59168898 true Clinical hypnosis for functional neurological disorder: a mixed-methods feasibility study of outcomes and acceptability Overall aim: To preliminarily evaluate the effectiveness, feasibility, and usability of clinical hypnosis as a treatment for individuals diagnosed with Functional Neurological Disorder (FND), using a mixed-methods design. Quantitative objectives: The quantitative component of the study will specifically aim to: 1. Assess psychological well-being: Determine the impact of clinical hypnosis on key indicators of psychological well-being, namely levels of anxiety, depression, stress, and health-related quality of life, at three time points: baseline, after a course of three fortnightly sessions (6 weeks in total), and at follow-up (4 weeks post-treatment) 2. Measure changes in functional symptoms:Evaluate whether there are differences in functional neurological symptoms (e.g. functional seizures, motor disturbances) by comparing symptom frequency and severity at baseline, after 6 weeks of clinical hypnosis, and at follow-up 3. Examine the sustainability of treatment effects: Investigate the persistence of any therapeutic benefits by assessing whether improvements in psychological well-being, quality of life, and symptom severity are maintained at follow-up Qualitative objectives: 1. Explore participants' experiences of receiving clinical hypnosis, including any perceived benefits and barriers to engagement 2. Understand how participants interpret any observed changes in symptoms or well-being in the context of their broader lived experience with FND 3. Identify service users' recommendations for improving the delivery and accessibility of hypnosis-based interventions for the FND population Background and study aims Functional Neurological Disorder (FND) is a condition that causes symptoms such as seizures, movement problems, weakness, sensory changes, and other neurological symptoms that cannot be explained by structural disease of the nervous system. Clinical hypnosis is already offered as part of routine care in the specialist FND service at Royal Preston Hospital, but more research is needed to understand how helpful and acceptable it is for people with FND. This study aims to explore whether clinical hypnosis may improve symptoms, psychological wellbeing, daily functioning, and quality of life for people with FND. It will also examine participants' experiences of receiving hypnosis and gather suggestions for improving this type of treatment. Who can participate? Adults aged 18 years or older with a confirmed diagnosis of FND who are patients of, or have been referred to, the specialist FND service at Royal Preston Hospital may be eligible to take part. Participants must be able to give informed consent and complete the study questionnaires in English. What does the study involve? Participants who agree to take part will first complete an online questionnaire before starting their course of clinical hypnosis. They will then receive three face-to-face hypnosis sessions as part of their usual NHS care. These sessions take place every 2 weeks over approximately 6 weeks and each session lasts about 45 to 60 minutes. Participants will complete a second online questionnaire after their third hypnosis session and a final questionnaire 4 weeks later. Each questionnaire takes around 20 minutes to complete. Some participants will also be invited to take part in a one-to-one interview about their experiences of hypnosis. The interview is optional, lasts around 30 to 60 minutes, and can take place by telephone or Microsoft Teams. Overall, participants will be involved in the study for approximately 10 weeks. What are the possible benefits and risks of participating? Participants may not receive any direct benefit from taking part. However, some people with FND have found hypnosis helpful for managing symptoms, and participants may value contributing to research that could help improve care for others with FND in the future. Clinical hypnosis is generally considered a low-risk intervention. Some people may temporarily feel tired, light-headed, emotional, or more aware of bodily sensations. Occasionally, symptoms may briefly worsen. Some questionnaire or interview questions may also bring up difficult thoughts or feelings. Participants can pause or stop any part of the study at any time without affecting their usual care. Where is the study run from? The study is being run through the specialist FND service at Royal Preston Hospital, part of Lancashire Teaching Hospitals NHS Foundation Trust, in collaboration with Lancaster University. When is the study starting and how long is it expected to run for? September 2026 to June 2027. Who is funding the study? The study is funded by Lancashire Teaching Hospitals NHS Foundation Trust (UK). Who is the main contact? Chief investigator: Dr Daniela Di Basilio Lancaster University, d.dibasilio@lancaster.ac.uk Principal investigator: Dr Abhijit Das Royal Preston Hospital, abhijit.das@lthtr.nhs.uk Clinical Global Impression – Improvement scale (CGI-I) a brief, clinician-rated tool that asks the treating professional to judge how much a patient’s condition has improved or worsened relative to baseline on a 7-point scale (from “very much improved” to “very much worse”). Because it is simple, fast, and applicable across diagnoses, it is widely used in neurological and FND-related practice to provide a standardised, global measure of treatment response in both clinical care and research settings T1 (baseline), T2 (week 10), T3 (week 14) Ethics approval required HRA Proportionate Review Service

2nd Floor, 2 Redman Place

London United Kingdom E20 1JQ 26/PR/0366 10.1186/ISRCTN59168898 361289 361289 Observational Prospective, longitudinal, mixed-methods observational cohort study 2027-06-30T00:00:00.000Z United Kingdom England Royal Preston Hospital Laboratory

Royal Preston Hospital Sharoe Green Lane Fulwood

Preston England PR2 9HT 693U0@2.16.840.1.113883.2.1.3.2.4.18.48 false 1. Diagnosis: Confirmed diagnosis of FND by a neurologist or specialist in the FND service (e.g. motor or sensory functional symptoms) 2. Age: Adults aged 18 years or above 3. Location of care: Currently a patient at the FND service (Lancashire Teaching Hospitals) or referred to this service for treatment 4. Consent capacity: Capable of giving informed consent to participate, and able to comply with study procedures (e.g. completing questionnaires and attending or participating in therapy sessions) 5. Language: Sufficient proficiency in English to understand the Participant Information Sheet (PIS), give consent, and engage in therapy and interview (as all materials and sessions will be conducted in English) Mixed 18 Years 99 Years All 40 0 1. Serious comorbid conditions: Presence of severe unmanaged physical or mental health conditions that would interfere with participation. For example, an active severe neurological disease other than FND, or severe psychiatric disorders (such as psychosis or significant cognitive impairment) that impair the ability to engage in hypnotherapy or complete questionnaires. These could confound results or pose safety/consent issues 2. Inability to consent or communicate: Individuals who lack capacity to give informed consent or who cannot participate in research activities due to communication barriers (e.g. non-English speakers without available translation, or those with severe language or cognitive barriers) will be excluded 3. Concurrent participation in conflicting research: Participants enrolled in another interventional clinical trial or research study that could conflict with this intervention’s outcomes will be excluded, to avoid confounding effects 4. Declines hypnotherapy: Patients who, after discussion and/or after trying an initial session of hypnotherapy, are unwilling to undergo hypnotherapy treatment would not be suitable, since the intervention is central to the study 2026-09-17T00:00:00.000Z 2027-04-30T00:00:00.000Z Functional Neurological Disorder (FND) Nervous System Diseases Participants with a confirmed diagnosis of Functional Neurological Disorder (FND) who are receiving, or are due to receive, clinical hypnosis as part of routine care at the Royal Preston Hospital FND service will be invited to take part. After reviewing the participant information sheet and providing electronic informed consent through REDCap, participants will complete baseline questionnaires before their first hypnosis session (T1). Participants will then receive three face-to-face clinical hypnosis sessions delivered fortnightly over approximately 6 weeks, with each session lasting around 45 to 60 minutes. At the end of the third session (T2), participants will complete a second set of questionnaires assessing symptoms, well-being, functioning, and treatment experiences. Four weeks after T2, participants will be contacted to complete a final follow-up questionnaire (T3). Information on any additional hypnosis sessions received during the follow-up period will also be recorded. A subset of approximately 10 to 15 participants who have consented to the qualitative component may also be invited to take part in a single semi-structured interview lasting approximately 30 to 60 minutes, conducted by telephone or Microsoft Teams, to discuss their experiences of clinical hypnosis. Total duration of observation: approximately 10 weeks (baseline to 4-week follow-up) Total duration of follow-up: 4 weeks (from post-treatment assessment at T2 to follow-up assessment at T3) Behavioural Not expected to be made available Protocol

Consent Form Stage One (Survey)

Consent Form Stage Two (Interview)

Stage One Evaluation of Intervention (Survey)

Stage Two (Interviews)

2b45befc-5c31-4d2b-8e4e-7464fb994a07 9a75dab9-f772-4d5c-bc62-f43d76c6f041 f5232835-8f26-4fe8-bf4d-df99feacadaa 1b08283b-1b13-4d9b-937e-a51c7b7ffa84 No Protocol file 50304 Study Protocol_FND and Hypnotherapy_Mixed-methods Feasibility Trial_v1.0_27Mar26.pdf b0caedb0-ff33-40d6-9e7e-513a172a6da4 true application/pdf 310212 fb8cbaab3325725a13ed8b8ef94a93fc Consent Form Stage Two (Interview) 50304 Consent Form_Stage Two (Interview)_v1.0_23Feb26.pdf d1f09bd3-be8f-4002-8d70-31e3f1de91af true application/pdf 67511 9c6c91ee688f4cf21291a4b8791db9da Consent Form Stage One (Survey) 50304 Consent Form_Stage One (Survey)_v1.0_23Feb26.pdf 72993ac9-37c2-426e-9c3e-d82c1ba90fb2 true application/pdf 69805 b5b5421e401f364ad0d8cab5afb16149 Stage Two (Interviews) 50304 PIS_Stage Two (Interviews)_v1.1_01May26.pdf 83065fec-7285-4288-9e45-5c0d96066017 true application/pdf 117537 e9465c95cfec5bad30f2bb002ce5d769 Stage One Evaluation of Intervention (Survey) 50304 PIS_Stage One_Evaluation of Intervention (Survey)_v1.1_01May26.pdf 90766b24-5774-487f-800b-5c88476acae7 true application/pdf 102444 fd15b7dda1cae50d5d27efeb505226ce Abhijit Das https://orcid.org/0000-0001-8800-8047 Principal investigator

Royal Preston Hospital Sharoe Green Lane

Preston United Kingdom PR2 9HT +44 1772523896 abhijit.das@lthtr.nhs.uk Public Daniela Di Basilio Scientific Public

Clinical Psychology Health Innovation One Sir John Fisher Drive Lancaster University

Lancaster United Kingdom LA1 4AT +44 1772523895 d.dibasilio@lancaster.ac.uk Public Lancashire Teaching Hospitals NHS Foundation Trust https://ror.org/02j7n9748 Non-commercial Lancashire Teaching Hospitals NHS Foundation Trust 94481360 true A link work intervention to support dental visiting in people with severe mental health difficulties: The mouth matters in mental health effectiveness and cost-effectiveness trial To evaluate the effectiveness and cost-effectiveness of a link work intervention for supporting people with severe mental illness to attend a planned dental appointment. There are two main outcomes, namely: i) attendance at a routine dental appointment; and ii) oral health quality of life. It is hypothesised that: 1. The link work intervention plus treatment as usual (TAU) will lead to greater likelihood of attendance at a planned dental appointment, compared with TAU alone. 2. The link work intervention plus TAU will lead to better oral health quality of life, compared with TAU alone. 3. The link work intervention plus TAU will be cost-effective compared with TAU alone. Background and study aims Severe mental illness affects around 1% of people. It includes depression, psychosis, and bipolar disorder. People with severe mental illness often have problems with their teeth and gums. For example, they are more likely to have missing and decayed teeth. This can affect everyday activities like eating, speaking, and smiling. It can place extra stress and burden on people living with severe mental illness. Dentists can treat teeth and gum problems. However, people living with severe mental illness often find attending a dentist difficult. This can be for many reasons. People can feel helpless, anxious, and fearful about attending. They can find it difficult to book, plan, and get to appointments. They may also struggle to pay or arrange access to free dental care. Current dental initiatives do not help people with severe mental illness to attend the dentist. We recently conducted a small trial where link workers helped people with severe mental illness to attend a dentist. This is called a link work intervention. Everyone taking part received their usual care, but half also received the link work intervention. We were able to recruit people to take part. We were able to follow people up over time. People liked and engaged with the intervention. The findings suggested that the link work intervention might help people to see a dentist and improve their quality of life. We want to test the intervention on a larger scale. We want to see if it will lead to better outcomes. We also want to see how much the intervention costs. We want to do this across five NHS sites. We aim to recruit 480 people to take part. Who can participate? People aged 18 years and older with a severe mental health difficulty currently accessing secondary care mental health services at the point of referral (e.g. community mental health team, early intervention for psychosis service), but who have not had a routine dental appointment in the past 3 years. What does the study involve? Participants will be randomly allocated to receive treatment as usual or treatment as usual plus the link work intervention. This will be decided by chance. The researchers will measure how often people in both groups visit the dentist. They will also assess their mental and oral health. They will collect this data when people come into the study and after 9 months. The team will offer interviews to patients receiving the link work intervention to understand how they found it. What are the possible benefits and risks of participating? The intervention aims to support people to access dental services. However, the effectiveness of the intervention is unknown, which is the reason for doing the research. Where is the study run from? Lancashire and South Cumbria NHS Foundation Trust (UK) When is the study starting and how long it is expected to run for? The research started in November 2025 and finishes in July 2029. We hope to open recruitment in May 2026. Who is funding the study? The National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research (HS&DR) Who is the main contact? Dr Jasper Palmier-Claus; j.palmier-claus@lancaster.ac.uk Attendance at a planned dental appointment data from the NHS Business Services Authority (BSA) 9-months Oral health related quality of life Oral Health Impact Profile - 14 item version (OHIP-14) 9-months Self-reported attendance at a planned dental appointment (private or NHS) self-report items 9-months Orofacial pain & disability Manchester Orofacial Pain Disability Scale 9-months Confidence around dental visiting a self-report item 9-months Self-esteem the Rosenberg Self-Esteem Scale 9-months Dental anxiety the Modified Dental Anxiety Scale 9-months Depression the Patient Health Questionnaire 9-months General anxiety the Generalised Anxiety Disorder Questionnaire (GAD-7) 9-months The number of planned dental appointments attended NHS Business Services Authority (BSA) data assessed 9-months Self-reported access to free/subsidised dental care self-report items 9-months Exemption status for dental care the NHS Business Services Authority (BSA) 9-months Completion of a course of dental treatment the NHS Business Services Authority (BSA) 9-months Self-reported utilisation of urgent or emergency dental services self-report items 9-months Quality adjusted life years the European Quality of Life Five-Dimensional Questionnaire (EQ-5D-5L) 9-months Utilisation of healthcare resources a co-designed health economics questionnaire 9-months Ethics approval required East Midlands - Leicester Central Research Ethics Committee

2 Redman Place Stratford

London United Kingdom E20 1JQ 26/EM/0030 10.1186/ISRCTN94481360 350197 CPMS: 65077, NIHR: 171340 350197 65077 171340 Interventional Randomized controlled trial Blinded (masking used) Uncontrolled Parallel Prevention Treatment Not applicable 2029-07-31T00:00:00.000Z United Kingdom England Lancashire and South Cumbria NHS Foundation Trust

The Lantern Centre Vicarage Lane Fulwood

Preston England PR2 8DW Greater Manchester Mental Health NHS Foundation Trust

Prestwich Hospital Bury New Road Prestwich

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

225 Old Street

Ashton-under-lyne England OL6 7SR 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 South London and Maudsley NHS Foundation Trust

Bethlem Royal Hospital Monks Orchard Road

Beckenham England BR3 3BX RV5@2.16.840.1.113883.2.1.3.2.4.18.48 false 1. Aged ≥18 years. 2. Receipt of care from community mental health or early intervention teams at the point of referral. 3. No routine dental appointment (e.g. high street dentist, special care dentist service) in the past three years. This would include any dental examination, diagnosis, advice or treatment (e.g. fillings, root canal, extractions, crowns, dentures, bridges) resulting from a routine (non-emergency) appointment at a dental service. We do not consider emergency dental care (e.g. emergency attendance at Accident & Emergency Department or a dental hospital) within this definition, although any follow-up routine and planned appointments with a dentist would exclude the person from taking part. 4. Able to provide informed consent as determined by trained researchers in consultation with the clinical team. Mixed 18 Years 120 Years All 480 0 Current key exclusion criteria as of 27/07/2026: 1. Current inpatient status on psychiatric ward. This does not include people in rehabilitation homes or supported accommodation in the community. 2. Immediate risk to self or others operationalised as the presence of active intent or planning to harm oneself or others in the near future (e.g. next month), or a suicide attempt in the past month (e.g. life-threatening self-harm, overdose). Where individuals are excluded on this basis, with the person’s consent, the researcher will aim to re-contact them and/or the referrer in approximately one-months’ time to determine if risk has subsided to a point where they are now eligible. 3. Enrolled in another dental randomised controlled trial. Previous key exclusion criteria: 1. Current inpatient status on psychiatric ward. This does not include people in rehabilitation homes or supported accommodation in the community. 2. Immediate risk to self or others operationalised as the presence of active intent or planning to harm oneself or others in the near future (e.g. next month). Where individuals are excluded on this basis, with the person’s consent, the researcher will aim to re-contact them and/or the referrer in approximately one-months’ time to determine if risk has subsided to a point where they are now eligible. 3. Enrolled in another dental randomised controlled trial. 2026-05-01T00:00:00.000Z 2028-04-30T00:00:00.000Z Access to planned dental care in people experiencing severe mental health difficulties. Oral Health Treatment as usual arm: Treatment as usual will include any treatments or services that the participant would normally have access to outside of the trial. For people with severe mental illness this may include support from a care coordinator, support worker, psychologist, occupational therapist, and/or psychiatrist for care around their mental health. Treatment as usual may include medication and case management. We will monitor, rather than withhold, assessment and treatment for oral health in the treatment as usual arm. Treatment as usual plus a link work intervention. Participants in this arm will receive treatment as usual plus the link work intervention. This will consist of six sessions with a link worker over nine-months who will offer practical and emotional support around accessing a routine dental appointment. A mental health link work intervention uses link workers to empower and assist people with severe mental illness currently supported by secondary care mental health services, but not dental services, to access planned dental appointments. Participants will be randomly allocated to one of the two groups with 1:1 ratio, stratified by site. We will follow-up both arms after nine-months. Behavioural Only the direct research team will have access to personal data of participants. Study material and data may be accessed by individuals from the participating Universities and National Health Service (NHS) Trusts, or regulatory authorities for auditing and monitoring purposes. Following publication of the trial results, we will make suitable arrangements for anonymised data to be available from the research team, in line with NIHR data sharing guidance. Available on request 098b0003-76ca-4de4-9c31-84b58d7cfe5d f8480b29-5591-45a0-9934-aa88d1c18500 edc124e0-4d1e-4dbe-bd4c-502b06ad7262 Yes Jasper Palmier-Claus https://orcid.org/0000-0002-4908-2137 Principal investigator Scientific Public

Health Innovation Campus Lancaster University

Lancaster United Kingdom LA14YW +44 (0)1524 65201 J.Palmier-Claus@lancaster.ac.uk Public Lancashire and South Cumbria NHS Foundation Trust Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 86380183 true Understanding the Wellbeing and Support Needs of Carers of Parents with Bipolar PPB Rationale: This study will explore the social care support needs of partners of parents with BD, in a cost-effective manner, by carrying out the study alongside an existing national project evaluating a digital intervention for parents with bipolar disorder (Integrated Bipolar Parenting Intervention, IBPI: https://www.isrctn.com/ISRCTN15962574). It will benefit from the recruitment infrastructure of the IBPI study with additional recruitment through self-referral and our social care and third sector partners. This work will increase understanding of carers’ wellbeing and support needs (including access to Care Act assessments) as well as the relationships between these and carer sociodemographic and clinical factors. This information will raise awareness of what carers need to help them flourish in these roles and improve social care practice in relation to these individuals. Aim: The aim of this study is to understand and address the wellbeing and support needs of partner carers of parents with bipolar. Towards this aim, we will pursue the following objectives: Objectives Work Package 1 (WP1): Online survey • To determine levels of and factors associated with carer wellbeing. • To determine carers’ needs for support including experiences of Care Act assessments. Work Package 2 (WP2): Qualitative interviews • To understand in depth the experiences of carers with respect to their wellbeing and support needs and how they intersect. Work Package 3 (WP3): Co-design • To create an impactful toolkit on identifying and addressing carers’ needs for frontline social care workers. Updated 08/06/2026: • To create two impactful toolkits identifying and addressing carers’ needs for (i) frontline social care workers and (ii) carers Outcomes WP1 will address these objectives using survey methodology and a combination of bespoke questions and standardised questionnaires. WP2 will address this aim through semi-structured qualitative interviews sampled for diversity of carer experience from participants in WP1. WP3 will address this objective through coproduction and implementation of a toolkit informed by WP1 and 2. Background and study aims Bipolar disorder is a common severe mental health issue. Many people living with bipolar disorder are parents. The extreme changes in mood which people with bipolar experience can make both parenting and day-to-day life difficult. Often parents with bipolar are cared for by their partners, who are also co-parenting their children. These partner carers experience many emotional and practical impacts, but there is little research on the specific well-being and support needs and experiences of partner carers. This research aims to understand the needs and experiences of partner carers. Our goal is to find out what needs partner carers have, how they want these needs addressed, and what influences these needs. We will use this information to work with carers and professionals to develop a toolkit to improve social care for these carers. Who can participate? Partners of a parent with bipolar, people living with a partner and child with bipolar and parents with bipolar who have at least one child, up to 18 years old, for whom they have parental responsibility. What does the study involve? The study will include three work packages (WP): WP1: Survey - This will measure well-being, support needs, and experiences with Care Act assessments of 98 partner carers. WP2: Interviews - We will interview 30 partner carers to gain deeper insights into their experiences WP3: Toolkit Development - Based on our survey and interview findings, we will co-produce a toolkit for social care workers about the needs of partner carers, working with 10 carers and 10 professionals. We will also co-produce a toolkit for carers, working with 10 lived experience experts and 10 professionals. Patient and Public Involvement: A member of our team with lived experience as a carer will lead on coordinating input from partner carers throughout the project. He will form a carer reference group which will meet at the beginning of the study and monthly throughout input into how the study is run and how the results are shared. Dissemination: The toolkit is a key output, which will help social care workers better support carers of parents with bipolar. What are the possible benefits and risks of participating? Participation in the survey may cause some emotional distress, as participants are asked to reflect on the challenges of supporting their partner and on their own mental health. To minimise this risk, survey questions were developed in collaboration with the Carer Reference Group (CRG) members who have lived experience. Based on their feedback, we provided clear explanations for why each question is asked and removed a question relating to carers’ hospitalisation history. If participants do experience distress, support resources are provided in the participant information sheet, including organisations such as Mind, Bipolar UK, the Samaritans, and NHS 111 for urgent support. Parenting- and caring-specific resources are also included, informed by CRG feedback. Participants may also experience distress during interviews, as sensitive issues may be discussed. Interviews will be conducted by an experienced researcher who will offer breaks, remind participants that they may choose not to answer any question, and reinforce their right to withdraw at any time. The interview participant information sheet includes the same support resources. Some participants may find taking part inconvenient or time-consuming, particularly for interviews and workshops. To reduce burden, all study activities will be conducted remotely, the survey will be accessible 24/7, allowing participants to complete it at their own pace. Vouchers will be provided for participation in each work package as a token of appreciation. Where is the study run from? Lancaster University, UK. When is the study starting and how long is it expected to run for? The recruitment for the study started in January 2026 and will continue until April 2027. All study activities will end on 30th June 2027 Who is funding the study? National Institute for Health and Care Research (NIHR), UK. Who is the main contact? Prof Stephen Jones, s.jones7@lancaster.ac.uk Carer wellbeing and support needs survey, interview a single timepoint Wellbeing, anxiety, depression, carer wellbeing and support and loneliness standardised measures of wellbeing (Warwick-Edinburgh Mental Wellbeing Scale), anxiety (GAD-7; Generalised Anxiety Disorder 7-item), depression (PHQ-8; Patient Health Questionnaire depression scale), carer wellbeing and support (Carer Wellbeing and Support Measure), and loneliness (using the ONS-recommended UCLA Loneliness Scale and a Direct Loneliness Question from the Community Life Survey) a single timepoint Ethics approval required East Midlands - Leicester South Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1J 25/EM/0245 10.1186/ISRCTN86380183 337057 CPMS: 59659, NIHR: 207571 337057 59659 207571 Observational A sequential mixed-methods study with a survey, interviews, and co-design workshops 2027-06-30T00:00:00.000Z United Kingdom England Lancashire and South Cumbria NHS Foundation Trust

LSCFT HQ, Sceptre Point, Sceptre Way Walton Summit, Bamber Bridge

Preston England PR5 6AW false 1. Age >= 18 years 2. Partner of a parent with bipolar 3. Living with partner and child 4. Parent with bipolar has at least one child, up to 18 years old, for whom they have parental responsibility. 5. Living in the UK Mixed 18 Years 100 Years All 98 0 1. Live outside of the UK. 2. Live separately from their partner or child. 3. Do not understand written English. 4. Do not have computer literacy skills required to complete the online questionnaire. 2026-01-08T00:00:00.000Z 2027-04-30T00:00:00.000Z • Partner of a parent with bipolar • Living with partner and child • Parent with bipolar has at least one child, up to 18 years old, for whom they have parental responsibility. Mental and Behavioural Disorders We will use both a quantitative survey and qualitative interviews to explore rates of use and experiences of carer’s assessments, as well as support needs and wellbeing. Survey: Our recruitment target for the survey is 98 participants. Participants will complete the survey online. It will be developed and hosted on the online survey software REDCap (Research Electronic Data Capture), which the research team has used previously an ongoing trial (IBPI trial). It will be a cross-sectional survey, so participants will complete the survey once. The survey has been designed with our Carer Reference Group to ensure it is focussed on relevant factors to them, and that it is written in accessible language. The survey includes questions on social demographic information of the carer and their family, including the carer’s age, gender, ethnicity, education, geographical location, and duration of caring. The survey will also ask about their partner’s and their child’s sociodemographic information, including age, gender, ethnicity and diagnoses and recent healthcare usage. These questions will be included to help characterise the sample, which will be used during interview sampling, as well as to explore the relationships between these factors and experiences of wellbeing, depression, and anxiety. The survey also includes questions on knowledge and experiences of Carer’s assessments. These questions will explore whether participants know what a carer’s assessment is and how to access one, and whether they have had one. If so, questions will ask to what extent it met their needs for support and their satisfaction with the process. Overall, this will help us to understand the proportion of this group who are accessing these assessments and what impact they have had. The survey will also include standardised measures of wellbeing, anxiety (GAD-7), depression (PHQ-8) and carer wellbeing and support. Using standardised measures will help us to compare this sample with other groups from other research. There will be questions on what support the participant feels they need, with open-ended response textboxes. Responses to these questions can be explored further during the interview and toolkit development. Finally, there will opportunity for the participant to consent to being invited to an interview and/or to the co-design workshops, or to request not to be contacted. Participants will also be able to opt-in to receiving a summary of the results after the study finishes. Interviews: Our recruitment target for the interviews is 30 participants. Participants will take part in interviews over phone or via video call, depending on their preference. The interviews are expected to last up to an hour, and will be recorded using an encrypted voice recorder. The research assistant (RA), who will be employed by Lancashire and South Cumbria NHS Foundation Trust, will be experienced in interviewing. They will prepare for these interviews by conducting practice interviews with other members of the research team, and with a member of the carer reference group. The RA will conduct the interviews in a semi-structured manner, using a topic guide but allowing participants to explore specific areas of importance to them. The topic guide will be co-developed with the Carer Reference Group, and will be informed by participant responses to the survey. Co-design workshops Our recruitment target for the workshops are 10 partners of parents with bipolar, and 10 social care workers. Each group will meet over five 2-hour sessions to co-design a resource for social care workers, providing guidance for supporting the partners of people with bipolar. Each session will be held online through video conferencing software. Updated 08/06/2026: Our recruitment target for the social care toolkit workshops are 10 partners of parents with bipolar, and 10 social care workers. Each group will meet over five 2-hour sessions to co-design a resource for social care workers, providing guidance for supporting the partners of people with bipolar. Our recruitment target for the carer’s toolkit workshops are 10 lived experience experts and 10 social care workers. Each group will meet for two 2-hour sessions to co-design a resource for carers, providing guidance on the support available for partners of people with bipolar. Each session will be held online through video conferencing software. Other The datasets generated during the current study will be stored in a publicly available repository (Lancaster University Research Directory (Pure Portal: https://portal.lancaster.ac.uk/ask/pure/)). Survey data: The anonymised .csv survey dataset and codebook will be stored on the Lancaster University PURE repository for a minimum of 10 years. This will be available for research purposes under controlled access, after approval from the CI or delegated individual. Interview transcripts: The anonymised survey transcripts in .docx format will be archived on the Lancaster University PURE repository but will be a closed dataset due to the potentially identifying nature of the narratives. A collection of quotes from the interviews will also be stored on PURE and will be available on request with approval from the CI or delegated individual. Co-design workshop filed noted: The anonymised fieldnotes from the codesign sessions will also be stored on PURE and will be available on request with approval from the CI or delegated individual. Stored in publicly available repository Protocol

39bfe005-e33d-4ede-9f95-8d7c56400d42 fa1a4d4c-6ad6-49e9-bd50-55588ac04685 fba68a01-e122-4da2-bd9f-0b449ed4b993 9fe7e92f-7f6d-4874-ba7c-1e65b0035a73 Yes Protocol file 48724_PROTOCOL_V1.1_06Nov2025.docx a2272174-0268-46ce-afdd-be9a2b5223d1 true application/vnd.openxmlformats-officedocument.wordprocessingml.document 410240 7bfb58aad11bae6a0dffad32e5b6cc08 Protocol file ISRCTN86380183_Protocol_V2.1_27Apr26.pdf 9ff698ab-93f2-4f1a-aa32-4a0e51ad8836 true application/pdf 772128 e8270a041e71e547a9462405002b9dfa Steven Jones Principal investigator

Lancaster University Health Innovation One Sir John Fisher Drive

Lancaster United Kingdom LA1 4AT +44 01524593382 s.jones7@lancaster.ac.uk Public Ragin John Public Scientific

Lancashire & South Cumbria NHS Foundation Trust The Lantern Centre, Vicarage Lane, Fulwood  

Preston United Kingdom PR2 8DW +44 1524 522391 Ragin.John@lscft.nhs.uk Public Lancaster University https://ror.org/04f2nsd36 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 24994668 true In-Touch: Implementation of a person-centered palliative care iNtervention To imprOve comfort, QUality of Life and social engagement of people with advanced dementia in Care Homes In-Touch The evidence-informed and stakeholder co-created In-Touch intervention (i.e., Namaste Care integrated with the Family Carer Decision Support (FCDS) intervention) for nursing home residents with advanced dementia effectively improves residents’ comfort and a range of other resident, family and staff outcomes. Background and study aims The In-Touch project is a research study looking at how to improve the quality of life and care for people with advanced dementia living in nursing homes, as well as support for their family caregivers. The study is testing a new approach that combines two types of support: group sessions that use gentle, sensory activities to comfort and connect with residents (based on Namaste Care), and conversations between nursing staff and family caregivers to help plan future care (based on the Family Carer Decision Support intervention). The study is taking place in seven European countries. Who can participate? Nursing homes can take part if they have at least 30 beds, are typical for their country, are within two hours of the partner university, and can recruit enough residents. Residents can take part if they have advanced dementia and a family caregiver who is involved in their care. The caregiver doesn’t need to be a legal representative. Nursing home staff and unpaid volunteers who help care for these residents can also take part. What does the study involve? Residents will be invited to take part in gentle, multi-sensory group sessions designed to bring comfort and connection. Their family caregivers will be invited to have structured conversations with nursing staff to help plan care that respects the resident’s needs and wishes. Staff and volunteers will also be involved in delivering the sessions and supporting the residents. What are the possible benefits and risks of participating? Taking part may help improve the comfort and well-being of residents with dementia. Family caregivers may feel more supported and confident in making care decisions. Staff may feel more skilled and satisfied in their work. There are no major risks expected, but some participants may find it emotional to talk about future care or end-of-life issues. Participation is voluntary, and people can stop at any time. Where is the study run from? University College Cork (Ireland) When is the study starting and how long is it expected to run for? January 2024 to December 2027 Who is funding the study? European Union Horizon programme and Innovate UK. Who is the main contact? Professor Nicola Cornally, n.cornally@ucc.ie Resident comfort assessed with the observational Discomfort Scale – Dementia of Alzheimer Type (DS-DAT) collected at baseline and at 4 time points with 3 monthly intervals over a 12 month period Collected at baseline and at 4 time points with 3 monthly intervals over a 12 month period, where applicable: 1. Quality of life is measured using the Quality of Life in Late-Stage Dementia scale (QUALID) 2. Pain is measured using the Pain Assessment in Advanced Dementia scale (PAINAD) 3. Agitation is measured using the Cohen-Mansfield Agitation Inventory – Short Form (CMAI-SF) 4. Neuropsychiatric symptoms are measured using the Neuropsychiatric Inventory – Nursing Home version (NPI-NH) 5. Social engagement is measured using Resident Daily Activity Logs at baseline, and continuous for 12 months 6. Psychotropic medication use is measured using medication administration records 7. Adverse events (pressure ulcers, infections, and hospital transfers) are measured using clinical records 8. Care planning is measured using Chart Extraction Tool and Family Meeting Activity Logs at baseline and continuous for 12 months 9. Decisional conflict is measured using the Decisional Conflict Scale 10. Anticipatory and post-death grief are measured using the Prolonged Grief Disorder Scale (PG-13) 11. Personal quality of life (family) is measured using the EuroQol 5-Dimension Questionnaire (EQ-5D) 12. Satisfaction with care is measured using the Satisfaction With Care – End-of-Life in Dementia scale (EOLD-SWC) 13. Perceived comfort in dying is measured using the Comfort Assessment in Dying scale (EOLD-CAD) 14. Understanding of dementia as a terminal illness is measured using a single item in the Family Survey 15. Burnout is measured using the Maslach Burnout Inventory (MBI) 16. Job satisfaction is measured using a 7-point Likert scale 17. Personal quality of life (staff) is measured using the EuroQol 5-Dimension Questionnaire (EQ-5D) 18. Attitudes and perceptions of dementia care are measured using the Person-Centred Care Assessment Tool (P-CAT) 19. Competence and communication self-efficacy are measured using the Sense of Competence in Dementia Care Staff scale (SCIDS) Ethics approval required lékařská fakulta Univerzity Karlovy Etická komise

Ruská 87/2411, 100 00 Praha 10

Prague Czech Republic Nil known UK3LF/320332/2025-1 Comitato di Bioetica di Ateneo

Via Bogino 9

Torino Italy 10123 0234986 Clinical Research Ethics Committee Of the Cork Teaching Hospitals University College Cork

Lancaster Hall 6 Little Hanover Street

Cork Ireland T12 E30P Nil known METC Oost-Nederland

Radboudumc, Philips van Leydenlaan 25 (route 348)

Nijmegen Netherlands 6525 GA 2025-18187 Komisja ds. Etyki Badań Naukowych Uniwersytetu Jagiellońskiego Collegium Medicum

31-066 Kraków ul Skawińska 8

Kraków Poland Nil known Nil known Health & Social Care Research Ethics Committee B

Office of Research Ethics Committees NI Unit 4 Lissue Industrial Estate Moira Rd

Lisburn United Kingdom BT28 2RF 25/NI/0094 10.1186/ISRCTN24994668 353731 101137270 353731 101137270 Parallel-group cluster randomized controlled trial Interventional Mixed-methods design including nested economic and process evaluation Quality of life Treatment 2027-12-31T00:00:00.000Z United Kingdom England Northern Ireland Czech Republic Ireland Italy Netherlands Poland Portugal To be added later

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- England - Health professional Resident Other 1. Nursing homes must have a typical number of beds with a minimum of 30, representing the predominant provider type in that country 2. Nursing homes must be located within a two-hour travel time from the partner university 3. Nursing homes must be able to recruit a sufficient number of eligible residents 4. Residents must have advanced dementia, defined as moderately severe to severe dementia according to FAST stage 6 or 7 5. Residents must have a family caregiver (care partner, care supporter, or advocate) involved in their care and support, including in care decisions 6. The participating adult family caregiver is not required to have legal representative status or decision-making authority for the resident 7. Nursing home staff and unpaid volunteers involved in the care of eligible residents are also included Senior All 284 0 1. Nursing homes that already provide Namaste Care or the FCDS intervention at baseline 2. Nursing homes that participate in another clinical trial or research study involving residents with dementia 3. Residents for whom there is no consenting family caregiver available to take part in the trial 4. Residents who are unable or unwilling to be brought to a common social space 5. Residents who are actively dying, with death expected in the coming days or weeks as judged by nursing home staff 6. Residents who are acutely unwell or have been recently transferred from acute care and are not well enough to participate 7. Residents who have capacity to consent and refuse to take part in the trial 2026-03-30T00:00:00.000Z 2026-08-31T00:00:00.000Z Dementia Mental and Behavioural Disorders We will conduct a two-arm, parallel-group, pragmatic, cluster-randomised controlled trial with nursing homes in each of the seven participating countries, with embedded process and economic evaluation. Care as usual and intervention will be performed at the cluster level and outcomes will be measured at the participant level. All participating nursing homes will undergo an initial baseline data collection period. Following this, intervention sites will receive training on the In-Touch program, while control sites will only receive general trial information. The intervention or care as usual will then be implemented for 12 months, by the site staff. Intervention Arm: The In-Touch intervention consists of two key components: 1. In-Touch Daily Sessions are delivered to the residents and these are sensory-based, person-centred group activities delivered by trained nursing home staff, based on the Namaste Care programme. The sessions focus on engaging residents through gentle touch, soothing music, aromatherapy, meaningful activities, and social interaction to improve their comfort and quality of life. Sessions will ideally take place twice daily for two hours in a designated, calm space within the nursing home over a 12-month period. 2. In-Touch Family Meetings occur with the family members and are structured discussions facilitated by trained staff, using the Comfort Care Booklet, to guide the conversation on shared decision-making about the resident’s care. The meetings help families understand the progression of dementia, discuss preferences for current and future care, and facilitate advanced care planning. The meetings will take place twice during the study for family members of residents enrolled in the intervention arm of the cRCT. Control Arm: Residents in the control nursing homes will receive care as usual and will not be excluded from the normal psychosocial activity of the nursing home or any other care/therapy interventions recommended for them. Care as usual will be described for each control site as part of the baseline situational analysis. While the primary outcome is measured at 3 months will also plan to collect data at 3 additional time points [T2, (6 months), T3 (9 months), T4 (12 months)] this is the same for both study arms. For intervention sites, there will be an additional 6 months of limited data collection focused on post-trial sustainability. This extended period allows researchers to assess the long-term viability and impact of the In-Touch program beyond the initial trial phase. Randomisation will be performed using a computer-generated randomisation procedure computer randomised schedule with a 1:1 allocation ratio of nursing homes matched for size to one of the arms, intervention or care as usual. The randomisation will be provided by a statistician who is not part of the In-Touch team, based in the Health Research Board Clinical Research Facility at University College Cork. Behavioural The quantitative non-identifiable resident-level raw and processed data will be made findable and shared for reuse and/or verification. Staff data when sufficient numbers or omitting characteristics ensures non-identifiability. Codebooks and questionnaires / eCRF in Castor as necessary. Readme.text to explain the data and data structure. Quantitative data will be archived in Data Acquisition Collection (DAC) and/or a Research Documentation Collection (RDC) in the Radboud Data Repository (RDR), and made findable and potentially shared for reuse at EU repository Zenodo when the project ends, and also aggregate qualitative data may be considered for archiving in a repository. The pseudonymized data will be accessible in the RDR repository under restricted access by the research team, and the data may be anonymized (links to IDs destroyed) when moved to Zenodo at the end of the project. Requests for access to pseudonymized or anonymized data will be checked by the Consortium Executive Committee of In-Touch, against the conditions for sharing the data as described in the signed Informed Consent and the consortium agreement. Stored in non-publicly available repository Stored in publicly available repository

Study website Migrated from study website field

763a7f00-f2fc-49be-b2d4-88cb72e6209b db614fe5-4cf6-4514-a0d1-31386889616b 7da08277-3d92-400b-980e-09dc454ec65a f9910714-fe46-4106-b052-48c406a80e8e a0c3b9b1-42a9-4e49-8e89-70b923d39b3b 7590dfd1-5f2e-4c09-928d-8cd13ecc88d9 cc6cef79-37cf-48ec-a495-6bad7fb0cce6 73038390-e6ce-4621-8567-968c29eeb489 ec0b06d8-4aa0-4469-b173-a9b1123707da a4633169-3879-4837-b31c-4fb8380afc6e 711ac826-0739-4e28-9e00-a9cb5f6b79f7 Yes Nicola Cornally https://orcid.org/0000-0003-0644-0026 Public Scientific Principal investigator

Brookfield Health Science Complex, University College Cork

Cork Ireland T12 YN60 +353 21 4901458 n.cornally@ucc.ie Public University College Cork University/education https://ror.org/03265fv13 Non-commercial Masarykova univerzita (MUNI) University/education Non-commercial Jagiellonian University (Uniwersytet Jagielloński) University/education Non-commercial University of Turin (Università degli Studi di Torino) University/education Non-commercial Radboud University Medical Center University/education https://ror.org/05wg1m734 Non-commercial Lancaster University University/education https://ror.org/04f2nsd36 Non-commercial Queen's University Belfast University/education https://ror.org/00hswnk62 Non-commercial Universidade Católica Portuguesa University/education https://ror.org/03b9snr86 Non-commercial European Union (grant no. 101137270) Innovate UK 12744098 true ACTIVATE: A randomised Controlled evaluation of Thumos: a cognitive-behavioural InterVention for medicAl sTudEnts ACTIVATE Medical students receiving Thumos, a cognitive behavioural intervention, will have improved psychological resilience at 4 month follow up in comparison to medical students receiving services as usual. Background and study aims Medical students experience high rates of burnout and mental health distress, with approximately half reporting burnout, one-third experiencing depression, and one-tenth having suicidal thoughts. These issues are exacerbated during clinical placements and contribute to workforce attrition after qualification. Existing interventions are largely generic and show limited effectiveness. Thumos, a cognitive-behavioural therapy (CBT)-based intervention specifically tailored for healthcare professionals and students, addresses the stressful situations intrinsic to medical training and practice. This study will evaluate whether Thumos improves psychological resilience, confidence, burnout, and depression in medical students compared with services as usual (SAU). Who can participate? UK medical students in years involving clinical placements (e.g., Y4/Y5) nationally, aged 18 years and over. What does the study involve? Participants will be asked to complete a consent form and some baseline questionnaires. Random allocation will occur 1:1 to either the intervention or the control group. The intervention group will be asked to participate in a CBT intervention of two online group workshops and one individual video/phone call. The control group will continue with SAU. A follow-up questionnaire will be sent to all participants at post-intervention, 4 and 9 months. As part of the process evaluation, all participants will be asked to complete an evaluation questionnaire, and a subset of intervention participants will be invited to attend a qualitative interview. What are the possible benefits and risks of participating? Potential benefits for intervention arm participants include improved psychological wellbeing through engaging with the CBT intervention: Thumos. Risks are minimal, but for all participants, may include some emotional distress when responding to the questionnaires or discussing personal experiences in the interviews. For intervention arm participants, it is possible that the intervention may not be effective for everyone. Where is the study run from? Hull York Medical School, UK. The study will be run remotely using an online video platform. When is the study starting and how long is it expected to run for? December 2024 to March 2027 Who is funding the study? The MPS Foundation, UK Who is the main contact? Dr Judith Johnson, University of Manchester, judith.johnson@manchester.ac.uk Psychological resilience will be measured using the 6-item Brief Resilience Scale (BRS) at baseline, post-intervention, 4- and 9-month follow-up. The primary endpoint is psychological resilience at the 4-month follow-up. The following secondary outcome measures are assessed at baseline, post-intervention, 4- and 9-month follow-up: 1. Confidence in coping with adverse events measured using the Confidence in Coping with Adverse Events (CCAE) questionnaire 2. Burnout measured using the Oldenburg Burnout Inventory (OLBI) 3. Depression measured using the Patient-Health Questionnaire-9 (PHQ-9) 4. Areas of Quality of Life will be measured using the Recovery of Quality of Life-Utility Index (ReQoL-UI) 5. Self-reported sickness absence measured using two question items. The first question asks about total days lost within the past 4 weeks; the second question asks how many working or studying days specifically were lost within this timeframe. Removed 21/09/2026: 6. Support access will be measured using four question items. Four question items will be used to assess whether participants are accessing any form of psychological wellbeing service, which type of support they are accessing, when they began accessing this, and when they anticipate they will stop accessing this Ethics approval required University of Manchester Research Ethics Committee 1

2nd Floor, Christie Building, The University of Manchester, Oxford Road

Manchester United Kingdom M139PL 2024-21589-38791 10.1186/ISRCTN12744098 TMPSF2024001 TMPSF2024001 Randomized controlled parallel groups intervention trial Interventional Randomised controlled trial Efficacy 2027-03-31T00:00:00.000Z United Kingdom England Northern Ireland Scotland Wales Hull York Medical School

York Medical School Siwards Way Heslington

Hull England YO10 5DD Aston Medical School

Aston University

Birmingham England B4 7ET Barts and the London School of Medicine and Dentistry

Garrod Building, Turner St

London England E1 2AD Brighton and Sussex Medical School

94 N - S Rd, Falmer

Brighton England BN1 9PX Brunel University London

Kingston Lane

Uxbridge England UB8 3PH 10000961@2.16.840.1.113883.2.1.3.8.2.9.1 Cardiff University

Park PLACE

Cardiff Wales CF10 3AT 10007814@2.16.840.1.113883.2.1.3.8.2.9.1 City St George's, University of London

Northampton Square

London England EC1V 0HB 10001478@2.16.840.1.113883.2.1.3.8.2.9.1 Edge Hill Medical School

Edge HIll University, St Helens Rd

Ormskirk England L39 4QP Imperial College London

Exhibition Rd, South Kensington

London England SW7 2AZ Kent and Medway Medical School

Pears Building

Canterbury England CT2 7FS Keele University Medical School

David Weatherall building University Road Keele University

Staffordshire England ST5 5BG King's College London

Strand

London England WC2R 2LS Lancaster Medical School, Lancaster University

Bailrigg House, Bailrigg

Lancaster England LA1 4YE Leicester Medical School

George Davies Centre, Lancaster Rd

Leicester England LE1 7HA Lincoln Medical School

University of Lincoln Brayford Pool

Lincoln England LN6 7TS Newcastle University

-

Newcastle upon Tyne England NE1 7RU University Medical Centre

University of East Anglia Earlham Road

Norwich England NR4 7TJ RM12C@2.16.840.1.113883.2.1.3.2.4.18.48 Queen Mary University of London

327 Mile End Road

London England E1 4NS 10007775@2.16.840.1.113883.2.1.3.8.2.9.1 Queen's University of Belfast

University Road

Belfast Northern Ireland BT7 1NN 10005343@2.16.840.1.113883.2.1.3.8.2.9.1 University of Dundee

ScotGEM (University of St Andrews and University of Dundee), Nethergate

Dundee Scotland DD1 4HN Swansea University Medical School

Institute of Life Science 2, Sketty

Swansea England SA2 8QA University of Ulster

Cromore Road

Coleraine Northern Ireland BT52 1SA 10007807@2.16.840.1.113883.2.1.3.8.2.9.1 University College London

Gower St

London England WC1E 6BT University of Aberdeen

Regent Walk

Aberdeen Scotland AB24 3FX 10007783@2.16.840.1.113883.2.1.3.8.2.9.1 University of Birmingham

-

Birmingham England B15 2TT University of Bristol

Senate House Tyndall Avenue

Bristol England BS8 1TH 10007786@2.16.840.1.113883.2.1.3.8.2.9.1 University of Buckingham

Yeomanry House Hunter Street

Buckingham England MK18 1EG 10007787@2.16.840.1.113883.2.1.3.8.2.9.1 University of Cambridge

The Old School Trinity Lane

Cambridge England CB2 1TN 10007788@2.16.840.1.113883.2.1.3.8.2.9.1 University of Central Lancashire

Fylde Rd

Preston England PR1 2HE University of Chester

Parkgate Road

Chester England CH1 4BJ 10007848@2.16.840.1.113883.2.1.3.8.2.9.1 University of Dundee

Perth Road

Dundee Scotland DD1 4HN 10007852@2.16.840.1.113883.2.1.3.8.2.9.1 University of Edinburgh

Old College South Bridge

Edinburgh Scotland EH8 9YL 10007790@2.16.840.1.113883.2.1.3.8.2.9.1 University of Exeter

Stocker Road

Exeter England EX4 4PY 10007792@2.16.840.1.113883.2.1.3.8.2.9.1 University of Glasgow

University Avenue

Glasgow Scotland G12 8QQ 10007794@2.16.840.1.113883.2.1.3.8.2.9.1 University of Leeds

Woodhouse Lane

Leeds England LS2 9JT 10007795@2.16.840.1.113883.2.1.3.8.2.9.1 University of Leicester

University Road

Leicester England LE1 7RH 10007796@2.16.840.1.113883.2.1.3.8.2.9.1 University of Liverpool

Foundation Building, 765 Brownlow Hl

Liverpool England L69 7ZX University of Manchester

Oxford Rd

Manchester England M13 9PL University of Nottingham

University Park

Nottingham England NG7 2RD 10007154@2.16.840.1.113883.2.1.3.8.2.9.1 University of Oxford

University Offices

Oxford England OX1 2JD 10007774@2.16.840.1.113883.2.1.3.8.2.9.1 University of Portsmouth

University House

Portsmouth England PO1 2UP 10007155@2.16.840.1.113883.2.1.3.8.2.9.1 University of Sheffield

Western Bank

Sheffield England S10 2TN 10007157@2.16.840.1.113883.2.1.3.8.2.9.1 University of Southampton

University Road

Southampton England SO17 1BJ RW1YS@2.16.840.1.113883.2.1.3.2.4.18.48 University of St Andrews

College Gate North Street

St. Andrews Scotland KY16 9AJ 10007803@2.16.840.1.113883.2.1.3.8.2.9.1 University of Sunderland

Chester Road

Sunderland England SR1 3SD 10007159@2.16.840.1.113883.2.1.3.8.2.9.1 University of Surrey

Stag Hill Campus

Guildford England GU2 7XH 10007160@2.16.840.1.113883.2.1.3.8.2.9.1 University of Warwick

University House Gibbet Hill Road

Coventry England CV4 7AL 10007163@2.16.840.1.113883.2.1.3.8.2.9.1 University of Worcester

Henwick Grove

Worcester England WR2 6AJ 10007139@2.16.840.1.113883.2.1.3.8.2.9.1 Health professional Learner/student UK medical students in years involving clinical placements (e.g., Y4/Y5) nationally. We will recruit from these groups for the main trial until the recruitment target is reached Mixed 18 Years 100 Years All 220 232 Not meeting the participant inclusion criteria 2025-06-16T00:00:00.000Z 2026-04-30T00:00:00.000Z Improvement of psychological resilience in UK medical students Mental and Behavioural Disorders UK medical students in clinical placement years will be randomised 1:1 to receive either Thumos (a CBT intervention of two online group workshops and one individual video/phone call) or Services As Usual (SAU). Assessments will occur at baseline, post-intervention, 4-month, and 9-month follow-up. A mixed-methods process evaluation will assess acceptability and implementation with CBT therapists and medical educators from participating medical schools. Both control and intervention arm students will be invited to complete process questionnaires; only intervention arm medical students will be invited to take part in qualitative interviews. The study will invite UK medical educators from medical schools with participating students within the intervention arm to qualitative interviews as part of the process evaluation. It will also invite the cognitive behavioural therapists/clinical psychologists delivering the intervention to participate in qualitative interviews as part of the process evaluation. Added 11/06/2025: Participants will be randomised using simple 1:1 allocation via the Sealed Envelope platform, which generates the allocation sequence and maintains allocation concealment to ensure investigators remain blinded to treatment assignment. With 220 participants undergoing individual-level randomisation, simple randomisation is expected to achieve adequate balance between treatment arms without the need for blocking or stratification. Any post-randomisation covariate imbalances will be addressed through standard statistical adjustment methods during analysis. Behavioural The datasets generated during and/or analyzed during the current study will be stored in a publicly available repository: University of Manchester research repository - (https://figshare.manchester.ac.uk/) Available on request Stored in publicly available repository Protocol

342c59ca-a6b7-4482-872e-ca64a049d4e2 8c68d346-19a5-4c2f-880d-9102b189a0b1 4824f0b0-b8e7-45f3-9f39-fe22f53f1e24 Yes Protocol file ISRCTN12744098_Protocol_V2.3_15Jan2026.pdf 807b2256-9211-4590-8c68-15fe5938366f true application/pdf 918458 b959b1d5f837a16120d4f86718731d16 Statistical Analysis Plan ISRCTN12744098_SAP_V0.6_16Dec2025.pdf 832927a6-44d3-4ea7-9010-daa09edd0570 true application/pdf 918453 f65414e0b522102b3562747ea7c733b2 Statistical Analysis Plan ISRCTN12744098_SAP_V1.pdf 9fe9922c-3b8a-4ea3-9e75-db6625835ed7 true application/pdf 708416 2f30dfae2e6ecb83c0bac1caf6cb3706 Judith Johnson https://orcid.org/0000-0003-0431-013X Public Scientific Principal investigator

University of Manchester Jean McFarlane Building 176 Oxford Road

Manchester United Kingdom M13 9PY +44 (0)161 306 7811 judith.johnson@manchester.ac.uk Public University of Manchester University/education https://ror.org/027m9bs27 Non-commercial The MPS Foundation 17872625 true Evaluating CBT Bytesize: a mixed-methods feasibility trial of a blended digital CBT intervention for adolescent anxiety and low mood CBT Bytesize Current study objectives as of 08/07/2025: 1. Estimating enrolment and uptake: Measured as the proportion of eligible young people referred by NHS clinicians who were enrolled in the CBT Bytesize programme. (Target: >30% of those referred engage with the programme) 2. Assessing retention and engagement: Defined as the proportion of enrolled participants who attended at least 75% of the core intervention sessions (i.e. ≥9 out of 12 sessions). (Target: >70% session completion rate) 3. Completeness of outcome measures: Measured by the proportion of participants who completed key clinical outcome measures (RCADS, YP-CORE) at baseline and end-of-study (Target: >80% data completion across timepoints) 4. Acceptability of the intervention: Evaluated through qualitative feedback and user engagement data, including self-reported satisfaction and willingness to recommend the programme. (Target: >80% reporting satisfaction with content and format) 5. Feasibility of trial procedures: Assessed via clinician and service feedback regarding referral, delivery, and data collection processes. (Target: majority positive feedback from participating clinicians and low procedural burden) _____ Previous study objectives: Primary hypothesis: 1. CBT Bytesize will be effective in reducing anxiety symptoms in children and young people (CYP) compared to a matched historical control group receiving treatment as usual (TAU) online CBT. Secondary hypotheses: 1. CBT Bytesize will be feasible and usable for CYP, as demonstrated by adherence to the intervention protocol and positive feedback from participants and clinicians. 2. CYP participating in CBT Bytesize will report positive therapeutic experiences, including perceived support and satisfaction with the hybrid delivery model (app + therapist interaction). 3. Clinicians delivering CBT Bytesize will find the model acceptable and manageable, with insight into its adaptability, potential benefits, and challenges in routine practice. 4. Therapeutic improvements (e.g., anxiety reduction) will be maintained at 6-month follow-up among participants in the CBT Bytesize group. 5. CYP receiving CBT Bytesize will demonstrate improvement on routine outcome measures (ROMs) such as the RCADS, YP-CORE, and GBOs from baseline to post-intervention. 6. Compared to the TAU group, the CBT Bytesize group will show greater gains in specific domains such as engagement, session completion, and goal attainment. Background and study aims Anxiety is common in children and young people and can affect their daily lives, including school, family, and friendships. CBT Bytesize is a new digital mental health programme designed to make therapy more accessible by combining online self-help tools with support from a therapist. The aim of the study is to test whether CBT Bytesize is easy to use and whether it helps reduce anxiety in young people. Who can participate? The study included children and young people aged 8 to 17 who had been referred to a mental health service for anxiety-related difficulties. To take part, they needed to have access to the internet, be able to understand and speak English, and be suitable for a short course of CBT. Clinicians who delivered the CBT Bytesize programme were also invited to take part in focus groups to share their experiences. What does the study involve? Young people in the study took part in the CBT Bytesize programme, which included short online learning modules and therapist support, delivered either remotely or in person. Their progress was compared to that of similar young people who had previously received standard online CBT. Researchers looked at whether anxiety and low mood improved after completing CBT Bytesize. They also examined how many young people continued using the programme and what they thought about it. Feedback from clinicians who delivered the programme was gathered through focus groups and analysed using thematic analysis. What are the possible benefits and risks of participating? The programme may help young people manage anxiety more effectively and provide a more flexible way to access therapy. There are minimal risks, but some young people might find it challenging to engage with digital content or talk about difficult feelings. Where is the study run from? The study was coordinated by Manchester Metropolitan University and delivered in partnership with Healios Ltd, a digital mental health service provider. When is the study starting and how long is it expected to run for? December 2021 to August 2023 Who is funding the study? The study was jointly funded by Manchester Metropolitan University and Healios Ltd (UK) Who is the main contact? Dr Daniela Di Basilio, d.dibasilio@lancaster.ac.uk Current primary outcome measure as of 08/07/2025: 1. Symptoms of various anxiety disorders and low mood, measured using the Revised Child Anxiety and Depression Scale (RCADS) at baseline (T1), mid-intervention (T2) and post-intervention (T3). _____ Previous primary outcome measure: Symptoms of various anxiety disorders and low mood, measured using the Revised Child Anxiety and Depression Scale (RCADS) at baseline, post-intervention, and 6-month follow-up Current secondary outcome measures as of 08/07/2025: 1. Psychological distress and functioning measured using the Young Person’s CORE (YP-CORE) at baseline (T1), mid-intervention (T2) and post-intervention (T3). 2. Feasibility, assessed through session attendance and completion rates over the intervention period. 3. Acceptability, evaluated post-intervention using qualitative interviews and satisfaction surveys with participants (young people) and therapists. _____ Previous secondary outcome measures: 1. Psychological distress and functioning measured using the Young Person’s CORE (YP-CORE) at baseline, post-intervention, and 6-month follow-up 2. Progress toward self-identified goals measured using the Goal-Based Outcomes (GBOs) at baseline, post-intervention, and 6-month follow-up 3. Feasibility assessed through session attendance and completion rates over the intervention period 4. Acceptability evaluated using qualitative interviews and satisfaction surveys with participants and therapists post-intervention Ethics approval required Manchester Metropolitan University REC

Ormond Building, Lower Ormond Street

Manchester United Kingdom M15 6BX 34434 10.1186/ISRCTN17872625 34434 34434 Matched mixed-methods feasibility and usability trial Interventional Case-control study Diagnostic Other Prevention Screening 2023-08-01T00:00:00.000Z United Kingdom England Scotland Wales Manchester Metropolitan University

All Saints Grosvenor Square

Manchester United Kingdom M15 6BH 10004180@2.16.840.1.113883.2.1.3.8.2.9.1 Patient Service user Current inclusion criteria as of 08/07/2025: 1. Being referred to Healios by contracted NHS trusts supporting young people in the UK 2. Having anxiety symptoms/anxiety disorder(s) and low mood as the primary presentation(s). Young people with comorbidities were not excluded, as long as the primary presentation was ‘anxiety’. 3. Access to a smartphone and the Internet 4. Good level of conversational English 5. Aged 11 to 17 years 6. Willing to talk about their experiences and provide feedback on the CBT Bitesize programme _____ Previous inclusion criteria: 1. Children and young people (CYP) aged 8 to 17 years 2. Referred to a CAMHS (Child and Adolescent Mental Health Services) team for anxiety-related difficulties 3. Deemed clinically appropriate for brief cognitive-behavioural therapy (CBT) by their care team 4. Able to understand and communicate in English, sufficient to engage with the intervention and complete outcome measures 5. Have access to a device (e.g., smartphone, tablet, or computer) and the internet to engage with the digital content 6. Provided informed consent/assent (with parental/guardian consent as appropriate based on age and service policy) Child 11 Years 17 Years All 50 192 Current exclusion criteria as of 08/07/2025: 1. Presence of sight/hearing problems 2. Suicide attempts within the last three months and/or actively suicidal 3. Current safeguarding concerns, safeguarding investigations or criminal investigations 4. Not able/willing to provide assent to take part in CBT Bytesize, or parents/legal guardians not providing consent to take part in the programme. _____ Previous exclusion criteria: 1. Primary presenting difficulties that are not anxiety-related (e.g., severe depression, eating disorders, trauma, or psychosis) and are not suitable for brief CBT. 2. Level of clinical complexity or risk (e.g., high self-harm or safeguarding concerns) that would require more intensive or specialist interventions. 3. Insufficient English proficiency to understand intervention content or complete outcome measures. 4. Significant cognitive impairments or learning difficulties that would prevent engagement with the app-based or self-guided content. 5. Lack of access to a digital device or the internet, preventing full participation in the hybrid model of care. 2021-12-21T00:00:00.000Z 2023-02-01T00:00:00.000Z Anxiety disorders in children and young people Mental and Behavioural Disorders Current interventions as of 08/07/2025: The intervention group consisted of children and young people who voluntarily opted into the CBT Bitesize programme following identification from Healios’ existing waiting list to access mental health support. Clinicians screened potential participants against the inclusion/exclusion criteria. Those deemed eligible were contacted via telephone by Healios clinicians and offered the option to either remain on the waiting list or begin the CBT Bitesize programme. Comprehensive information about the intervention was also sent to families via email, and only participants who gave informed consent to participate were enrolled. A matched control group was retrospectively assembled from Healios clinical records, comprising young people who had previously received treatment-as-usual (TAU) online CBT during a comparable period. Participants in the control group were matched to those in the intervention group based on key demographic and clinical characteristics, including age, gender, type and severity of presenting difficulties. If more than one match existed for a CBT Bitesize client, one match was randomly selected. The matched young person was then removed from the sample of clients engaging with TAU to ensure that the same young person could not be a match for multiple CBT Bitesize participants. This matching procedure aimed to enhance group comparability and reduce potential confounding, acknowledging the limitations inherent in non-randomised study designs. In addition to quantitative outcome measures collected via self-report at baseline, post-treatment, and follow-up time points, the study incorporated a qualitative component to explore participants' and clinicians’ experiences of the intervention. Semi-structured interviews were conducted with young people following completion of the programme, and focus groups were held with participating clinicians. These qualitative data were analysed thematically to provide in-depth insights into the feasibility, usability, and perceived value of the CBT Bitesize intervention. This mixed-methods approach was selected to enable a comprehensive evaluation of a novel, digitally delivered CBT programme within a real-world service context, addressing both measurable outcomes and experiential factors relevant to its future scalability and implementation. _____ Previous interventions: Participants were randomised using a computer-generated random number sequence with block randomisation to ensure equal allocation. The intervention under evaluation is CBT Bytesize, a brief, hybrid-format cognitive-behavioural therapy (CBT) programme designed for children and young people (CYP) experiencing anxiety. It combines digital self-help content delivered through an online platform with therapist-guided sessions, aiming to improve accessibility, engagement, and therapeutic outcomes in routine clinical settings. CBT Bytesize includes: 1. Structured, brief CBT modules aligned with core CBT principles (e.g., psychoeducation, cognitive restructuring, behavioural experiments). 2. Interactive digital content, such as videos, exercises, and reflective tasks, tailored to a younger audience. 3. Therapist support, provided either face-to-face or via telehealth, to reinforce learning, personalise content, and maintain therapeutic engagement. 4. Typically delivered over 6–8 sessions, the programme is designed to be time-efficient while still therapeutically effective. The comparator is a matched historical control group that received treatment-as-usual (TAU) online CBT, representing standard care previously delivered by the service. TAU included more traditional CBT protocols without the streamlined, digital–hybrid enhancements of the CBT Bytesize model. Mixed The dataset generated during the current study is not expected to be made available due to the need to protect children and young people's data on sensitive topics such as their mental health. The ethical approval received for this study covers data storage and handling for the purposes of the study, but the participants and their caregivers have not given their informed consent for their personal data to be publicly shared. Not expected to be made available 265106de-ee22-4db8-9dd3-5d6cb9fe78e9 3c8eef5a-8bc4-48aa-b0e6-497286cb5a29 ae62f753-08c7-4f93-ac4d-9e455bcff94a 9c6fefb0-d059-4a99-9b06-5daee63022ab bf624eb5-182d-44f4-81f2-5d166461eb11 fcc4fe0b-f174-48a0-a469-d2e8f9959b86 fa3e7485-587c-4fc3-89d3-ef1d1a3db9ab No Daniela Di Basilio https://orcid.org/0000-0003-3786-442X Public Scientific Principal investigator

Sir John Fisher Drive Bailrigg

Lancaster United Kingdom LA1 4YW +44 (0)7312255301 d.dibasilio@lancaster.ac.uk Public Frank Burbach https://orcid.org/0000-0002-2402-3376 Public Scientific

Healios Ltd 4a Tileyard Studios Tileyard Road Kings Cross

London United Kingdom N7 9AH Protected Polly Haselton Public Scientific

Healios Ltd 4a Tileyard Studios Tileyard Road Kings Cross

London United Kingdom N7 9AH Protected Manchester Metropolitan University University/education https://ror.org/02hstj355 Non-commercial Healios Ltd Industry Commercial Manchester Metropolitan University http://dx.doi.org/10.13039/100010014 Healios Ltd 10480648 true What is the clinical and cost-effectiveness of a patient-initiated follow-up (PIFU) strategy compared to traditional care pathways in people with inflammatory arthritis treated with long-term immune-suppressing therapies? TaILOR The study aims to assess whether patient-initiated follow-up (PIFU) care is superior to standard care in terms of musculoskeletal quality of life (QoL) outcomes for patients with inflammatory arthritis. Background and study aims People with inflammatory arthritis usually require long-term treatment with arthritis drugs (medications) (though some manage without specific medication) and typically have routine follow-up appointments every 6-12 months. Some of these appointments may be unnecessary as people can be well at the time of the appointment, and people with inflammatory arthritis have told us they feel they are wasting their time and also NHS resources. NHS England has recently proposed that many people with inflammatory arthritis should no longer have routine follow-up appointments but instead be seen if and when they have a flare or need advice on managing their condition, using an approach called Patient Initiated Follow-Up or PIFU. Researchers working with the British Society for Rheumatology have produced a short video about PIFU which can be accessed via this link (https://bit.ly/3WcFDmf). They have also created a list of frequently asked questions and answers which may be helpful to read to find out more about PIFU. This can be found here: https://bit.ly/3PvfMCl. There is very little information about whether PIFU is better than routine follow-up appointments. This study aims to find out whether PIFU is better than standard routine follow-up for those with inflammatory arthritis in terms of the impact on patient’s quality of life, disease activity and what this might potentially save the NHS. Who can participate? Adults who have been diagnosed with inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, undifferentiated arthritis) for at least 2 years and whose health care team consider their disease to be generally well-controlled. Patients that have ever been on PIFU for their inflammatory arthritis, would not be eligible to take part. What does the study involve? Of those who agree to take part in the study, half will remain to have what is called standard care – this would mean that they would continue to come into the hospital approximately every 6-12 months to see their rheumatology care team, the other half will move to PIFU where they will not have any follow-up appointments made but instead be given a guide to PIFU and how to contact their care team if you need some advice or an appointment. Regardless of what treatment group they are assigned to, participants would come to the clinic for an appointment at the start of the study and again at 24 months. These visits would include a routine disease assessment and several questionnaires for completion. Participants will also be sent questionnaires at 1 week and 6, 12 and 18 months to complete at home. If participants agree, they may be invited to take part in 1-2 interviews during the study to help us understand their experience of PIFU. What are the possible benefits and risks of participating? Participants may not directly benefit from taking part in this study but they will be making a significant contribution to research to help us to understand whether PIFU or standard care is better and which patients would benefit from PIFU. It is also hoped that study results will help to understand what PIFU costs the NHS compared to regular follow-up. Where is the study run from? The University of Oxford and 30 NHS secondary sites in the UK. When is the study starting and how long is it expected to run for? April 2024 to February 2028 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK) Who is the main contact? Gretchen Brewer, tailor@ndorms.ox.ac.uk Current primary outcome(s) as of 21/04/2026: Musculoskeletal quality of life is measured using MSK-HQ at 24 months. _____ Previous primary outcome(s): Musculoskeletal quality of life is measured using MSK-HQ score over 24 months (measured at baseline, months 6, 12, 18 and 24) Current key secondary outcome(s) as of 21/04/2026: 1. Musculoskeletal quality of life is measured using MSK-HQ over 24 months. 2. Musculoskeletal quality of life is measured using MSK-HQ at 6, 12 & 18 months. 3. Overall health-related quality of life is measured using EQ-5D-5L and EQ-VAS scores at baseline, months 12 and 24. 4. Incremental cost measured using patient health resource use and costs at baseline, months 6, 12, 18 and 24. 5. Incremental cost measured using hospital-reported health resource use and costs at 12 months prior to baseline through month 24 6. Cost-effectiveness measured using Cost per quality-adjusted life year (QALY) gained over the 24-month time horizon 7. Progression from no treatment to first-line DMARD measured using the proportion of patients starting a first-line DMARD during the study 8. Progression from conventional drugs to biologic therapies measured using the proportion of patients starting a first biologic during the study 9. Disease activity is measured using disease-specific activity score (CDAI, DAS28-CRP, ASDAS, DAPSA) at baseline and 24 months 10. Disease activity is measured using the number of patient-reported flares from baseline to 24 months 11. Disease activity is measured using the number of hospital-reported flares from baseline to 24 months 12. Patient efficacy is measured using perceived efficacy in patient-physician interactions (PEPPI) score at baseline and 24 months 13. Depression is measured using PHQ-4 score at baseline and 24 months 14. Acceptability of PIFU to patients is measured using qualitative methods at Weeks 2-12 and Months 16-24. 15. Acceptability of PIFU health professionals/service providers is measured using qualitative methods once the site has been open to recruitment for at least 12 months _____ Previous key secondary outcome(s): 1. Musculoskeletal quality of life is measured using MSK-HQ score at baseline, months 6, 12, 18 and 24 2. Overall health-related quality of life is measured using EQ-5D-5L and EQ-VAS scores at baseline, months 12 and 24 3. Incremental cost measured using patient health resource use and costs at baseline, months 6, 12, 18 and 24 4. Incremental cost measured using hospital-reported health resource use and costs at 12 months prior to baseline through month 24 5. Cost-effectiveness measured using Cost per quality-adjusted life year (QALY) gained over the 24-month time horizon 6. Progression from no treatment to first-line DMARD measured using the proportion of patients starting a first-line DMARD during the study 7. Progression from conventional drugs to biologic therapies measured using the proportion of patients starting a first biologic during the study 8. Disease activity is measured using disease-specific activity score (CDAI, DAS28-CRP, ASDAS, DAPSA) at baseline and 24 months 9. Disease activity is measured using the number of patient-reported flares from baseline to 24 months 10. Disease activity is measured using the number of hospital-reported flares from baseline to 24 months 11. Patient efficacy is measured using perceived efficacy in patient-physician interactions (PEPPI) score at baseline and 24 months 12. Depression is measured using PHQ-4 score at baseline and 24 months 13. Acceptability of PIFU to patients is measured using qualitative methods at Weeks 2-12 and Months 16-24 14. Acceptability of PIFU health professionals/service providers is measured using qualitative methods once the site has been open to recruitment for at least 12 months Ethics approval required South East Scotland Research Ethics Committee 1

2nd Floor, Waverley Gate

Edinburgh United Kingdom EH1 3EG 25/SS/0004 10.1186/ISRCTN10480648 329838 CPMS: 56645, NIHR: 156922, NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC) Grant Codes: 329838 56645 156922 NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC) Grant Codes: Randomized controlled study Interventional Randomised controlled trial Treatment 2028-02-28T00:00:00.000Z United Kingdom England Northern Ireland Scotland Wales John Radcliffe Hospital

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Trust Headquarters Marlborough Street

Bristol England BS1 3NU RA7@2.16.840.1.113883.2.1.3.2.4.18.48 Patient false 1. Age 18 years or over 2. Diagnosis of inflammatory arthritis (RA, PsA, axSpA, undifferentiated arthritis) for at least 2 years 3. Stable disease: defined as a level of disease control that the physician feels is suitable for PIFU; on the same conventional, targeted synthetic or biologic DMARD(s), or no treatment, for at least the previous 3 months; and with no escalation in therapy planned 4. Able to contact the Rheumatology team when required 5. Suitable for PIFU in the opinion of their consultant 6. Willing and able to give consent and comply with study procedures Mixed 18 Years 100 Years All 438 438 1. Currently or previously on PIFU for inflammatory arthritis 2. Safeguarding/consent/capacity concerns (using General Medical Council guidance) 3. Health literacy concerns from the treating clinician related to inflammatory arthritis 4. Women who are pregnant or planning to start a family 5. Currently undergoing radiotherapy, immunotherapy or chemotherapy for malignancy 6. Patients on end-of-life care pathways 2025-03-21T00:00:00.000Z 2026-01-31T00:00:00.000Z Inflammatory arthritis Musculoskeletal Diseases The study aims to recruit 438 patients with stable inflammatory arthritis from approximately 30 centres from varied demographic areas in the UK. Patients will primarily be approached during their routine clinic visits or invited via letter ahead of their appointment. If a patient is assessed to be suitable for PIFU and is eligible and happy to join the study, informed consent will be requested ahead of study procedures. Demographic, disease and treatment history information will be collected and recorded for the purposes of the study. Clinical data from patients' routine care will also be recorded from their medical notes (disease activity score including a physical exam and CRP measurement from blood draw) as well as hospital-reported resource use. Participants will complete questionnaires to collect patient-reported outcomes. Patient-reported outcomes include questionnaires about quality of life (musculoskeletal and overall), mental health, participation in health care decisions, and management of health care. Hospital-reported resource use will be collected for the 12 months prior to baseline. No additional procedures for the purpose of the study will take place at the baseline visit. Patients will then be randomised 1:1 into either PIFU or standard care with routine remote or face-to-face follow-up appointments at 6-12 months in accordance with local practice. Patients randomised into the PIFU arm will be provided with information about PIFU and how to access rheumatology follow-up care if they become unwell due to their arthritis. The study team will not be blinded to intervention but the protocol requests, but does not insist on, a blinded assessor for participants' disease activity score which is assessed at the beginning of the start and month 24 of the study. At week 1, all patients will be asked to complete remote, self-reported questionnaires about the decision-making process relating to taking part in the study as well as questions about time spent accessing patient education materials about managing their care. At 6-8 weeks and 11 months, a member of the study team will confirm that patients have been assigned to the correct pathway (PIFU or standard care). At months 6, 12 and 18 all patients will be asked to complete remote, self-reported questionnaires to assess quality of life, costs relating to medical care for their arthritis and flare information for the previous 6 months. At 24 months, all patients will be seen in their rheumatology outpatient clinic as part of routine care for both PIFU and standard care. Patients will have been sent questionnaires to be completed remotely ahead of their visit. Clinical data from their visit will be recorded. Clinical data from patients' routine care will also be collected from their medical notes (disease activity score including a physical exam and CRP measurement from blood draw). At 24 months, hospital-reported flare information and resource use will be collected for the duration of the study. The recruitment target of 438 participants allows for a 20% crossover/dropout rate. No interim analysis is planned but an independent data monitoring committee will review data every 6-12 months. Additionally, PROMS completion rates will be reported monthly to the TMG by the trial management group. The grant includes a qualitative sub-study led by Prof Emma Dures from The University of the West of England, Bristol. She is a co-applicant on the main NIHR grant (also sponsored by Oxford University). She will lead both the anonymous survey to understand why potential participants choose not to take part in the TaILOR randomised clinical study (described in the following paragraph) and the qualitative interviews. Patients who decline the study will be offered the opportunity to complete an anonymous electronic or paper survey. The survey aims to help us understand the reasons for not wanting to take part in the study as well as understand the demographics of these patients. As this is an anonymous survey that will not be collecting identifiable information, respondents will not be consented for this activity. Sites will provide the survey to patients who decline to take part (either via e-survey or paper survey to be posted back to CTU). No personal data will be collected. The qualitative sub-study (interviews) aims to further understand the acceptability of PIFU by patients, healthcare professionals and administrators. Participants in the main study will be given the option to consent to be contacted by the qualitative team about taking part in interviews. Of those that consent to be contacted, 30-45 participants will be selected for interviews to take place at 2-12 weeks and/or 16-24 months post-randomisation. Additionally, 25 healthcare and service professionals from TaiLOR research sites will also be invited to tell us about their experiences with PIFU. These interviews will take place once the associated sites have been open to recruitment for 12 months through the last patient, and last visit. All qualitative interviews will take place over TEAMS or by telephone. Three patient partners were extensively involved in the design of the study along with a project supported by the British Society for Rheumatology to develop a PIFU manual for hospital sites as well as educational materials for patients. Patient partners were involved in the selection of primary and secondary outcomes, the main metric they wanted was 'good care' where patients were satisfied with their care and disease management. Four patient partners were involved with the development of the PIS, infographic, patient-facing letters and questionnaires. Specifically, patients provided critical feedback in the phrasing of instructions and questions of PROMS related to specific secondary outcomes. They will provide ongoing support with decisions relating to the execution of the study in relation to recruitment, site support and study burden. They will also assist in the interpretation of overall grant findings and dissemination. Other The datasets generated during and/or analysed during the current study will be available upon request from Professor Laura Coates (laura.coates@ndorms.ox.ac.uk) and the Oxford Clinical Trials Research Unit (OCTRU; octrutrialshub@ndorms.ox.ac.uk) once the study findings have been published in full and for as long as this data is useful. Participant consent was obtained for sharing with researchers or collaborators (this may include commercial organisations), in the UK and abroad; however, some specific data items may not be shared in order to maintain participant anonymity. Available on request 2026 Protocol article in https://pubmed.ncbi.nlm.nih.gov/42400057/ (added 09/09/2026) Protocol

Study website Migrated from study website field

899585df-4866-43f4-bfd6-1a87185d23a6 a39ca044-f4e7-4943-8434-068a6cf3c0f9 c9b0db53-2375-4d08-b1f1-98ea15907cbb Yes Laura Coates https://orcid.org/0000-0002-4756-663X Public Scientific Principal investigator

Botnar Research Centre University of Oxford Windmill Road Headington

Oxford United Kingdom OX3 7LF +44 (0)1865 613739 tailor@ndorms.ox.ac.uk Public University of Oxford Hospital/treatment centre https://ror.org/052gg0110 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 16655955 true Food, Pregnancy and Me: Exploring food insecurity in pregnancy in the UK to inform future public health intervention needs This study aims to explore the prevalence, experiences and health impact of FI in pregnancy in England to develop strategic recommendations for intervention strategies. Background and study aims In the UK, we don’t have much information about what food is eaten and how it is accessed during pregnancy. We would like to find out more about the food you eat, how you access food, any barriers you face in accessing food, and your health and wellbeing during your pregnancy. This information will help us to better understand whether pregnant women and people need more support to access the food and nutrients they need. Who can participate? Women who are pregnant and in their third trimester (29-40 weeks’ gestation) may be invited to take part if they receive care at either Queen Elizabeth Hospital Gateshead or University Hospital Coventry and Warwickshire. What does the study involve? The first part of the study involves completing a questionnaire, either on paper or online. There are many things that affect what we eat and how we access food, lots of which are not in our control. For this research to find out what will help pregnant women and people who are struggling in the future, it is important that you answer the questionnaire honestly. We would like around 600 people to complete the questionnaire. To say thank you for your time, we will provide £20 supermarket gift vouchers. We would also like to talk to around 40 people (20 each from Coventry and Gateshead maternity units) in more detail about their experiences accessing food during pregnancy. This is called a research interview. Participants in these interviews will receive an additional £25 voucher as a thank you for your time. When you complete your questionnaire for part one of this research, you will be asked if you are happy to be contacted about the interview. What are the possible benefits and risks of participating? There is no immediate benefit to you if you take part. However, you will receive a £20 voucher to thank you for taking the time to complete and return the questionnaire. You will need to complete the whole questionnaire to receive the voucher. If you miss any questions, the research team may contact you directly using the contact details you provide on the questionnaire, if you give permission for us to do so. There may be benefits to future pregnant people if this research helps to find out what support pregnant people need to access food. There are no anticipated risks to taking part in this study. Where is the study run from? Newcastle University, University of Birmingham & Lancaster University (UK) When is the study starting and how long is it expected to run for? January 2023 to October 2025 Who is funding the study? This study has been funded by the National Institute for Health and Social Care Research, School for Public Health Research (UK) Who is the main contact? Professor Nicola Heslehurst, FPandMe@newcastle.ac.uk 1. Maternal antenatal depression measured using the Edinburgh Postnatal Depression Scale in the third trimester of pregnancy 2. Infant preterm delivery (less than 37 weeks gestation) will be obtained from routine maternity records after delivery 3. An understanding of the experiences and support needs of food insecure pregnant people collected during interviews in the third trimester or after delivery 1. Maternal outcomes measured during pregnancy and delivery: gestational diabetes, preeclampsia, pregnancy induced hypertension, mode of delivery, induction, length of stay in maternity unit, maternal diet/nutrition measured using an adapted version of the Brief Diet Quality Assessment Tool 2. Child outcomes measured at birth and in the neonatal period: birthweight, large- and small-for gestational age, breastfeeding initiated/at discharge from maternity services, admission to special care baby units (and length of stay), Apgar score Ethics approval required Newcastle & North Tyneside 1 Research Ethics Committee

2nd Floor, 2 Redman Place

Stratford United Kingdom E20 1JQ 24/NE/0027 10.1186/ISRCTN16655955 326070 CPMS: 60504 326070 60504 Multi-centre observational cohort study and qualitative interview study Observational Cohort study Other 2025-10-31T00:00:00.000Z United Kingdom England Gateshead Hospitals NHS Trust

Queen Elizabeth Hospital Sherriff Hill

Gateshead United Kingdom NE9 6SX RE2@2.16.840.1.113883.2.1.3.2.4.18.48 University Hospitals Coventry and Warwickshire NHS Trust

University Hospital Clifford Bridge Road

Coventry United Kingdom CV2 2DX Population Service user Current key inclusion criteria as of 15/10/2025: 1. Pregnant women and people 2. Age 16 years and above 3. In their third trimester of a viable pregnancy (28-40 weeks gestation) 4. Registered for maternity services at Queen Elizabeth Hospital Gateshead or University Hospital Coventry _____ Previous key inclusion criteria: 1. Women and pregnant people 2. Age 16 years and above 3. Pregnant and in their third trimester of a viable pregnancy (28-40 weeks gestation) 4. Registered for maternity services at Queen Elizabeth Hospital Gateshead or University Hospital Coventry Adult 16 Years Female 605 610 1. Under 16 years of age 2. Non-residents of the UK 3. Pregnant but less than 38 weeks gestation 4. Post-partum 5. Receiving care by maternity services other than those based at Queen Elizabeth Hospital Gateshead or University Hospital Coventry 2024-07-08T00:00:00.000Z 2025-05-31T00:00:00.000Z Food insecurity during pregnancy Pregnancy and Childbirth Questionnaires exploring diet quality, food security, mental health, and other health behaviours will be distributed to all women and pregnant people in their third trimester in two NHS Trusts in England 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 2025 Protocol article in https://pubmed.ncbi.nlm.nih.gov/40334223/ (added 08/05/2025) Protocol

Study website Migrated from study website field

20bd49df-f972-4a55-bd84-f0d4ca8acd77 848700e4-53b6-4c9f-be5c-a43cda58792f de0212fc-af6b-431d-9fe6-c276a19b9d4c bf4e8e52-a8ec-4d04-a589-da7cab5da3ff fb808649-860e-4325-838b-194f0638dc98 3fccacbe-b654-4f1b-b0f9-277c29c848e1 15cd6cf0-bdc3-42d4-b8e1-fcd905520821 ef05d59b-362f-44ed-9177-cf1124bc7093 No Participant information sheet 46350Participant Information Sheet.pdf 14cda40f-2aa3-4e28-9834-768a3ea88840 true application/pdf 728605 74b2ac44137ed3ad2831075ad2530a03 Nicola Heslehurst https://orcid.org/0000-0001-8656-2319 Principal investigator

Population Health Sciences Institute Newcastle University

Newcastle upon Tyne United Kingdom NE24AX +44 191 2083823 nicola.heslehurst@newcastle.ac.uk Public Kiya Hurley https://orcid.org/0000-0002-5084-5410 Scientific

University of Birmingham

Birmingham United Kingdom B15 2TT +44 7483331986 k.hurley@bham.ac.uk Public Kate Jolly https://orcid.org/0000-0002-6224-2115 Scientific

University of Birmingham

Birmingham United Kingdom B15 2TT +44 7745 914757 c.b.jolly@bham.ac.uk Public Heather Brown https://orcid.org/0000-0002-0067-991X Scientific

University of Lancaster

Lancaster United Kingdom LA1 4YW +44 1524 65201 h.w.brown@lancaster.ac.uk Public Zainab Akhter https://orcid.org/0000-0001-8878-5970 Public

Population Health Sciences Institute Newcastle University

Newcastle upon Tyne United Kingdom NE24AX +44 1912083823 zainab.akhter@newcastle.ac.uk Public Eleanor Dyer https://orcid.org/0000-0002-4797-1459 Public

Population Health Sciences Institute Newcastle University

Newcastle upon Tyne United Kingdom NE24AX +44 1912083823 eleanor.dyer@newcastle.ac.uk Public Newcastle University University/education https://ror.org/01kj2bm70 Non-commercial School for Public Health Research http://dx.doi.org/10.13039/501100012349 22229432 true Comprehensive geriatric assessment (CGA) to sustain independence for older people living with heart failure with preserved ejection fraction (HFpEF) and frailty: The CHART Trial CHART To establish whether Comprehensive Geriatric Assessment (CGA) including a 12-week progressive rehabilitation programme (plus usual care) sustains Instrumental Activities of Daily Living IADL at 12 months post-randomisation. Background and study aims Frailty is a condition that is common in older age. It develops because as we get older our bodies change and can lose their resilience. This means that older people with frailty can experience sudden, dramatic changes in their wellbeing when they have health problems. Heart failure (HF) is a complex condition where the heart muscle doesn’t pump blood as well as it should because it has become too weak or stiff. People with heart failure with preserved ejection fraction (HFpEF) have symptoms of heart failure even though their heart pumps blood well. Current NHS services are not well developed for people who have multiple health problems. This means people with frailty and HFpEF may not receive the right sort of care they need. Comprehensive Geriatric Assessment (CGA) involves older people as well as their families, carers and healthcare professionals to identify and help manage multiple health problems and prevent new ones arising. Rehabilitation helps people to do what is important to them. Our research aims to work out if, CGA (including rehabilitation at home) in addition to usual care helps frail older people with HFpEF maintain their ability to carry out everyday activities. This will be compared to people getting usual care alone. Who can participate? We aim to recruit 433 people from 17 sites who have HFpEF and frailty, and are aged 65 years or above. Potential participants will be invited to take part from cardiology services and followed-up by a researcher who will confirm eligibility and take consent and complete Baseline assessments. What does the study involve? Participants in the study will be randomised to receive either CGA, 12 weeks of home-based rehabilitation, and their usual care or, their usual care only. We will follow-up participants at 6 and 12 months after they agreed to take part and continue to collect information about them from NHS registries, such as NHS England until 24 months. What are the possible benefits and risks of participating? BENEFITS: Although we don’t know if our new treatment programme helps people with heart failure, you might find it useful to you. You may have more frequent contact with a care team, which you may find helpful. You will also be contributing to important research that may benefit patients in future. RISKS: We do not expect there to be many risks to taking part. Agreeing to take part in the study means that if you receive the new treatment programme you will need to attend additional appointments and allow member(s) of the physiotherapy team to visit you at home. As the treatment involves activities you may experience muscle soreness. The physiotherapy team member will make sure that the exercise is appropriate for you. You will give up some of your time to complete questionnaires. We will ask you some questions about your health and wellbeing. You don’t have to answer any questions you don’t wish to. Where is the study run from? University of Leeds (UK) When is the study starting and how long is it expected to run for? March 2024 to February 2029 Who is funding the study? National Institute for Health and Care Research (NIHR) (UK). Who is the main contact? Hollie Wilkes / CHART Trial Team, ctru-chart@leeds.ac.uk To establish whether CGA including a 12-week progressive rehabilitation programme (plus usual care) sustains IADL – measured using the Participant reported Nottingham Extended Activities of Daily Living (NEADL) at 12 months post-randomisation. 1. To establish whether the intervention reduces hospitalisation (all-cause; HF-specific; falls; MACCE) and mortality – measured using Hospital Episodes Statistics (HES) / Civil Registrations data at 6-, 12- and 24-months post-randomisation 2. To establish whether the intervention sustains basic ADL, health-related quality of life and mental health – measured using Participant reported NEADL; Barthel Index; EuroQol 5-dimension health questionnaire (EQ5D-5L); Patient Health Questionnaire (PHQ-8); ICEpop CAPability measure for Older People (ICECAP-O) at baseline, 6- and 12-months post-randomisation 3. To establish whether the intervention improves Days alive and out of hospital – measured using Hospital Episodes Statistics (HES) / Civil Registrations data at 6-, 12- and 24-months post-randomisation 4. To establish whether the intervention reduces home care requirement, new care home placement, and overall health/social care resource – measured using Hospital Episodes Statistics (HES) / Civil Registrations data; participant reported health and social care resource use; researcher review of address at 6- and 12-months post-randomisation Ethics approval required Yorkshire & The Humber - Leeds East Research Ethics Committee

2 Redman Place, Stratford

London United Kingdom E20 1JQ 24/YH/0185 10.1186/ISRCTN22229432 345486 CPMS: 55645, NIHR: 155936 345486 55645 155936 Interventional randomized controlled trial Interventional Randomised controlled trial Treatment 2029-02-14T00:00:00.000Z United Kingdom Bradford Teaching Hospitals NHS Foundation Trust

Bradford Royal Infirmary Duckworth Lane

Bradford England BD9 6RJ RAE@2.16.840.1.113883.2.1.3.2.4.18.48 Leeds Teaching Hospitals NHS Trust

St. James's University Hospital Beckett Street

Leeds England LS9 7TF RR8@2.16.840.1.113883.2.1.3.2.4.18.48 Calderdale and Huddersfield NHS Foundation Trust

Trust Headquarters Acre Street Lindley

Huddersfield England HD3 3EA RWY@2.16.840.1.113883.2.1.3.2.4.18.48 Harrogate and District NHS Foundation Trust

Harrogate District Hospital Lancaster Park Road

Harrogate England HG2 7SX RCD@2.16.840.1.113883.2.1.3.2.4.18.48 Hull University Teaching Hospitals NHS Trust

Hull Royal Infirmary Anlaby Road

Hull England HU3 2JZ RWA@2.16.840.1.113883.2.1.3.2.4.18.48 Mid Yorkshire Teaching NHS Trust

Pinderfields Hospital Aberford Road

Wakefield England WF1 4DG RXF@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Devon University Healthcare NHS Foundation Trust

Royal Devon University NHS Ft Barrack Road

Exeter England EX2 5DW RH8@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Cornwall Hospitals NHS Trust

Royal Cornwall Hospital Treliske

Truro England TR1 3LJ REF@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 Torbay and South Devon NHS Foundation Trust

Torbay Hospital Newton Road

Torquay England TQ2 7AA RA9@2.16.840.1.113883.2.1.3.2.4.18.48 Liverpool University Hospitals NHS Foundation Trust

Royal Liverpool University Hospital Prescot Street

Liverpool England L7 8XP REM@2.16.840.1.113883.2.1.3.2.4.18.48 Manchester University NHS Foundation Trust

Cobbett House Oxford Road

Manchester England M13 9WL R0A@2.16.840.1.113883.2.1.3.2.4.18.48 Bolton NHS Foundation Trust

The Royal Bolton Hospital Minerva Road Farnworth

Bolton England BL4 0JR RMC@2.16.840.1.113883.2.1.3.2.4.18.48 Patient Current inclusion criteria as of 11/09/2026: 1. Aged ≥65 years 2. Clinical diagnosis of HFpEF* 3. Mild, moderate or severe frailty based on the Clinical Frailty Scale (CFS 5-7) 4. Capacity to provide informed consent (assessed prior to registration) 5. Most recent echocardiogram or other alternative appropriate imaging modality within the last 2 years and consistent with HFpEF (i.e., LVEF ≥50%, systolic function or ejection fraction described as ‘normal’ or ‘preserved’) *Diagnosis confirmed by a cardiology specialist. Retrospective identification from clinic letters is a reasonable ‘reference standard as this diagnosis will have been based on guideline standard at the time. Previous inclusion criteria as of 04/11/2025: 1. Aged ≥65 years 2. Clinical diagnosis of HFpEF* 3. Mild, moderate or severe frailty based on the Clinical Frailty Scale (CFS 5-7) 4. Capacity to provide informed consent (assessed prior to registration) 5. Most recent echocardiogram within the last 2 years and showing LVEF ≥50% *Diagnosis confirmed by a cardiology specialist. Retrospective identification from clinic letters is a reasonable reference standard as this diagnosis will have been based on guideline standard at the time. Previous inclusion criteria: 1. Aged >= 65 years 2. Clinical diagnosis of HFpEF* 3. Mild, moderate or severe frailty based on the Clinical Frailty Scale (CFS 5-7) 4. Capacity to provide informed consent (assessed prior to registration) *Diagnosis confirmed by a cardiology specialist. Retrospective identification from clinic letters is a reasonable reference standard as this diagnosis will have been based on guideline standard at the time. N.B. As per guidelines LVEF of 40-49% should not be considered eligible. Senior 65 Years 110 Years All 433 0 Current exclusion criteria as of 28/01/2025: 1. Not frail (as determined by a score on CFS 1-4) 2. Very severe frailty (CFS 8) 3. Terminally ill with an anticipated life expectancy of <6 months 4. Care home resident 5. Unstable angina* 6. New York Heart Association (NYHA) class IV HF (assessed after registration by a CHART researcher) 7. Another household member participating in the trial** 8. Moderate/severe cognitive impairment (Face-to-face Montreal Cognitive Assessment MoCA score of <18 or Blind Montreal Cognitive Assessment MoCA score of <13) (assessed after registration by a CHART researcher) 9. Significant alternative valvular/structural cardiac disease to explain symptoms*** 10. Current hospitalisation or within the last 3 months with decompensated heart failure 11. Referred or receiving CGA and/or exercise-based rehabilitation as part of a clinical service or another research project**** *A CHART researcher will ask the participant at time of registration whether they have angina and then ask if they have symptoms at rest to determine eligibility. **A CHART researcher will ask the participant at time of registration whether anyone in their household is also participating in CHART. ***Valve disease exclusions include: severe aortic stenosis, severe aortic regurgitation, severe mitral regurgitation, moderate or severe mitral stenosis. Participants with these exclusions will be screened out prior to initial approach for the study. **** Patients referred to or currently being seen in community frailty services, outpatient geriatric medicine services or outpatient/community falls prevention services. A CHART researcher will assess through discussion with the potential participant Previous exclusion criteria: 1. Not frail (as determined by a score on CFS 1-4) 2. Very severe frailty (CFS 8) 3. Terminally ill (CFS 9) 4. Care home resident 5. Unstable angina* 6. New York Heart Association (NYHA) class IV HF (assessed after registration by a CHART researcher) 7. Another household member participating in the trial** 8. Moderate/severe dementia (Montreal Cognitive Assessment MoCA score < 18) (assessed after registration by a CHART researcher) 9. Under regular review from geriatric medicine services 10. Significant alternative valvular/structural cardiac disease to explain symptoms*** 11. Current hospitalisation with decompensated heart failure 12. Receiving or referred for CGA as part of a clinical service or another research project**** *A CHART researcher will ask the participant at time of registration whether they have angina and then ask if they have symptoms at rest to determine eligibility. **A CHART researcher will ask the participant at time of registration whether anyone in their household is also participating in CHART. ***Valve disease exclusions include: severe aortic stenosis, severe aortic regurgitation, severe mitrial regurgitation, moderate or severe mitral stenosis. Participants with these exclusions will be screened out prior to initial approach for the study. ****Patients seen in community frailty services, outpatient geriatric services, outpatient clinic-based falls services will be screened out prior to study invitation. CHART researchers will do a further check of involvement in these services prior to randomisation. 2025-02-07T00:00:00.000Z 2027-12-31T00:00:00.000Z Older people living with heart failure with preserved ejection fraction and frailty Circulatory System The study is called an individually randomised controlled trial with participants being randomly allocated to the control group (usual care only) or the intervention group (usual care plus comprehensive geriatric assessment and a 12-week home-based rehabilitation programme). The home-based rehabilitation programme will be supported by a trained therapist. We need a control group to help us check that any changes we see are not due to chance. The study will aim to recruit a total of 433 participants. We will be recruiting the participants from 17 UK hospitals with cardiology services. To ensure the delivery of the study is feasible, we will review participant recruitment rates and the number of participants who have had their CGA assessment as part of an internal pilot. Nine sites will be included in the pilot, and we will assess the progression after nine months of recruitment. Recruitment will take place from a minimum of 17 sites across three hubs (North West, Yorkshire & Humber, South West). Participants will be identified in three main ways: 1. Prospective identification - participants with HFpEF seen in cardiology services will be identified by site staff. 2. Site staff will screen electronic records and heart failure clinic letters to identify potential participants diagnosed with HFpEF. 3. Identification of participants via the National Institute for Health and Care Research-British Heart Foundation Cardiovascular Partnership national registry. In all routes of identification, participants will be provided with an invitation to take part in the study, alongside a Summary Study Leaflet. Participants who express an interest will be contacted by a CHART researcher who will explain more about the study and provide them with a full information sheet. They will also seek verbal consent to collect some information about the potential participant and confirm eligibility. If the study is suitable for the participant, they will be invited to provide written consent and then be randomised onto the study. Participants will be notified by letter of the outcome of the randomisation. The letter and accompanying leaflet will provide information on the next steps. Participants allocated to the CHART programme will be approached by a member of the geriatrics team in their local hospital to arrange an appointment for the comprehensive geriatric assessment. At the assessment, they will discuss what is important to the participant and come up with a care plan. There will be at least one more follow-up appointment with this team. For the home-based therapy part of the CHART programme, a member of the physiotherapy team will contact the participant and arrange a time to visit the participant and introduce them to a programme that aims to improve strength, balance, and movement. Participants will have weekly contact with the member of the therapy team with a mixture of face-to-face appointments in the participant's home and telephone calls. As part of this study, we will define "usual care" within the study population by asking participants what services they have accessed. Usual care would broadly be summarised as the wide range of care provided in the community, such as GP appointments, hospital appointments, community, and social services. To help further understand the CHART treatment programme (intervention) and usual care, researchers will be looking at the care appointments participants have and will also be performing interviews with staff and participants in a sample of willing participants. This is called an embedded process evaluation. Additional data (follow-up) will be collected from all participants at 6 and 12 months following randomisation. The data will be self-reported with participants either completing postal questionnaires or electronic questionnaires. Participants may also complete the questionnaires over the telephone or in their own home with the support of a researcher. Researchers will also have access to participants' health records to check addresses and confirm status before contact points. Researchers collecting follow-up data will be unaware of the participant's allocation (blind) and will be asked to document if they become aware of the participant's allocation during the study. The study team will also collect health and treatment information about participants held in central NHS databases, via providers such as NHS England. This data will be collected at 6, 12, and 24 months after randomisation. Other De-identified individual participant data datasets generated and/or analysed during the current study will be available upon request from the Clinical Trials Research Unit, University of Leeds (contact CTRU-DataAccess@leeds.ac.uk in the first instance). Data will be made available at the end of the trial, i.e. usually when all primary and secondary endpoints have been met and all key analyses are complete. Data will remain available from then on for as long as CTRU retains the data. CTRU makes data available by a 'controlled access' approach. Data will only be released for legitimate secondary research purposes, where the Chief Investigator, Sponsor and CTRU agree that the proposed use has scientific value and will be carried out to a high standard (in terms of scientific rigour and information governance and security), and that there are resources available to satisfy the request. Data will only be released in line with participants' consent, all applicable laws relating to data protection and confidentiality, and any contractual obligations to which the CTRU is subject. No individual participant data will be released before an appropriate agreement is in place setting out the conditions of release. The agreement will govern data retention, usually stipulating that data recipients must delete their copy of the released data at the end of the planned project. The CTRU encourages a collaborative approach to data sharing, and believe it is best practice for researchers who generated datasets to be involved in subsequent uses of those datasets. Recipients of trial data for secondary research will also receive data dictionaries, copies of key trial documents and any other information required to understand and reuse the released datasets. The conditions of release for aggregate data may differ from those applying to individual participant data. Requests for aggregate data should also be sent to the above email address to discuss and agree suitable requirements for release. Available on request

Participant information sheet Migrated from patient info sheet field

Study website Migrated from study website field

5740e8ed-2baa-4c55-befb-f5749ebd0e0e 67f2241d-7293-4984-a061-9c6946d52f6e b69e8cf3-9f0f-44d6-83f7-14cd67186ed1 c9197693-7101-4a10-b505-1062dca4513d 9d7c0c71-93ea-43c3-8f5f-3881c166a501 Yes Hollie Wilkes Public

CHART Trial Team Clinical Trials Research Unit Leeds Institute of Clinical Trials Research University of Leeds

Leeds United Kingdom LS2 9JT - ctru-chart@leeds.ac.uk Public Andrew Clegg https://orcid.org/0000-0001-5972-1097 Scientific

Academic Unit for Ageing and Stroke Research, Bradford Institute for Health Research, Temple Bank House, Bradford Royal Infirmary, Duckworth Lane

Bradford United Kingdom BD9 6RJ +44 127 438 3440 a.p.clegg@leeds.ac.uk Public Victoria Goodwin https://orcid.org/0000-0003-3860-9607 Scientific

University of Exeter, Medical School Building, St Luke’s Campus, Magdalen Road

Exeter United Kingdom EX1 2LU - v.goodwin@exeter.ac.uk Public Bradford Teaching Hospitals NHS Foundation Trust Hospital/treatment centre https://ror.org/05gekvn04 Non-commercial National Institute for Health and Care Research http://dx.doi.org/10.13039/501100000272 49040930 true A long-term safety and efficacy study of N-Acetyl-GED-0507-34-LEVO gel 5%, in subjects with acne vulgaris (GEDACNE-LT) GEDACNE LT The primary objective of the study is to determine the long-term safety of 5% N-Acetyl-GED-0507-34-Levo gel, applied once daily (OD) for a total treatment period up to 52 weeks in patients with acne vulgaris. Efficacy will be evaluated as a secondary objective. Efficacy will be assessed by the investigator using acne lesion count and IGA at V2/Day1 (Baseline) and weeks 4, 12, 26, 38 and 52. Acne lesion count and IGA will also be performed for inclusion at V1 (screening) and in case of Early Termination Visit (ETV). Background and study aims This study is to assess the efficacy and safety of a gel in the long-term treatment (up to 52 weeks) in patients with acne vulgaris. The study is an open-label, non- comparative study, which means that all participants will receive the treatment gel for the duration of the study. Who can participate? Males or females aged between >9 and <50 years of age suffering from acne vulgaris may be able to take part. What does the study involve? Study participants will be required to apply the gel treatment themselves, once daily for a minimum of 12 weeks. From week 12 up to 52 weeks, patients’ treatment will be determined by an assessment of acne symptoms. The study will include up to 8 on-site study visits for a duration of up to 52 weeks. These visits would last for approximately 1-2 hours, some of which will include physical assessments and investigations, including an assessment of acne symptoms and collection of height, weight, and vital signs. Blood samples will also be collected for safety analysis, and a urine pregnancy test will be performed for females of childbearing potential. Participants will also complete a questionnaire, which will assess how their condition affects their daily life. In previous studies, the treatment gel has been shown to be safe and well tolerated and a reduction of acne symptoms was found. This study will help gather further information on the effects of this gel and may offer an alternative treatment for patients suffering from acne vulgaris. The study is taking place in multiple sites across 5 EU Countries, and 400 participants will be recruited. In the UK, 16 sites will be taking part, including both primary and secondary care NHS sites and some private research sites. What are the possible benefits and risks of participating? Benefits: Not provided at time of registration Risks: Based on the results from two previous large Phase II studies, the active IMP (N-Acetyl-GED-0507-34-LEVO gel 5% (5 mg/100 mg)), is considered to be safe and well tolerated, and there were no significant differences between the proposed pediatric and adult populations. In a large randomised double blind controlled clinical trial (NAC-GED-0507-ACN-01-18), the percentage of patients who had one or more AEs was 19%, 16% and 19% in the NAC-GED 5%, NAC-GED 2% and vehicle groups, respectively. In general, the administration of the IMP may result in some minor side effects such as an allergic or irritant reaction, which may manifest as itching or redness of the skin with papules and blisters. In rare cases, there may be more generalised dermal sensitisation responses, which improve once the treatment stops. Moreover, as the amount to be applied to the skin is relatively small, no systemic side effects are expected. For those participants who will be assigned to receive no treatment for a duration of the study (from week 12- 52), as their condition will not be treated with an active medication for that time, their acne symptoms may become worse, stay the same or improve. In terms of study procedures, blood draws may result in bruising or pain where the sample is taken and in some cases, there is a risk of infection, lightheadedness and/ or fainting. With regards to risks associated with pregnancy and breastfeeding, the safety of the study drug for embryos/fetuses is not fully known. Females who are pregnant or breastfeeding, or those who plan to become pregnant during the study period will be excluded from enrollment. Additionally, all females of childbearing potential will be required to undertake a pregnancy test and shall also be required to use an acceptable effective contraceptive method throughout the entire study. Although acne is not a life-threatening condition, it can be a significant source of distress for patients and can be associated with depression, anxiety and poor self-esteem. Patients will be required to complete either a Dermatology Life Quality Index (DLQI) (age 17 and older) or a Children’s Dermatology Life Quality Index (C-DLQI) (for 16 years and younger). By completing these questionnaires, there is a risk that some participants may experience some psychological or emotional stress. Similarly, as there is a chance that participants' acne symptoms may become worse or remain the same during the study, this may also contribute to participants experiencing psychological or emotional stress. However, the participants' health and wellbeing will be closely monitored during the study and will include collection of all Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAES), Adverse Drug Reactions (ADRs) and Serious Adverse Events (SAEs). Changes from baseline of vital signs, laboratory tests and local tolerability plus physical examinations and an assessment of overall application of site irritation, will also be conducted to ensure prompt follow-up with participants if required. Moreover, additional phone calls will be included for all patients aged 9 to <12 years to ensure that any local tolerability or safety issues are promptly identified. The Investigator will be asked to promptly fill in the eCRF page relating to the phone contact. In case of safety issues, an immediate automatic notification will be sent to the Data Safety Monitoring Board (DSMB). A DSMB will also be established to undertake periodic risk-benefit assessments during the clinical trial. The study will include up to 8 on-site visits over a duration of 52 weeks. The visits will last for 1-2 hours and will include some physical assessments and investigations. Participants will be appropriately reimbursed for any travel expenses incurred and will be made fully aware of the commitment required before consenting. At four selected sites in the UK, participants will also have the option to consent to the collection of photographic scar monitoring of which images of the participants face will be shared: internally (to the attention of PPM Services’ collaborators) and/or externally (to the attention of the public and/or health care professionals during any event and/or manifestation whatsoever). This type of assessment has the potential to cause some emotional stress however, information will be provided to participants via a participant information sheet in a way that enables them to clearly understand what is involved in the study, should they consent to take part. Taking into account these risks and benefits, the performance of the trial can be considered low risk for all ages considered, since the expected benefits appear greater at present than the risks for the volunteers. Where is the study run from? The research will be conducted in the UK by LINK Medical Research, a Clinical Research Organisation. When is the study starting and how long is it expected to run for? June 2024 to December 2026 Who is funding the study? PPM Services S.A. (Switzerland) Who is the main contact? Elisha Peers Dr Simon Royal, Simon.Royal@nottingham.ac.uk Safety will be evaluated as the primary objective of the study up to 52 weeks: 1. Incidence of all Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAES), Adverse Drug Reactions (ADRs), Serious Adverse Events (SAEs) throughout the study; with special attention to local TEAEs concerning the treated facial area (local dermal safety), and systemic TEAEs 2. Frequency of discontinuation of treatment due to TEAEs 3. Changes from baseline of vital signs during the study 4. Physical examination during the study 5. Changes from baseline of laboratory test at V5/Wk12 and V8/Wk52 6. Change from baseline of local tolerability- Application site signs/symptoms during the study* 7. Assessment of overall application site irritation at V5/Wk12, V6/Wk26, V7/Wk38 and V8/Wk52. *Local tolerability will be evaluated based on the following signs and symptoms: application site non-lesional erythema, application site exfoliation, and application site dryness, stinging, burning, itching. For each sign/symptom, a severity score will be assigned using a 4-point scale from 0 = absent to 3 = severe. Efficacy will be evaluated as a secondary objective. IGA and PGA and lesion count assessments are to be performed by a qualified investigator. Training is required for all evaluators who perform IGA/PGA/ lesion count. Efficacy will be assessed by the investigator using acne lesion count and IGA at V2/Day1 (Baseline), Wk4, Wk12, Wk26, Wk38, Wk52. Acne lesion count and IGA will also be performed for inclusion at V1 (screening) and in case of Early Termination Visit [ETV]). Acne lesion count: Inflammatory (papules, pustules and nodules) and non-inflammatory lesions (open [blackheads] and closed [whiteheads ] comedones) on the face (including the nose) and on the trunk will be accurately counted and recorded at each visit as detailed in the study schedule. Total lesions will be calculated as the sum of inflammatory plus non-inflammatory lesions. IGA (Face): Overall severity of acne will be assessed using a 5-point scale from 0 = clear to 4 = severe at each visit as detailed in the study schedule. PGA (Trunk): Overall severity will be assessed using a 5-point scale from 0 = clear to 4 = severe at each visit as detailed in the study schedule. Secondary Efficacy endpoints: To evaluate the efficacy of 5% N-Acetyl-GED-0507-34-Levo gel after a treatment period up to 52 Wks on the following parameters: FACE 1. Percentage of patients who have improvement of IGA score at each time point (Wk4, Wk8, Wk12, Wk26, Wk38, Wk52), vs baseline score 2. The percentage change from baseline in total lesion count (inflammatory plus non-inflammatory) at each time point (Wk4, Wk8, Wk12, Wk26, Wk38, Wk52) 3. Absolute change from baseline in total lesion count at each time point (Wk4, Wk8, Wk12, Wk26, Wk38, Wk52) 4. Change from baseline in inflammatory lesion count (percentage and absolute), at each time point (Wk4, Wk8, Wk12, Wk26, Wk38, Wk52) 5. Change from baseline in non-inflammatory lesion count (percentage and absolute), at each time point (Wk4, Wk8, Wk12, Wk26, Wk38, Wk52) TRUNK 1. Percentage of patients who have improvement of PGA score at each time point (1,2 points), vs baseline score 2. The percentage change from baseline in total lesion count (inflammatory plus non-inflammatory) at each time point 3. Absolute change from baseline in total lesion count at each time point 4. Change from baseline in inflammatory lesion count (percentage and absolute), at each time point 5. Change from baseline in non-inflammatory lesion count (percentage and absolute), at each time point. OTHER ASSESSMENTS 1. Dermatology Life Quality Index (DLQI) / Children’s Dermatology Life Quality Index (C-DLQI for patients from 9 to 16 years old), completed by the patient at Baseline, Wk12, and Wk52 visits (prior to any Investigator assessments to not impact the patient’s answers to the quality-of-life questionnaires) 2. Scar Assessment by Scale for Acne Scar Severity (SCAR-S) at Baseline, Wk12, Wk26, Wk38 and Wk52 visits. 3. At selected sites, at Baseline, Wk12 and Wk52 scar 3D photographic documentation will be optional. The area defined for scar assessments is only the face. Baseline will be the last evaluation before N-Acetyl-GED-0507-34-Levo gel 5% intake. Ethics approval required London Hampstead Research Ethics Committee

Previously Royal Free Hospital and Medical School Research Ethics Committee then North West London REC 2

London United Kingdom - 24/LO/0552 10.1186/ISRCTN49040930 2023-510342-24 1010207 CPMS: 60291, NAC-GED-0507-ACN-01-23-LT 2023-510342-24 1010207 60291 NAC-GED-0507-ACN-01-23-LT Interventional non randomized Interventional Non randomised study Safety Efficacy 2026-12-31T00:00:00.000Z United Kingdom England Scotland Wales France Italy Poland Spain Albany House Medical Centre

3 Queen Street

Wellingborough United Kingdom NN8 4RW NL512@2.16.840.1.113883.2.1.3.2.4.18.48 Chilwell Valley and Meadows Practice

Chilwell Meadows Surgery Ranson Road Chilwell

Nottingham United Kingdom NG9 6DX C84120@2.16.840.1.113883.2.1.3.2.4.18.48 Cripps Health Centre

University Park

Nottingham United Kingdom NG7 2QW RHADV@2.16.840.1.113883.2.1.3.2.4.18.48 FutureMeds Birmingham

247-251 Soho Rd

Birmingham United Kingdom B21 9RY FutureMeds North Tees

University Hospital of North Tees, Middlefield Centre, Hardwick Rd

Stockton-on-Tees United Kingdom TS19 8PE FutureMeds Ltd

45 Bridle Rd Birkenhead

Wirral United Kingdom CH62 6EE 12521988@1.2.826.0 Harrogate and District NHS Foundation Trust

Harrogate District Hospital Lancaster Park Road

Harrogate United Kingdom HG2 7SX RCD@2.16.840.1.113883.2.1.3.2.4.18.48 Heath Lane Surgery

Westfield Ave, Earl Shilton

Leicester United Kingdom LE9 7RT Marine Lake Medical Practice

Marine Lake Health & Wellbeing Ctr Orrysdale Road West Kirby

Wirral United Kingdom CH48 5AA N85002@2.16.840.1.113883.2.1.3.2.4.18.48 South Tees Hospitals NHS Foundation Trust

James Cook University Hospital Marton Road

Middlesbrough United Kingdom TS4 3BW RTR@2.16.840.1.113883.2.1.3.2.4.18.48 Staploe Medical Centre

Brewhouse Lane Soham

Ely United Kingdom CB7 5JD 5PP28@2.16.840.1.113883.2.1.3.2.4.18.48 The Adam Practice

306 Blandford Road Hamworthy

Poole United Kingdom BH15 4JQ White Horse Medical Practice

Volunteer Way

Faringdon United Kingdom SN7 7YU Clarence Medical Centre

West Rhyl Primary Care Centre West Kinmel Street

Rhyl United Kingdom LL18 1DA W91003@2.16.840.1.113883.2.1.3.2.4.18.48 The Practice of Health

31 Barry Road

Barry United Kingdom CF63 1BA W97611@2.16.840.1.113883.2.1.3.2.4.18.48 FutureMeds Glasgow

99 Firhill Road

Glasgow United Kingdom G20 7BE Patient 1. Informed consent obtained. Written informed consent, before any study-related procedure, personally signed and dated by the patient if the patient is ≥18 years old or signed and dated by the parents or the legal guardian(s) if the patient is ≥9 to< 18 years old. An additional informed assent form must be signed by the patient if ≥9 to <18 years old to confirm his willingness to participate in the study. If the patient becomes 18 years of age during the study, the patient must provide written informed consent at that time to continue study participation. 2. Sex and age: Male and female patients aged ≥9 and <50 years. Patients who turn 50 during the pivotal study can roll over to the LT study. 3. Diagnosis at screening and baseline visits: 3.1. Patients affected by facial acne vulgaris with an Investigator’s Global Assessment (IGA) score: =1 or 2 for pivotal-naïve* patients not included in pivotal 12 Week treatment studies ≥0 for patients completing the treatment period of pivotal Phase 3 trials (NAC-GED-0507-ACN-01-23-A and NAC-GED-0507-ACN-01-23-B) 3.2. Patients affected by truncal acne (optional criteria) on areas of the trunk (shoulders, upper back and upper anterior chest) accessible for patient’s self-application of study medication with a Physician Global Assessment (PGA) severity grade: =1 or 2 for pivotal-naïve* patients not included in the pivotal 12Week treatment studies ≥0 and <4 for patients completing the treatment period of pivotal Phase 3 trials (NAC-GED-0507-ACN-01-23-A and NAC-GED-0507-ACN-01-23-B)*Pivotal-naïve: Patients not rolling over from NAC-GED-0507-ACN-01-23-A and NAC-GED-0507-ACN-01-23-B. If the pivotal-naïve patient is ≥ 9 and ≤ 14 years old and declined participation to the pivotal Phase 3 study, a 12-week period should run before inclusion in the present study. 4. Full comprehension Patients and their parents/legal guardian(s) (for <18 years old patients) can comprehend the whole nature and purpose of the study, including possible risks and side effects, and are able to cooperate with the Investigator and to comply with the requirements of the entire study. 5. Contraception and fertility: Women of childbearing potential must be using an effective contraception method during the entire duration of the study. Effective contraception methods are those considered at least“acceptable” according to CTFG Recommendations. A prior stable treatment period is required for the following reliable methods of contraception: 5.1. Hormonal oral, implantable, transdermal, or injectable contraceptives must be stable for at least 6 months before the screening visit 5.2. A non-hormonal intrauterine device (IUD) must be started at least 2 months before the screening visit. Mixed 9 Years 50 Years All 400 428 1. Acne: 1.1. Patients with generalized or localized acne forms other than acne vulgaris, e.g., acne conglobata, acne fulminans, acne rosacea, secondary acne (chloracne, drug-induced acne, etc), nodule-cystic acne 1.2. Patients with acne requiring systemic treatment 2. Beard and facial/body hair, tattoos: 2.1. Patients with a beard or who intend to grow a beard and/or to perform a facial tattoo during the study 2.2. Patients with facial hair or facial tattoos that could interfere with study assessments in the investigator’s opinion 2.3. For patients with truncal acne: body hair, tattoos (or who intend to perform them) on the shoulders, upper back/upper anterior chest accessible to self-application of study medication by the patient (evaluable area) that may interfere with study assessments in investigator’s opinion. 3. Skin diseases: Patients with other active skin diseases (e.g., urticaria, atopic dermatitis, sunburn, seborrheic dermatitis, perioral dermatitis, rosacea, skin malignancies) or active skin infections in the facial or truncal region (bacterial, fungal, or viral) or any other facial or truncal disease or condition that might interfere with evaluation of acne or place the patient at unacceptable risk 4. Allergy: Known or suspected hypersensitivity to any active or inactive ingredient in the study medication. Patients with a history of an allergic reaction or significant sensitivity to the formulations’ ingredients. 5. Topical therapies: Patients who are currently using, plan to use during the study, or discontinued less than 4 weeks before study baseline the use of prescribed or over-the-counter topical therapies for the treatm. of acne, including but not limited to: corticosteroids, antibiotics, azelaic acid, benzoyl peroxide, salicylates, α-hydroxy/glycolic acid, any other topical cosmetic therapy for acne and retinoids on the face/trunk. 6. Topical skin care products and procedures: Patients who are currently using, plan to use during the study, or discontinued less than 4 weeks before study baseline the use of products for facial/truncal application containing glycolic or other acids, masks, washes or soaps containing benzoyl peroxide or salicylic acid, non-mild cleansers or moisturizers containing retinol, salicylic or alpha- or beta-hydroxy acids, facial/truncal procedures such as chemical peel, laser treatment, photodynamic therapy, acne surgery, cryodestruction or chemodestruction, x-ray therapy, intralesional steroids, dermabrasion; 7. Phototherapy: Patients who are currently using, plan to use during the study, or discontinued less than 4 weeks before study baseline phototherapy for the treatment of acne, including but not limited to: UV-A, UV-B, heliotherapy. Patients who have the need or plan to be exposed to artificial tanning devices or excessive sunlight during the study. 8. Systemic therapies: Patients who are currently using, plan to use during the study, or discontinued less than 12 weeks before study baseline the use of systemic therapies for the treatment of acne, including but not limited to: antibiotics, isotretinoin. Other systemic therapy that could affect the patient’s acne (i.e., anabolics, lithium, EGRF inhibitors, iodides, systemic corticosteroids - except inhaled corticosteroids or intrathecal corticosteroids - or other immunosuppressants), in the opinion of the investigator. 9. Known systemic diseases that can lead to acneiform eruptions: 9.1. Increased androgen production. 1) Adrenal origin: e.g., Cushing’s disease, 21-hydroxylase deficiency; 2) Ovarian origin: e.g., polycystic ovarian syndrome, ovarian hyperthecosis 9.2. Cryptococcosis disseminated 9.3. Dimorphic fungal infections 9.4. Behçet’s disease 9.5. Systemic lupus erythematosus (SLE) 10. Investigative studies: Participation in the evaluation of any other investigational product or device within 24 weeks before study baseline 11. Diseases: Patients with underlying uncontrolled or unstable conditions (including but not limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal) which in the Investigator's opinion could significantly compromise the patient’s safety and/or place the patient at an unacceptable risk. Any condition that in the investigator’s opinion would make it unsafe for the patient to participate in the study 12. Alcohol and other substance abuse: History of alcohol or other substance abuse within one year before screening. 13. Communication: Patient(s) and parents/legal guardian(s) (if applicable) unable to communicate or cooperate with the investigator due to e.g., language problems, impaired cerebral function, impaired mental conditions. 14. Reliability: Patients who may be unreliable for the study including patients who are unable to return for the scheduled visits. 15. Pregnancy*: Pregnant or breastfeeding women or women of childbearing potential who are planning to become pregnant during the study. *For all female patients 2024-09-01T00:00:00.000Z 2025-04-22T00:00:00.000Z Acne vulgaris Skin and Connective Tissue Diseases IMP: N-Acetyl-GED-0507-34-Levo 5% gel (5 mg/100 mg) Each patient will apply a bean-sized amount of gel as a thin film, once daily (OD), to the entire facial skin area and the affected skin areas of the trunk accessible for self-application (i.e., shoulders, upper back, and upper anterior chest). The application is to dry and, cleansed skin, avoiding the eyes, lip region, and mucous membranes. The treatment period will be 52 weeks (364 applications). For patients from the Phase 3 pivotal studies (NAC-GED-0507-ACN-01-23-A and NAC-GED-0507-ACN-01-23-B) this treatment duration includes the 12-week treatment period. These patients will apply the active medication once a day (OD) for an additional 9 months of treatment (for a total of up to 12 months; 0 or 3 months in the Phase 3 pivotal study [blinded assignment to IMP or placebo] and an additional 9 months in this open-label long-term extension study). Drug Phase III N-Acetyl-GED-0507-34-Levo 5% g [(S)-3-(4-ACETAMIDOPHENYL)-2-METHOXYPROPANOIC ACID] All data generated or analysed during this study will be included in the subsequent results publication Published as a supplement to the results publication Protocol

b3a065df-36bb-4047-ab80-d50a4cd72340 c4435b5e-b8ad-4b59-b311-9e9e6717e82a 74ab8e33-d7ad-4c39-81c9-1be9836af47a ef7d6b4d-6ae5-45f7-936c-8d4fdc3eeac8 Yes Protocol file ISRCTN49040930_PROTOCOL_V2.0_41Jan25.pdf 4d995dc2-f890-4e2f-b668-5be3eabb9f0e true application/pdf 1557561 1f6f8f26c35bcdebf5258beef0dc7924 Elisha Peers Scientific

10 John Street

London United Kingdom WC1N 2EB Protected Simon Royal Principal investigator

Cripps Health Centre, University Park

Nottingham United Kingdom NG7 2QW +44 115 8468888 Simon.Royal@nottingham.ac.uk Public PPM Services S.A Industry Commercial PPM Services S.A