverse participants) and five 1:1 interviews. Analysis: Descriptive statistics will be used to assess training fidelity and feasibility outcomes. Other data will be analysed using thematic analysis to generate important themes and patterns. For the secondary outcomes, means, confidence intervals, and intracluster correlation coefficient (ICC) of the outcome measures (both within-study and between-study clusters) will be estimated to determine which outcome(s) are most sensitive to change and provide sample size calculation for a definitive trial. WP2: A pilot stepped wedge cluster randomised trial of e-learning for mental health professionals Aims & Objectives: The aim is to evaluate the feasibility and acceptability of e-learning to develop a methodology to inform the implementation evaluation in a future trial (phase 3). Design: A pragmatic stepped wedge cluster randomised trial (SWCRT) design will be adopted with random and sequential crossover of clusters (youth mental health teams) from control to intervention (the e-learning module) until all clusters are exposed. Methods: There will be a phased and sequential implementation of the e-learning at regular intervals across teams and trusts over 6 months (months 4-9). Staff will complete the training outcome measure before and after the e-learning. The training will be deployed in a staggered manner in line with the stepped wedge approach. Starting in the first trust (Forward Thinking Birmingham (FTB)) in month 4 and rolled out to the 4 teams in staggered intervals. The training will then be rolled out in the second trust (Black Country – Early Interventions) with staggered implementation between months 6-9. Throughout implementation, staff focus groups and semi-structured interviews will be conducted. Setting: FTB, part of the Birmingham Women’s and Children’s Mental Health Trust, is a 0–25-year community and inpatient mental health service and is the primary mental health service regionally for this population. Within FTB there are 4 specialist Early Intervention Services (EIS) that offer intensive community support to young people with a first episode of psychosis. The second trust is Black Country Healthcare in which the Dudley and Walsall EIS team will be targeted, which provides community support to young people with psychosis between the ages of 14 and 65 years. Randomisation: Cross-over of clusters (clinical team; n=6) from control to intervention will occur approximately every 4 weeks. Population: A range of professionals (n=120) will be expected to complete the training, including psychiatrists, psychologists, community psychiatric nurses, occupational therapists, support workers and social workers. A purposive sampling method will be used to recruit staff to the focus groups and 1:1 interviews ensuring a balance of staff backgrounds, experience, and representation from across different teams and trusts. INCLUDE guidelines will be adhered to ensure diversity and inclusion in the sampling. Intervention: The intervention is a 20-minute certified e-learning module targeted at professional systems and public organisations involved in mental health care pathways. Informed by lived experience, the e-learning seeks to raise awareness of sociocultural diversities, awareness of cultural barriers, multicultural knowledge, and sensitivity and responsiveness to patients from Black ethnoracial backgrounds. Control: The control condition will be the unexposed observation period before sequentially crossing over to the exposed observation period (receiving the intervention). Sample Size: Formal power calculations are not necessary as no hypothesis testing for trial effectiveness is being evaluated. A sample of 120 meets sample size recommendations for pilot and feasibility studies and is sufficient to provide precision of feasibility parameters and estimates of study summary measures for a definitive trial. Analysis: Process outcomes will be analysed in the same manner as WP1. Parameters will be estimated for the power calculations for the secondary outcomes making adjustments for the temporal trend, ICC and number of steps. WP3: Mixed-methods Study: Systems Mapping and Systems Change The aim is to undertake formative research to underpin a proposed whole systems approach to evaluating the impacts of the tiered approach described in WP1/2. Specifically, this will include two key areas of work: Systems map: A systems map will be developed in three phases: 1) Firstly, a concept mapping workshop involving key stakeholders (patients, research team, providers and policymakers) will be undertaken. This will be guided by a draft model produced by the team (who consist of mental health experts in the region) which will then be introduced and amended using an iterative consensus-building process in a face-to-face workshop. 2) This will be followed by a modified two-stage Delphi survey inviting regional mental health experts to provide their agreement or disagreement with the systems map and willingness to be involved in semi-structured interviews with the research team. 3) Those willing to take part in interviews will then be invited to share their opinions on how the tiered intervention may impact the system map and in particular their opinion on potential outcomes which should be measured at a system-wide level. Exploring the early impacts of co-stars: To identify whether the intervention is providing tangible impacts on a system-wide level, a data-driven impact evaluation will be piloted. An interrupted time series (ITS) will be undertaken to ascertain whether the introduction of the intervention leads to a change in the relevant outcomes identified in the systems mapping process. This type of analytical approach has been advocated for use in public health evaluations and is related to structural break modelling. This pilot evaluation will be undertaken in three phases: Identification of suitable data sources: Guided by health data science expertise in the research team (JSC/FC), expert opinion from the systems mapping process and through open source searching, a directory of suitable datasets and outcomes which could inform the systems-wide impact of the intervention will be compiled (e.g. the use of West Midlands Police Data to assess the rate of s136 interventions in Black males). Trial of ITS model: Using available datasets (those open access or those already accessible by the research team), a pilot ITS will be undertaken. The study period will be set between 2022-2024. Incidence rates (calculated by the number of new cases divided by the denominator given by the at-risk population) will be analysed monthly (weekly where possible) throughout the study period and these trends will be depicted graphically. The primary breakpoint to be examined is the introduction of the intervention; therefore, for the ITS modelling, monthly data one year prior and one year following this timepoint will be included. The sensitivity of the analysis around this breakpoint will be examined. Stakeholder engagement: Three focus groups (consisting of 6-8 people) with key stakeholders (patients, providers and commissioners) will be undertaken to demonstrate the findings from the trial to unpick the possible mechanisms for these changes as a result of the impact of the intervention of the systems map. The secondary aim of these focus groups will be to optimise the strategy to undertake such systems change evaluation on a broader scale when the intervention is rolled out for a full trial. WP4: Economic evaluation to examine cost-effectiveness and social return on investment This tiered approach is likely to reduce direct health costs (admission and healthcare usage), but it could also have important cost implications for the healthcare sector, public sector and society more broadly. For example, if it is effective at improving mental wellbeing, there are likely to be important cost implications for the healthcare sector, public sector and society more broadly. The primary base case analysis will adopt a public sector perspective in line with NICE guidelines, with a wider societal perspective explored as a secondary analysis. Data collection: Firstly, and most relevant to WP1/2, resource use data will be used to estimate the costs associated with each of the intervention and control arms. This will include i) intervention costs; ii) healthcare resource use; iii) wider public sector resource use; and iv) private costs. Information on unit costs or prices will be sourced to attach to each resource use item, to enable an overall cost to be calculated (e.g. PSSRU Unit Costs of Health and Social Care). Cost-effectiveness: To compare intervention arms with the control, a within-study analysis and a model-based economic analysis will be undertaken. This will primarily use the data collected within the trial and from the quasi-experimental study. Initially, the base case analysis will be framed in terms of a cost-consequences analysis, and data will be reported in a disaggregated manner on the incremental cost and important consequences assessed in WP1/2. The main economic analysis will assess cost-effectiveness based on the costs and health outcomes collected in WP1/2. The economic evaluation will be conducted and reported in accordance with relevant guidelines (e.g., CHEERS checklist) and recommended methodologies. Social return on investment: As not all costs are quantifiable, an SROI will also be explored. The PPI panel (and work undertaken during the QR-funded period) will help determine which items (including ones where costs are intangible) matter and discuss how they should be quantified. This is particularly relevant when considering the impacts of how the wider system changes in response to this intervention (for example, the impacts of improved community connectedness). Patient and Public Involvement & Engagement (PPIE): This programme of work from conception through to delivery has been informed by PPIE, including young people with lived experience and charitable partners who have provided advice on study management, training and support for PPIE, as well as inputting into the lay summary. Good practice in line with UK Standards for Involvement has been ensured. A diverse PPI advisory group will be appointed to advise on the ethical and delivery aspects of the project. Individuals from the Youth Advisory Group at the Institute for Mental Health, the West Midlands School for Public Health Consortium (PHRESH) and NIHR applied research collaboration (ARC) as well as the partnership with Catalyst4Change CIC – a grassroots charity supporting the mental health needs of Black African and Black Caribbean communities across Birmingham – will be identified. Mixed All information collected for this study will be subject to the General Data Protection Regulation and Data Protection Act 2018. We will ensure your confidentiality by storing your personal data electronically on a secure network at the University of Birmingham using encrypted files. Data will only be accessed by authorised members of the research team via password-protected University of Birmingham-issued computers. Paper copies of study documents will be stored in a locked filing cabinet in a locked room at the University of Birmingham, accessible only to authorized research personnel. Any information that could identify you (e.g., name, address, etc.) will be removed from your study data, and your study data will be linked by a unique code. The document which links your unique code with your identifiable personal information will be stored separately allowing the research team to identify your data. Audio recordings will be destroyed as soon as transcripts have been generated and checked for accuracy. Any personally identifying data will be removed from interview transcripts and workshop observation notes at the earliest possible opportunity, and pseudonyms will be used instead of real names. The third-party transcription service will be bound by a confidentiality agreement. Any demographic information reported in publications (e.g., age, sex, ethnicity) will be summarized for the group as a whole to prevent identification of individuals. We may share the data with third parties if they request raw data for their review or systematic review. In such cases, we will ensure that any data which could identify you individually will not be shared. Available on request 2026 Protocol article in https://pubmed.ncbi.nlm.nih.gov/41857862/ (added 23/03/2026) Protocol

Migrated from patient info sheet field

Migrated from study website field

0c0ef35d-ab58-4e17-b7bb-97c1fcc805d9 0bf1e9a0-d1e9-488b-bd7b-a0dfc0032b29 6f8af7c5-7ffa-45a4-8653-3b8a5bd4f7b7 2671d8ae-8cf4-4832-a6a0-b09a2ca4b34b Yes Protocol file 46480_Protocol.PDF 7f299692-d69e-410d-89bd-a649a20a2b60 true application/pdf 292006 b88a12516fd871fc57c933243a9ec512 Participant information sheet 46480_PIS [WP1]_v1_27Sept2024.pdf 5b6944c0-f6bf-42a4-8f3c-8c984f028eeb true application/pdf 166654 d70bf9dec93a615ed7d766b8fa2ee5b2 Statistical Analysis Plan 46480_SAP within Protocol.PDF e64b0539-b206-45f2-981e-1e6300d8f8f5 true application/pdf 292006 b88a12516fd871fc57c933243a9ec512 Participant information sheet 46480_PIS [WP2]_v1_27Sept2024.pdf 708349f6-bfdc-459c-abd1-40e842de3b4f true application/pdf 268404 0f62bf8414c19bb8975c02c730d0c531 Sian Lowri Griffiths https://orcid.org/0000-0003-0031-7174 Principal investigator

Room 131, Gisbert Kapp Building, University of Birmingham

Birmingham United Kingdom B15 2TT +44 (0)121 414 3344 s.l.griffiths@bham.ac.uk Public Balachandran Kumarendran https://orcid.org/0000-0001-7786-5932 Public Scientific

Room 113, Gisbert Kapp Building, University of Birmingham

Birmingham United Kingdom B15 2TT +44 (0)121 414 3344 b.kumarendran@bham.ac.uk Public University of Birmingham University/education https://ror.org/03angcq70 Non-commercial UK Research and Innovation http://dx.doi.org/10.13039/100014013 36536677 true A 3-arm multi-centre randomised placebo-controlled trial of glycopyrrolate or hyoscine hydrobromide for the treatment of clozapine-induced hypersalivation GOTHIC2 Primary objective: To ascertain the efficacy of either hyoscine hydrobromide or glycopyrrolate in comparison to placebo in the treatment of CIH. Secondary objectives: 1. To establish which of glycopyrrolate or hyoscine hydrobromide, if any, is associated with fewer cognitive side-effects using a validated assessment measure. 2. To establish which of glycopyrrolate or hyoscine hydrobromide, if any, is associated with fewer ADRs. Added 01/05/2024: Exploratory objective: 1. To establish whether clozapine plasma levels are associated with clozapine ADRs (moved from secondary objectives) Updated 27/05/2026: The open-label phase was removed: Open-label objectives: 1. To increase knowledge of the safety profile of the active IMPs in the treatment of CIH. 2. To establish the effectiveness of active IMPs over the open-label phase. Background and study aims Clozapine is an antipsychotic medication used to help treat the symptoms of schizophrenia and is also sometimes used to treat other mental health conditions. It is the most effective antipsychotic medication for many people and it is important to keep taking it. Clozapine can cause different side effects and people tell us one of the most upsetting is excessive drooling. Doctors call this ‘clozapine-induced hypersalivation’ (CIH or drooling). People with CIH/drooling tell us they often have to wipe the saliva from their mouth during the day and their pillow becomes very wet at night which can sometimes make the skin on their face sore. CIH can be very embarrassing and lead to some patients wanting to stop clozapine treatment. For most patients this is not a good idea as their mental illness is likely to come back and they may need to be admitted to hospital. Currently, there is no proven treatment for CIH. The medication usually prescribed is called hyoscine but we don’t know if hyoscine helps although doctors think it might. Hyoscine can cause unpleasant side effects such as bowel problems (constipation) and thinking problems (making attention and concentration worse). Some studies suggest a different medication called glycopyrrolate might be helpful for CIH and may cause fewer thinking problems. But it may still cause other side effects like constipation. Patients have told us that it is important for them to know which medications may improve CIH and what the side effects are so they can make an informed choice about whether or not to take any of these medicines based on their mental illness symptoms and experience of side effects. Our study will find out if either hyoscine or glycopyrrolate can improve CIH/drooling by comparing patients taking these medications with patients taking a dummy treatment (placebo). If both help reduce CIH/drooling we will compare the two medications to see which one causes fewer side effects and ask which one patients prefer. Who can participate? Patients aged 18 - 65 years, with clozapine-induced hypersalivation. What does the study involve? Participants will be randomly assigned to receive either hyoscine hydrobromide, glycopyrronium bromide (glycopyrrolate), or a placebo over a period of 12 weeks. What are the possible benefits and risks of participating? Benefits: Not provided at time of registration Risks: Burden of visits and assessments: Treatment visits have been aligned with routine care clozapine clinic visits (every 4 weeks). Visits at home instead of the clozapine clinic can be arranged if participants prefer. Service users have been involved in GOTHIC2 throughout its development. The participant pathway and all patient-facing documentation have been developed with full PPIE involvement and use of the FAST-R service. Treatment Intervention: A summary of the more important risks are as follows: Hyoscine hydrobromide (Kwells): Very common side effects (more than one in 10) include feeling a bit sleepy or dizzy, eyesight being a bit blurry and having a dry mouth. Constipation is also possible. All of these side effects can also happen with clozapine (nIMP) so participants may not notice any difference. There is a very small chance participants might find it more difficult to concentrate or think clearly. The comprehensive list of undesirable effects is listed in the relevant SmPC. Side effects from a placebo are unlikely as it is a dummy capsule with inactive ingredients. The main ingredient, Magnesium stearate, is generally safe to consume but too much of it can have a laxative effect. Glycopyrronium bromide (Glycopyrrolate): Very common side effects (more than 1 in 10) include dry mouth, constipation, diarrhoea, vomiting, flushed skin, nasal congestion, having difficulty emptying the bladder (urinary retention), feeling irritable and experiencing a reduction in chest secretions. Common side effects (experienced by one in 10 to 1 in 100 people) include chest infections (including pneumonia), urine infections, feeling agitated or drowsy, nose bleeds, rash and fever. The comprehensive list of undesirable effects is listed in the relevant SmPC. Placebo side effects are unlikely as it is a dummy capsule with inactive ingredients. The main ingredient, Magnesium stearate, is generally safe to consume but too much of it can have a laxative effect. This is also a component of clozapine (nIMP). Treatment modifications: trial participants should not be prescribed any other CIH treatment. Participants are prescribed two capsules per day in week one and three capsules per day from week two until the end of treatment at week twelve. Should the treating clinician have any concerns about tolerance then the dose may be reduced in week one to one capsule per day and the dose can be reduced in weeks 2-12 to one or two capsules per day. The reduction and reason for the reduction should be recorded in the appropriate eCRF. Dose modifications: Participants who discontinue clozapine treatment should also discontinue trial treatment. The discontinuation of trial treatment and reason must be recorded in the appropriate eCRF. Where is the study run from? University of Liverpool (UK) When is the study starting and how long is it expected to run for? November 2023 to August 2027 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK). Who is the main contact? Ms Julie Perry, gothic2@liverpool.ac.uk Dr Inti Qurashi, Inti.Qurashi@merseycare.nhs.uk Current primary outcome as of 27/05/2026: Hypersalivation measured using the Drooling Rating Scale at Baseline, T 1, 2, 4, 6, 8, 12 Previous primary outcome: Hypersalivation measured using the Drooling Rating Scale at Baseline, T 1, 2, 4, 6, 8, 12 and Optional T16, 20, 24 1. Neuroleptic side-effects measured using the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS) PROM (participant reported outcome measure) at Baseline, T 4, 8, 12 and Optional T16, 20, 24 2. Anticholinergic side effects measured using the Liverpool Anticholinergic Side-effects Scale (LASS) PROM at Baseline, T 4, 8, 12 and Optional T16, 20, 24 3. Sustained attention and Verbal Recognition Memory (VRM) measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB) via a pre-loaded tablet device at Baseline and T12 4. Nocturnal hypersalivation measured using the Nocturnal Hypersalivation Rating Scale (NHRS) PROM at Baseline, T 1, 2, 4, 6, 8, 12 and Optional T16, 20, 24 5. Self-esteem measured using the Rosenberg Self-esteem scale (RSE) PROM at Baseline and T12 6. Hospital admission (whether for physical or psychiatric reasons) from Consent up to T12 and Optional follow-up to T24 7. Constipation measured using the Patient assessment of constipation and symptoms (PAC-SYM) at Baseline, T4, 8, 12 and Optional T24 8. Social functioning measured using the Personal and Social Performance scale (PSP) conducted via interview at Baseline and T12 9. Symptoms of schizophrenia measured using the Positive and negative syndrome scale (PANSS) conducted via interview at Baseline and T12 10. Effect and tolerability of treatment measured by premature discontinuation of study treatment/Continuation at T12 11. Discontinuation of clozapine 12. Serious Adverse Events reported from Consent up to T12 and Optional follow-up to T24 Updated 01/05/2024: Exploratory outcome measure: 1. Clozapine plasma levels from blood analysis at Baseline and T12 (moved from secondary outcome measures) Ethics approval required London - Fulham Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 23/LO/1002 10.1186/ISRCTN36536677 1008055 CPMS: 58120, UoL001694 1008055 58120 UoL001694 Interventional double-blind randomized controlled trial Interventional Randomised controlled trial Efficacy Safety 2027-08-01T00:00:00.000Z United Kingdom England Wales 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 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 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 Birmingham and Solihull Mental Health NHS Foundation Trust

Unit 1 50 Summer Hill Road

Birmingham England B1 3RB RXT@2.16.840.1.113883.2.1.3.2.4.18.48 Pennine Care NHS Foundation Trust

225 Old Street

Ashton-under-lyne England OL6 7SR RT2@2.16.840.1.113883.2.1.3.2.4.18.48 Somerset NHS Foundation Trust

Trust Management Lydeard House Musgrove Park Hospital

Taunton England TA1 5DA RH5@2.16.840.1.113883.2.1.3.2.4.18.48 Dorset Healthcare University NHS Foundation Trust

Sentinel House 4-6 Nuffield Road Nuffield Industrial Estate

Poole England BH17 0RB RDY@2.16.840.1.113883.2.1.3.2.4.18.48 Cardiff and Vale U H B

St. Davids Hospital Cowbridge Road East

Cardiff Wales CF11 9XB V11409@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 England WF1 3SP RXG@2.16.840.1.113883.2.1.3.2.4.18.48 Cornwall Partnership NHS Foundation Trust

Carew House Beacon Technology Park Dunmere Road

Bodmin England PL31 2QN RJ8@2.16.840.1.113883.2.1.3.2.4.18.48 Patient false 1. Aged 18 to 65 years inclusive. 2. English speaking. 3. Prescribed clozapine for a minimum of three months. 4. Experiencing hypersalivation with a minimum score of 4 on the Drooling Rating Scale (DRS) and are either: 4.1. Currently not receiving treatment for CIH, OR 4.2. Receiving drug treatment for CIH and agreeable to a 48-hour washout period 5. Written and informed consent obtained from participant (with capacity and ability) and agreement of participant to comply with the requirements of the trial prior to study specific procedures. Mixed 18 Years 65 Years All 180 0 Current participant exclusion criteria as of 27/05/2026: 1. Medical conditions that could influence hypersalivation (e.g., Parkinson’s Disease). 2. Neurological conditions that could affect cognitive functioning during the course of the study (e.g., unstable epilepsy). 3. History of an allergic reaction to hyoscine hydrobromide 4. History of an allergic reaction to glycopyrrolate. 5. Any of the following contra-indications to hyoscine hydrobromide or glycopyrrolate as stated in the British National Formulary: 5.1. Prostatic enlargement 5.2. Myasthenia gravis 5.3. Pyloric stenosis 5.4. Paralytic ileus 5.5. Glaucoma 5.6. Hepatic Impairment 6. Any of the following cautions to hyoscine hydrobromide or glycopyrrolate as stated in the British National Formulary: 6.1. Chronic heart failure 6.2. Stomach ulcer 6.3. Ulcerative colitis 6.4. Significant liver disease that in the opinion of the CI or PI is a contraindication 6.5. Down’s syndrome 6.6. Arrhythmia and/or history of myocardial infarction 6.7. Overactive thyroid gland. 6.8. Unstable angina 7. Current prescription for potassium chloride, digoxin, amantadine, levodopa, tricyclic antidepressants or monoamine oxidase inhibitors 8. Pregnant, trying to conceive or breastfeeding. 9. Participation in another drug study within the preceding 12 weeks (or within 5 half-lives of an IMP, whichever is longer) or use of other investigational drugs. 10. Active suicidal ideation as assessed within usual care. 11. Known sensitivity to any interventions or excipients. 12. Known history of intestinal obstruction. 13. Known history of urinary retention. 14. Severe renal impairment (eGFR <30 ml/min/1.73m2). 15. Known history of brain tumour or encephalitis. 16. Any contraindication to dispensing monthly supply of medications. 17. Unable to swallow tablets. Previous participant exclusion criteria as of 07/03/2024: 1. Medical conditions that could influence hypersalivation (e.g., Parkinson’s Disease). 2. Neurological conditions that could affect cognitive functioning during the course of the study (e.g., unstable epilepsy). 3. History of an allergic reaction to hyoscine hydrobromide 4. History of an allergic reaction to glycopyrrolate. 5. Any of the following contra-indications to hyoscine hydrobromide or glycopyrrolate as stated in the British National Formulary: 5.1. Prostatic enlargement 5.2. Myasthenia gravis 5.3. Pyloric stenosis 5.4. Paralytic ileus 5.5. Glaucoma 5.6. Hepatic Impairment 6. Any of the following cautions to hyoscine hydrobromide or glycopyrrolate as stated in the British National Formulary: 6.1. Chronic heart failure 6.2. Stomach ulcer 6.3. Ulcerative colitis 6.4. Significant liver disease that in the opinion of the CI or PI is a contraindication 6.5. Down’s syndrome 6.6. Arrhythmia and/or history of myocardial infarction 6.7. Overactive thyroid gland. 6.8. Unstable angina 7. Current prescription for potassium chloride, digoxin, amantadine, levodopa, tricyclic antidepressants or monoamine oxidase inhibitors 8. Pregnant, trying to conceive or breastfeeding. 9. Sexually active heterosexual patients who are unable or unwilling to use contraception during the study (see section 10.4). 10. Participation in another drug study within the preceding 12 weeks (or within 5 half-lives of an IMP, whichever is longer) or use of other investigational drugs. 11. Active suicidal ideation as assessed within usual care. 12. Known sensitivity to any interventions or excipients. 13. Known history of intestinal obstruction. 14. Known history of urinary retention. 15. Severe renal impairment (eGFR <30 ml/min/1.73m2). 16. Known history of brain tumour or encephalitis. Previous participant exclusion criteria: 1. Medical conditions that could influence hypersalivation (e.g., Parkinson’s Disease). 2. Neurological conditions that could affect cognitive functioning during the course of the study (e.g., unstable epilepsy). 3. History of an allergic reaction to hyoscine hydrobromide 4. History of an allergic reaction to glycopyrrolate. 5. Any of the following contra-indications to hyoscine hydrobromide or glycopyrrolate as stated in the British National Formulary: 5.1. Prostatic enlargement 5.2. Myasthenia gravis 5.3. Pyloric stenosis 5.4. Paralytic ileus 5.5. Glaucoma 5.6. Hepatic Impairment 6. Any of the following cautions to hyoscine hydrobromide or glycopyrrolate as stated in the British National Formulary: 6.1. Chronic heart failure 6.2. Stomach ulcer 6.3. Ulcerative colitis 6.4. Significant liver disease that in the opinion of the CI or PI is a contraindication 6.5. Down’s syndrome 6.6. Arrythmia and/or history of myocardial infarction 6.7. Overactive thyroid gland. 6.8. Unstable angina 7. Current prescription for a) potassium chloride, b) digoxin, c) amantadine, or d) levodopa. 8. Pregnant, trying to conceive or breastfeeding. 9. Patients who are unable or unwilling to use contraception during the study or abstain from sexual intercourse (see section 10.4). 10. Participation in another drug study within the preceding 12 weeks or use of other investigational drugs. 11. Active suicidal ideation as assessed within usual care. 12. Known sensitivity to any interventions or excipients. 13. Known history of intestinal obstruction. 14. Known history of urinary retention. 15. Severe renal impairment (eGFR <30 ml/min/1.73m2). 16. Known history of brain tumour or encephalitis. 2024-08-20T00:00:00.000Z 2026-11-01T00:00:00.000Z Clozapine induced hypersalivation (CIH) Mental and Behavioural Disorders Participants will be randomised via a secure (24-hour) web-based randomisation system controlled centrally by the LCTC to receive either hyoscine hydrobromide, glycopyrronium bromide (glycopyrrolate) or placebo in a ratio of 1:1:1. Route of administration: capsules for oral administration IMP1: Hyoscine hydrobromide (over-encapsulated) Dose: Week 1: 300 micrograms (1 capsule) twice daily Weeks 2-12: 300 micrograms (1 capsule) three times daily IMP2: Glycopyrronium bromide (glycopyrrolate) (over-encapsulated) Dose: Week 1: 1 mg (1 capsule) twice daily Weeks 2-12: 1 mg (1 capsule) three times daily Placebo: capsules filled with a lactose & magnesium stearate blend Dose: Week 1: 1 capsule twice daily Weeks 2-12: 1 capsule three times daily Trial treatment duration is 12 weeks with an optional 12-week open-label follow-up period. Updated 28/05/2026: Trial treatment duration is 12 weeks. Drug Phase III Hyoscine Hydrobromide [Hyoscine Hydrobromide 300 microgram] , Glycopyrronium Bromide [Glycopyrronium Bromide] The datasets generated during and/or analysed during the current study are/will be available upon request. Requests should be made to LCTC by email to gothic2@liverpool.ac.uk At the end of the trial, after the primary results have been published, the individual participant data (IPD) and associated documentation (e.g. protocol, statistical analysis plan, annotated blank CRF) will be prepared in order to be shared with external researchers. IPD will only be shared with external researchers if the participants have consented to this onward disclosure in accordance with the Common Law Duty of Confidentiality, or if the external researchers obtain approval to waive this Common Law requirement (i.e. Section 251 Approval via the Confidentiality Advisory Group (CAG) / approval from the Public Benefit & Privacy Panel for Health & Social Care (PBPP)) or if the IPD has been fully anonymised prior to sharing. All requests for access to the IPD will be assessed by the Sponsor and must be agreed by all Data Controller organisations. If a request is approved, it will be processed by LCTC. Available on request

39a0b66a-404a-4b8f-9926-b66574b29397 295731ab-0023-4701-9a0e-732acf9dd806 897bbdf5-33b1-4e08-b60a-cfb4215d6acf 28e4b75e-3559-4da5-82ee-186a7f6a29e7 Yes Julie Perry Public Scientific

Liverpool Clinical Trials Centre , Block C, Waterhouse Building, 1-3 Brownlow Street

Liverpool United Kingdom L69 3GL +44 151 795 8577 gothic2@liverpool.ac.uk Public Inti Qurashi Principal investigator

Parkbourn

Liverpool United Kingdom L31 1HW +44 151 472 4045 Inti.Qurashi@merseycare.nhs.uk Public University of Liverpool University/education https://ror.org/04xs57h96 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 63917405 true Aripiprazole/sertraline combination: clinical and cost-effectiveness in comparison with quetiapine for the treatment of bipolar depression. An open label randomised controlled trial ASCEnD The primary objective of the trial is to test the hypothesis that improvement in depression will be greater in participants randomised to aripiprazole/sertraline combination than those randomised to quetiapine. The study's secondary objectives will compare the impact of aripiprazole/sertraline combination versus quetiapine over a 24-week follow up period. This will be achieved by asking participants to complete questionnaires to assess changes in their symptoms, overall wellbeing, their health related quality of life and assessing the cost-effectiveness of these treatments. Background and study aims Bipolar disorder (BP) affects more than 1 person in 100, negatively impacts people’s lives and places a tremendous strain on caregivers, the NHS and society. It causes earlier-than-expected death, including by suicide. Depression is common in BP (“bipolar depression”). People with unipolar depression usually improve with a standard antidepressant or talking therapy, but only specialist psychological treatments are recommended in BP. These are not widely available and have not convincingly been shown to treat bipolar depression. Similarly, in BP, antidepressant drugs, when taken by themselves, show no therapeutic value. In light of this, the National Institute of Clinical Excellence (NICE) largely recommends treatment with so-called 'antipsychotic' drugs. These are often poorly tolerated causing sedation, weight gain, sleep disturbance and diabetes. Most current treatment options are also only recommended to be started by psychiatrists. So, additional treatment options are needed and this has been identified by the James Lind Alliance (JLA) as a priority for patients. A previous small trial indicated a combination of the antipsychotic aripiprazole with an antidepressant may be effective in bipolar depression, with a reduced burden of side effects compared to current treatments. It is time now for a large trial to see if this combination works. Who can participate? Adults aged over 18 years old with BP from primary and secondary care services What does the study involve? Participants will be randomised to receive an aripiprazole/sertraline combination or quetiapine. The participants will be followed up for 24 weeks using questionnaires to examine any longer-term benefits on depressive symptoms, quality of life and costs. 10 NHS trusts will take part in the study. What are the possible benefits and risks of participating? The study team think there are minimal risks to being part of this study as all the medications are currently used in the NHS. However, all medications carry some risks. Some of the common side effects of these drugs may include headaches, weight gain, feeling sleepy and nausea. Participants will be in regular contact with study central research assistants and asked to report side effects they may experience via ePRO and discuss these with an investigator at their participating site. If at any point during the study, the investigator thinks it would be beneficial for a participant to stop taking part, they will be withdrawn. Participants will also be required to answer a large number of questionnaires throughout the study, but this was acceptable in the similar PAX-BD study and has been reviewed by our PPI group. Where is the study run from? St Nicholas Hospital (UK) When is the study starting and how long is it expected to run for? September 2022 to December 2027 Who is funding the study? National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) Programme Who is the main contact? ASCEND study team, ASCEND@newcastle.ac.uk Improvement in depression measured using the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) weekly following randomisation To compare the impact of the aripiprazole/sertraline combination versus quetiapine on the following secondary outcomes: 1. The trajectories of symptom change, measured via the QIDS-SR reported weekly from screening 2. Treatment satisfaction, measured via the Treatment Satisfaction Questionnaire for Medication (TSQM) at baseline and weeks 4, 14 and 24 3. Tolerability, measured via the Glasgow Antipsychotic Side-effect Scale (GASS) at baseline and weeks 4, 14 and 24 4. Pattern of medication adherence, measured via weekly questions in ePro regarding dosages of study medications taken on each of the preceding 7 days. This will be supported by the use of the Medication Adherence Rating Scale (MARS) at baseline and weeks 4, 14 and 24. 5. Pattern of non-randomised antidepressant/antipsychotic medication use, measured via analysis of concomitant medications weekly from screening 6. Change in anxiety symptoms, measured via the General Anxiety Disorder-7 (GAD-7) scale weekly from baseline 7. Change in manic symptoms and rates of relapse to a hypomanic or manic episode, measured via the Altman Self-Rating Mania Scale (ASRM) weekly from baseline 8. Psychosocial functioning, measured via the Work and Social Adjustment Scale (WSAS) at baseline and weeks 4, 14 and 24 9. Health-related quality of life, measured via the EQ-5D-5L questionnaire weekly from baseline 10. Capability well-being, measured via the ICEpop CAPability measure for Adults (ICECAP-A) and the Oxford CAPabilities Questionnaire-Mental Health (OxCAP-MH) at baseline and weeks 4, 14 and 24 11. Costs and incremental cost-effectiveness, based on the Health Economics Questionnaire (HEQ), measured at baseline and weeks 4, 14 and 24 12. Informal carers’ health-related quality of life, capability well-being and costs of caring measured via the EQ-5D-5L, the ICEpop CAPability measure for Adults (ICECAP-A), the Oxford CAPabilities Questionnaire-Mental Health (OxCAP-MH) and the Caregiver Indirect and Informal Care Cost Assessment Questionnaire (CIIQ) at baseline and weeks 4, 14 and 24 Ethics approval required North East - Newcastle & North Tyneside 1 Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 23/NE/0132 10.1186/ISRCTN63917405 1007468 CPMS: 57451, RES-20-32 1007468 57451 RES-20-32 Randomized active-controlled open-label parallel-group study Interventional Randomised controlled trial Efficacy Safety 2027-12-31T00:00:00.000Z United Kingdom England Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust

St. Nicholas Hospital Jubilee Road Gosforth

Newcastle Upon Tyne England NE3 3XT Avon and Wiltshire Mental Health Partnership NHS Trust

Bath NHS House Newbridge Hill

Bath England BA1 3QE Camden and Islington NHS Foundation Trust

St Pancras Hospital 4 St Pancras Way

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

Warneford Hospital Warneford Lane Headington

Oxford England OX3 7JX Birmingham and Solihull Mental Health NHS Foundation Trust

The Barberry 25 Vincent Dr

Birmingham England B1 3RB Cornwall Partnership NHS Foundation Trust

The Kernow Building Wilson Way Pool

Redruth England PL31 2QN Tees, Esk and Wear Valleys NHS Foundation Trust

Flatts Lane Centre Flatts Lane Normanby

Middlesborough England TS6 0SZ Hampshire and Isle of Wight Healthcare NHS Foundation Trust

Tatchbury Mount Hospital, Calmore

Southampton England SO40 2RZ Nottinghamshire Healthcare NHS Trust

D Floor Institute of Mental Health Triumph Road

Nottingham England NG7 2TU Patient Patients must fulfil all of the following criteria to progress to randomisation: 1. Aged 18 years old and over at the point of consent. 2. Able to provide written informed consent. 3. A current (i.e., within 7 days) Diagnostic and Statistical Manual-5-Text Revision (DSM-5-TR) confirmed diagnosis of a major depressive episode within bipolar disorder. This will be confirmed using the SCID-5-RV. 4. A current (i.e., within 7 days) QIDS-SR greater than 10. 5. Clinical uncertainty regarding the next course of treatment and judgement that the sertraline/aripiprazole combination and quetiapine treatment arms are both clinically appropriate and represent equipoise. This judgment includes consideration of reproductive risks. 6. In the opinion of the clinician, the participant is able to follow trial prescription instructions, complete weekly questionnaires and engage in weekly telephone calls with the cRAs throughout the 24-week follow-up period of the trial. Mixed 18 Years 99 Years All 270 0 Any of the following criteria prevent progression to randomisation: 1. Currently participating in any other interventional clinical trial that may affect the outcome of ASCEnD. 2. DSM-5-TR defined severe substance use disorder. 3. Any known contraindications to aripiprazole, sertraline or quetiapine. 4. Currently pregnant, planning to become pregnant during the trial and/or breastfeeding. 2024-03-18T00:00:00.000Z 2027-08-31T00:00:00.000Z Bipolar depression Mental and Behavioural Disorders The ASCEnD trial is a prospective, two-arm, open-label, superiority, individually 1:1 randomised, controlled, pragmatic, parallel-group, type A open-label clinical trial. It aims to determine whether a sertraline/aripiprazole medication combination is an effective treatment for bipolar depression. The trial will be carried out at UK sites including primary, secondary and tertiary care mental health services. A target of 270 patients will be randomised (1:1 ratio) to receive either sertraline/aripiprazole combination or quetiapine. The effectiveness of sertraline/aripiprazole combination in reducing depressive symptoms will be assessed 12-16 weeks after randomisation. Patients and their main informal carers will continue to be followed up for 24 weeks. Over this period, the cost-effectiveness and the effect of the sertraline/aripiprazole combination on symptoms of depression, anxiety and mania will be assessed. Assessments will be completed by participants and their main informal carer online using electronic Patient Reported Outcomes (ePRO) or, for participants where this is not possible, via telephone or videoconference with a cRA. The study will recruit patients with a pre-existing diagnosis of bipolar disorder, as well as those whose bipolar disorder is not yet recognised. The Clinical Research Networks (CRNs) will support recruitment which will be via a number of routes. The eligibility criteria for this trial are pragmatic, in line with UK clinical practice. There is no upper or lower limit of bipolar disorder treatment resistance, duration of current depressive episode, time since initial symptoms or time since the diagnosis of bipolar disorder. Patients will not be excluded if they are receiving, planning to receive or have recently received psychological or digital therapies. Patients must fulfil all of the following criteria to progress to randomisation: aged 18 or over at the point of consent; able to provide written informed consent; A current (i.e., within 7 days) DSM-5-TR confirmed diagnosis of a major depressive episode within bipolar disorder, be confirmed using the SCID-5-RV; a current (i.e., within 7 days) QIDS-SR >10; clinical uncertainty regarding the next course of treatment and judgement that the sertraline/aripiprazole combination and quetiapine treatment arms are both clinically appropriate and represent equipoise., and in the opinion of the clinician, the participant is able to follow trial prescription instructions, complete weekly questionnaires and engage in weekly telephone calls with the cRAs throughout the 24 weeks follow up period of the trial. Any of the following criteria prevent progression to randomisation: currently participating in any other interventional clinical trial that may affect the outcome of ASCEnD; DSM-5-TR-defined severe substance use disorder; any known contraindications to aripiprazole, sertraline or quetiapine; and currently pregnant, planning to become pregnant during the trial and/or breastfeeding. The electronic data capture system used in ASCEnD is Red Pill. ePRO is a function of the data capture system that allows participants to enter questionnaire responses directly into the clinical trial database. Participants will be encouraged to complete questionnaires weekly via ePRO throughout the study via email or text prompts. If a participant does not have access to the internet or is otherwise unable to enter data directly into ePRO, this process will be supported by the cRAs who will complete the questionnaires by telephone or videoconference with the participant and enter data on their behalf directly into the appropriate electronic Case Report Forms (eCRFs). The screening and consent appointment will be conducted by the site PI, or delegate, who is a GMC registered doctor. The site PI, or delegate, will discuss the trial with the potential participant, encourage them to ask questions about the trial and inform them of their right to withdraw at any time without any impact on the standard of care they will receive or their legal rights. The appointment serves to (i) Enable the potential participant to make an informed and capacious decision about whether to participate in the study. (ii) Formally take and record study consent. (iii) Confirm all eligibility criteria for study participation are met. This includes completion of the SCID-5-RV diagnostic interview and QIDS-SR on paper (a paper study questionnaire booklet is available), and entry of this information directly into the appropriate eCRFs by delegated site staff. (iv) Collect relevant study information including method of identification, current concomitant medications, recent (within 6 months) current and planned psychological therapy, medical history (time since diagnosis) and demographic details (including initials, age, sex at birth, gender, highest level of education, family status (single/divorced/married), ethnicity and post-code), and entry of this information directly into the appropriate eCRFs by delegated site staff. (v) Provide the potential participant with access to ePRO and support with completion and use of the system. Participants will be prompted after their first login to change their password to something that only they know. Consent for trial participation must be sought by the site PI, or delegate, who is a GMC registered doctor. Eligibility for the ASCEnD trial must be assessed by a GMC-registered doctor after receiving written informed consent from a patient to take part in the study. Once a participant is confirmed as eligible to take part in the study, a baseline appointment will be arranged. The screening and baseline appointments are likely to occur during the same visit. Baseline measures will be completed on paper. Eligible participants will be randomised in a 1:1 ratio to aripiprazole/sertraline combination or quetiapine. Randomisation will incorporate block stratification using three variables (being in mental health secondary care services at screening (y/n), being prescribed antidepressants at screening (y/n), and being prescribed an antipsychotic at screening (y/n)). Randomisation will be conducted by a delegated and trained member of the site team at each site using Red Pill (a central, secure, 24-hour web-based randomisation system, which is owned by Sealed Envelope™). Randomisation should take place as soon as possible and no more than one week after a participant has been confirmed as eligible. Prescriptions for study medications will be written by the participant’s clinical team. The study does not mandate the use of specific medication dosages or dose escalation procedures. Instead, clinicians are encouraged to use their judgement in accordance with clinical guidelines and the BNF dose schedule. Dosage decisions and decisions regarding the ongoing use of study medications taken during the study remain the responsibility of the prescribing clinician but are informed by a participant’s weekly clinical scale scores and reported side effects. Further guidance is provided in Appendix 1 of the protocol. Participants who discontinue trial medication will be encouraged to remain in the trial and to continue to provide outcome data. ASCEnD has clear progression criteria and the progress of the study will be continually monitored by the study team and Funder. All participants are followed up for 24 weeks while taking trial medication, with weekly measures completed through to week 24, with additional measures completed at weeks 4, 14 and 24. After 24 weeks of follow-up, participants who are being seen in research clinics will be transferred to standard clinical pathways. The study will not prompt change in ongoing drug treatment and study medication will not stop because the study has ended. Participants will be contacted and thanked for their participation. The end of the trial is defined as the last patient, last visit (LPLV) date. Drug Phase III Aripiprazole, sertraline, quetiapine The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request from ascend@newcastle.ac.uk Available on request

Study website Migrated from study website field

533e39b6-03cb-4884-80fa-fabad24672d8 540728d7-b01a-4993-a36b-f43429eb406e 5f56f08f-91c6-4626-a8af-de80cd65ecc9 08775203-6253-4953-9c9b-1b11e922d226 Yes Stuart Watson Scientific Principal investigator

St Nicholas Hospital

Newcastle upon Tyne United Kingdom NE3 3XT +44(0)191 2468606 stuart.watson@newcastle.ac.uk Public ASCEnD Trial Management Team Public

Newcastle Clinical Trials Unit 1-4 Claremont Terrace Newcastle University

Newcastle upon Tyne United Kingdom NE2 4AE None provided ASCEND@newcastle.ac.uk Public Cumbria Northumberland Tyne and Wear NHS Foundation Trust Hospital/treatment centre https://ror.org/01ajv0n48 Non-commercial Health Technology Assessment Programme http://dx.doi.org/10.13039/501100000664 57406593 true Secure Care Hospital Evaluation of Manualised (interpersonal) Art-psychotherapy: a randomised controlled trial SCHEMA Is interpersonal art therapy effective at reducing the frequency and severity of aggressive behaviour in adult secure care? Background and study aims In the past people who have a learning disability were often excluded from taking part in research. This means that knowing what works well for them is not always clear. Lots of psychotherapies available to help people with mental health difficulties are based on talking, which might not always be the best approach for people with learning disabilities/difficulties. Doing artwork or creative things within art psychotherapy can be a helpful way for people to communicate about themselves. Interpersonal art psychotherapy has been designed to help people with learning disabilities in secure care. The art psychotherapist encourages people to use creative ways to express the things they would like to feel better about. We want to find out if interpersonal art psychotherapy is helpful and value for money for people with learning difficulties who are in secure care. We will be testing if interpersonal art psychotherapy works better than the standard care that is being provided. Who can participate? Patients aged 18 to 60 years, with a Learning Disability Screening Questionnaire (LSDQ) score of 57 or below (indicating the presence of learning disability/borderline intellectual functioning/learning difficulty). What does the study involve? During the study a computer will decide which people in the research get art therapy straight away and which people wait a bit longer. All participants will be asked to complete some questionnaires about your mental and physical health. You will be asked questions at the start, after four months, and after nine months. What are the possible benefits and risks of participating? Art therapy may help participants to feel better. Participants will have to give up some of their free time to take part and Sometimes people can feel emotional during and after art therapy, but your art therapist or staff will help you with this Where is the study run from? Cumbria Northumberland Tyne and Wear NHS Foundation Trust (UK) When is the study starting and how long is it expected to run for? July 2022 to August 2025 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK). Who is the main contact? Paula Foscarini-Craggs, Schema@cardiff.ac.uk Aggressive behaviour is measured using the Modified Overt Aggression Scale (MOAS) at week 19, weekly between week 19-38, and week 38 1. Health Economic analysis will be measured using the EQ5D, the Recovery Quality of Life Scale, and a resource use questionnaire, at baseline, week 19, and week 38 2. Patient distress attributed to psychiatric symptoms is measured using the brief symptom inventory and is measure at week 19 and week 38 Old ethics approval format Approved 10/01/2023, London - City & East Research Ethics Committee (Level 3, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT, UK; +44 207 1048134; cityandeast.rec@hra.nhs.uk), ref: 23/LO/0026 10.1186/ISRCTN57406593 319325 CPMS: 54895, NIHR: 301264 319325 54895 301264 Interventional randomized controlled trial Interventional Randomised controlled trial Treatment 2025-08-31T00:00:00.000Z United Kingdom England Scotland Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust

St Nicholas Hospital Jubilee Road Gosforth

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

Robert Dolan House 9 Alie Street

London England E1 8DE RWK@2.16.840.1.113883.2.1.3.2.4.18.48 Birmingham and Solihull Mental Health NHS Foundation Trust

Unit 1 50 Summer Hill Road

Birmingham England B1 3RB RXT@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 Nottinghamshire Healthcare NHS Foundation Trust

The Resource, Trust Hq Duncan Macmillan House Porchester Road

Nottingham England NG3 6AA RHA@2.16.840.1.113883.2.1.3.2.4.18.48 NHS Lothian

Waverley Gate 2-4 Waterloo Place

Edinburgh Scotland EH1 3EG SS999@2.16.840.1.113883.2.1.3.8.2.16.1 Kneesworth House Hospital

Kneesworth House Old North Road Bassingbourn

Royston England SG8 5JP NTY04@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Current inclusion criteria as of 28/02/2024: 1. An inpatient in an NHS secure hospital/unit/service with the presence of learning disability/borderline intellectual functioning indicated by either (a) meeting validated assessment criteria (recognised cognitive testing and adapting functioning assessment), or (b) a score of 57 or below on the Learning Disability Screening Questionnaire (LDSQ) 2. Age 18 to 60 years 3. Able to give informed consent 4. A HONOS (Health of the Nation Outcome Scale) score between 1 and 4 for item 1 (Overactive, aggressive, disruptive, or agitated behaviour / Behavioural problems directed at others) 5. The participants' involvement in the study is supported by their responsible clinician and/or multidisciplinary team (MDT) Previous inclusion criteria: 1. An inpatient in an NHS secure hospital/unit/service with a Learning Disability Screening Questionnaire (LSDQ) score of 57 or below (indicating the presence of learning disability/borderline intellectual functioning/learning difficulty) 2. Age 18 to 60 years (within the age range for the service) 3. Able to give informed consent 4. A score between 1 and 4 on question 1 of the Health of the Nation Outcome Scale Working Age Adult or Learning Disability version (HONOS-WAA or HONOS-LD) 5. The patient’s involvement in the study is supported by their responsible clinician and/or multidisciplinary team (MDT) Adult 18 Years 60 Years All 150 50 Current exclusion criteria as of 28/02/2024: 1. Unable to give informed consent 2. Learning disability/borderline intellectual functioning not indicated based on a validated assessment or screening questionnaire (i.e. not meeting validated assessment criteria or a LDSQ Score >57) 3. A HONOS score of 0 for item 1 4. Planned discharge within 12 months of the start of the study 5. Unstable/unmanaged psychotic symptoms requiring active assessment or treatment including medication dose titration (i.e., dose adjustment in the previous 4 weeks or with potential further dose adjustment planned for the following 4 weeks) Previous exclusion criteria: 1. LDSQ Screening score >57 2. Unable to give informed consent 3. A score of 0 on question 1 of the HONOS-WAA or HONOS-LD 4. Planned discharge within 12 months of the start of the study 5. Receiving active assessment or treatment for acute or unstable/unmanaged psychotic symptoms including medication dose titration 2023-02-01T00:00:00.000Z 2024-11-30T00:00:00.000Z Learning disorders Mental and Behavioural Disorders Participants will be randomised on a one-to-one basis to receive either interpersonal art therapy or be placed on a wait list to receive interpersonal art therapy after they complete their trial participation. Randomisation will be stratified by diagnosis of psychosis and sex. The interpersonal art therapy comprises 12 sessions with up to 3 additional sessions (a total of 15 possible sessions) which look at personal goals, coping and self-managed, life events and imagined futures. Therapy sessions will be audio recorded. The recordings will be analysed as part of the assessment of the therapeutic process. An assessment of the frequency and severity of aggressive behaviours will be completed weekly after the completion of therapy up to 38 weeks post-randomisation. During the trial, participants will complete two assessments of the quality of life, and a measure of distress associated with psychiatric symptoms at 19 and 38 weeks post-randomisation. At 19 weeks and 38 weeks post-randomisations, healthcare staff will complete proxy measures of the participant's quality of life, and healthcare resource use. After the 38 week follow-up has been completed, participants will be offered the opportunity to participate in the interpersonal art therapy. A subset of participants will also be asked if they want to take part in an interview to assess their experiences of taking part in interpersonal art therapy. Interviews will last approximately 1 hour. Therapists will also be asked to take part in interviews to assess their experience of providing therapy and its implications for clinical practice. Behavioural The data set will be available upon request by emailing Dr Paula Foscarini-Craggs (schema@Cardiff.ac.uk) at the end of the trial. While there are no specific criteria, any data requests will be reviewed in accordance with the Centre for Trials Research data sharing policy and procedures. Available on request 2025 Protocol article in https://pubmed.ncbi.nlm.nih.gov/40242277/ (added 17/04/2025) Results Basic results see attached file ISRCTN57406593_BasicResults_17Aug2026.pdf (added 17/08/2026)

Added from spreadsheet

Pictorial PIS

Therapist information sheet

0ac73263-bb98-4341-acf0-a28d5a9ec35a 18f28f2f-aa44-4ba8-86b4-7c71429f4a1f 429219c0-5722-47de-8287-091ce22022e6 8cc38624-d647-4489-b833-88317018b926 Yes Protocol file 43060 SCHEMA Protocol V1.3 22.11.2022.pdf a37da840-fdb9-47e2-8e57-434609ac0a9e true application/pdf 757158 aa2927b48610bcba988c8ac31c5f14eb Participant information sheet 43060 SCHEMA PIS V1.3 13.01.2023.pdf 4e5c8e16-bed6-4451-8037-0e5efc031235 true application/pdf 498831 df922bcf119391c94193c15e94e01181 Pictorial PIS 43060 SCHEMA Pictorial PIS V1.2 13.01.2023.pdf 39837ecf-3203-4112-9b86-b03d2b0f2709 true application/pdf 725392 d010aa2ae2eb6721081ef428030e649a Therapist information sheet 43060 SCHEMA Therapist Information Sheet V1.2 13.01.2023.pdf a483ba2e-1559-4c1b-b099-fdbec78fff67 true application/pdf 505664 6b6108df897ecd6f7574c249dc9fbfd3 Plain English results ISRCTN57406593_PlainEnglishResults_17Aug2026.pdf 96e37e1f-7fb2-4bab-a081-82718522f86a true application/pdf 105286 df60f864254a21e205e797fa29c05d6f Basic results ISRCTN57406593_BasicResults_17Aug2026.pdf 9783b946-8da0-4ee9-b663-2a9e3f8a4bee true application/pdf 664223 a6fbadd47d13c6ca3cb4acd9d8613877 Paula Foscarini-Craggs Scientific

Centre for Trials Research School of Medicine College of Biomedical & Life Sciences Cardiff University 4th Floor, Neuadd Meirionnydd Heath Park

Cardiff United Kingdom CF14 4YS +44 (0)29 206 87522 Schema@cardiff.ac.uk Public Cumbria Northumberland Tyne and Wear NHS Foundation Trust Hospital/treatment centre https://ror.org/01ajv0n48 Non-commercial NIHR Academy National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 17381762 true Assessing the Clinical and cost-Effectiveness of inpatient mental health Rehabilitation services provided by the NHS and independent sector (ACER) ACER V1.0 1. Do sociodemographic and clinical characteristics of patients differ between people receiving inpatient rehabilitation in the NHS and the independent sector? 2. Does service quality differ between inpatient rehabilitation units provided by the NHS and the independent sector? 3. Do the experiences of treatment and care, from the perspectives of patients, informal carers and staff, differ between inpatient rehabilitation services provided by the NHS and the independent sector? 4. Is inpatient rehabilitation clinically more effective at preventing readmission when provided by the independent sector or the NHS, after adjusting for differences between the sectors in terms of patient characteristics and length of stay? 5. Is inpatient rehabilitation more cost-effective when provided by the independent sector or the NHS, after adjusting for differences between the sectors in terms of key predictors of costs such as patient characteristics and length of stay? Background and study aims Mental health rehabilitation services provide specialist treatment to people with particularly severe and complex problems. These services include inpatient units and supported accommodation in the community. Over half of the 4400 mental health inpatient rehabilitation beds in England are provided by the independent sector, but there have been no studies investigating the effectiveness of inpatient rehabilitation services that have included the independent sector. Our study aims to address this gap. Who can participate? Any patient with an adequate understanding of English at one of the mental health inpatient rehabilitation units selected for this study. What does the study involve? A research interview which takes about 30 min where participants will be asked a series of questions about how satisfied they are with different aspects of their life, how they spend their time, the freedom they have to make day-to-day decisions, and how they feel about the care you receive from the inpatient rehabilitation service. The research team will also invite participants to a brief 5 min interview at 6, 12, and 18 months after the first interview. These interviews will be done over the telephone or video call (e.g. Zoom or Microsoft Teams). The research team will also ask participants for their permission to ask a staff member about their abilities, needs, any specific difficulties they may have, their activities in the community, and whether they have been at risk or posed any risk to others. The research team will then contact staff involved in the participant's healthcare at regular intervals over the next 18 months to see if they have been discharged from the inpatient rehabilitation service, and, if they have been discharged, details of where they have been discharged to and whether they have had any readmissions. Participants may ask the researcher to see a copy of these questions. The research team would also ask participants for their permission to collect some information from their healthcare records about the care they have received from mental health services in the past. What are the possible benefits and risks of participating? By participating in this study, participants will help the research team to assess the effectiveness of NHS and independent sector inpatient mental health rehabilitation services. It is hoped that the information collected from this study will help to improve inpatient rehabilitation services in the future. Each participant will be offered £20 in recognition of the time they have given to be involved in the study. Where is the study run from? University College London (UK) When is the study starting and how long is it expected to run for? From December 2019 to October 2025 Who is funding the study? National Institute for Health and Care Research (NIHR) Health Services Delivery Research programme (UK) Who is the main contact? Christian Dalton-Locke (Project Manager) c.dalton-locke@ucl.ac.uk Cohort study: Successful discharge from inpatient rehabilitation, defined as being discharged to the community without readmission, measured using staff reports collected at 6, 12, and 18 months Health economic evaluation: Incremental cost-effectiveness ratio (ICER) comparing rehabilitation in the independent sector and rehabilitation in an NHS service calculated using cost-utility analysis (CUA) where the QALYs are measured using patient responses to the EuroQol 5-dimension 5-level (EQ-5D-5L) questionnaire collected at baseline, 6, 12, and 18 months Cohort study: Total inpatient days over the follow-up period measured using staff reports collected at 6, 12, and 18 months Old ethics approval format Approved 08/06/2022, North East - Newcastle & North Tyneside 2 Research Ethics Committee (NHS BT Blood Donor Centre, Holland Drive, Newcastle upon Tyne, Tyne and Wear, NE2 4NQ; +44 (0)2071048086; newcastlenorthtyneside2.rec@hra.nhs.uk), ref: 22/NE/0067 10.1186/ISRCTN17381762 311434 CPMS: 52629, NIHR: 130693, award ID: 311434 52629 130693 award ID: Observational cohort study Observational Cohort study Treatment 2025-10-31T00:00:00.000Z United Kingdom England Camden and Islington NHS Foundation Trust

St Pancras Hospital 4 St Pancras Way

London United Kingdom NW1 0PE TAF@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 Birmingham and Solihull Mental Health NHS Foundation Trust

Unit 1 50 Summer Hill Road

Birmingham United Kingdom B1 3RB RXT@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 United Kingdom NW1 3AX RV3@2.16.840.1.113883.2.1.3.2.4.18.48 Coventry and Warwickshire Partnership NHS Trust

Wayside House Wilsons Lane

Coventry United Kingdom CV6 6NY RYG@2.16.840.1.113883.2.1.3.2.4.18.48 Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust

St Nicholas Hospital Jubilee Road Gosforth

Newcastle upon Tyne United Kingdom NE3 3XT RX4@2.16.840.1.113883.2.1.3.2.4.18.48 Devon Partnership NHS Trust

Wonford House Hospital Dryden Road

Exeter United Kingdom EX2 5AF RWV@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 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 Leeds and York Partnership NHS Foundation Trust

2150 Century Way Thorpe Park

Leeds United Kingdom LS15 8ZB RGD@2.16.840.1.113883.2.1.3.2.4.18.48 Lincolnshire Partnership NHS Foundation Trust

St George's Long Leys Road

Lincoln United Kingdom LN1 1FS RP7@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 United Kingdom L34 1PJ RW4@2.16.840.1.113883.2.1.3.2.4.18.48 North Staffordshire Combined Healthcare NHS Trust

Lawton House Bellringer Road Trentham

Stoke-on-trent United Kingdom ST4 8HH RLY@2.16.840.1.113883.2.1.3.2.4.18.48 Nottinghamshire Healthcare NHS Foundation Trust

The Resource, Trust Hq Duncan Macmillan House Porchester Road

Nottingham United Kingdom NG3 6AA RHA@2.16.840.1.113883.2.1.3.2.4.18.48 Pennine Care NHS Foundation Trust

225 Old Street

Ashton-under-lyne United Kingdom OL6 7SR RT2@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 United Kingdom DN4 8QN RXE@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 United Kingdom BR3 3BX RV5@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 United Kingdom SW17 7DJ RQY@2.16.840.1.113883.2.1.3.2.4.18.48 Sussex Partnership NHS Foundation Trust

Trust Hq Swandean Arundel Road

Worthing United Kingdom BN13 3EP RX2@2.16.840.1.113883.2.1.3.2.4.18.48 Tees, Esk and Wear Valleys NHS Foundation Trust

Trust Headquarters West Park Hospital Edward Pease Way

Darlington United Kingdom DL2 2TS RX3@2.16.840.1.113883.2.1.3.2.4.18.48 St Andrew's Healthcare

Billing Road

Northampton United Kingdom NN1 5DG Priory Group

Priory Head Office Floor 5 Hammersmith Road

London United Kingdom W14 8UD Barnet, Enfield and Haringey Mental Health NHS Trust

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

London United Kingdom N15 3TH RRP@2.16.840.1.113883.2.1.3.2.4.18.48 Oxleas NHS Foundation Trust

Pinewood House Pinewood PLACE

Dartford United Kingdom DA2 7WG RPG@2.16.840.1.113883.2.1.3.2.4.18.48 Lancashire and South Cumbria NHS Foundation Trust

Sceptre Point Sceptre Way Walton Summit

Preston United Kingdom PR5 6AW Hampshire and Isle of Wight Healthcare NHS Foundation Trust

Tatchbury Mount Hospital Calmore

Southampton United Kingdom SO40 2RZ RW1@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Patients: 1. Inpatients at rehabilitation units that are participating in the study 2. Provide informed consent to participate in the study. All efforts will be made to maximise the capacity of each patient to be able to provide informed consent for the study (for example, by explaining the purpose and process of the study in simple terms and over a number of meetings), and any patient with capacity who declines participation will not be included. However, for eligible patients who lack capacity to give informed consent we will seek advice from a consultee on their participation. Further detail on the procedure for seeking informed consent and assessing capacity is provided in section 8. Research data for participants lacking capacity will be collected via staff interview and healthcare records (as described above), but these participants will not be asked to participate in an interview themselves. The researchers expect only a minority of eligible patients to lack capacity (around 8% based on the REAL study) but it is important they are included in the study in order to prevent sample bias. Services: 1. High dependency, community, or longer-term high dependency rehabilitation units 2. Community rehabilitation units will only be included if they are registered with CQC as an inpatient unit (rather than supported housing or residential care) Adult All 500 755 Patients: 1. Unavailable during the researcher's visit, because they are on leave from the ward during the visit or are otherwise unavailable 2. Do not have an adequate understanding of English to understand the main purpose of the research and what participating would involve for them Services: 1. Highly specialist units that focus on sub-groups (such as people with a diagnosis on the autism spectrum or those with neurodegenerative disease) 2. Specialist forensic mental health units (i.e. low secure rehabilitation units) as they do not form part of the standard mental health rehabilitation care pathway and are subject to specialist commissioning by NHS England 2022-06-08T00:00:00.000Z 2025-09-30T00:00:00.000Z Mental health Mental and Behavioural Disorders As we cannot compare NHS and independent sector services through a randomised trial, our programme will draw together findings from four components to assess the effectiveness of these services: 1. Survey of 60 inpatient mental health rehabilitation services across England (30 NHS and 30 independent sector) 2. In-depth interviews with users, relatives/carers, staff, and commissioners of these services to explore their experiences and perspectives 3. Cohort study to compare outcomes for 600 patients of the NHS and independent sector rehabilitation services surveyed in Component 1, using statistical methods that take account of any differences between them such as the severity of their mental health problems 4. Health economic evaluation to assess the cost-effectiveness of inpatient rehabilitation services provided by the NHS and the independent sector Survey: We aim to recruit 500 patients from 60 inpatient mental health rehabilitation units across England (30 NHS and 30 independent sector) over a 12-month period to participate in a survey (patients at this stage will be asked to consent to take part in Components 1 and 3). Once selected services have agreed to participate, researchers will visit the unit and describe the project to staff. The staff will be asked to introduce the patients to the researchers who will then provide the patient with a Participant Information Sheet. The study will be fully explained to the patient, including the purpose of the study, what their participation would involve, what data will be collected and how it will be collected, and that they are free to withdraw from the study at any point without it affecting their clinical care. The patient will have at least 24 hours to consider whether they would like to participate and have the opportunity to ask the researcher any questions. Patients who provide their informed consent by completing the consent form will then participate in a research interview where data will be collected using standardised measures regarding their quality of life (DIALOG, Recovering Quality of Life, EQ-5D-5L), autonomy (Resident Choice Scale), engagement in activities (Time Use Diary), satisfaction with care (Client Assessment of Treatment), and healthcare costs (Client Receipt Inventory). In addition, staff will be asked to complete standardised measures on the patient's social functioning (Life Skills Profile), challenging behaviours (Special Problems Rating Scale), alcohol and drug use (Clinical Alcohol and Drug Scale), needs (Camberwell Assessment of Needs, and activities (Time Use Diary). Sociodemographic, healthcare service use, current and previous risk, and engagement in community-based activities will be collected from the patient's healthcare records. Also, researchers will complete the QuIRC with the managers of each service. The QuIRC is a quality assessment tool developed specifically for inpatient mental health rehabilitation units. In-depth interview (qualitative) study: We will select and invite 10 inpatient rehabilitation units (5 NHS and 5 independent sector) participating in Component 1 to participate in Component 2. We will invite all staff from these services to participate in a focus group and ask about their experience and perspective of working in these services. We will also conduct additional staff interviews, including interviews with senior service managers, commissioners, and community care coordinators, to expand on any themes not adequately covered in the focus group, including the decision-making process about where an individual receives their inpatient rehabilitation. From these participating services, we will also aim to interview between three and five patients from each service (between 30 and 50 in total) and ask about their experiences and perspectives on the care they are receiving. We will ask these patient participants for permission to contact and invite their relatives/carers to participate in an in-depth interview. We aim to recruit around 20 relatives/carers in total. Interviews with relatives/carers will take place via telephone or videoconferencing. Cohort study: Participants recruited into Component 1 will comprise the cohort for Component 3. The researchers will contact the services managers of the inpatient rehabilitation units participating in Component 1 once a month for 18 months to ask if any of the participants have been discharged from the unit, and if they have been discharged, information about where they have been discharged to including contact details of relevant staff (i.e. their 'key informant') who we may complete future monthly follow-ups with. We expect on most occasions this will be the participant’s community care coordinator. We will invite all participants to a short research interview via telephone or video call (Teams of Zoom) at six, 12, and 18 months to complete two quality of life measures (Recovering Quality of Life and EQ-5D-5L). In addition, at six, 12, and 18 months we will ask key informants of participants who have been discharged from the inpatient rehabilitation service they were recruited from about any subsequent inpatient service use, and social care costs (use of supported accommodation and any individual ‘care packages’). Health economic evaluation: Using data collected in Components 1 and 3 analyses will be conducted to investigate the cost-effectiveness of NHS and independent inpatient rehabilitation services by calculating quality-adjusted life-years. Other The data sharing plans for the current study are unknown and will be made available at a later date Data sharing statement to be made available at a later date 2024 Protocol article in https://doi.org/10.1186/s12888-024-05524-6 (added 07/02/2024) Protocol

Added from spreadsheet

Study website Migrated from study website field

ed7dec09-5495-4856-a130-60c99daf896b 5a450f9e-2514-47c7-867b-f5c2692a8651 da008537-1d15-4859-82c1-8d25ed63e4c3 530832f6-1bf2-4052-999d-2eb2fa6e99eb No Protocol file 42032_Protocol_V1.3_07Jun22.pdf dd5dfdb0-0440-410e-9c55-4b12a696b07a true application/pdf 639856 babd16edce8b0f3131c540fb372b7950 Helen Killaspy https://orcid.org/0000-0003-2481-4802 Principal investigator

University College London UCL Division of Psychiatry Maple House 149 Tottenham Court Road

London United Kingdom W1T 7NF +44 (0)207 679 9710 h.killaspy@ucl.ac.uk Public Christian Dalton-Locke Scientific

University College London UCL Division of Psychiatry Maple House 149 Tottenham Court Road

London United Kingdom W1T 7BN +44 (0)20 7679 9632 c.dalton-locke@ucl.ac.uk Public Camden and Islington NHS Foundation Trust Hospital/treatment centre https://ror.org/03ekq2173 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272